Cardiology News

President Joe Biden has announced a host of new plans to rein in COVID-19’s runaway transmission in the United States, including sweeping vaccine mandates that will affect 100 million American workers, nearly two-thirds of the country’s workforce.

itsmejust/Thinkstock

“As your president, I’m announcing tonight a new plan to get more Americans vaccinated to combat those blocking public health,” he said Sept. 9.

As part of a six-part plan unveiled in a speech from the State Dining Room of the White House, President Biden said he would require vaccinations for nearly 4 million federal workers and the employees of companies that contract with the federal government.

He has also directed the Occupational Safety and Health Administration to develop a rule that will require large employers -- those with at least 100 employees -- to ensure their workers are vaccinated or tested weekly.

Nearly 17 million health care workers will face new vaccine mandates as part of the conditions of participation in the Medicare and Medicaid programs.

President Biden said the federal government will require staff at federally funded Head Start programs and schools to be vaccinated. He’s also calling on all states to mandate vaccines for teachers.

“A distinct minority of Americans, supported by a distinct minority of elected officials, are keeping us from turning the corner,” PresidentBiden said. “These pandemic politics, as I refer to them, are making people sick, causing unvaccinated people to die.”

One public health official said he was glad to see the president’s bold action.

“What I saw today was the federal government trying to use its powers to create greater safety in the American population,” said Ashish K. Jha, MD, dean of the school of public health at Brown University, Providence, R.I., in a call with reporters after the speech.

National Nurses United, the largest union of registered nurses in the United States, issued a statement in support of President Biden’s new vaccination requirements, but pushed back on his language.

“…as advocates for public health, registered nurses want to be extremely clear: There is no such thing as a pandemic of only the unvaccinated. The science of epidemiology tells us there is just one deadly, global pandemic that has not yet ended, and we are all in it together. To get out of it, we must act together. All of us,” the statement says.

A host of other professional groups, including the American Medical Association and the Association of State and Territorial Health Officials, also issued statements of support for President Biden’s plan.

But the plan was not well received by all.

“I will pursue every legal option available to the state of Georgia to stop this blatantly unlawful overreach by the Biden Administration,” said Georgia Governor Brian Kemp, a Republican, in a Tweet.

The National Council for Occupational Safety and Health called the plan “a missed opportunity” because it failed to include workplace protections for essential workers such as grocery, postal, and transit workers.

“Social distancing, improved ventilation, shift rotation, and protective equipment to reduce exposure are important components of an overall plan to reduce risk and stop the virus. These tools are missing from the new steps President Biden announced today,” said Jessica Martinez, co-executive director of the group.

In addition to the new vaccination requirements, President Biden said extra doses would be on the way for people who have already been fully vaccinated in order to protect against waning immunity, starting on Sept. 20. But he noted that those plans would be contingent on the Food and Drug Administration’s approval for third doses and the Centers for Disease Control and Prevention’s recommendation of the shots.

President Biden pledged to use the Defense Production Act to ramp up production of at-home tests, which have been selling out across the nation as the Delta variant spreads.

He also announced plans to expand access to COVID-19 testing, including offering testing for free at thousands of pharmacies nationwide and getting major retailers to sell at-home COVID-19 tests at cost.

The BinaxNow test kit, which currently retails for $23.99, will now cost about $15 for two tests at Kroger, Amazon, and Walmart, according to the White House. Food banks and community health centers will get free tests, too.

He called on states to set up COVID-19 testing programs at all schools.

Jha said that in his view, the big, game-changing news out of the president’s speech was the expansion of testing.

“Our country has failed to deploy tests in a way that can really bring this pandemic under control,” Jha said. “There are plenty of reasons, data, experience to indicate that if these were widely available, it would make a dramatic difference in reducing infection numbers across our country.”.

Dr. Jha said the private market had not worked effectively to make testing more widely available, so it was “absolutely a requirement of the federal government to step in and make testing more widely available,” he said.

President Biden also announced new economic stimulus programs, saying he’s expanding loan programs to small businesses and streamlining the loan forgiveness process.

President Biden said he’s boosting help for overburdened hospitals, doubling the number of federal surge response teams sent to hard-hit areas to reduce the strain on local health care workers. He said he would increase the pace of antibody treatments to states by 50%.

“We made so much progress during the past 7 months of this pandemic. Even so, we remain at a critical moment, a critical time,” he said. “We have the tools. Now, we just have to finish the job with truth, with science, with confidence and together as one nation.”

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

President Joe Biden has announced a host of new plans to rein in COVID-19’s runaway transmission in the United States, including sweeping vaccine mandates that will affect 100 million American workers, nearly two-thirds of the country’s workforce.

itsmejust/Thinkstock

“As your president, I’m announcing tonight a new plan to get more Americans vaccinated to combat those blocking public health,” he said Sept. 9.

As part of a six-part plan unveiled in a speech from the State Dining Room of the White House, President Biden said he would require vaccinations for nearly 4 million federal workers and the employees of companies that contract with the federal government.

He has also directed the Occupational Safety and Health Administration to develop a rule that will require large employers -- those with at least 100 employees -- to ensure their workers are vaccinated or tested weekly.

Nearly 17 million health care workers will face new vaccine mandates as part of the conditions of participation in the Medicare and Medicaid programs.

President Biden said the federal government will require staff at federally funded Head Start programs and schools to be vaccinated. He’s also calling on all states to mandate vaccines for teachers.

“A distinct minority of Americans, supported by a distinct minority of elected officials, are keeping us from turning the corner,” PresidentBiden said. “These pandemic politics, as I refer to them, are making people sick, causing unvaccinated people to die.”

One public health official said he was glad to see the president’s bold action.

“What I saw today was the federal government trying to use its powers to create greater safety in the American population,” said Ashish K. Jha, MD, dean of the school of public health at Brown University, Providence, R.I., in a call with reporters after the speech.

National Nurses United, the largest union of registered nurses in the United States, issued a statement in support of President Biden’s new vaccination requirements, but pushed back on his language.

“…as advocates for public health, registered nurses want to be extremely clear: There is no such thing as a pandemic of only the unvaccinated. The science of epidemiology tells us there is just one deadly, global pandemic that has not yet ended, and we are all in it together. To get out of it, we must act together. All of us,” the statement says.

A host of other professional groups, including the American Medical Association and the Association of State and Territorial Health Officials, also issued statements of support for President Biden’s plan.

But the plan was not well received by all.

“I will pursue every legal option available to the state of Georgia to stop this blatantly unlawful overreach by the Biden Administration,” said Georgia Governor Brian Kemp, a Republican, in a Tweet.

The National Council for Occupational Safety and Health called the plan “a missed opportunity” because it failed to include workplace protections for essential workers such as grocery, postal, and transit workers.

“Social distancing, improved ventilation, shift rotation, and protective equipment to reduce exposure are important components of an overall plan to reduce risk and stop the virus. These tools are missing from the new steps President Biden announced today,” said Jessica Martinez, co-executive director of the group.

In addition to the new vaccination requirements, President Biden said extra doses would be on the way for people who have already been fully vaccinated in order to protect against waning immunity, starting on Sept. 20. But he noted that those plans would be contingent on the Food and Drug Administration’s approval for third doses and the Centers for Disease Control and Prevention’s recommendation of the shots.

President Biden pledged to use the Defense Production Act to ramp up production of at-home tests, which have been selling out across the nation as the Delta variant spreads.

He also announced plans to expand access to COVID-19 testing, including offering testing for free at thousands of pharmacies nationwide and getting major retailers to sell at-home COVID-19 tests at cost.

The BinaxNow test kit, which currently retails for $23.99, will now cost about $15 for two tests at Kroger, Amazon, and Walmart, according to the White House. Food banks and community health centers will get free tests, too.

He called on states to set up COVID-19 testing programs at all schools.

Jha said that in his view, the big, game-changing news out of the president’s speech was the expansion of testing.

“Our country has failed to deploy tests in a way that can really bring this pandemic under control,” Jha said. “There are plenty of reasons, data, experience to indicate that if these were widely available, it would make a dramatic difference in reducing infection numbers across our country.”.

Dr. Jha said the private market had not worked effectively to make testing more widely available, so it was “absolutely a requirement of the federal government to step in and make testing more widely available,” he said.

President Biden also announced new economic stimulus programs, saying he’s expanding loan programs to small businesses and streamlining the loan forgiveness process.

President Biden said he’s boosting help for overburdened hospitals, doubling the number of federal surge response teams sent to hard-hit areas to reduce the strain on local health care workers. He said he would increase the pace of antibody treatments to states by 50%.

“We made so much progress during the past 7 months of this pandemic. Even so, we remain at a critical moment, a critical time,” he said. “We have the tools. Now, we just have to finish the job with truth, with science, with confidence and together as one nation.”

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

President Joe Biden has announced a host of new plans to rein in COVID-19’s runaway transmission in the United States, including sweeping vaccine mandates that will affect 100 million American workers, nearly two-thirds of the country’s workforce.

itsmejust/Thinkstock

“As your president, I’m announcing tonight a new plan to get more Americans vaccinated to combat those blocking public health,” he said Sept. 9.

As part of a six-part plan unveiled in a speech from the State Dining Room of the White House, President Biden said he would require vaccinations for nearly 4 million federal workers and the employees of companies that contract with the federal government.

He has also directed the Occupational Safety and Health Administration to develop a rule that will require large employers -- those with at least 100 employees -- to ensure their workers are vaccinated or tested weekly.

Nearly 17 million health care workers will face new vaccine mandates as part of the conditions of participation in the Medicare and Medicaid programs.

President Biden said the federal government will require staff at federally funded Head Start programs and schools to be vaccinated. He’s also calling on all states to mandate vaccines for teachers.

“A distinct minority of Americans, supported by a distinct minority of elected officials, are keeping us from turning the corner,” PresidentBiden said. “These pandemic politics, as I refer to them, are making people sick, causing unvaccinated people to die.”

One public health official said he was glad to see the president’s bold action.

“What I saw today was the federal government trying to use its powers to create greater safety in the American population,” said Ashish K. Jha, MD, dean of the school of public health at Brown University, Providence, R.I., in a call with reporters after the speech.

National Nurses United, the largest union of registered nurses in the United States, issued a statement in support of President Biden’s new vaccination requirements, but pushed back on his language.

“…as advocates for public health, registered nurses want to be extremely clear: There is no such thing as a pandemic of only the unvaccinated. The science of epidemiology tells us there is just one deadly, global pandemic that has not yet ended, and we are all in it together. To get out of it, we must act together. All of us,” the statement says.

A host of other professional groups, including the American Medical Association and the Association of State and Territorial Health Officials, also issued statements of support for President Biden’s plan.

But the plan was not well received by all.

“I will pursue every legal option available to the state of Georgia to stop this blatantly unlawful overreach by the Biden Administration,” said Georgia Governor Brian Kemp, a Republican, in a Tweet.

The National Council for Occupational Safety and Health called the plan “a missed opportunity” because it failed to include workplace protections for essential workers such as grocery, postal, and transit workers.

“Social distancing, improved ventilation, shift rotation, and protective equipment to reduce exposure are important components of an overall plan to reduce risk and stop the virus. These tools are missing from the new steps President Biden announced today,” said Jessica Martinez, co-executive director of the group.

In addition to the new vaccination requirements, President Biden said extra doses would be on the way for people who have already been fully vaccinated in order to protect against waning immunity, starting on Sept. 20. But he noted that those plans would be contingent on the Food and Drug Administration’s approval for third doses and the Centers for Disease Control and Prevention’s recommendation of the shots.

President Biden pledged to use the Defense Production Act to ramp up production of at-home tests, which have been selling out across the nation as the Delta variant spreads.

He also announced plans to expand access to COVID-19 testing, including offering testing for free at thousands of pharmacies nationwide and getting major retailers to sell at-home COVID-19 tests at cost.

The BinaxNow test kit, which currently retails for $23.99, will now cost about $15 for two tests at Kroger, Amazon, and Walmart, according to the White House. Food banks and community health centers will get free tests, too.

He called on states to set up COVID-19 testing programs at all schools.

Jha said that in his view, the big, game-changing news out of the president’s speech was the expansion of testing.

“Our country has failed to deploy tests in a way that can really bring this pandemic under control,” Jha said. “There are plenty of reasons, data, experience to indicate that if these were widely available, it would make a dramatic difference in reducing infection numbers across our country.”.

Dr. Jha said the private market had not worked effectively to make testing more widely available, so it was “absolutely a requirement of the federal government to step in and make testing more widely available,” he said.

President Biden also announced new economic stimulus programs, saying he’s expanding loan programs to small businesses and streamlining the loan forgiveness process.

President Biden said he’s boosting help for overburdened hospitals, doubling the number of federal surge response teams sent to hard-hit areas to reduce the strain on local health care workers. He said he would increase the pace of antibody treatments to states by 50%.

“We made so much progress during the past 7 months of this pandemic. Even so, we remain at a critical moment, a critical time,” he said. “We have the tools. Now, we just have to finish the job with truth, with science, with confidence and together as one nation.”

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

Mortality is consistently twice as high in transgender people receiving hormone treatment, compared with cisgender individuals in the general population and has not decreased over time, results of a 5 decades–long study from the Netherlands indicate.

Origovisualis/Getty Images

Particularly concerning is that trans women (male to female) had a mortality risk nearly double that of cis men (born and remain male) in the general Dutch population (standardized mortality ratio, 1.8), while it was nearly triple that of cis women (SMR, 2.8).

Compared with cisgender women, transgender women were more than twice as likely to die from heart disease, three times more likely to die from lung cancer, and almost nine times more likely to die from infection. HIV-related disease mortality risk was nearly 50 times higher for trans women than cis women, and the risk of suicide was almost seven times greater.  

Suicide and other nonnatural causes of death were more common in trans men, compared with cis women.

The report, by Christel J.M. de Blok, MD, of Amsterdam University Medical Center and colleagues, was published online Sept. 2 in The Lancet Diabetes & Endocrinology.

The study included trans men who received testosterone to transition from female to male and trans women who received estrogen plus an antiandrogen to transition from male to female.
 

Is gender-affirming hormone therapy associated with increased mortality?

Senior author Martin den Heijer, MD, also of Amsterdam University Medical Center, said: “The findings of our large, nationwide study highlight a substantially increased mortality risk among transgender people that has persisted for decades.”

But he pointed out that, overall, the data do not appear to suggest the premature deaths were related to gender-affirming hormone treatment.

However, he conceded that more work is needed on this aspect of care. “There is insufficient evidence at present to determine long-term safety of [gender-affirming hormone treatment]. More research is needed to fully establish whether it in any way affects mortality risk for transgender people,” said Dr. den Heijer.

Endocrinologist Will Malone, MD, of Twin Falls, Idaho, told this news organization, “The study confirms, like others before it, that individuals taking cross-sex hormones are more likely to die prematurely from a number of causes.”

“While the authors speculate that this higher mortality rate is not connected to cross-sex hormones, the study was not designed to be able to make such a claim,” he said, pointing to limited follow-up times. 

In an accompanying commentary, Vin Tangpricha, MD, PhD, an endocrinologist from Emory University, Atlanta, noted: “Transgender men do not appear to have as significantly increased comorbidity following receipt of gender-affirming hormone therapy when compared with transgender women.”

Dr. Tangpricha added future studies should examine which factors – hormone regimen, hormone concentrations, access to health care, or other biological factors – explain the higher increased risk of morbidity and mortality observed in trans women as opposed to trans men.

However, Dr. de Blok and colleagues note that, as there were relatively few deaths among transgender men in the cohort, analysis on cause of death in this group is limited.

Transgender individuals more likely to die younger

For their study, Dutch researchers retrospectively examined data from 4,568 transgender people attending their clinic (2,927 transgender women and 1,641 transgender men) treated in 1972-2018. People were excluded if they started treatment before the age of 17 or if they had received puberty-blocking drugs.

Data on age at start of hormone treatment, type of treatment, smoking habits, medical history, and last date of follow-up were gathered from medical records. Where possible, SMRs were determined for deaths among trans men and trans women, compared with rates for the adult Dutch general population.

Median age at the start of cross-sex hormone treatment was 30 years in transgender women and 23 years in transgender men. But the median follow-up time was only 11 years in transgender women and 5 years in transgender men.

A total of 317 (10.8%) trans women died, and 44 (2.7%) trans men died. The findings were higher than expected, compared with the general population of cisgender women (SMR, 1.8) but not cisgender men (SMR 1.2).

Mortality risk did increase more in transgender people who started gender-affirming hormone treatment in the past 2 decades compared with earlier, a fact that Dr. de Blok said was surprising.

Trans men, for example, compared with cis women, had an SMR of 2.1-2.4 in 2000-2018 (compared with 1.8 overall).

“This may be due to changes in clinical practice. ... In the past, health care providers were reluctant to provide hormone treatment to people with a history of comorbidities such as cardiovascular disease. However, because of the many benefits of enabling people to access hormone therapy, nowadays this rarely results in treatment being denied,” Dr. de Blok noted.
 

More research needed, especially in trans-identifying youth

Dr. Malone remarked that previous studies have shown associations between taking cross-sex hormones and elevated mortality, while also “not designed to detect causality,” have “generally accepted that natal males who take estrogen have estrogen-related increases in the rates of heart disease, stroke, and deep venous thrombosis.” 

He added that the risks of testosterone use in natal females were less well established, “but testosterone is also felt to increase their risk of heart disease.” 

He stressed the limited follow-up times in the study by Dr. de Blok and colleagues.

This “strongly suggests that the rate of elevated mortality far exceeds the doubling measured by the study, especially for natal females.”

Dr. Malone is one of several clinicians and researchers who has formed the Society for Evidence-Based Gender Medicine, a nonprofit organization that now has at least 100 physician members. SEGM is concerned about the lack of quality evidence for the use of hormonal and surgical interventions as first-line treatment, especially for young people with gender dysphoria.  

Dr. Tangpricha also highlighted that the findings do not apply to transgender people who began treatment before age 17 years or those who had taken puberty blockers before gender-affirming hormone treatment.

There are no long-term data on transgender individuals who have received gender-affirming hormone therapies close to the time of puberty.

These data, such as those from the Trans Youth Care study, should be available in the future, he added.

The authors have reported no relevant financial relationships. Dr. Tangpricha has reported receiving funding from the National Institutes of Health and served as past president of the World Professional Association for Transgender Health. He is editor-in-chief of Endocrine Practice and has provided expert testimony for Kirkland and Ellis.

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

Mortality is consistently twice as high in transgender people receiving hormone treatment, compared with cisgender individuals in the general population and has not decreased over time, results of a 5 decades–long study from the Netherlands indicate.

Origovisualis/Getty Images

Particularly concerning is that trans women (male to female) had a mortality risk nearly double that of cis men (born and remain male) in the general Dutch population (standardized mortality ratio, 1.8), while it was nearly triple that of cis women (SMR, 2.8).

Compared with cisgender women, transgender women were more than twice as likely to die from heart disease, three times more likely to die from lung cancer, and almost nine times more likely to die from infection. HIV-related disease mortality risk was nearly 50 times higher for trans women than cis women, and the risk of suicide was almost seven times greater.  

Suicide and other nonnatural causes of death were more common in trans men, compared with cis women.

The report, by Christel J.M. de Blok, MD, of Amsterdam University Medical Center and colleagues, was published online Sept. 2 in The Lancet Diabetes & Endocrinology.

The study included trans men who received testosterone to transition from female to male and trans women who received estrogen plus an antiandrogen to transition from male to female.
 

Is gender-affirming hormone therapy associated with increased mortality?

Senior author Martin den Heijer, MD, also of Amsterdam University Medical Center, said: “The findings of our large, nationwide study highlight a substantially increased mortality risk among transgender people that has persisted for decades.”

But he pointed out that, overall, the data do not appear to suggest the premature deaths were related to gender-affirming hormone treatment.

However, he conceded that more work is needed on this aspect of care. “There is insufficient evidence at present to determine long-term safety of [gender-affirming hormone treatment]. More research is needed to fully establish whether it in any way affects mortality risk for transgender people,” said Dr. den Heijer.

Endocrinologist Will Malone, MD, of Twin Falls, Idaho, told this news organization, “The study confirms, like others before it, that individuals taking cross-sex hormones are more likely to die prematurely from a number of causes.”

“While the authors speculate that this higher mortality rate is not connected to cross-sex hormones, the study was not designed to be able to make such a claim,” he said, pointing to limited follow-up times. 

In an accompanying commentary, Vin Tangpricha, MD, PhD, an endocrinologist from Emory University, Atlanta, noted: “Transgender men do not appear to have as significantly increased comorbidity following receipt of gender-affirming hormone therapy when compared with transgender women.”

Dr. Tangpricha added future studies should examine which factors – hormone regimen, hormone concentrations, access to health care, or other biological factors – explain the higher increased risk of morbidity and mortality observed in trans women as opposed to trans men.

However, Dr. de Blok and colleagues note that, as there were relatively few deaths among transgender men in the cohort, analysis on cause of death in this group is limited.

Transgender individuals more likely to die younger

For their study, Dutch researchers retrospectively examined data from 4,568 transgender people attending their clinic (2,927 transgender women and 1,641 transgender men) treated in 1972-2018. People were excluded if they started treatment before the age of 17 or if they had received puberty-blocking drugs.

Data on age at start of hormone treatment, type of treatment, smoking habits, medical history, and last date of follow-up were gathered from medical records. Where possible, SMRs were determined for deaths among trans men and trans women, compared with rates for the adult Dutch general population.

Median age at the start of cross-sex hormone treatment was 30 years in transgender women and 23 years in transgender men. But the median follow-up time was only 11 years in transgender women and 5 years in transgender men.

A total of 317 (10.8%) trans women died, and 44 (2.7%) trans men died. The findings were higher than expected, compared with the general population of cisgender women (SMR, 1.8) but not cisgender men (SMR 1.2).

Mortality risk did increase more in transgender people who started gender-affirming hormone treatment in the past 2 decades compared with earlier, a fact that Dr. de Blok said was surprising.

Trans men, for example, compared with cis women, had an SMR of 2.1-2.4 in 2000-2018 (compared with 1.8 overall).

“This may be due to changes in clinical practice. ... In the past, health care providers were reluctant to provide hormone treatment to people with a history of comorbidities such as cardiovascular disease. However, because of the many benefits of enabling people to access hormone therapy, nowadays this rarely results in treatment being denied,” Dr. de Blok noted.
 

More research needed, especially in trans-identifying youth

Dr. Malone remarked that previous studies have shown associations between taking cross-sex hormones and elevated mortality, while also “not designed to detect causality,” have “generally accepted that natal males who take estrogen have estrogen-related increases in the rates of heart disease, stroke, and deep venous thrombosis.” 

He added that the risks of testosterone use in natal females were less well established, “but testosterone is also felt to increase their risk of heart disease.” 

He stressed the limited follow-up times in the study by Dr. de Blok and colleagues.

This “strongly suggests that the rate of elevated mortality far exceeds the doubling measured by the study, especially for natal females.”

Dr. Malone is one of several clinicians and researchers who has formed the Society for Evidence-Based Gender Medicine, a nonprofit organization that now has at least 100 physician members. SEGM is concerned about the lack of quality evidence for the use of hormonal and surgical interventions as first-line treatment, especially for young people with gender dysphoria.  

Dr. Tangpricha also highlighted that the findings do not apply to transgender people who began treatment before age 17 years or those who had taken puberty blockers before gender-affirming hormone treatment.

There are no long-term data on transgender individuals who have received gender-affirming hormone therapies close to the time of puberty.

These data, such as those from the Trans Youth Care study, should be available in the future, he added.

The authors have reported no relevant financial relationships. Dr. Tangpricha has reported receiving funding from the National Institutes of Health and served as past president of the World Professional Association for Transgender Health. He is editor-in-chief of Endocrine Practice and has provided expert testimony for Kirkland and Ellis.

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

Mortality is consistently twice as high in transgender people receiving hormone treatment, compared with cisgender individuals in the general population and has not decreased over time, results of a 5 decades–long study from the Netherlands indicate.

Origovisualis/Getty Images

Particularly concerning is that trans women (male to female) had a mortality risk nearly double that of cis men (born and remain male) in the general Dutch population (standardized mortality ratio, 1.8), while it was nearly triple that of cis women (SMR, 2.8).

Compared with cisgender women, transgender women were more than twice as likely to die from heart disease, three times more likely to die from lung cancer, and almost nine times more likely to die from infection. HIV-related disease mortality risk was nearly 50 times higher for trans women than cis women, and the risk of suicide was almost seven times greater.  

Suicide and other nonnatural causes of death were more common in trans men, compared with cis women.

The report, by Christel J.M. de Blok, MD, of Amsterdam University Medical Center and colleagues, was published online Sept. 2 in The Lancet Diabetes & Endocrinology.

The study included trans men who received testosterone to transition from female to male and trans women who received estrogen plus an antiandrogen to transition from male to female.
 

Is gender-affirming hormone therapy associated with increased mortality?

Senior author Martin den Heijer, MD, also of Amsterdam University Medical Center, said: “The findings of our large, nationwide study highlight a substantially increased mortality risk among transgender people that has persisted for decades.”

But he pointed out that, overall, the data do not appear to suggest the premature deaths were related to gender-affirming hormone treatment.

However, he conceded that more work is needed on this aspect of care. “There is insufficient evidence at present to determine long-term safety of [gender-affirming hormone treatment]. More research is needed to fully establish whether it in any way affects mortality risk for transgender people,” said Dr. den Heijer.

Endocrinologist Will Malone, MD, of Twin Falls, Idaho, told this news organization, “The study confirms, like others before it, that individuals taking cross-sex hormones are more likely to die prematurely from a number of causes.”

“While the authors speculate that this higher mortality rate is not connected to cross-sex hormones, the study was not designed to be able to make such a claim,” he said, pointing to limited follow-up times. 

In an accompanying commentary, Vin Tangpricha, MD, PhD, an endocrinologist from Emory University, Atlanta, noted: “Transgender men do not appear to have as significantly increased comorbidity following receipt of gender-affirming hormone therapy when compared with transgender women.”

Dr. Tangpricha added future studies should examine which factors – hormone regimen, hormone concentrations, access to health care, or other biological factors – explain the higher increased risk of morbidity and mortality observed in trans women as opposed to trans men.

However, Dr. de Blok and colleagues note that, as there were relatively few deaths among transgender men in the cohort, analysis on cause of death in this group is limited.

Transgender individuals more likely to die younger

For their study, Dutch researchers retrospectively examined data from 4,568 transgender people attending their clinic (2,927 transgender women and 1,641 transgender men) treated in 1972-2018. People were excluded if they started treatment before the age of 17 or if they had received puberty-blocking drugs.

Data on age at start of hormone treatment, type of treatment, smoking habits, medical history, and last date of follow-up were gathered from medical records. Where possible, SMRs were determined for deaths among trans men and trans women, compared with rates for the adult Dutch general population.

Median age at the start of cross-sex hormone treatment was 30 years in transgender women and 23 years in transgender men. But the median follow-up time was only 11 years in transgender women and 5 years in transgender men.

A total of 317 (10.8%) trans women died, and 44 (2.7%) trans men died. The findings were higher than expected, compared with the general population of cisgender women (SMR, 1.8) but not cisgender men (SMR 1.2).

Mortality risk did increase more in transgender people who started gender-affirming hormone treatment in the past 2 decades compared with earlier, a fact that Dr. de Blok said was surprising.

Trans men, for example, compared with cis women, had an SMR of 2.1-2.4 in 2000-2018 (compared with 1.8 overall).

“This may be due to changes in clinical practice. ... In the past, health care providers were reluctant to provide hormone treatment to people with a history of comorbidities such as cardiovascular disease. However, because of the many benefits of enabling people to access hormone therapy, nowadays this rarely results in treatment being denied,” Dr. de Blok noted.
 

More research needed, especially in trans-identifying youth

Dr. Malone remarked that previous studies have shown associations between taking cross-sex hormones and elevated mortality, while also “not designed to detect causality,” have “generally accepted that natal males who take estrogen have estrogen-related increases in the rates of heart disease, stroke, and deep venous thrombosis.” 

He added that the risks of testosterone use in natal females were less well established, “but testosterone is also felt to increase their risk of heart disease.” 

He stressed the limited follow-up times in the study by Dr. de Blok and colleagues.

This “strongly suggests that the rate of elevated mortality far exceeds the doubling measured by the study, especially for natal females.”

Dr. Malone is one of several clinicians and researchers who has formed the Society for Evidence-Based Gender Medicine, a nonprofit organization that now has at least 100 physician members. SEGM is concerned about the lack of quality evidence for the use of hormonal and surgical interventions as first-line treatment, especially for young people with gender dysphoria.  

Dr. Tangpricha also highlighted that the findings do not apply to transgender people who began treatment before age 17 years or those who had taken puberty blockers before gender-affirming hormone treatment.

There are no long-term data on transgender individuals who have received gender-affirming hormone therapies close to the time of puberty.

These data, such as those from the Trans Youth Care study, should be available in the future, he added.

The authors have reported no relevant financial relationships. Dr. Tangpricha has reported receiving funding from the National Institutes of Health and served as past president of the World Professional Association for Transgender Health. He is editor-in-chief of Endocrine Practice and has provided expert testimony for Kirkland and Ellis.

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

Physicians caring for COVID-19 survivors should routinely check kidney function, which is often damaged by the SARS-CoV-2 virus months after both severe and milder cases, new research indicates.

The largest study to date with the longest follow-up of COVID-19-related kidney outcomes also found that every type of kidney problem, including end-stage kidney disease (ESKD), was far more common in COVID-19 survivors who were admitted to the ICU or experienced acute kidney injury (AKI) while hospitalized.

Researchers analyzed U.S. Veterans Health Administration data from more than 1.7 million patients, including more than 89,000 who tested positive for COVID-19, for the study, which was published online Sept. 1, 2021, in the Journal of the American Society of Nephrology.

The risk of kidney problems “is more robust or pronounced in people who have had severe infection, but present in even asymptomatic and mild disease, which shouldn’t be discounted. Those people represent the majority of those with COVID-19,” said senior author Ziyad Al-Aly, MD, of the Veteran Affairs St. Louis Health Care System.

“That’s why the results are important, because even in people with mild disease to start with, the risk of kidney problems is not trivial,” he told this news organization. “It’s smaller than in people who were in the ICU, but it’s not ... zero.”

Experts aren’t yet certain how COVID-19 can damage the kidneys, hypothesizing that several factors may be at play. The virus may directly infect kidney cells rich in ACE2 receptors, which are key to infection, said nephrologist F. Perry Wilson, MD, of Yale University, New Haven, Conn., and a member of Medscape’s advisory board.

Kidneys might also be particularly vulnerable to the inflammatory cascade or blood clotting often seen in COVID-19, Dr. Al-Aly and Wilson both suggested.
 

COVID-19 survivors more likely to have kidney damage than controls

“A lot of health systems either have or are establishing post-COVID care clinics, which we think should definitely incorporate a kidney component,” Dr. Al-Aly advised. “They should check patients’ blood and urine for kidney problems.”

This is particularly important because “kidney problems, for the most part, are painless and silent,” he added.

“Realizing 2 years down the road that someone has ESKD, where they need dialysis or a kidney transplant, is what we don’t want. We don’t want this to be unrecognized, uncared for, unattended to,” he said.

Dr. Al-Aly and colleagues evaluated VA health system records, including data from 89,216 patients who tested positive for COVID-19 between March 2020 and March 2021, as well as 1.7 million controls who did not have COVID-19. Over a median follow-up of about 5.5 months, participants’ estimated glomerular filtration rate and serum creatinine levels were tracked to assess kidney health and outcomes according to infection severity.

Results were striking, with COVID-19 survivors about one-third more likely than controls to have kidney damage or significant declines in kidney function between 1 and 6 months after infection. More than 4,700 COVID-19 survivors had lost at least 30% of their kidney function within a year, and these patients were 25% more likely to reach that level of decline than controls.

Additionally, COVID-19 survivors were nearly twice as likely to experience AKI and almost three times as likely to be diagnosed with ESKD as controls.
 

If your patient had COVID-19, ‘it’s reasonable to check kidney function’

“This information tells us that if your patient was sick with COVID-19 and comes for follow-up visits, it’s reasonable to check their kidney function,” Dr. Wilson, who was not involved with the research, told this news organization.

“Even for patients who were not hospitalized, if they were laid low or dehydrated ... it should be part of the post-COVID care package,” he said.

If just a fraction of the millions of COVID-19 survivors in the United States develop long-term kidney problems, the ripple effect on American health care could be substantial, Dr. Wilson and Dr. Al-Aly agreed.

“We’re still living in a pandemic, so it’s hard to tell the total impact,” Dr. Al-Aly said. “But this ultimately will contribute to a rise in burden of kidney disease. This and other long COVID manifestations are going to alter the landscape of clinical care and health care in the United States for a decade or more.”

Because renal problems can limit a patient’s treatment options for other major diseases, including diabetes and cancer, COVID-related kidney damage can ultimately impact survivability.

“There are a lot of medications you can’t use in people with advanced kidney problems,” Dr. Al-Aly said.

The main study limitation was that patients were mostly older White men (median age, 68 years), although more than 9,000 women were included in the VA data, Dr. Al-Aly noted. Additionally, controls were more likely to be younger, Black, living in long-term care, and have higher rates of chronic health conditions and medication use.

The experts agreed that ongoing research tracking kidney outcomes is crucial for years to come.

“We also need to be following a cohort of these patients as part of a research protocol where they come in every 6 months for a standard set of lab tests to really understand what’s going on with their kidneys,” Dr. Wilson said.

“Lastly – and a much tougher sell – is we need biopsies. It’s very hard to infer what’s going on in complex disease with the kidneys without biopsy tissue,” he added.

The study was funded by the American Society of Nephrology and the Department of Veterans Affairs. Dr. Al-Aly and Dr. Wilson reported no relevant financial relationships.

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

Physicians caring for COVID-19 survivors should routinely check kidney function, which is often damaged by the SARS-CoV-2 virus months after both severe and milder cases, new research indicates.

The largest study to date with the longest follow-up of COVID-19-related kidney outcomes also found that every type of kidney problem, including end-stage kidney disease (ESKD), was far more common in COVID-19 survivors who were admitted to the ICU or experienced acute kidney injury (AKI) while hospitalized.

Researchers analyzed U.S. Veterans Health Administration data from more than 1.7 million patients, including more than 89,000 who tested positive for COVID-19, for the study, which was published online Sept. 1, 2021, in the Journal of the American Society of Nephrology.

The risk of kidney problems “is more robust or pronounced in people who have had severe infection, but present in even asymptomatic and mild disease, which shouldn’t be discounted. Those people represent the majority of those with COVID-19,” said senior author Ziyad Al-Aly, MD, of the Veteran Affairs St. Louis Health Care System.

“That’s why the results are important, because even in people with mild disease to start with, the risk of kidney problems is not trivial,” he told this news organization. “It’s smaller than in people who were in the ICU, but it’s not ... zero.”

Experts aren’t yet certain how COVID-19 can damage the kidneys, hypothesizing that several factors may be at play. The virus may directly infect kidney cells rich in ACE2 receptors, which are key to infection, said nephrologist F. Perry Wilson, MD, of Yale University, New Haven, Conn., and a member of Medscape’s advisory board.

Kidneys might also be particularly vulnerable to the inflammatory cascade or blood clotting often seen in COVID-19, Dr. Al-Aly and Wilson both suggested.
 

COVID-19 survivors more likely to have kidney damage than controls

“A lot of health systems either have or are establishing post-COVID care clinics, which we think should definitely incorporate a kidney component,” Dr. Al-Aly advised. “They should check patients’ blood and urine for kidney problems.”

This is particularly important because “kidney problems, for the most part, are painless and silent,” he added.

“Realizing 2 years down the road that someone has ESKD, where they need dialysis or a kidney transplant, is what we don’t want. We don’t want this to be unrecognized, uncared for, unattended to,” he said.

Dr. Al-Aly and colleagues evaluated VA health system records, including data from 89,216 patients who tested positive for COVID-19 between March 2020 and March 2021, as well as 1.7 million controls who did not have COVID-19. Over a median follow-up of about 5.5 months, participants’ estimated glomerular filtration rate and serum creatinine levels were tracked to assess kidney health and outcomes according to infection severity.

Results were striking, with COVID-19 survivors about one-third more likely than controls to have kidney damage or significant declines in kidney function between 1 and 6 months after infection. More than 4,700 COVID-19 survivors had lost at least 30% of their kidney function within a year, and these patients were 25% more likely to reach that level of decline than controls.

Additionally, COVID-19 survivors were nearly twice as likely to experience AKI and almost three times as likely to be diagnosed with ESKD as controls.
 

If your patient had COVID-19, ‘it’s reasonable to check kidney function’

“This information tells us that if your patient was sick with COVID-19 and comes for follow-up visits, it’s reasonable to check their kidney function,” Dr. Wilson, who was not involved with the research, told this news organization.

“Even for patients who were not hospitalized, if they were laid low or dehydrated ... it should be part of the post-COVID care package,” he said.

If just a fraction of the millions of COVID-19 survivors in the United States develop long-term kidney problems, the ripple effect on American health care could be substantial, Dr. Wilson and Dr. Al-Aly agreed.

“We’re still living in a pandemic, so it’s hard to tell the total impact,” Dr. Al-Aly said. “But this ultimately will contribute to a rise in burden of kidney disease. This and other long COVID manifestations are going to alter the landscape of clinical care and health care in the United States for a decade or more.”

Because renal problems can limit a patient’s treatment options for other major diseases, including diabetes and cancer, COVID-related kidney damage can ultimately impact survivability.

“There are a lot of medications you can’t use in people with advanced kidney problems,” Dr. Al-Aly said.

The main study limitation was that patients were mostly older White men (median age, 68 years), although more than 9,000 women were included in the VA data, Dr. Al-Aly noted. Additionally, controls were more likely to be younger, Black, living in long-term care, and have higher rates of chronic health conditions and medication use.

The experts agreed that ongoing research tracking kidney outcomes is crucial for years to come.

“We also need to be following a cohort of these patients as part of a research protocol where they come in every 6 months for a standard set of lab tests to really understand what’s going on with their kidneys,” Dr. Wilson said.

“Lastly – and a much tougher sell – is we need biopsies. It’s very hard to infer what’s going on in complex disease with the kidneys without biopsy tissue,” he added.

The study was funded by the American Society of Nephrology and the Department of Veterans Affairs. Dr. Al-Aly and Dr. Wilson reported no relevant financial relationships.

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

Physicians caring for COVID-19 survivors should routinely check kidney function, which is often damaged by the SARS-CoV-2 virus months after both severe and milder cases, new research indicates.

The largest study to date with the longest follow-up of COVID-19-related kidney outcomes also found that every type of kidney problem, including end-stage kidney disease (ESKD), was far more common in COVID-19 survivors who were admitted to the ICU or experienced acute kidney injury (AKI) while hospitalized.

Researchers analyzed U.S. Veterans Health Administration data from more than 1.7 million patients, including more than 89,000 who tested positive for COVID-19, for the study, which was published online Sept. 1, 2021, in the Journal of the American Society of Nephrology.

The risk of kidney problems “is more robust or pronounced in people who have had severe infection, but present in even asymptomatic and mild disease, which shouldn’t be discounted. Those people represent the majority of those with COVID-19,” said senior author Ziyad Al-Aly, MD, of the Veteran Affairs St. Louis Health Care System.

“That’s why the results are important, because even in people with mild disease to start with, the risk of kidney problems is not trivial,” he told this news organization. “It’s smaller than in people who were in the ICU, but it’s not ... zero.”

Experts aren’t yet certain how COVID-19 can damage the kidneys, hypothesizing that several factors may be at play. The virus may directly infect kidney cells rich in ACE2 receptors, which are key to infection, said nephrologist F. Perry Wilson, MD, of Yale University, New Haven, Conn., and a member of Medscape’s advisory board.

Kidneys might also be particularly vulnerable to the inflammatory cascade or blood clotting often seen in COVID-19, Dr. Al-Aly and Wilson both suggested.
 

COVID-19 survivors more likely to have kidney damage than controls

“A lot of health systems either have or are establishing post-COVID care clinics, which we think should definitely incorporate a kidney component,” Dr. Al-Aly advised. “They should check patients’ blood and urine for kidney problems.”

This is particularly important because “kidney problems, for the most part, are painless and silent,” he added.

“Realizing 2 years down the road that someone has ESKD, where they need dialysis or a kidney transplant, is what we don’t want. We don’t want this to be unrecognized, uncared for, unattended to,” he said.

Dr. Al-Aly and colleagues evaluated VA health system records, including data from 89,216 patients who tested positive for COVID-19 between March 2020 and March 2021, as well as 1.7 million controls who did not have COVID-19. Over a median follow-up of about 5.5 months, participants’ estimated glomerular filtration rate and serum creatinine levels were tracked to assess kidney health and outcomes according to infection severity.

Results were striking, with COVID-19 survivors about one-third more likely than controls to have kidney damage or significant declines in kidney function between 1 and 6 months after infection. More than 4,700 COVID-19 survivors had lost at least 30% of their kidney function within a year, and these patients were 25% more likely to reach that level of decline than controls.

Additionally, COVID-19 survivors were nearly twice as likely to experience AKI and almost three times as likely to be diagnosed with ESKD as controls.
 

If your patient had COVID-19, ‘it’s reasonable to check kidney function’

“This information tells us that if your patient was sick with COVID-19 and comes for follow-up visits, it’s reasonable to check their kidney function,” Dr. Wilson, who was not involved with the research, told this news organization.

“Even for patients who were not hospitalized, if they were laid low or dehydrated ... it should be part of the post-COVID care package,” he said.

If just a fraction of the millions of COVID-19 survivors in the United States develop long-term kidney problems, the ripple effect on American health care could be substantial, Dr. Wilson and Dr. Al-Aly agreed.

“We’re still living in a pandemic, so it’s hard to tell the total impact,” Dr. Al-Aly said. “But this ultimately will contribute to a rise in burden of kidney disease. This and other long COVID manifestations are going to alter the landscape of clinical care and health care in the United States for a decade or more.”

Because renal problems can limit a patient’s treatment options for other major diseases, including diabetes and cancer, COVID-related kidney damage can ultimately impact survivability.

“There are a lot of medications you can’t use in people with advanced kidney problems,” Dr. Al-Aly said.

The main study limitation was that patients were mostly older White men (median age, 68 years), although more than 9,000 women were included in the VA data, Dr. Al-Aly noted. Additionally, controls were more likely to be younger, Black, living in long-term care, and have higher rates of chronic health conditions and medication use.

The experts agreed that ongoing research tracking kidney outcomes is crucial for years to come.

“We also need to be following a cohort of these patients as part of a research protocol where they come in every 6 months for a standard set of lab tests to really understand what’s going on with their kidneys,” Dr. Wilson said.

“Lastly – and a much tougher sell – is we need biopsies. It’s very hard to infer what’s going on in complex disease with the kidneys without biopsy tissue,” he added.

The study was funded by the American Society of Nephrology and the Department of Veterans Affairs. Dr. Al-Aly and Dr. Wilson reported no relevant financial relationships.

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

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

One month of dual antiplatelet therapy followed by 11 months of clopidogrel monotherapy failed to prove noninferiority to 12 unbroken months of DAPT for net clinical benefit in a multicenter Japanese trial that randomized more than 4,000 patients who underwent percutaneous coronary intervention (PCI) after a recent acute coronary syndrome episode.

© Astrid Gast/Thinkstock

The outcomes showed that while truncating DAPT duration could, as expected, cut major bleeding episodes roughly in half, it also led to a significant near doubling of myocardial infarction and showed a strong trend toward also increasing a composite tally of several types of ischemic events. These data were reported this week by Hirotoshi Watanabe, MD, PhD, at the virtual annual congress of the European Society of Cardiology. All study patients had undergone PCI with cobalt-chromium everolimus-eluting (CCEE) coronary stents (Xience).

These findings from the STOPDAPT-2 ACS trial highlighted the limits of minimizing DAPT after PCI in patients at high ischemic risk, such as after an acute coronary syndrome (ACS) event.

It also was a counterpoint to a somewhat similar study also reported at the congress, MASTER DAPT, which showed that 1 month of DAPT was noninferior to 3 or more months of DAPT for net clinical benefit in a distinctly different population of patients undergoing PCI (and using a different type of coronary stent) – those at high bleeding risk and with only about half the patients having had a recent ACS.

The results of STOPDAPT-2 ACS “do not support use of 1 month of DAPT followed by P2Y12 inhibitor monotherapy with clopidogrel compared with standard DAPT,” commented Robert A. Byrne, MBBCh, PhD, designated discussant for the report and professor at the RCSI University of Medicine and Health Sciences in Dublin.

“Although major bleeding was significantly reduced with this approach, there appeared to be a significant increase in adverse ischemic events, and there was a clear signal in relation to overall mortality, the ultimate arbiter of net clinical benefit,” added Dr. Byrne, who is also director of cardiology at Mater Private Hospital in Dublin.

He suggested that a mechanistic explanation for the signal of harm seem in STOPDAPT-2 ACS was the relatively low potency of clopidogrel (Plavix) as an antiplatelet agent, compared with other P2Y12 inhibitors such as prasugrel (Effient) and ticagrelor (Brilinta), as well as the genetically driven variability in response to clopidogrel that’s also absent with alternative agents.

These between-agent differences are of “particular clinical relevance in the early aftermath of an ACS event,” Dr. Byrne said.
 

12-month DAPT remains standard for PCI patients with recent ACS

The totality of clinical evidence “continues to support a standard 12-month duration of DAPT – using aspirin and either prasugrel or ticagrelor – as the preferred default approach,” Dr. Byrne concluded.

He acknowledged that an abbreviated duration of DAPT followed by P2Y12 inhibitor monotherapy “might be considered as an alternative.” In patients following an ACS event who do not have high risk for bleeding, he said, the minimum duration of DAPT should be at least 3 months and with preferential use of a more potent P2Y12 inhibitor.

Twelve months of DAPT treatment with aspirin and a P2Y12 inhibitor for patients following PCI “remains the standard of care in guidelines,” noted Marco Roffi, MD, a second discussant at the congress. But several questions remain, he added, such as which P2Y12 inhibitors work best and whether DAPT can be less than 12 months.

“The investigators [for STOPDAPT-2 ACS] pushed these questions to the limit with 1 month of DAPT and clopidogrel monotherapy,” said Dr. Roffi, professor and director of interventional cardiology at University Hospital, Geneva.

“This was a risky bet, and the investigators lost by not proving noninferiority and with excess ischemic events,” he commented.
 

First came STOPDAPT-2

Dr. Watanabe and colleagues designed STOPDAPT-2 ACS as a follow-up to their prior STOPDAPT-2 trial, which randomly assigned slightly more than 3000 patients at 90 Japanese centers to the identical two treatment options: 1 month of DAPT followed by 11 months of clopidogrel monotherapy or 12 months of DAPT, except the trial enrolled all types of patients undergoing PCI. This meant that a minority, 38%, had a recent ACS event, while the remaining patients had chronic coronary artery disease. As in STOPDAPT-2 ACS, all patients in STOPDAPT-2 had received a CCEE stent.

STOPDAPT-2 also used the same primary endpoint to tally net clinical benefit as STOPDAPT-2 ACS: cardiovascular death, MI, stroke of any type, definite stent thrombosis, or TIMI major or minor bleeding classification.

In STOPDAPT-2, using the mixed population with both recent ACS and chronic coronary disease, the regimen of 1 month of DAPT followed by 11 months of clopidogrel monotherapy was both noninferior to and superior to 12 months of DAPT, reducing the net adverse-event tally by 36% relative to 12-month DAPT and by an absolute reduction of 1.34%, as reported in 2019.

Despite this superiority, the results from STOPDAPT-2 had little impact on global practice, commented Kurt Huber, MD, professor and director of the cardiology ICU at the Medical University of Vienna.

“STOP-DAPT-2 did not give us a clear message with respect to reducing antiplatelet treatment after 1 month. I thought that for ACS patients 1 month might be too short,” Dr. Huber said during a press briefing.
 

Focusing on post-ACS

To directly address this issue, the investigators launched STOPDAPT-2 ACS, which used the same design as the preceding study but only enrolled patients soon after an ACS event. The trial included for its main analysis 3,008 newly enrolled patients with recent ACS, and 1,161 patients who had a recent ACS event and had been randomly assigned in STOPDAPT-2, creating a total study cohort for the new analysis of 4136 patients treated and followed for the study’s full 12 months.

The patients averaged 67 years old, 79% were men, and 30% had diabetes. About 56% had a recent ST-elevation MI, about 20% a recent non–ST-elevation MI, and the remaining 24% had unstable angina. For their unspecified P2Y12 inhibition, roughly half the patients received clopidogrel and the rest received prasugrel. Adherence to the two assigned treatment regimens was very good, with a very small number of patients not adhering to their assigned protocol.

The composite adverse event incidence over 12 months was 3.2% among those who received 1-month DAPT and 2.83% in those on DAPT for 12 months, a difference that failed to achieve the prespecified definition of noninferiority for 1-month DAPT, reported Dr. Watanabe, an interventional cardiologist at Kyoto University.

The ischemic event composite was 50% lower among those on 12-month DAPT, compared with 1 month of DAPT, a difference that just missed significance. The rate of MI was 91% higher with 1-month DAPT, compared with 12 months, a significant difference.

One-month DAPT also significantly reduced the primary measure of bleeding events – the combination of TIMI major and minor bleeds – by a significant 54%, compared with 12-month DAPT. A second metric of clinically meaningful bleeds, those that meet either the type 3 or 5 definition of the Bleeding Academic Research Consortium, were reduced by a significant 59% by 1-month DAPT, compared with 12 months of DAPT.

The new findings from STOPDAPT-2 ACS contrasted with those from MASTER DAPT, but in an explicable way that related to different patient types, different P2Y12 inhibitors, different treatment durations, and different stents.

“We’ve seen in MASTER DAPT that if you use the right stent and use ticagrelor for monotherapy there may be some ability to shorten DAPT, but we still do not know what would happen in patients with very high ischemic risk,” concluded Dr. Huber.

“A reduction in DAPT duration might work in patients without high bleeding risk, but I would exclude patients with very high ischemic risk,” he added. “I also can’t tell you whether 1 month or 3 months is the right approach, and I think clopidogrel is not the right drug to use for monotherapy after ACS.”

STOPDAPT-2 and STOPDAPT-2 ACS were both sponsored by Abbott Vascular, which markets the CCEE (Xience) stents used in both studies. Dr. Watanabe has received lecture fees from Abbott and from Daiichi-Sankyo. Dr. Byrne has received research funding from Abbott Vascular as well as from Biosensors, Biotronik, and Boston Scientific. Roffi has received research funding from Biotronik, Boston Scientific, GE Healthcare, Medtronic, and Terumo. Dr. Huber has received lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, Sanofi-Aventis, and The Medicines Company.

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

When the Food and Drug Administration approved Semglee, the first interchangeable biosimilar insulin, the agency pitched it as having the potential to be less costly than insulins currently on the market, but lack of transparency in pharmaceutical pricing has left analysts and advocates guessing whether it will indeed be a source of relief.

iStock/ThinkStock

Semglee (Mylan Pharmaceuticals), first approved as a biosimilar in June 2020, costs about $100 a vial.

But receiving the “interchangeable designation” in July 2021, the first for any insulin, now allows Semglee to be substituted for the branded Lantus (insulin glargine, Sanofi) at the pharmacy without the need for a separate prescription, the same way as generic medicines.

A spokesperson for Viatris – Mylan’s parent company told this news organization that the interchangeable, with its new labeling, will be “introduced before the end of the year,” but it would not give any more details.

“Additional information, including pricing information, for interchangeable biosimilar Semglee will be provided at the time of product launch,” said the spokesperson.
 

Even at $100 a vial, it is not cheap

Ian Devaney, a spokesman for the advocacy group T1 International, said the organization is optimistic, given that “another player has been able to enter into a space that has for so long been dominated by Eli Lilly, Novo Nordisk, and Sanofi.” Increased competition “will help drive down the overall costs of insulin,” Mr. Devaney said in an interview. But, he added, for many people, especially in low-income countries, Semglee’s launch will have little to no impact on price.

Even at $100 a vial in the United States, “this is not an insignificant amount of money and presents a very difficult financial challenge for those dependent on insulin to survive,” he said.

A current Semglee user agreed, sharing her story with this news organization via T1 International. “My son uses three to five vials of long-acting insulin per month, and I use one to three vials per month,” said the woman, who prefers to remain anonymous. “If we were to lose Medicaid, we would still be paying up to $800 out of pocket monthly to survive, and that’s not even counting fast-acting insulin or other supplies. While $100 a vial may be cheaper, these costs are still outrageous.”

The woman also noted that, while new competitors are welcome, they also have been disruptive. After her doctor switched her to Semglee, she was notified that it was on back order. “It took a week to get it filled, and when it finally came in, it was in short supply,” she said, noting that she and her son received one Semglee pen each, “well short of the three and five each we were expecting.”
 

U.S. pricing is all ‘smoke and mirrors’

Sara W. Koblitz, a food and drug law attorney with Hyman Phelps in Washington, D.C., noted in a blog post that interchangeable Semglee will likely be awarded a year of marketing exclusivity, which will block other interchangeable competitors from entering the market during that time.

With no competition, “Mylan can price Semglee only slightly less than Lantus and still take market share, only marginally reducing costs to consumers,” she wrote.

Jing Luo, MD, MPH, an assistant professor of medicine at the University of Pittsburgh, who has studied insulin access and costs, said that having just one interchangeable on the market might not be enough to drive insulin costs down.

And, he told this news organization, “there’s even a possibility that Semglee prices will go up, but hopefully that will not be the case.”

Manufacturers like Mylan can also offer confidential discounts and rebates to pharmacy benefit managers (PBMs), health plans, and health plan sponsors (usually large companies that are self-insured) that make it difficult to assess the true cost, said David Steinberg, PharmD, director of pharmacy insights at Scripta Insights. The Wellesley, Mass.–based company advises self-insured employers on how to optimize pharmacy benefits.

When it comes to pricing, “it’s a lot of smoke and mirrors,” Dr. Steinberg said in an interview.

Dr. Steinberg also noted that some PBMs might choose to continue contracts with Sanofi that offer rebates for Lantus, leaving Semglee in a less-preferred position on a formulary, which could increase how much the patient pays at the pharmacy counter. 

Medicare and Medicaid, however, can put Semglee in the top-tier preferred formulary position. Most Medicaid plans cover Semglee, but it appears that Medicare has not added coverage yet.
 

Does current pricing predict the future?

The currently marketed Semglee has an average wholesale price (AWP) that is one third of Lantus’, and about half of what is published for Basaglar (insulin glargine, Eli Lilly), a “follow-on biologic” approved in 2015 that is similar to Lantus, Dr. Steinberg said.

The AWP is often cited by analysts when talking about costs. The AWP of the current Semglee 10-mL vial is $118.38; the Lantus 10-mL vial is $340.27, said Steinberg.

Five prefilled Semglee pens (each 3 mL) are $177.58; for Lantus, the AWP for five 3-mL pens is $510.37.

Dr. Luo said he has seen a box of Semglee pens retail between $177 and $195, compared with about $500 retail for the Lantus pens.

Currently, people with commercial insurance can get Semglee for $0-75 a month, for up to a year, using the company’s savings program.

Steinberg said it’s possible that Mylan could increase the list price for the interchangeable Semglee, but that move could backfire. “I think their goal initially is to get market share,” he said.

After Basaglar came on the market – in late 2016 – the price of Lantus came down significantly over the next few years, according to a 2019 study by Dr. Luo’s colleagues at the University of Pittsburgh.

But Basaglar has not hung on to market share, according to Scott Strumello, a person with autoimmune type 1 diabetes who tweets and blogs about insulin and other issues.

In early August, Mr. Strumello tweeted some Lilly data that showed U.S. sales of Basaglar declined 42% in the first two quarters of 2021, compared with the same period in 2020.

Dr. Steinberg noted that the decline may have to do with rebates being given to PBMs by competitors Sanofi and Novo Nordisk. Sanofi “is very aggressive when it comes to pricing with their PBM partners,” he said.

While Mr. Devaney said people with diabetes are hopeful that Semglee can break the big three manufacturers’ monopoly, he added: “We don’t see Semglee as something that is solving the root cause of the insulin price crisis, which is high list prices and pharmaceutical industry greed.”

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

When the Food and Drug Administration approved Semglee, the first interchangeable biosimilar insulin, the agency pitched it as having the potential to be less costly than insulins currently on the market, but lack of transparency in pharmaceutical pricing has left analysts and advocates guessing whether it will indeed be a source of relief.

iStock/ThinkStock

Semglee (Mylan Pharmaceuticals), first approved as a biosimilar in June 2020, costs about $100 a vial.

But receiving the “interchangeable designation” in July 2021, the first for any insulin, now allows Semglee to be substituted for the branded Lantus (insulin glargine, Sanofi) at the pharmacy without the need for a separate prescription, the same way as generic medicines.

A spokesperson for Viatris – Mylan’s parent company told this news organization that the interchangeable, with its new labeling, will be “introduced before the end of the year,” but it would not give any more details.

“Additional information, including pricing information, for interchangeable biosimilar Semglee will be provided at the time of product launch,” said the spokesperson.
 

Even at $100 a vial, it is not cheap

Ian Devaney, a spokesman for the advocacy group T1 International, said the organization is optimistic, given that “another player has been able to enter into a space that has for so long been dominated by Eli Lilly, Novo Nordisk, and Sanofi.” Increased competition “will help drive down the overall costs of insulin,” Mr. Devaney said in an interview. But, he added, for many people, especially in low-income countries, Semglee’s launch will have little to no impact on price.

Even at $100 a vial in the United States, “this is not an insignificant amount of money and presents a very difficult financial challenge for those dependent on insulin to survive,” he said.

A current Semglee user agreed, sharing her story with this news organization via T1 International. “My son uses three to five vials of long-acting insulin per month, and I use one to three vials per month,” said the woman, who prefers to remain anonymous. “If we were to lose Medicaid, we would still be paying up to $800 out of pocket monthly to survive, and that’s not even counting fast-acting insulin or other supplies. While $100 a vial may be cheaper, these costs are still outrageous.”

The woman also noted that, while new competitors are welcome, they also have been disruptive. After her doctor switched her to Semglee, she was notified that it was on back order. “It took a week to get it filled, and when it finally came in, it was in short supply,” she said, noting that she and her son received one Semglee pen each, “well short of the three and five each we were expecting.”
 

U.S. pricing is all ‘smoke and mirrors’

Sara W. Koblitz, a food and drug law attorney with Hyman Phelps in Washington, D.C., noted in a blog post that interchangeable Semglee will likely be awarded a year of marketing exclusivity, which will block other interchangeable competitors from entering the market during that time.

With no competition, “Mylan can price Semglee only slightly less than Lantus and still take market share, only marginally reducing costs to consumers,” she wrote.

Jing Luo, MD, MPH, an assistant professor of medicine at the University of Pittsburgh, who has studied insulin access and costs, said that having just one interchangeable on the market might not be enough to drive insulin costs down.

And, he told this news organization, “there’s even a possibility that Semglee prices will go up, but hopefully that will not be the case.”

Manufacturers like Mylan can also offer confidential discounts and rebates to pharmacy benefit managers (PBMs), health plans, and health plan sponsors (usually large companies that are self-insured) that make it difficult to assess the true cost, said David Steinberg, PharmD, director of pharmacy insights at Scripta Insights. The Wellesley, Mass.–based company advises self-insured employers on how to optimize pharmacy benefits.

When it comes to pricing, “it’s a lot of smoke and mirrors,” Dr. Steinberg said in an interview.

Dr. Steinberg also noted that some PBMs might choose to continue contracts with Sanofi that offer rebates for Lantus, leaving Semglee in a less-preferred position on a formulary, which could increase how much the patient pays at the pharmacy counter. 

Medicare and Medicaid, however, can put Semglee in the top-tier preferred formulary position. Most Medicaid plans cover Semglee, but it appears that Medicare has not added coverage yet.
 

Does current pricing predict the future?

The currently marketed Semglee has an average wholesale price (AWP) that is one third of Lantus’, and about half of what is published for Basaglar (insulin glargine, Eli Lilly), a “follow-on biologic” approved in 2015 that is similar to Lantus, Dr. Steinberg said.

The AWP is often cited by analysts when talking about costs. The AWP of the current Semglee 10-mL vial is $118.38; the Lantus 10-mL vial is $340.27, said Steinberg.

Five prefilled Semglee pens (each 3 mL) are $177.58; for Lantus, the AWP for five 3-mL pens is $510.37.

Dr. Luo said he has seen a box of Semglee pens retail between $177 and $195, compared with about $500 retail for the Lantus pens.

Currently, people with commercial insurance can get Semglee for $0-75 a month, for up to a year, using the company’s savings program.

Steinberg said it’s possible that Mylan could increase the list price for the interchangeable Semglee, but that move could backfire. “I think their goal initially is to get market share,” he said.

After Basaglar came on the market – in late 2016 – the price of Lantus came down significantly over the next few years, according to a 2019 study by Dr. Luo’s colleagues at the University of Pittsburgh.

But Basaglar has not hung on to market share, according to Scott Strumello, a person with autoimmune type 1 diabetes who tweets and blogs about insulin and other issues.

In early August, Mr. Strumello tweeted some Lilly data that showed U.S. sales of Basaglar declined 42% in the first two quarters of 2021, compared with the same period in 2020.

Dr. Steinberg noted that the decline may have to do with rebates being given to PBMs by competitors Sanofi and Novo Nordisk. Sanofi “is very aggressive when it comes to pricing with their PBM partners,” he said.

While Mr. Devaney said people with diabetes are hopeful that Semglee can break the big three manufacturers’ monopoly, he added: “We don’t see Semglee as something that is solving the root cause of the insulin price crisis, which is high list prices and pharmaceutical industry greed.”

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

When the Food and Drug Administration approved Semglee, the first interchangeable biosimilar insulin, the agency pitched it as having the potential to be less costly than insulins currently on the market, but lack of transparency in pharmaceutical pricing has left analysts and advocates guessing whether it will indeed be a source of relief.

iStock/ThinkStock

Semglee (Mylan Pharmaceuticals), first approved as a biosimilar in June 2020, costs about $100 a vial.

But receiving the “interchangeable designation” in July 2021, the first for any insulin, now allows Semglee to be substituted for the branded Lantus (insulin glargine, Sanofi) at the pharmacy without the need for a separate prescription, the same way as generic medicines.

A spokesperson for Viatris – Mylan’s parent company told this news organization that the interchangeable, with its new labeling, will be “introduced before the end of the year,” but it would not give any more details.

“Additional information, including pricing information, for interchangeable biosimilar Semglee will be provided at the time of product launch,” said the spokesperson.
 

Even at $100 a vial, it is not cheap

Ian Devaney, a spokesman for the advocacy group T1 International, said the organization is optimistic, given that “another player has been able to enter into a space that has for so long been dominated by Eli Lilly, Novo Nordisk, and Sanofi.” Increased competition “will help drive down the overall costs of insulin,” Mr. Devaney said in an interview. But, he added, for many people, especially in low-income countries, Semglee’s launch will have little to no impact on price.

Even at $100 a vial in the United States, “this is not an insignificant amount of money and presents a very difficult financial challenge for those dependent on insulin to survive,” he said.

A current Semglee user agreed, sharing her story with this news organization via T1 International. “My son uses three to five vials of long-acting insulin per month, and I use one to three vials per month,” said the woman, who prefers to remain anonymous. “If we were to lose Medicaid, we would still be paying up to $800 out of pocket monthly to survive, and that’s not even counting fast-acting insulin or other supplies. While $100 a vial may be cheaper, these costs are still outrageous.”

The woman also noted that, while new competitors are welcome, they also have been disruptive. After her doctor switched her to Semglee, she was notified that it was on back order. “It took a week to get it filled, and when it finally came in, it was in short supply,” she said, noting that she and her son received one Semglee pen each, “well short of the three and five each we were expecting.”
 

U.S. pricing is all ‘smoke and mirrors’

Sara W. Koblitz, a food and drug law attorney with Hyman Phelps in Washington, D.C., noted in a blog post that interchangeable Semglee will likely be awarded a year of marketing exclusivity, which will block other interchangeable competitors from entering the market during that time.

With no competition, “Mylan can price Semglee only slightly less than Lantus and still take market share, only marginally reducing costs to consumers,” she wrote.

Jing Luo, MD, MPH, an assistant professor of medicine at the University of Pittsburgh, who has studied insulin access and costs, said that having just one interchangeable on the market might not be enough to drive insulin costs down.

And, he told this news organization, “there’s even a possibility that Semglee prices will go up, but hopefully that will not be the case.”

Manufacturers like Mylan can also offer confidential discounts and rebates to pharmacy benefit managers (PBMs), health plans, and health plan sponsors (usually large companies that are self-insured) that make it difficult to assess the true cost, said David Steinberg, PharmD, director of pharmacy insights at Scripta Insights. The Wellesley, Mass.–based company advises self-insured employers on how to optimize pharmacy benefits.

When it comes to pricing, “it’s a lot of smoke and mirrors,” Dr. Steinberg said in an interview.

Dr. Steinberg also noted that some PBMs might choose to continue contracts with Sanofi that offer rebates for Lantus, leaving Semglee in a less-preferred position on a formulary, which could increase how much the patient pays at the pharmacy counter. 

Medicare and Medicaid, however, can put Semglee in the top-tier preferred formulary position. Most Medicaid plans cover Semglee, but it appears that Medicare has not added coverage yet.
 

Does current pricing predict the future?

The currently marketed Semglee has an average wholesale price (AWP) that is one third of Lantus’, and about half of what is published for Basaglar (insulin glargine, Eli Lilly), a “follow-on biologic” approved in 2015 that is similar to Lantus, Dr. Steinberg said.

The AWP is often cited by analysts when talking about costs. The AWP of the current Semglee 10-mL vial is $118.38; the Lantus 10-mL vial is $340.27, said Steinberg.

Five prefilled Semglee pens (each 3 mL) are $177.58; for Lantus, the AWP for five 3-mL pens is $510.37.

Dr. Luo said he has seen a box of Semglee pens retail between $177 and $195, compared with about $500 retail for the Lantus pens.

Currently, people with commercial insurance can get Semglee for $0-75 a month, for up to a year, using the company’s savings program.

Steinberg said it’s possible that Mylan could increase the list price for the interchangeable Semglee, but that move could backfire. “I think their goal initially is to get market share,” he said.

After Basaglar came on the market – in late 2016 – the price of Lantus came down significantly over the next few years, according to a 2019 study by Dr. Luo’s colleagues at the University of Pittsburgh.

But Basaglar has not hung on to market share, according to Scott Strumello, a person with autoimmune type 1 diabetes who tweets and blogs about insulin and other issues.

In early August, Mr. Strumello tweeted some Lilly data that showed U.S. sales of Basaglar declined 42% in the first two quarters of 2021, compared with the same period in 2020.

Dr. Steinberg noted that the decline may have to do with rebates being given to PBMs by competitors Sanofi and Novo Nordisk. Sanofi “is very aggressive when it comes to pricing with their PBM partners,” he said.

While Mr. Devaney said people with diabetes are hopeful that Semglee can break the big three manufacturers’ monopoly, he added: “We don’t see Semglee as something that is solving the root cause of the insulin price crisis, which is high list prices and pharmaceutical industry greed.”

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

Steal from the warm, give to the cold

If there’s one constant in life other than taxes, it’s elderly people moving to Florida. The Sunshine State’s reputation as a giant retirement home needs no elaboration, but why do senior citizens gravitate there? Well, many reasons, but a big one is that, the older you get, the more susceptible and sensitive you are to the cold. And now, according to a new study, we may have identified a culprit.

Elena Korenbaum/iStockphoto

Researchers from Yale University examined a group of mice and found that the older ones lacked ICL2 cells in their fatty tissue. These cells, at least in younger mice, help restore body heat when exposed to cold temperatures. Lacking these cells meant that older mice had a limited ability to burn their fat and raise their temperature in response to cold.

Well, job done, all we need to do now is stimulate production of ICL2 cells in elderly people, and they’ll be able to go outside in 80-degree weather without a sweater again. Except there’s a problem. In a cruel twist of fate, when the elderly mice were given a molecule to boost ICL2 cell production, they actually became less tolerant of the cold than at baseline. Oops.

The scientists didn’t give up though, and gave their elderly mice ICL2 cells from young mice. This finally did the trick, though we have to admit, if that treatment does eventually scale up to humans, the prospect of a bunch of senior citizens taking ICL2 cells from young people to stay warm does sound a bit like a bad vampire movie premise. “I vant to suck your immune cell group 2 innate lymphoid cells!” Not the most pithy catch phrase in the world.
 

Grocery store tapping your subconscious? It’s a good thing

We all know there’s marketing and functionality elements to grocery stores and how they’re set up for your shopping pleasure. But what if I told you that the good old supermarket subconscious trick works on how healthy food decisions are?

PxHere

In a recent study, researchers at the University of Southampton in England found that if you placed a wider selection of fruits and vegetables near the entrances and more nonfood items near checkouts, sales decreased on the sweets and increased on the produce. “The findings of our study suggest that a healthier store layout could lead to nearly 10,000 extra portions of fruit and vegetables and approximately 1,500 fewer portions of confectionery being sold on a weekly basis in each store,” lead author Dr. Christina Vogel explained.

You’re probably thinking that food placement studies aren’t new. That’s true, but this one went above and beyond. Instead of just looking at the influence placement has on purchase, this one took it further by trying to reduce the consumers’ “calorie opportunities” and examining the effect on sales. Also, customer loyalty, patterns, and diets were taken into account across multiple household members.

The researchers think shifting the layouts in grocery stores could shift people’s food choices, producing a domino effect on the population’s overall diet. With obesity, diabetes, and cardiology concerns always looming, swaying consumers toward healthier food choices makes for better public health overall.

So if you feel like you’re being subconsciously assaulted by veggies every time you walk into Trader Joe’s, just know it’s for your own good.
 

TikTokers take on tics

We know TikTok is what makes a lot of teens and young adults tick, but what if TikTokers are actually catching tic disorders from other TikTokers?

Bicanski/Pixnio

TikTok blew up during the pandemic. Many people were stuck at home and had nothing better to do than make and watch TikTok videos. The pandemic brought isolation, uncertainty, and anxiety. The stress that followed may have caused many people, mostly women and young girls, to develop tic disorders.

There’s a TikTok for everything, whether it’s a new dance or a recipe. Many people even use TikTok to speak out about their illnesses. Several TikTokers have Tourette’s syndrome and show their tics on their videos. It appears that some audience members actually “catch” the tics from watching the videos and are then unable to stop certain jerking movements or saying specific words.

Neurologists at the University of Calgary (Alta.), who were hearing from colleagues and getting referrals of such patients, called it “an epidemic within the pandemic.” The behavior is not actually Tourette’s, they told Vice, but the patients “cannot stop, and we have absolutely witnessed that.”

There is, of course, controversy over the issue. One individual with the condition said, “I feel like there’s a lot of really weird, backwards stigma on TikTok about tic disorders. Like, you aren’t allowed to have one unless it’s this one.”

Who would have guessed that people would disagree over stuff on the Internet?
 

Look on the bright side: Obesity edition

The pandemic may have postponed “Top Gun: Maverick” and “The Marvelous Mrs. Maisel” until who-knows-when, but we here at LOTME are happy to announce the nearly-as-anticipated return of Bacteria vs. the World.

© okeyphotos/iStockphoto.com

As you may recall from our last edition of BVTW, bacteria battled the ghost of Charles Darwin, who had taken the earthly form of antibiotics capable of stopping bacterial evolution. Tonight, our prokaryotic protagonists take on an equally relentless and ubiquitous challenger: obesity.

Specifically, we’re putting bacteria up against the obesity survival paradox, that phenomenon in which obesity and overweight seem to protect against – yes, you guessed it – bacterial infections.

A Swedish research team observed a group of 2,196 individual adults who received care for suspected severe bacterial infection at Skaraborg Hospital in Skövde. One year after hospitalization, 26% of normal-weight (body mass index, 18.5-24.99) patients were dead, compared with 17% of overweight (BMI, 25.0-29.99), 16% of obese (BMI, 30.0-34.99), and 9% of very obese (BMI >35) patients.

These results confirm the obesity survival paradox, but “what we don’t know is how being overweight can benefit the patient with a bacterial infection, or whether it’s connected with functions in the immune system and how they’re regulated,” lead author Dr. Åsa Alsiö said in a written statement.

A spokes-cell for the bacteria disputed the results and challenged the legitimacy of the investigators. When asked if there should be some sort of reexamination of the findings, he/she/it replied: “You bet your flagella.” We then pointed out that humans don’t have flagellum, and the representative raised his/her/its flagella in what could only be considered an obscene gesture.

Steal from the warm, give to the cold

If there’s one constant in life other than taxes, it’s elderly people moving to Florida. The Sunshine State’s reputation as a giant retirement home needs no elaboration, but why do senior citizens gravitate there? Well, many reasons, but a big one is that, the older you get, the more susceptible and sensitive you are to the cold. And now, according to a new study, we may have identified a culprit.

Elena Korenbaum/iStockphoto

Researchers from Yale University examined a group of mice and found that the older ones lacked ICL2 cells in their fatty tissue. These cells, at least in younger mice, help restore body heat when exposed to cold temperatures. Lacking these cells meant that older mice had a limited ability to burn their fat and raise their temperature in response to cold.

Well, job done, all we need to do now is stimulate production of ICL2 cells in elderly people, and they’ll be able to go outside in 80-degree weather without a sweater again. Except there’s a problem. In a cruel twist of fate, when the elderly mice were given a molecule to boost ICL2 cell production, they actually became less tolerant of the cold than at baseline. Oops.

The scientists didn’t give up though, and gave their elderly mice ICL2 cells from young mice. This finally did the trick, though we have to admit, if that treatment does eventually scale up to humans, the prospect of a bunch of senior citizens taking ICL2 cells from young people to stay warm does sound a bit like a bad vampire movie premise. “I vant to suck your immune cell group 2 innate lymphoid cells!” Not the most pithy catch phrase in the world.
 

Grocery store tapping your subconscious? It’s a good thing

We all know there’s marketing and functionality elements to grocery stores and how they’re set up for your shopping pleasure. But what if I told you that the good old supermarket subconscious trick works on how healthy food decisions are?

PxHere

In a recent study, researchers at the University of Southampton in England found that if you placed a wider selection of fruits and vegetables near the entrances and more nonfood items near checkouts, sales decreased on the sweets and increased on the produce. “The findings of our study suggest that a healthier store layout could lead to nearly 10,000 extra portions of fruit and vegetables and approximately 1,500 fewer portions of confectionery being sold on a weekly basis in each store,” lead author Dr. Christina Vogel explained.

You’re probably thinking that food placement studies aren’t new. That’s true, but this one went above and beyond. Instead of just looking at the influence placement has on purchase, this one took it further by trying to reduce the consumers’ “calorie opportunities” and examining the effect on sales. Also, customer loyalty, patterns, and diets were taken into account across multiple household members.

The researchers think shifting the layouts in grocery stores could shift people’s food choices, producing a domino effect on the population’s overall diet. With obesity, diabetes, and cardiology concerns always looming, swaying consumers toward healthier food choices makes for better public health overall.

So if you feel like you’re being subconsciously assaulted by veggies every time you walk into Trader Joe’s, just know it’s for your own good.
 

TikTokers take on tics

We know TikTok is what makes a lot of teens and young adults tick, but what if TikTokers are actually catching tic disorders from other TikTokers?

Bicanski/Pixnio

TikTok blew up during the pandemic. Many people were stuck at home and had nothing better to do than make and watch TikTok videos. The pandemic brought isolation, uncertainty, and anxiety. The stress that followed may have caused many people, mostly women and young girls, to develop tic disorders.

There’s a TikTok for everything, whether it’s a new dance or a recipe. Many people even use TikTok to speak out about their illnesses. Several TikTokers have Tourette’s syndrome and show their tics on their videos. It appears that some audience members actually “catch” the tics from watching the videos and are then unable to stop certain jerking movements or saying specific words.

Neurologists at the University of Calgary (Alta.), who were hearing from colleagues and getting referrals of such patients, called it “an epidemic within the pandemic.” The behavior is not actually Tourette’s, they told Vice, but the patients “cannot stop, and we have absolutely witnessed that.”

There is, of course, controversy over the issue. One individual with the condition said, “I feel like there’s a lot of really weird, backwards stigma on TikTok about tic disorders. Like, you aren’t allowed to have one unless it’s this one.”

Who would have guessed that people would disagree over stuff on the Internet?
 

Look on the bright side: Obesity edition

The pandemic may have postponed “Top Gun: Maverick” and “The Marvelous Mrs. Maisel” until who-knows-when, but we here at LOTME are happy to announce the nearly-as-anticipated return of Bacteria vs. the World.

© okeyphotos/iStockphoto.com

As you may recall from our last edition of BVTW, bacteria battled the ghost of Charles Darwin, who had taken the earthly form of antibiotics capable of stopping bacterial evolution. Tonight, our prokaryotic protagonists take on an equally relentless and ubiquitous challenger: obesity.

Specifically, we’re putting bacteria up against the obesity survival paradox, that phenomenon in which obesity and overweight seem to protect against – yes, you guessed it – bacterial infections.

A Swedish research team observed a group of 2,196 individual adults who received care for suspected severe bacterial infection at Skaraborg Hospital in Skövde. One year after hospitalization, 26% of normal-weight (body mass index, 18.5-24.99) patients were dead, compared with 17% of overweight (BMI, 25.0-29.99), 16% of obese (BMI, 30.0-34.99), and 9% of very obese (BMI >35) patients.

These results confirm the obesity survival paradox, but “what we don’t know is how being overweight can benefit the patient with a bacterial infection, or whether it’s connected with functions in the immune system and how they’re regulated,” lead author Dr. Åsa Alsiö said in a written statement.

A spokes-cell for the bacteria disputed the results and challenged the legitimacy of the investigators. When asked if there should be some sort of reexamination of the findings, he/she/it replied: “You bet your flagella.” We then pointed out that humans don’t have flagellum, and the representative raised his/her/its flagella in what could only be considered an obscene gesture.

Steal from the warm, give to the cold

If there’s one constant in life other than taxes, it’s elderly people moving to Florida. The Sunshine State’s reputation as a giant retirement home needs no elaboration, but why do senior citizens gravitate there? Well, many reasons, but a big one is that, the older you get, the more susceptible and sensitive you are to the cold. And now, according to a new study, we may have identified a culprit.

Elena Korenbaum/iStockphoto

Researchers from Yale University examined a group of mice and found that the older ones lacked ICL2 cells in their fatty tissue. These cells, at least in younger mice, help restore body heat when exposed to cold temperatures. Lacking these cells meant that older mice had a limited ability to burn their fat and raise their temperature in response to cold.

Well, job done, all we need to do now is stimulate production of ICL2 cells in elderly people, and they’ll be able to go outside in 80-degree weather without a sweater again. Except there’s a problem. In a cruel twist of fate, when the elderly mice were given a molecule to boost ICL2 cell production, they actually became less tolerant of the cold than at baseline. Oops.

The scientists didn’t give up though, and gave their elderly mice ICL2 cells from young mice. This finally did the trick, though we have to admit, if that treatment does eventually scale up to humans, the prospect of a bunch of senior citizens taking ICL2 cells from young people to stay warm does sound a bit like a bad vampire movie premise. “I vant to suck your immune cell group 2 innate lymphoid cells!” Not the most pithy catch phrase in the world.
 

Grocery store tapping your subconscious? It’s a good thing

We all know there’s marketing and functionality elements to grocery stores and how they’re set up for your shopping pleasure. But what if I told you that the good old supermarket subconscious trick works on how healthy food decisions are?

PxHere

In a recent study, researchers at the University of Southampton in England found that if you placed a wider selection of fruits and vegetables near the entrances and more nonfood items near checkouts, sales decreased on the sweets and increased on the produce. “The findings of our study suggest that a healthier store layout could lead to nearly 10,000 extra portions of fruit and vegetables and approximately 1,500 fewer portions of confectionery being sold on a weekly basis in each store,” lead author Dr. Christina Vogel explained.

You’re probably thinking that food placement studies aren’t new. That’s true, but this one went above and beyond. Instead of just looking at the influence placement has on purchase, this one took it further by trying to reduce the consumers’ “calorie opportunities” and examining the effect on sales. Also, customer loyalty, patterns, and diets were taken into account across multiple household members.

The researchers think shifting the layouts in grocery stores could shift people’s food choices, producing a domino effect on the population’s overall diet. With obesity, diabetes, and cardiology concerns always looming, swaying consumers toward healthier food choices makes for better public health overall.

So if you feel like you’re being subconsciously assaulted by veggies every time you walk into Trader Joe’s, just know it’s for your own good.
 

TikTokers take on tics

We know TikTok is what makes a lot of teens and young adults tick, but what if TikTokers are actually catching tic disorders from other TikTokers?

Bicanski/Pixnio

TikTok blew up during the pandemic. Many people were stuck at home and had nothing better to do than make and watch TikTok videos. The pandemic brought isolation, uncertainty, and anxiety. The stress that followed may have caused many people, mostly women and young girls, to develop tic disorders.

There’s a TikTok for everything, whether it’s a new dance or a recipe. Many people even use TikTok to speak out about their illnesses. Several TikTokers have Tourette’s syndrome and show their tics on their videos. It appears that some audience members actually “catch” the tics from watching the videos and are then unable to stop certain jerking movements or saying specific words.

Neurologists at the University of Calgary (Alta.), who were hearing from colleagues and getting referrals of such patients, called it “an epidemic within the pandemic.” The behavior is not actually Tourette’s, they told Vice, but the patients “cannot stop, and we have absolutely witnessed that.”

There is, of course, controversy over the issue. One individual with the condition said, “I feel like there’s a lot of really weird, backwards stigma on TikTok about tic disorders. Like, you aren’t allowed to have one unless it’s this one.”

Who would have guessed that people would disagree over stuff on the Internet?
 

Look on the bright side: Obesity edition

The pandemic may have postponed “Top Gun: Maverick” and “The Marvelous Mrs. Maisel” until who-knows-when, but we here at LOTME are happy to announce the nearly-as-anticipated return of Bacteria vs. the World.

© okeyphotos/iStockphoto.com

As you may recall from our last edition of BVTW, bacteria battled the ghost of Charles Darwin, who had taken the earthly form of antibiotics capable of stopping bacterial evolution. Tonight, our prokaryotic protagonists take on an equally relentless and ubiquitous challenger: obesity.

Specifically, we’re putting bacteria up against the obesity survival paradox, that phenomenon in which obesity and overweight seem to protect against – yes, you guessed it – bacterial infections.

A Swedish research team observed a group of 2,196 individual adults who received care for suspected severe bacterial infection at Skaraborg Hospital in Skövde. One year after hospitalization, 26% of normal-weight (body mass index, 18.5-24.99) patients were dead, compared with 17% of overweight (BMI, 25.0-29.99), 16% of obese (BMI, 30.0-34.99), and 9% of very obese (BMI >35) patients.

These results confirm the obesity survival paradox, but “what we don’t know is how being overweight can benefit the patient with a bacterial infection, or whether it’s connected with functions in the immune system and how they’re regulated,” lead author Dr. Åsa Alsiö said in a written statement.

A spokes-cell for the bacteria disputed the results and challenged the legitimacy of the investigators. When asked if there should be some sort of reexamination of the findings, he/she/it replied: “You bet your flagella.” We then pointed out that humans don’t have flagellum, and the representative raised his/her/its flagella in what could only be considered an obscene gesture.

New European guidelines for the management of valvular heart disease offer more than 45 revised or completely new recommendations relative to the previous version published in 2017, according to members of the writing committee who presented the changes during the annual congress of the European Society of Cardiology.

Science Photo Library

With their emphasis on early diagnosis and expansion of indications, these 2021 ESC/European Association for Cardio-Thoracic Surgery guidelines are likely to further accelerate the already steep growth in this area of interventional cardiology, according to Alec Vahanian, MD, a professor of cardiology at the University of Paris.

“Valvular heart disease is too often undetected, and these guidelines stress the importance of clinical examination and the best strategies for diagnosis as well as treatment,” he said.

Of the multiple sections and subsections, which follow the same format of the previous guidelines, the greatest number of revisions and new additions involve perioperative antithrombotic therapy, according to the document, which was published in conjunction with the ESC Congress.
 

Eleven new guidelines for anticoagulants

On the basis of evidence published since the previous guidelines, there are 11 completely new recommendations regarding the use of anticoagulants or antiplatelet therapies. The majority of these have received a grade I indication, which signifies “recommended” or “indicated.” These include indications for stopping or starting anticoagulants and which anticoagulants or antiplatelet drugs to consider in specific patient populations.

The next most common focus of new or revised recommendations involves when to consider surgical aortic valve repair (SAVR) relative to transcatheter aortic valve implantation (TAVI) in severe aortic stenosis. Most of these represent revisions from the previous guidelines, but almost all are also grade I recommendations.

“SAVR and TAVI are both excellent options in appropriate patients, but they are not interchangeable,” explained Bernard D. Prendergast, BMedSci, MD, director of the cardiac structural intervention program, Guy’s and St Thomas’ Hospital, London.

While the previous guidelines generally reserved TAVI for those not suitable for SAVR, the new guidelines are more nuanced.

As a rule, SAVR is generally preferred for younger patients. The reason, according to Dr. Prendergast, is concern that younger patients might outlive the expected lifespan of the prosthetic TAVI device.

No single criterion for selecting SAVR over TAVI

However, there are many exceptions and additional considerations beyond age. When both SAVR and TAVI are otherwise suitable options, but TAVI cannot be performed with a transfemoral access, Dr. Prendergast pointed out that SAVR might be a better choice.

Transfemoral access is the preferred strategy in TAVI, but Dr. Prendergast emphasized that a collaborative “heart team” should help patients select the most appropriate option. In fact, there is a grade IIb recommendation (“usefulness or efficacy is less well established”) to consider other access sites in patients at high surgical risk with contraindications for transfemoral TAVI.

Of new recommendations in the area of severe aortic stenosis, valvular repair may now be considered in asymptomatic patients with a left ventricular ejection fraction of less than 55%, according to a grade IIb recommendation. The 2017 guidelines did not address this issue.
 

Grade I recommendation for bioprostheses

A substantial number of the revisions involve minor clarifications without a change in the grade, but a revision regarding bioprosthetics is substantial. In the 2017 guidelines, there was a grade IIa recommendation (“weight of evidence is in favor”) to consider bioprosthetics in patients with a life expectancy less than the expected durability of the device. The 2021 guidelines have changed this to a grade I indication, adding an indication for bioprostheses in patients contraindicated for or unlikely to achieve good-quality anticoagulation.

On this same topic, there is a new grade IIb recommendation to consider bioprosthesis over alternative devices in patients already on a long-term non–vitamin K oral anticoagulant because of the high risk of thromboembolism.

University of Bern

There are two new recommendations in the realm of severe secondary mitral regurgitation, reported Fabien Praz, MD, an interventional cardiologist at the University of Bern (Switzerland). The first, which is perhaps the most significant, is a grade I recommendation for valve surgery in patients with severe secondary mitral regurgitation who remain symptomatic despite optimized medical therapy.

The second is a grade IIa recommendation for invasive procedures, such as a percutaneous coronary intervention, for patients with symptomatic secondary mitral regurgitation and coexisting coronary artery disease. In both cases, however, Dr. Praz emphasized language in the guidelines that calls for a collaborative heart team to agree on the suitability of these treatments.

Ultimately, none of these recommendations can be divorced from patient expectations and values, according to Friedhelm Beyersdorf, MD, chairman of the department of cardiovascular surgery at the Heart Center of the University of Freiburg (Germany).

Even if treatment is not expected to prolong life, “symptom relief on its own may justify intervention,” said Dr. Beyersdorf. However, he emphasized that “thoroughly informed” patients are an essential part of the process in selecting a treatment strategy most likely to satisfy patient goals.

Dr. Vahanian and Dr. Prendergast reported no conflicts of interest relevant to these guidelines. Dr. Praz reported a financial relationship with Edwards Lifesciences. Dr. Beyersdorf reported a financial relationship with Resuscitec.

New European guidelines for the management of valvular heart disease offer more than 45 revised or completely new recommendations relative to the previous version published in 2017, according to members of the writing committee who presented the changes during the annual congress of the European Society of Cardiology.

Science Photo Library

With their emphasis on early diagnosis and expansion of indications, these 2021 ESC/European Association for Cardio-Thoracic Surgery guidelines are likely to further accelerate the already steep growth in this area of interventional cardiology, according to Alec Vahanian, MD, a professor of cardiology at the University of Paris.

“Valvular heart disease is too often undetected, and these guidelines stress the importance of clinical examination and the best strategies for diagnosis as well as treatment,” he said.

Of the multiple sections and subsections, which follow the same format of the previous guidelines, the greatest number of revisions and new additions involve perioperative antithrombotic therapy, according to the document, which was published in conjunction with the ESC Congress.
 

Eleven new guidelines for anticoagulants

On the basis of evidence published since the previous guidelines, there are 11 completely new recommendations regarding the use of anticoagulants or antiplatelet therapies. The majority of these have received a grade I indication, which signifies “recommended” or “indicated.” These include indications for stopping or starting anticoagulants and which anticoagulants or antiplatelet drugs to consider in specific patient populations.

The next most common focus of new or revised recommendations involves when to consider surgical aortic valve repair (SAVR) relative to transcatheter aortic valve implantation (TAVI) in severe aortic stenosis. Most of these represent revisions from the previous guidelines, but almost all are also grade I recommendations.

“SAVR and TAVI are both excellent options in appropriate patients, but they are not interchangeable,” explained Bernard D. Prendergast, BMedSci, MD, director of the cardiac structural intervention program, Guy’s and St Thomas’ Hospital, London.

While the previous guidelines generally reserved TAVI for those not suitable for SAVR, the new guidelines are more nuanced.

As a rule, SAVR is generally preferred for younger patients. The reason, according to Dr. Prendergast, is concern that younger patients might outlive the expected lifespan of the prosthetic TAVI device.

No single criterion for selecting SAVR over TAVI

However, there are many exceptions and additional considerations beyond age. When both SAVR and TAVI are otherwise suitable options, but TAVI cannot be performed with a transfemoral access, Dr. Prendergast pointed out that SAVR might be a better choice.

Transfemoral access is the preferred strategy in TAVI, but Dr. Prendergast emphasized that a collaborative “heart team” should help patients select the most appropriate option. In fact, there is a grade IIb recommendation (“usefulness or efficacy is less well established”) to consider other access sites in patients at high surgical risk with contraindications for transfemoral TAVI.

Of new recommendations in the area of severe aortic stenosis, valvular repair may now be considered in asymptomatic patients with a left ventricular ejection fraction of less than 55%, according to a grade IIb recommendation. The 2017 guidelines did not address this issue.
 

Grade I recommendation for bioprostheses

A substantial number of the revisions involve minor clarifications without a change in the grade, but a revision regarding bioprosthetics is substantial. In the 2017 guidelines, there was a grade IIa recommendation (“weight of evidence is in favor”) to consider bioprosthetics in patients with a life expectancy less than the expected durability of the device. The 2021 guidelines have changed this to a grade I indication, adding an indication for bioprostheses in patients contraindicated for or unlikely to achieve good-quality anticoagulation.

On this same topic, there is a new grade IIb recommendation to consider bioprosthesis over alternative devices in patients already on a long-term non–vitamin K oral anticoagulant because of the high risk of thromboembolism.

University of Bern

There are two new recommendations in the realm of severe secondary mitral regurgitation, reported Fabien Praz, MD, an interventional cardiologist at the University of Bern (Switzerland). The first, which is perhaps the most significant, is a grade I recommendation for valve surgery in patients with severe secondary mitral regurgitation who remain symptomatic despite optimized medical therapy.

The second is a grade IIa recommendation for invasive procedures, such as a percutaneous coronary intervention, for patients with symptomatic secondary mitral regurgitation and coexisting coronary artery disease. In both cases, however, Dr. Praz emphasized language in the guidelines that calls for a collaborative heart team to agree on the suitability of these treatments.

Ultimately, none of these recommendations can be divorced from patient expectations and values, according to Friedhelm Beyersdorf, MD, chairman of the department of cardiovascular surgery at the Heart Center of the University of Freiburg (Germany).

Even if treatment is not expected to prolong life, “symptom relief on its own may justify intervention,” said Dr. Beyersdorf. However, he emphasized that “thoroughly informed” patients are an essential part of the process in selecting a treatment strategy most likely to satisfy patient goals.

Dr. Vahanian and Dr. Prendergast reported no conflicts of interest relevant to these guidelines. Dr. Praz reported a financial relationship with Edwards Lifesciences. Dr. Beyersdorf reported a financial relationship with Resuscitec.

New European guidelines for the management of valvular heart disease offer more than 45 revised or completely new recommendations relative to the previous version published in 2017, according to members of the writing committee who presented the changes during the annual congress of the European Society of Cardiology.

Science Photo Library

With their emphasis on early diagnosis and expansion of indications, these 2021 ESC/European Association for Cardio-Thoracic Surgery guidelines are likely to further accelerate the already steep growth in this area of interventional cardiology, according to Alec Vahanian, MD, a professor of cardiology at the University of Paris.

“Valvular heart disease is too often undetected, and these guidelines stress the importance of clinical examination and the best strategies for diagnosis as well as treatment,” he said.

Of the multiple sections and subsections, which follow the same format of the previous guidelines, the greatest number of revisions and new additions involve perioperative antithrombotic therapy, according to the document, which was published in conjunction with the ESC Congress.
 

Eleven new guidelines for anticoagulants

On the basis of evidence published since the previous guidelines, there are 11 completely new recommendations regarding the use of anticoagulants or antiplatelet therapies. The majority of these have received a grade I indication, which signifies “recommended” or “indicated.” These include indications for stopping or starting anticoagulants and which anticoagulants or antiplatelet drugs to consider in specific patient populations.

The next most common focus of new or revised recommendations involves when to consider surgical aortic valve repair (SAVR) relative to transcatheter aortic valve implantation (TAVI) in severe aortic stenosis. Most of these represent revisions from the previous guidelines, but almost all are also grade I recommendations.

“SAVR and TAVI are both excellent options in appropriate patients, but they are not interchangeable,” explained Bernard D. Prendergast, BMedSci, MD, director of the cardiac structural intervention program, Guy’s and St Thomas’ Hospital, London.

While the previous guidelines generally reserved TAVI for those not suitable for SAVR, the new guidelines are more nuanced.

As a rule, SAVR is generally preferred for younger patients. The reason, according to Dr. Prendergast, is concern that younger patients might outlive the expected lifespan of the prosthetic TAVI device.

No single criterion for selecting SAVR over TAVI

However, there are many exceptions and additional considerations beyond age. When both SAVR and TAVI are otherwise suitable options, but TAVI cannot be performed with a transfemoral access, Dr. Prendergast pointed out that SAVR might be a better choice.

Transfemoral access is the preferred strategy in TAVI, but Dr. Prendergast emphasized that a collaborative “heart team” should help patients select the most appropriate option. In fact, there is a grade IIb recommendation (“usefulness or efficacy is less well established”) to consider other access sites in patients at high surgical risk with contraindications for transfemoral TAVI.

Of new recommendations in the area of severe aortic stenosis, valvular repair may now be considered in asymptomatic patients with a left ventricular ejection fraction of less than 55%, according to a grade IIb recommendation. The 2017 guidelines did not address this issue.
 

Grade I recommendation for bioprostheses

A substantial number of the revisions involve minor clarifications without a change in the grade, but a revision regarding bioprosthetics is substantial. In the 2017 guidelines, there was a grade IIa recommendation (“weight of evidence is in favor”) to consider bioprosthetics in patients with a life expectancy less than the expected durability of the device. The 2021 guidelines have changed this to a grade I indication, adding an indication for bioprostheses in patients contraindicated for or unlikely to achieve good-quality anticoagulation.

On this same topic, there is a new grade IIb recommendation to consider bioprosthesis over alternative devices in patients already on a long-term non–vitamin K oral anticoagulant because of the high risk of thromboembolism.

University of Bern

There are two new recommendations in the realm of severe secondary mitral regurgitation, reported Fabien Praz, MD, an interventional cardiologist at the University of Bern (Switzerland). The first, which is perhaps the most significant, is a grade I recommendation for valve surgery in patients with severe secondary mitral regurgitation who remain symptomatic despite optimized medical therapy.

The second is a grade IIa recommendation for invasive procedures, such as a percutaneous coronary intervention, for patients with symptomatic secondary mitral regurgitation and coexisting coronary artery disease. In both cases, however, Dr. Praz emphasized language in the guidelines that calls for a collaborative heart team to agree on the suitability of these treatments.

Ultimately, none of these recommendations can be divorced from patient expectations and values, according to Friedhelm Beyersdorf, MD, chairman of the department of cardiovascular surgery at the Heart Center of the University of Freiburg (Germany).

Even if treatment is not expected to prolong life, “symptom relief on its own may justify intervention,” said Dr. Beyersdorf. However, he emphasized that “thoroughly informed” patients are an essential part of the process in selecting a treatment strategy most likely to satisfy patient goals.

Dr. Vahanian and Dr. Prendergast reported no conflicts of interest relevant to these guidelines. Dr. Praz reported a financial relationship with Edwards Lifesciences. Dr. Beyersdorf reported a financial relationship with Resuscitec.

For middle-aged individuals, walking at least 7,000 steps per day may reduce mortality risk up to 70%, based on prospective data from more than 2,000 people.

Findings were consistent regardless of race or sex, and step intensity had no impact on mortality risk, reported lead author Amanda E. Paluch, PhD, of the University of Massachusetts Amherst, and colleagues.

“In response to the need for empirical data on the associations of step volume and intensity with mortality in younger and diverse populations, we conducted a prospective study in middle-aged Black and White adults followed up for mortality for approximately 11 years,” the investigators wrote in JAMA Network Open. “The objectives of our study were to examine the associations of step volume and intensity with mortality overall and by race and sex.”
 

Steps per day is easy to communicate

Dr. Paluch noted that steps per day is a “very appealing metric to quantify activity,” for both researchers and laypeople.

“Steps per day is simple and easy to communicate in public health and clinical settings,” Dr. Paluch said in an interview. “Additionally, the dramatic growth of wearable devices measuring steps makes it appealing and broadens the reach of promoting physical activity to many individuals. Walking is an activity that most of the general population can pursue. It can also be accumulated throughout daily living and may seem more achievable to fit into busy lives than a structured exercise session.”

The present investigation was conducted as part of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The dataset included 2,110 participants ranging from 38-50 years of age, with a mean age of 45.2 years. A slightly higher proportion of the subjects were women (57.1%) and White (57.9%).

All participants wore an ActiGraph 7164 accelerometer for 1 week and were then followed for death of any cause, with a mean follow-up of 10.8 years. Multivariable-adjusted Cox proportional hazards models included a range of covariates, such as smoking history, body weight, alcohol intake, blood pressure, total cholesterol, and others. Step counts were grouped into low (less than 7,000 steps per day), moderate (7,000-9,999), and high (at least 10,000 steps per day) categories.

Compared with individuals who took less than 7,000 steps per day, those who took 7,000-9,000 steps per day had a 72% reduced risk of mortality (hazard ratio, 0.28; 95% confidence interval, 0.15-0.54). Going beyond 10,000 steps appeared to add no benefit, based on a 55% lower risk of all-cause mortality in the highly active group, compared with those taking less than 7,000 steps per day (HR, 0.45; 95% CI, 0.25-0.81).

Walking faster didn’t appear to help either, as stepping intensity was not associated with mortality risk; however, Dr. Paluch urged a cautious interpretation of this finding, calling it “inconclusive,” and suggesting that more research is needed.

“It is also important to note that this study only looked at premature all-cause mortality, and therefore the results may be different for other health outcomes, such as the risk of cardiovascular disease, or diabetes, cancer, or mental health outcomes,” Dr. Paluch said.

“The results from our study demonstrated that those who are least active have the most to gain,” Dr. Paluch said. “Even small incremental increases in steps per day are associated with a lower mortality risk during middle age. A walking plan that gradually works up toward 7,000-10,000 steps per day in middle-aged adults may have health benefits and lower the risk of premature mortality.”
 

Causality cannot be confirmed

According to Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), the study size, diverse population, and length of follow-up should increase confidence in the findings, although a causal relationship remains elusive.

“As this study is observational, causality between step count and mortality cannot be confirmed; however, the authors accounted for many factors, and the association was consistent in different analyses and with prior literature,” Dr. Joundi said in an interview. “The authors did not assess the risk of other important events like stroke and heart attack, and these could be addressed in a future study.”

Dr. Joundi, who recently published a study linking exercise with a 50% reduction in mortality after stroke, noted that “physical activity has innumerable benefits, and it’s important that people engage in activity that can be regular and consistent, regardless of the type or intensity.”

To this end, he highlighted the use of “devices capable of monitoring step count, which can be an important motivational tool,” and suggested that these findings may bring a sigh of relief to step counters who come up a little short on a common daily goal.

“A target of 10,000 steps is often used for public health promotion, and this study now provides convincing observational evidence that it may be an optimal step count target for mortality reduction,” Dr. Joundi said. “However, if 10,000 steps per day is not feasible, 7,000 steps seems to be a very reasonable target given its association with markedly lower mortality in this study.”
 

Not all step counters are equal

Unfortunately, such recommendations are complicated by uncertainty in measurement, as widely used step counting devices, like smart watches, may not yield the same results as research-grade accelerometers, according to Nicole L. Spartano, PhD, of Boston University.

“Many comparison studies have been conducted in laboratory settings among young healthy adults, but these do not necessarily reflect real-life wear experiences that will be generalizable to the population as a whole,” Dr. Spartano wrote in an accompanying editorial.

She called for large-scale comparison studies to compare research-grade and consumer devices.

“The reason for conducting comparison studies is not to develop distinct guidelines for different devices or subgroups of the population, but rather to understand the variability so that we can develop one clear message that is most appropriate to the public,” Dr. Spartano wrote. “Some devices may have bias in terms of step measurement at different activity intensity and may not record steps as accurately in older adults or individuals with obesity or mobility disorders. For example, when adults who were obese wore an ActiGraph monitor in a laboratory setting, the device only recorded 80% of steps walked at a moderate pace, while other devices recorded close to 100% of steps walked. If we in the public health community are to move toward using these devices more for physical activity prescription, these details will need to be explored in more depth.”

CARDIA was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Some study authors received grants from the National Institutes of Health and the Kaiser Foundation Research Institute. Dr Spartano disclosed relationships with Novo Nordisk, the American Heart Association, the Alzheimer’s Association, and the National Institutes of Health. Dr. Joundi and Dr. Paluch disclosed no relevant financial relationships.

For middle-aged individuals, walking at least 7,000 steps per day may reduce mortality risk up to 70%, based on prospective data from more than 2,000 people.

Findings were consistent regardless of race or sex, and step intensity had no impact on mortality risk, reported lead author Amanda E. Paluch, PhD, of the University of Massachusetts Amherst, and colleagues.

“In response to the need for empirical data on the associations of step volume and intensity with mortality in younger and diverse populations, we conducted a prospective study in middle-aged Black and White adults followed up for mortality for approximately 11 years,” the investigators wrote in JAMA Network Open. “The objectives of our study were to examine the associations of step volume and intensity with mortality overall and by race and sex.”
 

Steps per day is easy to communicate

Dr. Paluch noted that steps per day is a “very appealing metric to quantify activity,” for both researchers and laypeople.

“Steps per day is simple and easy to communicate in public health and clinical settings,” Dr. Paluch said in an interview. “Additionally, the dramatic growth of wearable devices measuring steps makes it appealing and broadens the reach of promoting physical activity to many individuals. Walking is an activity that most of the general population can pursue. It can also be accumulated throughout daily living and may seem more achievable to fit into busy lives than a structured exercise session.”

The present investigation was conducted as part of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The dataset included 2,110 participants ranging from 38-50 years of age, with a mean age of 45.2 years. A slightly higher proportion of the subjects were women (57.1%) and White (57.9%).

All participants wore an ActiGraph 7164 accelerometer for 1 week and were then followed for death of any cause, with a mean follow-up of 10.8 years. Multivariable-adjusted Cox proportional hazards models included a range of covariates, such as smoking history, body weight, alcohol intake, blood pressure, total cholesterol, and others. Step counts were grouped into low (less than 7,000 steps per day), moderate (7,000-9,999), and high (at least 10,000 steps per day) categories.

Compared with individuals who took less than 7,000 steps per day, those who took 7,000-9,000 steps per day had a 72% reduced risk of mortality (hazard ratio, 0.28; 95% confidence interval, 0.15-0.54). Going beyond 10,000 steps appeared to add no benefit, based on a 55% lower risk of all-cause mortality in the highly active group, compared with those taking less than 7,000 steps per day (HR, 0.45; 95% CI, 0.25-0.81).

Walking faster didn’t appear to help either, as stepping intensity was not associated with mortality risk; however, Dr. Paluch urged a cautious interpretation of this finding, calling it “inconclusive,” and suggesting that more research is needed.

“It is also important to note that this study only looked at premature all-cause mortality, and therefore the results may be different for other health outcomes, such as the risk of cardiovascular disease, or diabetes, cancer, or mental health outcomes,” Dr. Paluch said.

“The results from our study demonstrated that those who are least active have the most to gain,” Dr. Paluch said. “Even small incremental increases in steps per day are associated with a lower mortality risk during middle age. A walking plan that gradually works up toward 7,000-10,000 steps per day in middle-aged adults may have health benefits and lower the risk of premature mortality.”
 

Causality cannot be confirmed

According to Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), the study size, diverse population, and length of follow-up should increase confidence in the findings, although a causal relationship remains elusive.

“As this study is observational, causality between step count and mortality cannot be confirmed; however, the authors accounted for many factors, and the association was consistent in different analyses and with prior literature,” Dr. Joundi said in an interview. “The authors did not assess the risk of other important events like stroke and heart attack, and these could be addressed in a future study.”

Dr. Joundi, who recently published a study linking exercise with a 50% reduction in mortality after stroke, noted that “physical activity has innumerable benefits, and it’s important that people engage in activity that can be regular and consistent, regardless of the type or intensity.”

To this end, he highlighted the use of “devices capable of monitoring step count, which can be an important motivational tool,” and suggested that these findings may bring a sigh of relief to step counters who come up a little short on a common daily goal.

“A target of 10,000 steps is often used for public health promotion, and this study now provides convincing observational evidence that it may be an optimal step count target for mortality reduction,” Dr. Joundi said. “However, if 10,000 steps per day is not feasible, 7,000 steps seems to be a very reasonable target given its association with markedly lower mortality in this study.”
 

Not all step counters are equal

Unfortunately, such recommendations are complicated by uncertainty in measurement, as widely used step counting devices, like smart watches, may not yield the same results as research-grade accelerometers, according to Nicole L. Spartano, PhD, of Boston University.

“Many comparison studies have been conducted in laboratory settings among young healthy adults, but these do not necessarily reflect real-life wear experiences that will be generalizable to the population as a whole,” Dr. Spartano wrote in an accompanying editorial.

She called for large-scale comparison studies to compare research-grade and consumer devices.

“The reason for conducting comparison studies is not to develop distinct guidelines for different devices or subgroups of the population, but rather to understand the variability so that we can develop one clear message that is most appropriate to the public,” Dr. Spartano wrote. “Some devices may have bias in terms of step measurement at different activity intensity and may not record steps as accurately in older adults or individuals with obesity or mobility disorders. For example, when adults who were obese wore an ActiGraph monitor in a laboratory setting, the device only recorded 80% of steps walked at a moderate pace, while other devices recorded close to 100% of steps walked. If we in the public health community are to move toward using these devices more for physical activity prescription, these details will need to be explored in more depth.”

CARDIA was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Some study authors received grants from the National Institutes of Health and the Kaiser Foundation Research Institute. Dr Spartano disclosed relationships with Novo Nordisk, the American Heart Association, the Alzheimer’s Association, and the National Institutes of Health. Dr. Joundi and Dr. Paluch disclosed no relevant financial relationships.

For middle-aged individuals, walking at least 7,000 steps per day may reduce mortality risk up to 70%, based on prospective data from more than 2,000 people.

Findings were consistent regardless of race or sex, and step intensity had no impact on mortality risk, reported lead author Amanda E. Paluch, PhD, of the University of Massachusetts Amherst, and colleagues.

“In response to the need for empirical data on the associations of step volume and intensity with mortality in younger and diverse populations, we conducted a prospective study in middle-aged Black and White adults followed up for mortality for approximately 11 years,” the investigators wrote in JAMA Network Open. “The objectives of our study were to examine the associations of step volume and intensity with mortality overall and by race and sex.”
 

Steps per day is easy to communicate

Dr. Paluch noted that steps per day is a “very appealing metric to quantify activity,” for both researchers and laypeople.

“Steps per day is simple and easy to communicate in public health and clinical settings,” Dr. Paluch said in an interview. “Additionally, the dramatic growth of wearable devices measuring steps makes it appealing and broadens the reach of promoting physical activity to many individuals. Walking is an activity that most of the general population can pursue. It can also be accumulated throughout daily living and may seem more achievable to fit into busy lives than a structured exercise session.”

The present investigation was conducted as part of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. The dataset included 2,110 participants ranging from 38-50 years of age, with a mean age of 45.2 years. A slightly higher proportion of the subjects were women (57.1%) and White (57.9%).

All participants wore an ActiGraph 7164 accelerometer for 1 week and were then followed for death of any cause, with a mean follow-up of 10.8 years. Multivariable-adjusted Cox proportional hazards models included a range of covariates, such as smoking history, body weight, alcohol intake, blood pressure, total cholesterol, and others. Step counts were grouped into low (less than 7,000 steps per day), moderate (7,000-9,999), and high (at least 10,000 steps per day) categories.

Compared with individuals who took less than 7,000 steps per day, those who took 7,000-9,000 steps per day had a 72% reduced risk of mortality (hazard ratio, 0.28; 95% confidence interval, 0.15-0.54). Going beyond 10,000 steps appeared to add no benefit, based on a 55% lower risk of all-cause mortality in the highly active group, compared with those taking less than 7,000 steps per day (HR, 0.45; 95% CI, 0.25-0.81).

Walking faster didn’t appear to help either, as stepping intensity was not associated with mortality risk; however, Dr. Paluch urged a cautious interpretation of this finding, calling it “inconclusive,” and suggesting that more research is needed.

“It is also important to note that this study only looked at premature all-cause mortality, and therefore the results may be different for other health outcomes, such as the risk of cardiovascular disease, or diabetes, cancer, or mental health outcomes,” Dr. Paluch said.

“The results from our study demonstrated that those who are least active have the most to gain,” Dr. Paluch said. “Even small incremental increases in steps per day are associated with a lower mortality risk during middle age. A walking plan that gradually works up toward 7,000-10,000 steps per day in middle-aged adults may have health benefits and lower the risk of premature mortality.”
 

Causality cannot be confirmed

According to Raed A. Joundi, MD, DPhil, of the University of Calgary (Alta.), the study size, diverse population, and length of follow-up should increase confidence in the findings, although a causal relationship remains elusive.

“As this study is observational, causality between step count and mortality cannot be confirmed; however, the authors accounted for many factors, and the association was consistent in different analyses and with prior literature,” Dr. Joundi said in an interview. “The authors did not assess the risk of other important events like stroke and heart attack, and these could be addressed in a future study.”

Dr. Joundi, who recently published a study linking exercise with a 50% reduction in mortality after stroke, noted that “physical activity has innumerable benefits, and it’s important that people engage in activity that can be regular and consistent, regardless of the type or intensity.”

To this end, he highlighted the use of “devices capable of monitoring step count, which can be an important motivational tool,” and suggested that these findings may bring a sigh of relief to step counters who come up a little short on a common daily goal.

“A target of 10,000 steps is often used for public health promotion, and this study now provides convincing observational evidence that it may be an optimal step count target for mortality reduction,” Dr. Joundi said. “However, if 10,000 steps per day is not feasible, 7,000 steps seems to be a very reasonable target given its association with markedly lower mortality in this study.”
 

Not all step counters are equal

Unfortunately, such recommendations are complicated by uncertainty in measurement, as widely used step counting devices, like smart watches, may not yield the same results as research-grade accelerometers, according to Nicole L. Spartano, PhD, of Boston University.

“Many comparison studies have been conducted in laboratory settings among young healthy adults, but these do not necessarily reflect real-life wear experiences that will be generalizable to the population as a whole,” Dr. Spartano wrote in an accompanying editorial.

She called for large-scale comparison studies to compare research-grade and consumer devices.

“The reason for conducting comparison studies is not to develop distinct guidelines for different devices or subgroups of the population, but rather to understand the variability so that we can develop one clear message that is most appropriate to the public,” Dr. Spartano wrote. “Some devices may have bias in terms of step measurement at different activity intensity and may not record steps as accurately in older adults or individuals with obesity or mobility disorders. For example, when adults who were obese wore an ActiGraph monitor in a laboratory setting, the device only recorded 80% of steps walked at a moderate pace, while other devices recorded close to 100% of steps walked. If we in the public health community are to move toward using these devices more for physical activity prescription, these details will need to be explored in more depth.”

CARDIA was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham, Northwestern University, the University of Minnesota, and the Kaiser Foundation Research Institute. Some study authors received grants from the National Institutes of Health and the Kaiser Foundation Research Institute. Dr Spartano disclosed relationships with Novo Nordisk, the American Heart Association, the Alzheimer’s Association, and the National Institutes of Health. Dr. Joundi and Dr. Paluch disclosed no relevant financial relationships.

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

In an observational study of 250 middle-aged men with hypertension and erectile dysfunction, those whose eating patterns more closely matched a Mediterranean diet had significantly higher testosterone levels, better exercise capacity, and better erectile performance than their peers.

OksanaKiian/Getty Images

In addition, more closely following a Mediterranean diet – which emphasizes eating fruit, vegetables, whole grains, and olive oil, with modest consumption of dairy products and limited red meat – was associated with better coronary blood flow and less arterial stiffness, all after adjusting for age, body mass index, type 2 diabetes, statin use, and smoking.

Athanasios Angelis, MD, First Cardiology Clinic, Hippokration Hospital, School of Medicine, University of Athens, presented the study at the annual congress of the European Society of Cardiology.

“While we did not examine mechanisms,” Dr. Angelis said in a press release from the ESC, “it seems plausible that this dietary pattern may improve fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

“The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle-aged men with hypertension and erectile dysfunction,” he concluded.

“A Mediterranean diet may help erectile dysfunction by improving endothelial physiology,” Dr. Angelis said in an interview. “We suggest the Mediterranean diet as a basic parameter of hypertension and erectile dysfunction treatment. We advise all our patients to be careful regarding salt consumption and to try to exercise regularly.”

“Depending on the severity of the erectile dysfunction, we may suggest only lifestyle changes (e.g., quit smoking), at least for the beginning, or combination with medication,” consisting of phosphodiesterase type 5 (PDE5) inhibitors such as Viagra.
 

A ‘first-choice’ diet for men with ED, low T, high CVD risk?

This research “adds to the growing evidence that a Mediterranean diet is protective against erectile dysfunction,” said Joseph Whittaker, MSc, a clinical nutritionist from the University of Worcester (England) and coauthor of a related meta-analysis about dietary fat and testosterone.

This way of eating “also improves cardiovascular health, so it could become a low-risk, first choice treatment for these three pathologies (low testosterone, erectile dysfunction, increased risk of CVD), which so commonly coexist,” he wrote in an email.

“However, most of the research to date is observational,” he cautioned, which often has a “healthy user bias,” that is, the men eating a Mediterranean diet are probably health-conscious individuals, with other healthy habits such as exercise, good sleep, low stress, etc. “So, was it the diet, the healthy habits, or both?”

Randomized studies are needed to replicate the positive results of observational studies like this one, Mr. Whittaker added. In the meantime, “a Mediterranean diet will probably improve your health anyway,” he noted, “so trying it for the purposes of erectile function (before starting drugs) is a viable option.”

Previous research has shown that dietary fat and olive oil may boost testosterone levels, Mr. Whittaker noted, and nuts have also been shown to improve erectile function.

“So, the increase in healthy fats – mono- and polyunsaturated fatty acids (MUFAs and PUFAs, respectively) – on the Mediterranean diet is probably responsible for these benefits,” he speculated.
 

Middle-aged hypertensive men with ED

Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure, according to background information in the ESC press release.

Erectile dysfunction is thought to be a disorder of the small arteries, which lose their ability to dilate and increase blood flow. Declining testosterone levels in middle age also contribute to weakened erectile performance.

Physical fitness is linked with longer life in men with hypertension, and the Mediterranean diet is associated with lower blood pressure and fewer heart attacks and strokes in individuals at high cardiovascular risk.

Therefore, Dr. Angelis and colleagues aimed to see if greater adherence to a Mediterranean diet was associated with better exercise capacity, testosterone levels, coronary flow reserve, and erectile performance in middle-aged hypertensive men with erectile dysfunction.

Participants were a mean age of 56. They had a treadmill test to determine their exercise capacity, expressed as metabolic equivalent of tasks (METs), and a blood test to determine testosterone levels.

They replied to two questionnaires: a food questionnaire to determine a Mediterranean Diet score (range, 0-55, where higher scores indicate greater adherence to a Mediterranean diet) and a Sexual Health Inventory for Men (SHIM) questionnaire (score range, 0-25, where higher scores indicate better erectile performance).

Researchers used echocardiography to determine participants’ coronary flow reserve, a measure of the cardiovascular system’s ability to increase blood flow when needed. They used a SphygmoCor device to determine participants’ augmentation index and central pulse pressure, measures of arterial stiffness.

The men with a higher Mediterranean diet score (>29) had better erectile performance (SHIM scores > 14), as well as higher testosterone levels, higher coronary flow reserve, and less arterial stiffness than the other men.

The fitter men with greater exercise capacity (>10 METs) were more likely to adhere to a Mediterranean diet (scores > 25), and they also had better erectile performance (SHIM scores > 12), higher testosterone levels, greater coronary flow reserve, and less arterial stiffness than the other men.

The study did not receive any funding. The study authors and Mr. Whittaker have reported no relevant financial relationships.

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

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.

Hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with anakinra, compared with placebo, based on data from a phase 3, randomized trial of nearly 600 patients who also received standard of care treatment.

Anakinra, a recombinant interleukin (IL)-1 receptor antagonist that blocks activity for both IL-1 alpha and beta, showed a 70% decrease in the risk of progression to severe respiratory failure in a prior open-label, phase 2, proof-of-concept study, wrote Evdoxia Kyriazopoulou, MD, PhD, of National and Kapodistrian University of Athens, and colleagues.

Previous research has shown that soluble urokinase plasminogen activator receptor (suPAR) serum levels can signal increased risk of progression to severe disease and respiratory failure in COVID-19 patients, they noted.

Supported by these early findings, “the SAVE-MORE study (suPAR-guided anakinra treatment for validation of the risk and early management of severe respiratory failure by COVID-19) is a pivotal, confirmatory, phase 3, double-blind, randomized controlled trial that evaluated the efficacy and safety of early initiation of anakinra treatment in hospitalized patients with moderate or severe COVID-19,” the researchers said.

In the SAVE-MORE study published Sept. 3 in Nature Medicine, the researchers identified 594 adults with COVID-19 who were hospitalized at 37 centers in Greece and Italy and at risk of progressing to respiratory failure based on plasma suPAR levels of at least 6 ng/mL.

The primary objective was to assess the impact of early anakinra treatment on the clinical status of COVID-19 patients at risk for severe disease according to the 11-point, ordinal World Health Organization Clinical Progression Scale (WHO-CPS) at 28 days after starting treatment. All patients received standard of care, which consisted of regular monitoring of physical signs, oximetry, and anticoagulation. Patients with severe disease by the WHO definition were also received 6 mg of dexamethasone intravenously daily for 10 days. A total of 405 were randomized to anakinra and 189 to placebo. Approximately 92% of the study participants had severe pneumonia according to the WHO classification for COVID-19. The average age of the patients was 62 years, 58% were male, and the average body mass index was 29.5 kg/m².

At 28 days, 204 (50.4%) of the anakinra-treated patients had fully recovered, with no detectable viral RNA, compared with 50 (26.5%) of the placebo-treated patients (P < .0001). In addition, significantly fewer patients in the anakinra group had died by 28 days (13 patients, 3.2%), compared with patients in the placebo group (13 patients, 6.9%).

The median decrease in WHO-CPS scores from baseline to 28 days was 4 points in the anakinra group and 3 points in the placebo group, a statistically significant difference (P < .0001).

“Overall, the unadjusted proportional odds of having a worse score on the 11-point WHO-CPS at day 28 with anakinra was 0.36 versus placebo,” and this number remained the same in adjusted analysis, the researchers wrote.

All five secondary endpoints on the WHO-CPS showed significant benefits of anakinra, compared with placebo. These included an absolute decrease of WHO-CPS at day 28 and day 14 from baseline; an absolute decrease of Sequential Organ Failure Assessment scores at day 7 from baseline; and a significantly shorter mean time to both hospital and ICU discharge (1 day and 4 days, respectively) with anakinra versus placebo.

Follow-up laboratory data showed a significant increase in absolute lymphocyte count at 7 days, a significant decrease in circulating IL-6 levels at 4 and 7 days, and significantly decreased plasma C-reactive protein (CRP) levels at 7 days.

Serious treatment-emergent adverse events were reported in 16% with anakinra and in 21.7% with placebo; the most common of these events were infections (8.4% with anakinra and 15.9% with placebo). The next most common serious treatment-emergent adverse events were ventilator-associated pneumonia, septic shock and multiple organ dysfunction, bloodstream infections, and pulmonary embolism. The most common nonserious treatment-emergent adverse events were an increase of liver function tests and hyperglycemia (similar in anakinra and placebo groups) and nonserious anemia (lower in the anakinra group).

The study findings were limited by several factors, including the lack of patients with critical COVID-19 disease and the challenge of application of suPAR in all hospital settings, the researchers noted. However, “the results validate the findings of the previous SAVE open-label phase 2 trial,” they said. The results suggest “that suPAR should be measured upon admission of all patients with COVID-19 who do not need oxygen or who need nasal or mask oxygen, and that, if suPAR levels are 6 ng/mL or higher, anakinra treatment might be a suitable therapy,” they concluded.
 

Cytokine storm syndrome remains a treatment challenge

“Many who die from COVID-19 suffer hyperinflammation with features of cytokine storm syndrome (CSS) and associated acute respiratory distress syndrome,” wrote Randy Q. Cron, MD, and W. Winn Chatham, MD, of the University of Alabama at Birmingham, and Roberto Caricchio, MD, of Temple University, Philadelphia, in an accompanying editorial. They noted that the SAVE-MORE trial results contrast with another recent randomized trial of canakinumab, which failed to show notable benefits, compared with placebo, in treating hospitalized patients with COVID-19 pneumonia.

“There are some key differences between these trials, one being that anakinra blocks signaling of both IL-1 alpha and IL-1 beta, whereas canakinumab binds only IL-1 beta,” the editorialists explained. “SARS-CoV-2–infected endothelium may be a particularly important source of IL-1 alpha that is not targeted by canakinumab,” they noted.

Additional studies have examined IL-6 inhibition to treat COVID-19 patients, but data have been inconsistent, the editorialists said.

“One thing that is clearly emerging from this pandemic is that the CSS associated with COVID-19 is relatively unique, with only modestly elevated levels of IL-6, CRP, and ferritin, for example,” they noted. However, the SAVE-MORE study suggests that more targeted approaches, such as anakinra, “may allow earlier introduction of anticytokine treatment” and support the use of IL-1 blockade with anakinra for cases of severe COVID-19 pneumonia.
 

Predicting risk for severe disease

“One of the major challenges in the management of patients with COVID-19 is identifying patients at risk of severe disease who would warrant early intervention with anti-inflammatory therapy,” said Salim Hayek, MD, medical director of the University of Michigan’s Frankel Cardiovascular Center Clinics, in an interview. “We and others had found that soluble urokinase plasminogen activator receptor (suPAR) levels are the strongest predictor of severe disease amongst biomarkers of inflammation,” he said. “In this study, patients with high suPAR levels derived benefit from anakinra, compared to those with placebo. This study is a great example of how suPAR levels could be used to identify high-risk patients that would benefit from therapies targeting inflammation,” Dr. Hayek emphasized.

“The findings are in line with the hypothesis that patients with the highest degrees of inflammation would benefit the best from targeting the hyperinflammatory cascade using anakinra or other interleukin antagonists,” Dr. Hayek said. “Given suPAR levels are the best predictors of high-risk disease, it is not surprising to see that patients with high levels benefit from targeting inflammation,” he noted.

The take-home message for clinicians at this time is that anakinra effectively improves outcomes in COVID-19 patients with high suPAR levels, Dr. Hayek said. “SuPAR can be measured easily at the point of care. Thus, a targeted strategy using suPAR to identify patients who would benefit from anakinra appears to be viable,” he explained.

However, “Whether anakinra is effective in patients with lower suPAR levels (<6 ng/mL) is unclear and was not answered by this study,” he said. “We eagerly await results of other trials to make that determination. Whether suPAR levels can also help guide the use of other therapies for COVID-19 should be explored and would enhance the personalization of treatment for COVID-19 according to the underlying inflammatory state,” he added.

The SAVE-MORE study was funded by the Hellenic Institute for the Study of Sepsis and Sobi, which manufactures anakinra. Some of the study authors reported financial relationships with Sobi and other pharmaceutical companies.

Dr. Cron disclosed serving as a consultant to Sobi, Novartis, Pfizer, and Sironax. Dr. Cron and Dr. Chatham disclosed having received grant support from Sobi for investigator-initiated clinical trials, and Dr. Caricchio disclosed serving as a consultant to GlaxoSmithKline, Johnson & Johnson, Aurinia, and Bristol-Myers Squibb. Dr. Hayek had no relevant financial conflicts to disclose.