SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.

The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week^® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”

Jim Kling/Frontline Medical News

However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.

“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.

Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.

For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.

These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.

So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.

And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”

The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.

Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.

“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.

He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.

Dr. Siddique and Dr. Falk have no relevant financial disclosures.

SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.

The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week^® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”

Jim Kling/Frontline Medical News

However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.

“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.

Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.

For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.

These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.

So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.

And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”

The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.

Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.

“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.

He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.

Dr. Siddique and Dr. Falk have no relevant financial disclosures.

SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.

The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week^® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”

Jim Kling/Frontline Medical News

However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.

“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.

Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.

For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.

These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.

So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.

And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”

The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.

Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.

“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.

He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.

Dr. Siddique and Dr. Falk have no relevant financial disclosures.

Teamwork by a wide range of professional staff, coupled with support from leadership, enabled one academic community hospital to cut its rate of hospital-onset Clostridioides difficile infections (HO-CDIs) by almost two-thirds in 1 year and by over three-quarters in 3 years, a study published in the American Journal of Infection Control reports.

C. diff. is a major health threat. According to the U.S. Centers for Disease Control and Prevention, CDIs, mainly linked with hospitals, caused an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States in 2017.

“The interventions and outcomes of the project improved patient care by ensuring early testing, diagnosis, treatment if warranted, and proper isolation, which helped reduce C. diff. transmission to staff and other patients,” lead study author Cherith Walter, MSN, RN, a clinical nurse specialist at Emory Saint Joseph’s Hospital, Atlanta, told this news organization. “Had we not worked together as a team, we would not have had the ability to carry out such a robust project,” she added in an email.

Each HO-CDI case costs a health care system an estimated $12,313, and high rates of HO-CDIs incur fines from the Hospital-Acquired Condition Reduction Program of the Centers for Medicare & Medicaid Services (CMS), the authors write.
 

A diverse staff team collaborated

Emory Saint Joseph’s, a 410-bed hospital in Atlanta, had a history of being above the national CMS benchmark for HO-CDIs. To reduce these infections, comply with CMS requirements, and avoid fines, Ms. Walter and colleagues launched a quality improvement project between 2015 and 2020.

With the approval of the chief nursing officer, chief quality officer, and hospital board, researchers mobilized a diverse team of professionals: a clinical nurse specialist, a physician champion, unit nurse champions, a hospital epidemiologist, an infection preventionist, a clinical microbiologist, an antimicrobial stewardship pharmacist, and an environmental services representative.

The team investigated what caused their hospital’s HO-CDIs from 2014 through 2016 and developed appropriate, evidence-based infection prevention interventions. The integrated approach involved:

• Diagnostic stewardship, including a diarrhea decision-tree algorithm that enabled nurses to order tests of any loose or unformed stool for C. diff. during the first 3 days of admission.
• Enhanced environmental cleaning, which involved switching from sporicidal disinfectant only in isolation rooms to using a more effective Environmental Protection Agency–approved sporicidal disinfectant containing hydrogen peroxide and peracetic acid in all patient rooms for daily cleaning and after discharge. Every day, high-touch surfaces in C. diff. isolation rooms were cleaned and shared equipment was disinfected with bleach wipes. After patient discharge, staff cleaned mattresses on all sides, wiped walls with disinfectant, and used ultraviolet light.
• Antimicrobial stewardship. Formulary fluoroquinolones were removed as standalone orders and made available only through order sets with built-in clinical decision support.
• Education of staff on best practices, through emails, flyers, meetings, and training sessions. Two nurses needed to approve the appropriateness of testing specific specimens for CDI. All HO-CDIs were reviewed and findings presented at CDI team meetings.
• Accountability. Staff on the team and units received emailed notices about compliance issues and held meetings to discuss how to improve compliance.

After 1 year, HO-CDI incidence dropped 63% from baseline, from above 12 cases per 10,000 patient-days to 4.72 per 10,000 patient-days. And after 3 years, infections dropped 77% to 2.80 per 10,000 patient-days.

The hospital’s HO-CDI standardized infection ratio – the total number of infections divided by the National Healthcare Safety Network’s risk-adjusted predicted number of infections – dropped below the national benchmark, from 1.11 in 2015 to 0.43 in 2020.

The hospital also increased testing of appropriate patients for CDI within the first 3 days of admission, from 54% in 2014 to 81% in late 2019.

“By testing patients within 3 days of admission, we discovered that many had acquired C. diff. before admission,” Ms. Walter said. “I don’t think we realized how prevalent C. diff. was in the community.”

Benjamin D. Galvan, MLS(ASCP), CIC, an infection preventionist at Tampa General Hospital and a member of the Association for Professionals in Infection Control and Epidemiology, welcomed the study’s results.  

“Effective collaboration within the health care setting is a highly effective way to implement and sustain evidence-based practices related to infection reduction. When buy-in is obtained from the top, and pertinent stakeholders are engaged for their expertise, we can see sustainable change and improved patient outcomes,” Mr. Galvan, who was not involved in the study, said in an email.

“The researchers did a fantastic job,” he added. “I am grateful to see this important work addressed in the literature, as it will only improve buy-in for improvement efforts aimed at reducing infections moving forward across the health care continuum.”

Douglas S. Paauw, MD, a professor of medicine and chair for patient-centered clinical education at the University of Washington School of Medicine, Seattle, said that the team’s most important interventions were changing the environmental cleaning protocol and using agents that kill C. diff. spores.

“We know that as many as 10%-20% of hospitalized patients carry C. diff. Cleaning only the rooms where you know you have C. diff. (isolation rooms) will miss most of it,” said Dr. Paauw, who was also not involved in the study. “Cleaning every room with cleaners that actually work is very important but costs money.”
 

Handwashing with soap and water works, alcohol hand gels do not

“We know that handwashing with soap and water is the most important way to prevent hospital C. diff. transmission,” Dr. Paauw noted. “Handwashing protocols implemented prior to the study were probably a big part of the team’s success.”

Handwashing with soap and water works but alcohol hand gels do not, he cautioned.

“C. diff. rates in hospitals went up years ago when we started putting alcohol gels outside patients’ rooms,” Dr. Paauw explained. “Now, instead of washing their hands, staff quickly pump gel before they see patients. Applying gel is easy, but gel does not eliminate C. diff. spores. Handwashing is such a simple way to fix the C. diff. problem, but doctors don’t take the time.”

“We need to take the C. diff. problem seriously. We have enough information, and we know the right things to do. We need to wash our hands. We need to clean the rooms. We need to stop cutting corners if we want to give good care,” he said.

The authors plan to conduct further related research.

The study was not funded. All study authors, as well as Mr. Galvan and Dr. Paauw, have reported no relevant financial interests.

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

Teamwork by a wide range of professional staff, coupled with support from leadership, enabled one academic community hospital to cut its rate of hospital-onset Clostridioides difficile infections (HO-CDIs) by almost two-thirds in 1 year and by over three-quarters in 3 years, a study published in the American Journal of Infection Control reports.

C. diff. is a major health threat. According to the U.S. Centers for Disease Control and Prevention, CDIs, mainly linked with hospitals, caused an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States in 2017.

“The interventions and outcomes of the project improved patient care by ensuring early testing, diagnosis, treatment if warranted, and proper isolation, which helped reduce C. diff. transmission to staff and other patients,” lead study author Cherith Walter, MSN, RN, a clinical nurse specialist at Emory Saint Joseph’s Hospital, Atlanta, told this news organization. “Had we not worked together as a team, we would not have had the ability to carry out such a robust project,” she added in an email.

Each HO-CDI case costs a health care system an estimated $12,313, and high rates of HO-CDIs incur fines from the Hospital-Acquired Condition Reduction Program of the Centers for Medicare & Medicaid Services (CMS), the authors write.
 

A diverse staff team collaborated

Emory Saint Joseph’s, a 410-bed hospital in Atlanta, had a history of being above the national CMS benchmark for HO-CDIs. To reduce these infections, comply with CMS requirements, and avoid fines, Ms. Walter and colleagues launched a quality improvement project between 2015 and 2020.

With the approval of the chief nursing officer, chief quality officer, and hospital board, researchers mobilized a diverse team of professionals: a clinical nurse specialist, a physician champion, unit nurse champions, a hospital epidemiologist, an infection preventionist, a clinical microbiologist, an antimicrobial stewardship pharmacist, and an environmental services representative.

The team investigated what caused their hospital’s HO-CDIs from 2014 through 2016 and developed appropriate, evidence-based infection prevention interventions. The integrated approach involved:

• Diagnostic stewardship, including a diarrhea decision-tree algorithm that enabled nurses to order tests of any loose or unformed stool for C. diff. during the first 3 days of admission.
• Enhanced environmental cleaning, which involved switching from sporicidal disinfectant only in isolation rooms to using a more effective Environmental Protection Agency–approved sporicidal disinfectant containing hydrogen peroxide and peracetic acid in all patient rooms for daily cleaning and after discharge. Every day, high-touch surfaces in C. diff. isolation rooms were cleaned and shared equipment was disinfected with bleach wipes. After patient discharge, staff cleaned mattresses on all sides, wiped walls with disinfectant, and used ultraviolet light.
• Antimicrobial stewardship. Formulary fluoroquinolones were removed as standalone orders and made available only through order sets with built-in clinical decision support.
• Education of staff on best practices, through emails, flyers, meetings, and training sessions. Two nurses needed to approve the appropriateness of testing specific specimens for CDI. All HO-CDIs were reviewed and findings presented at CDI team meetings.
• Accountability. Staff on the team and units received emailed notices about compliance issues and held meetings to discuss how to improve compliance.

After 1 year, HO-CDI incidence dropped 63% from baseline, from above 12 cases per 10,000 patient-days to 4.72 per 10,000 patient-days. And after 3 years, infections dropped 77% to 2.80 per 10,000 patient-days.

The hospital’s HO-CDI standardized infection ratio – the total number of infections divided by the National Healthcare Safety Network’s risk-adjusted predicted number of infections – dropped below the national benchmark, from 1.11 in 2015 to 0.43 in 2020.

The hospital also increased testing of appropriate patients for CDI within the first 3 days of admission, from 54% in 2014 to 81% in late 2019.

“By testing patients within 3 days of admission, we discovered that many had acquired C. diff. before admission,” Ms. Walter said. “I don’t think we realized how prevalent C. diff. was in the community.”

Benjamin D. Galvan, MLS(ASCP), CIC, an infection preventionist at Tampa General Hospital and a member of the Association for Professionals in Infection Control and Epidemiology, welcomed the study’s results.  

“Effective collaboration within the health care setting is a highly effective way to implement and sustain evidence-based practices related to infection reduction. When buy-in is obtained from the top, and pertinent stakeholders are engaged for their expertise, we can see sustainable change and improved patient outcomes,” Mr. Galvan, who was not involved in the study, said in an email.

“The researchers did a fantastic job,” he added. “I am grateful to see this important work addressed in the literature, as it will only improve buy-in for improvement efforts aimed at reducing infections moving forward across the health care continuum.”

Douglas S. Paauw, MD, a professor of medicine and chair for patient-centered clinical education at the University of Washington School of Medicine, Seattle, said that the team’s most important interventions were changing the environmental cleaning protocol and using agents that kill C. diff. spores.

“We know that as many as 10%-20% of hospitalized patients carry C. diff. Cleaning only the rooms where you know you have C. diff. (isolation rooms) will miss most of it,” said Dr. Paauw, who was also not involved in the study. “Cleaning every room with cleaners that actually work is very important but costs money.”
 

Handwashing with soap and water works, alcohol hand gels do not

“We know that handwashing with soap and water is the most important way to prevent hospital C. diff. transmission,” Dr. Paauw noted. “Handwashing protocols implemented prior to the study were probably a big part of the team’s success.”

Handwashing with soap and water works but alcohol hand gels do not, he cautioned.

“C. diff. rates in hospitals went up years ago when we started putting alcohol gels outside patients’ rooms,” Dr. Paauw explained. “Now, instead of washing their hands, staff quickly pump gel before they see patients. Applying gel is easy, but gel does not eliminate C. diff. spores. Handwashing is such a simple way to fix the C. diff. problem, but doctors don’t take the time.”

“We need to take the C. diff. problem seriously. We have enough information, and we know the right things to do. We need to wash our hands. We need to clean the rooms. We need to stop cutting corners if we want to give good care,” he said.

The authors plan to conduct further related research.

The study was not funded. All study authors, as well as Mr. Galvan and Dr. Paauw, have reported no relevant financial interests.

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

Teamwork by a wide range of professional staff, coupled with support from leadership, enabled one academic community hospital to cut its rate of hospital-onset Clostridioides difficile infections (HO-CDIs) by almost two-thirds in 1 year and by over three-quarters in 3 years, a study published in the American Journal of Infection Control reports.

C. diff. is a major health threat. According to the U.S. Centers for Disease Control and Prevention, CDIs, mainly linked with hospitals, caused an estimated 223,900 cases in hospitalized patients and 12,800 deaths in the United States in 2017.

“The interventions and outcomes of the project improved patient care by ensuring early testing, diagnosis, treatment if warranted, and proper isolation, which helped reduce C. diff. transmission to staff and other patients,” lead study author Cherith Walter, MSN, RN, a clinical nurse specialist at Emory Saint Joseph’s Hospital, Atlanta, told this news organization. “Had we not worked together as a team, we would not have had the ability to carry out such a robust project,” she added in an email.

Each HO-CDI case costs a health care system an estimated $12,313, and high rates of HO-CDIs incur fines from the Hospital-Acquired Condition Reduction Program of the Centers for Medicare & Medicaid Services (CMS), the authors write.
 

A diverse staff team collaborated

Emory Saint Joseph’s, a 410-bed hospital in Atlanta, had a history of being above the national CMS benchmark for HO-CDIs. To reduce these infections, comply with CMS requirements, and avoid fines, Ms. Walter and colleagues launched a quality improvement project between 2015 and 2020.

With the approval of the chief nursing officer, chief quality officer, and hospital board, researchers mobilized a diverse team of professionals: a clinical nurse specialist, a physician champion, unit nurse champions, a hospital epidemiologist, an infection preventionist, a clinical microbiologist, an antimicrobial stewardship pharmacist, and an environmental services representative.

The team investigated what caused their hospital’s HO-CDIs from 2014 through 2016 and developed appropriate, evidence-based infection prevention interventions. The integrated approach involved:

• Diagnostic stewardship, including a diarrhea decision-tree algorithm that enabled nurses to order tests of any loose or unformed stool for C. diff. during the first 3 days of admission.
• Enhanced environmental cleaning, which involved switching from sporicidal disinfectant only in isolation rooms to using a more effective Environmental Protection Agency–approved sporicidal disinfectant containing hydrogen peroxide and peracetic acid in all patient rooms for daily cleaning and after discharge. Every day, high-touch surfaces in C. diff. isolation rooms were cleaned and shared equipment was disinfected with bleach wipes. After patient discharge, staff cleaned mattresses on all sides, wiped walls with disinfectant, and used ultraviolet light.
• Antimicrobial stewardship. Formulary fluoroquinolones were removed as standalone orders and made available only through order sets with built-in clinical decision support.
• Education of staff on best practices, through emails, flyers, meetings, and training sessions. Two nurses needed to approve the appropriateness of testing specific specimens for CDI. All HO-CDIs were reviewed and findings presented at CDI team meetings.
• Accountability. Staff on the team and units received emailed notices about compliance issues and held meetings to discuss how to improve compliance.

After 1 year, HO-CDI incidence dropped 63% from baseline, from above 12 cases per 10,000 patient-days to 4.72 per 10,000 patient-days. And after 3 years, infections dropped 77% to 2.80 per 10,000 patient-days.

The hospital’s HO-CDI standardized infection ratio – the total number of infections divided by the National Healthcare Safety Network’s risk-adjusted predicted number of infections – dropped below the national benchmark, from 1.11 in 2015 to 0.43 in 2020.

The hospital also increased testing of appropriate patients for CDI within the first 3 days of admission, from 54% in 2014 to 81% in late 2019.

“By testing patients within 3 days of admission, we discovered that many had acquired C. diff. before admission,” Ms. Walter said. “I don’t think we realized how prevalent C. diff. was in the community.”

Benjamin D. Galvan, MLS(ASCP), CIC, an infection preventionist at Tampa General Hospital and a member of the Association for Professionals in Infection Control and Epidemiology, welcomed the study’s results.  

“Effective collaboration within the health care setting is a highly effective way to implement and sustain evidence-based practices related to infection reduction. When buy-in is obtained from the top, and pertinent stakeholders are engaged for their expertise, we can see sustainable change and improved patient outcomes,” Mr. Galvan, who was not involved in the study, said in an email.

“The researchers did a fantastic job,” he added. “I am grateful to see this important work addressed in the literature, as it will only improve buy-in for improvement efforts aimed at reducing infections moving forward across the health care continuum.”

Douglas S. Paauw, MD, a professor of medicine and chair for patient-centered clinical education at the University of Washington School of Medicine, Seattle, said that the team’s most important interventions were changing the environmental cleaning protocol and using agents that kill C. diff. spores.

“We know that as many as 10%-20% of hospitalized patients carry C. diff. Cleaning only the rooms where you know you have C. diff. (isolation rooms) will miss most of it,” said Dr. Paauw, who was also not involved in the study. “Cleaning every room with cleaners that actually work is very important but costs money.”
 

Handwashing with soap and water works, alcohol hand gels do not

“We know that handwashing with soap and water is the most important way to prevent hospital C. diff. transmission,” Dr. Paauw noted. “Handwashing protocols implemented prior to the study were probably a big part of the team’s success.”

Handwashing with soap and water works but alcohol hand gels do not, he cautioned.

“C. diff. rates in hospitals went up years ago when we started putting alcohol gels outside patients’ rooms,” Dr. Paauw explained. “Now, instead of washing their hands, staff quickly pump gel before they see patients. Applying gel is easy, but gel does not eliminate C. diff. spores. Handwashing is such a simple way to fix the C. diff. problem, but doctors don’t take the time.”

“We need to take the C. diff. problem seriously. We have enough information, and we know the right things to do. We need to wash our hands. We need to clean the rooms. We need to stop cutting corners if we want to give good care,” he said.

The authors plan to conduct further related research.

The study was not funded. All study authors, as well as Mr. Galvan and Dr. Paauw, have reported no relevant financial interests.

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

Since the first case of monkeypox on May 6, reports of outbreaks have come from multiple countries, with the United Kingdom, Spain, and Portugal in the lead, followed by Canada, Israel, and Australia, among others. The United States has reported cases in Boston and New York, and presumed cases have occurred in Utah and Florida. As of May 25, close to 350 cases, either suspected (83) or confirmed (265), have been reported globally.

Monkeypox outbreaks have previously been confined to Central and West Africa, except for an impressively large outbreak in the United States in 2003, during which 47 people were infected across six states. The epidemic was traced to a Gambian rat, rope squirrels, and dormice that had been imported from Ghana as pets and that had infected prairie dogs at a large wholesale pet store.

“It’s amazing how many of these viruses – COVID, now monkeypox and others – [exist]. They’re out there in the wild in the animal reservoir,” said Dennis Hruby, PhD, executive VP/chief scientific officer and scientific founder of SIGA Technologies.

“When it comes to the human population, they sometimes behave in ways we’re not expecting. That and a few mutations change those strains and pathogenicity and can be pandemic,” he told this news organization.

Now that the virus is pandemic, there is an urgent interest in medicines and vaccines that might halt its spread.
 

Smallpox drug tecovirimat

SIGA’s drug is tecovirimat, initially known as ST-246 and now branded as TPOXX. The U.S. Food and Drug Administration approved an oral formulation to treat smallpox in 2018. While smallpox was eradicated by 1980, there have been ongoing concerns about its potential use in a bioterrorism attack.

Tecovirimat is also approved for smallpox in Canada. In Europe, the approval includes treatment of monkeypox, cowpox, and complications from immunization with vaccinia. On May 19, the FDA approved an IV formulation of tecovirimat for those unable to tolerate oral medications.

In a press release, SIGA notes that tecovirimat was “developed through funding and collaboration with the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services, as well as early-stage development supported by the National Institutes of Health, US Centers for Disease Control and Prevention, and the Department of Defense. Tecovirimat is stockpiled by the U.S. Government to mitigate the impact of a potential outbreak or bioterror attack.”

SIGA adds that, under Project Bioshield, “the United States maintains a stockpile of 1.7 million courses in the Strategic National Stockpile.” The drug is only available through the government’s stockpile.

Tecovirimat works by preventing the viruses from reproducing by interfering with a protein, VP37. The virus cannot escape the cell and so cannot infect other cells, Dr. Hruby explained.

Tecovirimat was developed under the FDA’s so-called Animal Rule, which allows approval on the basis of animal studies when human efficacy studies are unethical or impractical.

In a placebo-controlled human pharmacokinetic and safety study, only 2% of the 359 who received TPOXX had to have treatment stopped because of adverse reactions, a rate similar to placebo. The most common reactions (≥2%) were headache, nausea, and abdominal pain. Significant drug interactions were found with the coadministration of repaglinide and midazolam.

Of note is that tecovirimat’s efficacy may be reduced in immunocompromised patients. The smallpox vaccine is contraindicated for those who are immunocompromised. Those people should be offered vaccinia immune globulin.

With monkeypox, “the earlier the disease is recognized and you start treating, [the] more effective,” said Dr. Hruby. “In a monkey model which, much like humans, if we treat early on as the first lesions emerged or even several days after the lesions emerged, we see close to 100% protection.”

The other alternative drug for smallpox and (likely) monkeypox is Chimerix’s brincidofovir (BCV, Tembexa), a lipid conjugate of cidofovir, a drug for cytomegalovirus. Brincidofovir has a better safety profile than cidofovir and was also approved under the Animal Rule.

UpToDate suggests that tecovirimat is the drug of choice for monkeypox. They note that for severely infected patients, it can be combined with brincidofovir after consultation with the CDC or state health department officials.
 

Two vaccines available

Two vaccines are currently available. The oldest is ACAM2000, a replication-competent vaccine that replaced Dryvax, whose use was stopped in 1977, the last year in which naturally occurring cases of smallpox occurred. ACAM2000 is used to immunize military recruits. It was produced by Sanofi and is now produced by Emergent Biosolutions. Being a live vaccinia vaccine, it is contraindicated for people who are immunocompromised or pregnant, as well as for children and those with eczema, because serious and occasionally fatal reactions have occurred. Because of unexpected cardiac complications in first responders who received Dryvax, having a history of cardiac disease or significant risk factors is considered a contraindication to replication-competent (live) vaccination except in the setting of a bioterrorism event.

ACAM2000 is not FDA approved for monkeypox, but it is readily available. The United States stockpile has more than 100 million doses, according to the CDC.

“ACAM is not very different from Dryvax in terms of safety profile,” Melvin Sanicas, MD, a vaccinologist and health educator, told this news organization.

The newest option is a replication-deficient modified vaccinia Ankara vaccine called Jynneos in the United States (Imvanex in Europe; Imvamune in Canada). The vaccine is made by Denmark-based Bavarian Nordic. The FDA approved Jynneos in 2019. It, too, is available through BARDA’s stockpiles; 1,000 doses are available now and more are on order.

In the current monkeypox outbreak, Jynneos has been offered to higher-risk contacts in the United Kingdom. The CDC is planning to provide it to high-risk contacts of infected persons in the United States. This strategy is called “ring vaccination,” through which only close contacts are immunized initially. The rings are then enlarged to include more people as needed. Ring vaccination works well for easily identified diseases such as monkeypox and in situations in which there are few cases. It has been used very effectively for smallpox and Ebola.

Jynneos is not associated with the same risks as the live vaccine. In solicited reactions, injection-site reactions were common. Other reported systemic symptoms were muscle pain (42.8%), headache (34.8%), fatigue (30.4%), nausea (17.3%), and chills (10.4%).

Other vaccines are expected to be developed. Moderna has just thrown its hat into the ring, announcing it is beginning preclinical trials for monkeypox.
 

Prolonged close contact

Monkeypox is spread by large droplets or contact with infected lesions or body fluids. It’s thought to require prolonged close contact. In an email interview, Dr. Sanicas told this news organization that the “contact can be with (1) skin lesions of an infected person, (2) respiratory droplets in prolonged face-to-face contact, (3) fomites. The cases in the United Kingdom are in men having sex with men, but it does not mean the disease is now sexually transmitted. People do not need to have sex to be infected, but of course, sexual contact means there is prolonged contact.” The household transmission rate is less than 10%.

Dr. Sanicas confirmed that, as with smallpox, monkeypox could be transmitted by contact with clothing or bedding that has been contaminated through contact with the infected lesions, as smallpox was transmitted to Native Americans by colonizers. Airborne transmission is a theoretical possibility but is not considered likely. Being a DNA virus, monkeypox is less likely to mutate than COVID. “If it were as infectious as flu or coronavirus, there would be more infections and outbreaks in countries where MPX [monkeypox] is endemic in Western Africa or Congo Basin,” said Dr. Sanicas.

Fortunately, this clade of monkeypox, which appears to have originated in West Africa, is estimated to have a mortality rate of about 1%. In contrast, the Congo Basin clade has a death rate of up to 10%.

Dr. Sanicas concluded, “Be cautious, but there’s no need for further fear and panic on top of what we have for COVID-19. Monkeypox is not COVID and will not cause the same devastation/death/lockdowns as COVID-19.”

Dr. Hruby is an employee and stockholder of SIGA. Dr. Sanicas reports no relevant financial relationships.

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

Since the first case of monkeypox on May 6, reports of outbreaks have come from multiple countries, with the United Kingdom, Spain, and Portugal in the lead, followed by Canada, Israel, and Australia, among others. The United States has reported cases in Boston and New York, and presumed cases have occurred in Utah and Florida. As of May 25, close to 350 cases, either suspected (83) or confirmed (265), have been reported globally.

Monkeypox outbreaks have previously been confined to Central and West Africa, except for an impressively large outbreak in the United States in 2003, during which 47 people were infected across six states. The epidemic was traced to a Gambian rat, rope squirrels, and dormice that had been imported from Ghana as pets and that had infected prairie dogs at a large wholesale pet store.

“It’s amazing how many of these viruses – COVID, now monkeypox and others – [exist]. They’re out there in the wild in the animal reservoir,” said Dennis Hruby, PhD, executive VP/chief scientific officer and scientific founder of SIGA Technologies.

“When it comes to the human population, they sometimes behave in ways we’re not expecting. That and a few mutations change those strains and pathogenicity and can be pandemic,” he told this news organization.

Now that the virus is pandemic, there is an urgent interest in medicines and vaccines that might halt its spread.
 

Smallpox drug tecovirimat

SIGA’s drug is tecovirimat, initially known as ST-246 and now branded as TPOXX. The U.S. Food and Drug Administration approved an oral formulation to treat smallpox in 2018. While smallpox was eradicated by 1980, there have been ongoing concerns about its potential use in a bioterrorism attack.

Tecovirimat is also approved for smallpox in Canada. In Europe, the approval includes treatment of monkeypox, cowpox, and complications from immunization with vaccinia. On May 19, the FDA approved an IV formulation of tecovirimat for those unable to tolerate oral medications.

In a press release, SIGA notes that tecovirimat was “developed through funding and collaboration with the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services, as well as early-stage development supported by the National Institutes of Health, US Centers for Disease Control and Prevention, and the Department of Defense. Tecovirimat is stockpiled by the U.S. Government to mitigate the impact of a potential outbreak or bioterror attack.”

SIGA adds that, under Project Bioshield, “the United States maintains a stockpile of 1.7 million courses in the Strategic National Stockpile.” The drug is only available through the government’s stockpile.

Tecovirimat works by preventing the viruses from reproducing by interfering with a protein, VP37. The virus cannot escape the cell and so cannot infect other cells, Dr. Hruby explained.

Tecovirimat was developed under the FDA’s so-called Animal Rule, which allows approval on the basis of animal studies when human efficacy studies are unethical or impractical.

In a placebo-controlled human pharmacokinetic and safety study, only 2% of the 359 who received TPOXX had to have treatment stopped because of adverse reactions, a rate similar to placebo. The most common reactions (≥2%) were headache, nausea, and abdominal pain. Significant drug interactions were found with the coadministration of repaglinide and midazolam.

Of note is that tecovirimat’s efficacy may be reduced in immunocompromised patients. The smallpox vaccine is contraindicated for those who are immunocompromised. Those people should be offered vaccinia immune globulin.

With monkeypox, “the earlier the disease is recognized and you start treating, [the] more effective,” said Dr. Hruby. “In a monkey model which, much like humans, if we treat early on as the first lesions emerged or even several days after the lesions emerged, we see close to 100% protection.”

The other alternative drug for smallpox and (likely) monkeypox is Chimerix’s brincidofovir (BCV, Tembexa), a lipid conjugate of cidofovir, a drug for cytomegalovirus. Brincidofovir has a better safety profile than cidofovir and was also approved under the Animal Rule.

UpToDate suggests that tecovirimat is the drug of choice for monkeypox. They note that for severely infected patients, it can be combined with brincidofovir after consultation with the CDC or state health department officials.
 

Two vaccines available

Two vaccines are currently available. The oldest is ACAM2000, a replication-competent vaccine that replaced Dryvax, whose use was stopped in 1977, the last year in which naturally occurring cases of smallpox occurred. ACAM2000 is used to immunize military recruits. It was produced by Sanofi and is now produced by Emergent Biosolutions. Being a live vaccinia vaccine, it is contraindicated for people who are immunocompromised or pregnant, as well as for children and those with eczema, because serious and occasionally fatal reactions have occurred. Because of unexpected cardiac complications in first responders who received Dryvax, having a history of cardiac disease or significant risk factors is considered a contraindication to replication-competent (live) vaccination except in the setting of a bioterrorism event.

ACAM2000 is not FDA approved for monkeypox, but it is readily available. The United States stockpile has more than 100 million doses, according to the CDC.

“ACAM is not very different from Dryvax in terms of safety profile,” Melvin Sanicas, MD, a vaccinologist and health educator, told this news organization.

The newest option is a replication-deficient modified vaccinia Ankara vaccine called Jynneos in the United States (Imvanex in Europe; Imvamune in Canada). The vaccine is made by Denmark-based Bavarian Nordic. The FDA approved Jynneos in 2019. It, too, is available through BARDA’s stockpiles; 1,000 doses are available now and more are on order.

In the current monkeypox outbreak, Jynneos has been offered to higher-risk contacts in the United Kingdom. The CDC is planning to provide it to high-risk contacts of infected persons in the United States. This strategy is called “ring vaccination,” through which only close contacts are immunized initially. The rings are then enlarged to include more people as needed. Ring vaccination works well for easily identified diseases such as monkeypox and in situations in which there are few cases. It has been used very effectively for smallpox and Ebola.

Jynneos is not associated with the same risks as the live vaccine. In solicited reactions, injection-site reactions were common. Other reported systemic symptoms were muscle pain (42.8%), headache (34.8%), fatigue (30.4%), nausea (17.3%), and chills (10.4%).

Other vaccines are expected to be developed. Moderna has just thrown its hat into the ring, announcing it is beginning preclinical trials for monkeypox.
 

Prolonged close contact

Monkeypox is spread by large droplets or contact with infected lesions or body fluids. It’s thought to require prolonged close contact. In an email interview, Dr. Sanicas told this news organization that the “contact can be with (1) skin lesions of an infected person, (2) respiratory droplets in prolonged face-to-face contact, (3) fomites. The cases in the United Kingdom are in men having sex with men, but it does not mean the disease is now sexually transmitted. People do not need to have sex to be infected, but of course, sexual contact means there is prolonged contact.” The household transmission rate is less than 10%.

Dr. Sanicas confirmed that, as with smallpox, monkeypox could be transmitted by contact with clothing or bedding that has been contaminated through contact with the infected lesions, as smallpox was transmitted to Native Americans by colonizers. Airborne transmission is a theoretical possibility but is not considered likely. Being a DNA virus, monkeypox is less likely to mutate than COVID. “If it were as infectious as flu or coronavirus, there would be more infections and outbreaks in countries where MPX [monkeypox] is endemic in Western Africa or Congo Basin,” said Dr. Sanicas.

Fortunately, this clade of monkeypox, which appears to have originated in West Africa, is estimated to have a mortality rate of about 1%. In contrast, the Congo Basin clade has a death rate of up to 10%.

Dr. Sanicas concluded, “Be cautious, but there’s no need for further fear and panic on top of what we have for COVID-19. Monkeypox is not COVID and will not cause the same devastation/death/lockdowns as COVID-19.”

Dr. Hruby is an employee and stockholder of SIGA. Dr. Sanicas reports no relevant financial relationships.

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

Since the first case of monkeypox on May 6, reports of outbreaks have come from multiple countries, with the United Kingdom, Spain, and Portugal in the lead, followed by Canada, Israel, and Australia, among others. The United States has reported cases in Boston and New York, and presumed cases have occurred in Utah and Florida. As of May 25, close to 350 cases, either suspected (83) or confirmed (265), have been reported globally.

Monkeypox outbreaks have previously been confined to Central and West Africa, except for an impressively large outbreak in the United States in 2003, during which 47 people were infected across six states. The epidemic was traced to a Gambian rat, rope squirrels, and dormice that had been imported from Ghana as pets and that had infected prairie dogs at a large wholesale pet store.

“It’s amazing how many of these viruses – COVID, now monkeypox and others – [exist]. They’re out there in the wild in the animal reservoir,” said Dennis Hruby, PhD, executive VP/chief scientific officer and scientific founder of SIGA Technologies.

“When it comes to the human population, they sometimes behave in ways we’re not expecting. That and a few mutations change those strains and pathogenicity and can be pandemic,” he told this news organization.

Now that the virus is pandemic, there is an urgent interest in medicines and vaccines that might halt its spread.
 

Smallpox drug tecovirimat

SIGA’s drug is tecovirimat, initially known as ST-246 and now branded as TPOXX. The U.S. Food and Drug Administration approved an oral formulation to treat smallpox in 2018. While smallpox was eradicated by 1980, there have been ongoing concerns about its potential use in a bioterrorism attack.

Tecovirimat is also approved for smallpox in Canada. In Europe, the approval includes treatment of monkeypox, cowpox, and complications from immunization with vaccinia. On May 19, the FDA approved an IV formulation of tecovirimat for those unable to tolerate oral medications.

In a press release, SIGA notes that tecovirimat was “developed through funding and collaboration with the Biomedical Advanced Research and Development Authority (BARDA) at the U.S. Department of Health & Human Services, as well as early-stage development supported by the National Institutes of Health, US Centers for Disease Control and Prevention, and the Department of Defense. Tecovirimat is stockpiled by the U.S. Government to mitigate the impact of a potential outbreak or bioterror attack.”

SIGA adds that, under Project Bioshield, “the United States maintains a stockpile of 1.7 million courses in the Strategic National Stockpile.” The drug is only available through the government’s stockpile.

Tecovirimat works by preventing the viruses from reproducing by interfering with a protein, VP37. The virus cannot escape the cell and so cannot infect other cells, Dr. Hruby explained.

Tecovirimat was developed under the FDA’s so-called Animal Rule, which allows approval on the basis of animal studies when human efficacy studies are unethical or impractical.

In a placebo-controlled human pharmacokinetic and safety study, only 2% of the 359 who received TPOXX had to have treatment stopped because of adverse reactions, a rate similar to placebo. The most common reactions (≥2%) were headache, nausea, and abdominal pain. Significant drug interactions were found with the coadministration of repaglinide and midazolam.

Of note is that tecovirimat’s efficacy may be reduced in immunocompromised patients. The smallpox vaccine is contraindicated for those who are immunocompromised. Those people should be offered vaccinia immune globulin.

With monkeypox, “the earlier the disease is recognized and you start treating, [the] more effective,” said Dr. Hruby. “In a monkey model which, much like humans, if we treat early on as the first lesions emerged or even several days after the lesions emerged, we see close to 100% protection.”

The other alternative drug for smallpox and (likely) monkeypox is Chimerix’s brincidofovir (BCV, Tembexa), a lipid conjugate of cidofovir, a drug for cytomegalovirus. Brincidofovir has a better safety profile than cidofovir and was also approved under the Animal Rule.

UpToDate suggests that tecovirimat is the drug of choice for monkeypox. They note that for severely infected patients, it can be combined with brincidofovir after consultation with the CDC or state health department officials.
 

Two vaccines available

Two vaccines are currently available. The oldest is ACAM2000, a replication-competent vaccine that replaced Dryvax, whose use was stopped in 1977, the last year in which naturally occurring cases of smallpox occurred. ACAM2000 is used to immunize military recruits. It was produced by Sanofi and is now produced by Emergent Biosolutions. Being a live vaccinia vaccine, it is contraindicated for people who are immunocompromised or pregnant, as well as for children and those with eczema, because serious and occasionally fatal reactions have occurred. Because of unexpected cardiac complications in first responders who received Dryvax, having a history of cardiac disease or significant risk factors is considered a contraindication to replication-competent (live) vaccination except in the setting of a bioterrorism event.

ACAM2000 is not FDA approved for monkeypox, but it is readily available. The United States stockpile has more than 100 million doses, according to the CDC.

“ACAM is not very different from Dryvax in terms of safety profile,” Melvin Sanicas, MD, a vaccinologist and health educator, told this news organization.

The newest option is a replication-deficient modified vaccinia Ankara vaccine called Jynneos in the United States (Imvanex in Europe; Imvamune in Canada). The vaccine is made by Denmark-based Bavarian Nordic. The FDA approved Jynneos in 2019. It, too, is available through BARDA’s stockpiles; 1,000 doses are available now and more are on order.

In the current monkeypox outbreak, Jynneos has been offered to higher-risk contacts in the United Kingdom. The CDC is planning to provide it to high-risk contacts of infected persons in the United States. This strategy is called “ring vaccination,” through which only close contacts are immunized initially. The rings are then enlarged to include more people as needed. Ring vaccination works well for easily identified diseases such as monkeypox and in situations in which there are few cases. It has been used very effectively for smallpox and Ebola.

Jynneos is not associated with the same risks as the live vaccine. In solicited reactions, injection-site reactions were common. Other reported systemic symptoms were muscle pain (42.8%), headache (34.8%), fatigue (30.4%), nausea (17.3%), and chills (10.4%).

Other vaccines are expected to be developed. Moderna has just thrown its hat into the ring, announcing it is beginning preclinical trials for monkeypox.
 

Prolonged close contact

Monkeypox is spread by large droplets or contact with infected lesions or body fluids. It’s thought to require prolonged close contact. In an email interview, Dr. Sanicas told this news organization that the “contact can be with (1) skin lesions of an infected person, (2) respiratory droplets in prolonged face-to-face contact, (3) fomites. The cases in the United Kingdom are in men having sex with men, but it does not mean the disease is now sexually transmitted. People do not need to have sex to be infected, but of course, sexual contact means there is prolonged contact.” The household transmission rate is less than 10%.

Dr. Sanicas confirmed that, as with smallpox, monkeypox could be transmitted by contact with clothing or bedding that has been contaminated through contact with the infected lesions, as smallpox was transmitted to Native Americans by colonizers. Airborne transmission is a theoretical possibility but is not considered likely. Being a DNA virus, monkeypox is less likely to mutate than COVID. “If it were as infectious as flu or coronavirus, there would be more infections and outbreaks in countries where MPX [monkeypox] is endemic in Western Africa or Congo Basin,” said Dr. Sanicas.

Fortunately, this clade of monkeypox, which appears to have originated in West Africa, is estimated to have a mortality rate of about 1%. In contrast, the Congo Basin clade has a death rate of up to 10%.

Dr. Sanicas concluded, “Be cautious, but there’s no need for further fear and panic on top of what we have for COVID-19. Monkeypox is not COVID and will not cause the same devastation/death/lockdowns as COVID-19.”

Dr. Hruby is an employee and stockholder of SIGA. Dr. Sanicas reports no relevant financial relationships.

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

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

From Sharp Memorial Hospital, San Diego, CA (Drs. Poremba, Dehner, Perreiter, Semma, and Mills), Sharp Rees-Stealy Medical Group, San Diego, CA (Dr. Sakoulas), and Collaborative to Halt Antibiotic-Resistant Microbes (CHARM), Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA (Dr. Sakoulas).

Abstract

Objective: To compare the costs of hospitalization of patients with moderate-to-severe COVID-19 who received intravenous immunoglobulin (IVIG) with those of patients of similar comorbidity and illness severity who did not.

Design: Analysis 1 was a case-control study of 10 nonventilated, moderately to severely hypoxic patients with COVID-19 who received IVIG (Privigen [CSL Behring]) matched 1:2 with 20 control patients of similar age, body mass index, degree of hypoxemia, and comorbidities. Analysis 2 consisted of patients enrolled in a previously published, randomized, open-label prospective study of 14 patients with COVID-19 receiving standard of care vs 13 patients who received standard of care plus IVIG (Octagam 10% [Octapharma]).

Setting and participants: Patients with COVID-19 with moderate-to-severe hypoxemia hospitalized at a single site located in San Diego, California.

Measurements: Direct cost of hospitalization.

Results: In the first (case-control) population, mean total direct costs, including IVIG, for the treatment group were $21,982 per IVIG-treated case vs $42,431 per case for matched non-IVIG-receiving controls, representing a net cost reduction of $20,449 (48%) per case. For the second (randomized) group, mean total direct costs, including IVIG, for the treatment group were $28,268 per case vs $62,707 per case for untreated controls, representing a net cost reduction of $34,439 (55%) per case. Of the patients who did not receive IVIG, 24% had hospital costs exceeding $80,000; none of the IVIG-treated patients had costs exceeding this amount (P = .016, Fisher exact test).

Conclusion: If allocated early to the appropriate patient type (moderate-to-severe illness without end-organ comorbidities and age <70 years), IVIG can significantly reduce hospital costs in COVID-19 care. More important, in our study it reduced the demand for scarce critical care resources during the COVID-19 pandemic.

Keywords: IVIG, SARS-CoV-2, cost saving, direct hospital costs.

Intravenous immunoglobulin (IVIG) has been available in most hospitals for 4 decades, with broad therapeutic applications in the treatment of Kawasaki disease and a variety of inflammatory, infectious, autoimmune, and viral diseases, via multifactorial mechanisms of immune modulation.¹ Reports of COVID-19−associated multisystem inflammatory syndrome in adults and children have supported the use of IVIG in treatment.^2,3 Previous studies of IVIG treatment for COVID-19 have produced mixed results. Although retrospective studies have largely been positive,^4-8 prospective clinical trials have been mixed, with some favorable results^9-11 and another, more recent study showing no benefit.¹² However, there is still considerable debate regarding whether some subgroups of patients with COVID-19 may benefit from IVIG; the studies that support this argument, however, have been diluted by broad clinical trials that lack granularity among the heterogeneity of patient characteristics and the timing of IVIG administration.^13,14 One study suggests that patients with COVID-19 who may be particularly poised to benefit from IVIG are those who are younger, have fewer comorbidities, and are treated early.⁸

At our institution, we selectively utilized IVIG to treat patients within 48 hours of rapidly increasing oxygen requirements due to COVID-19, targeting those younger than 70 years, with no previous irreversible end-organ damage, no significant comorbidities (renal failure, heart failure, dementia, active cancer malignancies), and no active treatment for cancer. We analyzed the costs of care of these IVIG (Privigen) recipients and compared them to costs for patients with COVID-19 matched by comorbidities, age, and illness severity who did not receive IVIG. To look for consistency, we examined the cost of care of COVID-19 patients who received IVIG (Octagam) as compared to controls from a previously published pilot trial.¹⁰

Methods

Setting and Treatment

All patients in this study were hospitalized at a single site located in San Diego, California. Treatment patients in both cohorts received IVIG 0.5 g/kg adjusted for body weight daily for 3 consecutive days.

Patient Cohort #1: Retrospective Case-Control Trial

Intravenous immunoglobulin (Privigen 10%, CSL Behring) was utilized off-label to treat moderately to severely ill non-intensive care unit (ICU) patients with COVID-19 requiring ≥3 L of oxygen by nasal cannula who were not mechanically ventilated but were considered at high risk for respiratory failure. Preset exclusion criteria for off-label use of IVIG in the treatment of COVID-19 were age >70 years, active malignancy, organ transplant recipient, renal failure, heart failure, or dementia. Controls were obtained from a list of all admitted patients with COVID-19, matched to cases 2:1 on the basis of age (±10 years), body mass index (±1), gender, comorbidities present at admission (eg, hypertension, diabetes mellitus, lung disease, or history of tobacco use), and maximum oxygen requirements within the first 48 hours of admission. In situations where more than 2 potential matched controls were identified for a patient, the 2 controls closest in age to the treatment patient were selected. One IVIG patient was excluded because only 1 matched-age control could be found. Pregnant patients who otherwise fulfilled the criteria for IVIG administration were also excluded from this analysis.

Patient Cohort #2: Prospective, Randomized, Open-Label Trial

Use of IVIG (Octagam 10%, Octapharma) in COVID-19 was studied in a previously published, prospective, open-label randomized trial.¹⁰ This pilot trial included 16 IVIG-treated patients and 17 control patients, of which 13 and 14 patients, respectively, had hospital cost data available for analysis.¹⁰ Most notably, COVID-19 patients in this study were required to have ≥4 L of oxygen via nasal cannula to maintain arterial oxygen saturationof ≤96%.

Outcomes

Cost data were independently obtained from our finance team, which provided us with the total direct cost and the total pharmaceutical cost associated with each admission. We also compared total length of stay (LOS) and ICU LOS between treatment arms, as these were presumed to be the major drivers of cost difference.

Statistics

Nonparametric comparisons of medians were performed with the Mann-Whitney U test. Comparison of means was done by Student t test. Categorical data were analyzed by Fisher exact test.

This analysis was initiated as an internal quality assessment. It received approval from the Sharp Healthcare Institutional Review Board ([email protected]), and was granted a waiver of subject authorization and consent given the retrospective nature of the study.

Results

Case-Control Analysis

A total of 10 hypoxic patients with COVID-19 received Privigen IVIG outside of clinical trial settings. None of the patients was vaccinated against SARS-CoV-2, as hospitalization occurred prior to vaccine availability. In addition, the original SARS-CoV-2 strain was circulating while these patients were hospitalized, preceding subsequent emerging variants. Oxygen requirements within the first 48 hours ranged from 3 L via nasal cannula to requiring bi-level positive pressure airway therapy with 100% oxygen; median age was 56 years and median Charlson comorbidity index was 1. These 10 patients were each matched to 2 control patients hospitalized during a comparable time period and who, based on oxygen requirements, did not receive IVIG. The 20 control patients had a median age of 58.5 years and a Charlson comorbidity index of 1 (Table 1). Rates of comorbidities, such as hypertension, diabetes mellitus, and obesity, were identical in the 2 groups. None of the patients in either group died during the index hospitalization. Fewer control patients received glucocorticoids, which was reflective of lower illness severity/degree of hypoxia in some controls.

Health care utilization in terms of costs and hospital LOS between the 2 groups are shown in Table 2. The mean total direct hospital cost per case, including IVIG and other drug costs, for the 10 IVIG-treated COVID-19 patients was $21,982 vs $42,431 for the matched controls, a reduction of $20,449 (48%) per case (P = .6187) with IVIG. This difference was heavily driven by 4 control patients (20%) with hospital costs >$80,000, marked by need for ICU transfer, mechanical ventilation during admission, and longer hospital stays. This reduction in progression to mechanical ventilation was consistent with our previously published, open-label, randomized prospective IVIG study, the financial assessment of which is reviewed below. While total direct costs were lower in the treatment arm, the mean drug cost for the treatment arm was $3122 greater than the mean drug cost in the control arm (P = .001622), consistent with the high cost of IVIG therapy (Table 2).

LOS information was obtained, as this was thought to be a primary driver of direct costs. The average LOS in the IVIG arm was 8.4 days, and the average LOS in the control arm was 13.6 days (P = NS). The average ICU LOS in the IVIG arm was 0 days, while the average ICU LOS in the control arm was 5.3 days (P = .04). As with the differences in cost, the differences in LOS were primarily driven by the 4 outlier cases in our control arm, who each had a LOS >25 days, as well as an ICU LOS >20 days.

Randomized, Open-Label, Patient Cohort Analysis

Patient characteristics, LOS, and rates of mechanical ventilation for the IVIG and control patients were previously published and showed a reduction in mechanical ventilation and hospital LOS with IVIG treatment.¹⁰ In this group of patients, 1 patient treated with IVIG (6%) and 3 patients not treated with IVIG (18%) died. To determine the consistency of these results from the case-control patients with a set of patients obtained from clinical trial randomization, we examined the health care costs of patients from the prior study.¹⁰ As with the case-control group, patients in this portion of the analysis were hospitalized before vaccines were available and prior to any identified variants.

Comparing the hospital cost of the IVIG-treated patients to the control patients from this trial revealed results similar to the matched case-control analysis discussed earlier. Average total direct cost per case, including IVIG, for the IVIG treatment group was $28,268, vs $62,707 per case for non-IVIG controls. This represented a net cost reduction of $34,439 (55%) per case, very similar to that of the prior cohort.

IVIG Reduces Costly Outlier Cases

The case-control and randomized trial groups, yielding a combined 23 IVIG and 34 control patients, showed a median cost per case of $22,578 (range $10,115-$70,929) and $22,645 (range $4723-$279,797) for the IVIG and control groups, respectively. Cases with a cost >$80,000 were 0/23 (0%) vs 8/34 (24%) in the IVIG and control groups, respectively (P = .016, Fisher exact test).

Improving care while simultaneously keeping care costs below reimbursement payment levels received from third-party payers is paramount to the financial survival of health care systems. IVIG appears to do this by reducing the number of patients with COVID-19 who progress to ICU care. We compared the costs of care of our combined case-control and randomized trial cohorts to published data on average reimbursements hospitals receive for COVID-19 care from Medicaid, Medicare, and private insurance (Figure).¹⁵ IVIG demonstrated a reduction in cases where costs exceed reimbursement. Indeed, a comparison of net revenue per case of the case-control group showed significantly higher revenue for the IVIG group compared to controls ($52,704 vs $34,712, P = .0338, Table 2).

Discussion

As reflected in at least 1 other study,¹⁶ our hospital had been successfully utilizing IVIG in the treatment of viral acute respiratory distress syndrome (ARDS) prior to COVID-19. Therefore, we moved quickly to perform a randomized, open-label pilot study of IVIG (Octagam 10%) in COVID-19, and noted significant clinical benefit that might translate into hospital cost savings.¹⁰ Over the course of the pandemic, evidence has accumulated that IVIG may play an important role in COVID-19 therapeutics, as summarized in a recent review.¹⁷ However, despite promising but inconsistent results, the relatively high acquisition costs of IVIG raised questions as to its pharmacoeconomic value, particularly with such a high volume of COVID-19 patients with hypoxia, in light of limited clinical data.

COVID-19 therapeutics data can be categorized into either high-quality trials showing marginal benefit for some agents or low-quality trials showing greater benefit for other agents, with IVIG studies falling into the latter category.¹⁸ This phenomenon may speak to the pathophysiological heterogeneity of the COVID-19 patient population. High-quality trials enrolling broad patient types lack the granularity to capture and single out relevant patient subsets who would derive maximal therapeutic benefit, with those subsets diluted by other patient types for which no benefit is seen. Meanwhile, the more granular low-quality trials are criticized as underpowered and lacking in translatability to practice.

Positive results from our pilot trial allowed the use of IVIG (Privigen) off-label in hospitalized COVID-19 patients restricted to specific criteria. Patients had to be moderately to severely ill, requiring >3 L of oxygen via nasal cannula; show high risk of clinical deterioration based on respiratory rate and decline in respiratory status; and have underlying comorbidities (such as hypertension, obesity, or diabetes mellitus). However, older patients (>age 70 years) and those with underlying comorbidities marked by organ failure (such as heart failure, renal failure, dementia, or receipt of organ transplant) and active malignancy were excluded, as their clinical outcome in COVID-19 may be considered less modifiable by therapeutics, while simultaneously carrying potentially a higher risk of adverse events from IVIG (volume overload, renal failure). These exclusions are reflected in the overall low Charlson comorbidity index (mean of 1) of the patients in the case-control study arm. As anticipated, we found a net cost reduction: $20,449 (48%) per case among the 10 IVIG-treated patients compared to the 20 matched controls.

We then went back to the patients from the randomized prospective trial and compared costs for the 13 of 16 IVIG patients and 14 of 17 of the control patients for whom data were available. Among untreated controls, we found a net cost reduction of $34,439 (55%) per case. The higher costs seen in the randomized patient cohort compared to the latter case-control group may be due to a combination of the fact that the treated patients had slightly higher comorbidity indices than the case-control group (median Charlson comorbidity index of 2 in both groups) and the fact that they were treated earlier in the pandemic (May/June 2020), as opposed to the case-control group patients, who were treated in November/December 2020.

It was notable that the cost savings across both groups were derived largely from the reduction in the approximately 20% to 25% of control patients who went on to critical illness, including mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and prolonged ICU stays. Indeed, 8 of 34 of the control patients—but none of the 23 IVIG-treated patients—generated hospital costs in excess of $80,000, a difference that was statistically significant even for such a small sample size. Therefore, reducing these very costly outlier events translated into net savings across the board.

In addition to lowering costs, reducing progression to critical illness is extremely important during heavy waves of COVID-19, when the sheer volume of patients results in severe strain due to the relative scarcity of ICU beds, mechanical ventilators, and ECMO. Therefore, reducing the need for these resources would have a vital role that cannot be measured economically.

The major limitations of this study include the small sample size and the potential lack of generalizability of these results to all hospital centers and treating providers. Our group has considerable experience in IVIG utilization in COVID-19 and, as a result, has identified a “sweet spot,” where benefits were seen clinically and economically. However, it remains to be determined whether IVIG will benefit patients with greater illness severity, such as those in the ICU, on mechanical ventilation, or ECMO. Furthermore, while a significant morbidity and mortality burden of COVID-19 rests in extremely elderly patients and those with end-organ comorbidities such as renal failure and heart failure, it is uncertain whether their COVID-19 adverse outcomes can be improved with IVIG or other therapies. We believe such patients may limit the pharmacoeconomic value of IVIG due to their generally poorer prognosis, regardless of intervention. On the other hand, COVID-19 patients who are not that severely ill, with minimal to no hypoxia, generally will do well regardless of therapy. Therefore, IVIG intervention may be an unnecessary treatment expense. Evidence for this was suggested in our pilot trial¹⁰ and supported in a recent meta-analysis of IVIG therapy in COVID-19.¹⁹

Several other therapeutic options with high acquisition costs have seen an increase in use during the COVID-19 pandemic despite relatively lukewarm data. Remdesivir, the first drug found to have a beneficial effect on hospitalized patients with COVID-19, is priced at $3120 for a complete 5-day treatment course in the United States. This was in line with initial pricing models from the Institute for Clinical and Economic Review (ICER) in May 2020, assuming a mortality benefit with remdesivir use. After the SOLIDARITY trial was published, which showed no mortality benefit associated with remdesivir, ICER updated their pricing models in June 2020 and released a statement that the price of remdesivir was too high to align with demonstrated benefits.^20,21 More recent data demonstrate that remdesivir may be beneficial, but only if administered to patients with fewer than 6 days of symptoms.²² However, only a minority of patients present to the hospital early enough in their illness for remdesivir to be beneficial.²²

Tocilizumab, an interleukin-6 inhibitor, saw an increase in use during the pandemic. An 800-mg treatment course for COVID-19 costs $3584. The efficacy of this treatment option came into question after the COVACTA trial failed to show a difference in clinical status or mortality in COVID-19 patients who received tocilizumab vs placebo.^23,24 A more recent study pointed to a survival benefit of tocilizumab in COVID-19, driven by a very large sample size (>4000), yielding statistically significant, but perhaps clinically less significant, effects on survival.²⁵ This latter study points to the extremely large sample sizes required to capture statistically significant benefits of expensive interventions in COVID-19, which our data demonstrate may benefit only a fraction of patients (20%-25% of patients in the case of IVIG). A more granular clinical assessment of these other interventions is needed to be able to capture the patient subtypes where tocilizumab, remdesivir, and other therapies will be cost effective in the treatment of COVID-19 or other virally mediated cases of ARDS.

Conclusion

While IVIG has a high acquisition cost, the drug’s use in hypoxic COVID-19 patients resulted in reduced costs per COVID-19 case of approximately 50% and use of less critical care resources. The difference was consistent between 2 cohorts (randomized trial vs off-label use in prespecified COVID-19 patient types), IVIG products used (Octagam 10% and Privigen), and time period in the pandemic (waves 1 and 2 in May/June 2020 vs wave 3 in November/December 2020), thereby adjusting for potential differences in circulating viral strains. Furthermore, patients from both groups predated SARS-CoV-2 vaccine availability and major circulating viral variants (eg, delta, omicron), thereby eliminating confounding on outcomes posed by these factors. Control patients’ higher costs of care were driven largely by the approximately 25% of patients who required costly hospital critical care resources, a group mitigated by IVIG. When allocated to the appropriate patient type (patients with moderate-to-severe but not critical illness, <age 70 without preexisting comorbidities of end-organ failure or active cancer), IVIG can reduce hospital costs for COVID-19 care. Identification of specific patient populations where IVIG has the most anticipated benefits in viral illness is needed.

Corresponding author: George Sakoulas, MD, Sharp Rees-Stealy Medical Group, 2020 Genesee Avenue, 2nd Floor, San Diego, CA 92123; [email protected]

Disclosures: Dr Sakoulas has worked as a consultant for Abbvie, Paratek, and Octapharma, has served as a speaker for Abbvie and Paratek, and has received research funding from Octapharma. The other authors did not report any disclosures.

Study Overview

Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.

Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.

Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m² on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.

Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.

Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.

Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.

Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.

Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).

Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.

Commentary

The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.¹ However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.² The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.

Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.

Application for Clinical Practice

The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection. 

—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI

Study Overview

Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.

Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.

Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m² on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.

Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.

Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.

Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.

Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.

Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).

Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.

Commentary

The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.¹ However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.² The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.

Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.

Application for Clinical Practice

The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection. 

—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI

Study Overview

Objective: To evaluate whether the addition of the potent androgen-receptor inhibitor (ARA) darolutamide to the standard doublet androgen-deprivation therapy (ADT) and docetaxel in metastatic, hormone-sensitive prostate cancer (mHSPC) would increase survival.

Design: A randomized, double-blind, placebo-controlled, multicenter, phase 3 study. The results reported in this publication are from the prespecified interim analysis.

Intervention: Patients with mHSPC were randomly assigned to receive either darolutamide 600 mg twice daily or placebo. All patients received standard ADT with 6 cycles of docetaxel 75 mg/m² on day 1 every 21 days along with prednisone given within 6 weeks after randomization. Patients receiving luteinizing hormone–releasing hormone (LHRH) agonists as ADT were bridged with at least 4 weeks of first-generation antiandrogen therapy, which was discontinued before randomization. Treatments were continued until symptomatic disease progression, a change in neoplastic therapy, unacceptable toxicity, patient or physician decision, death, or nonadherence.

Setting and participants: Eligible patients included those newly diagnosed with mHSPC with metastases detected on contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and bone scan. Patients were excluded if they had regional lymph node–only involvement or if they had received more than 12 weeks of ADT before randomization. Between November 2016 and June 2018, 1306 patients (651 in the darolutamide group and 655 in the placebo group) were randomized in a 1:1 manner to receive darolutamide 600 mg twice daily or placebo in addition to ADT and docetaxel. Randomization was stratified based on the TNM staging system (M1a—nonregional lymph node–only metastasis, M1b—bone metastasis with or without lymph node, or M1c—bone metastases) as well as baseline alkaline phosphatase levels.

Main outcome measures: The primary end point for the study was overall survival. Other meaningful secondary end points included time to castration resistance, time to pain progression, time to first symptomatic skeletal event, symptomatic skeletal event-free survival, time to subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, initiation of opioid therapy for ≥7 days, and safety.

Results: The baseline and demographic characteristics were well balanced between the 2 groups. Median age was 67 years. Nearly 80% of patients had bone metastasis, and approximately 17% had visceral metastasis. At the data cutoff date for the primary analysis, the median duration of therapy was 41 months for darolutamide compared with 16.7 months in the placebo group; 45.9% in the darolutamide group and 19.1% in the placebo group were receiving the allotted trial therapy at the time of the analysis. Six cycles of docetaxel were completed in approximately 85% of patients in both arms. Median overall survival follow-up was 43.7 months (darolutamide) and 42.4 months (placebo). A significant improvement in overall survival was observed in the darolutamide group. The risk of death was 32.5% lower in the darolutamide cohort than in the placebo cohort (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P < .001). The overall survival at 4 years was 62.7% (95% CI, 58.7-66.7) in the darolutamide arm and 50.4% (95% CI, 46.3-54.6) in the placebo arm. The overall survival results remained favorable across most subgroups.

Darolutamide was associated with improvement in all key secondary endpoints. Time to castration-resistance was significantly longer in the darolutamide group (HR, 0.36; 95% CI, 0.30-0.42; P < .001). Time to pain progression was also significantly longer in the darolutamide group (HR, 0.79; 95% CI, 0.66-0.95; P = .01). Time to first symptomatic skeletal events (HR, 0.71; 95% CI, 0.54-0.94; P = .02) and time to initiation of subsequent systemic therapy (HR, 0.39; 95% CI, 0.33-0.46; P < .001) were also found to be longer in the darolutamide group.

Safety: The risk of grade 3 or higher adverse events was similar across the 2 groups. Most common adverse events were known toxic effects of docetaxel therapy and were highest during the initial period when both groups received this therapy. These side effects progressively decreased after the initial period. The most common grade 3 or 4 adverse event was neutropenia, and its frequency was similar between the darolutamide and placebo groups (33.7% and 34.2%, respectively). The most frequently reported adverse events were alopecia, neutropenia, fatigue, and anemia and were similar between the groups. Adverse events of special significance, including fatigue, falls, fractures, and cardiovascular events, were also similar between the 2 groups. Adverse events causing deaths in each arm were low and similar (4.1% in the darolutamide group and 4.0% in the placebo group). The rates of discontinuation of darolutamide or placebo were similar (13.5% and 10.6%, respectively).

Conclusion: Among patients with mHSPC, overall survival was significantly longer among patients who received darolutamide plus ADT and docetaxel than among those who received ADT and docetaxel alone. This was observed despite a high percentage of patients in the placebo group receiving subsequent systemic therapy at the time of progression. The survival benefit of darolutamide was maintained across most subgroups. An improvement was also observed in the darolutamide arm in terms of key secondary end points. The adverse events were similar across the groups and were consistent with known safety profiles of ADT and docetaxel, and no new safety signals were identified in this trial.

Commentary

The results of the current study add to the body of literature supporting multi-agent systemic therapy in newly diagnosed mHSPC. Prior phase 3 trials of combination therapy using androgen-receptor pathway inhibitors, ADT, and docetaxel have shown conflicting results. The results from the previously reported PEACE-1 study showed improved overall survival among patients who received abiraterone with ADT and docetaxel as compared with those who received ADT and docetaxel alone.¹ However, as noted by the authors, the subgroup of patients in the ENZAMET trial who received docetaxel, enzalutamide, and ADT did not appear to have a survival advantage compared with those who received ADT and docetaxel alone.² The results from the current ARASENS trial provide compelling evidence in a population of prospectively randomized patients that combination therapy with darolutamide, docetaxel, and ADT improves overall survival in men with mHSPC. The survival advantage was maintained across subgroups analyzed in this study. Improvements were observed in regards to several key secondary end points with use of darolutamide. This benefit was maintained despite many patients receiving subsequent therapy at the time of progression. Importantly, there did not appear to be a significant increase in toxicity with triplet therapy. However, it is important to note that this cohort of patients appeared largely asymptomatic at the time of enrollment, with 70% of patients having an Eastern Cooperative Oncology Group performance status of 0.

Additionally, the average age in this study was 67 years, with only about 15% of the population being older than 75 years. In the reported subgroup analysis, those older than 75 years appeared to derive a similar benefit in overall survival, however. Whether triplet therapy should be universally adopted in all patients remains unclear. For example, there is a subset of patients with mHSPC with favorable- risk disease (ie, those with recurrent metastatic disease, node-only disease). In this population, the risk-benefit analysis is less clear, and whether these patients should receive this combination is not certain. Nevertheless, the results of this well-designed study are compelling and certainly represent a potential new standard treatment option for men with mHSPC. One of the strengths of this study was its large sample size that allowed for vigorous statistical analysis to evaluate the efficacy of darolutamide in combination with ADT and docetaxel.

Application for Clinical Practice

The ARASENS study provides convincing evidence that in men with mHSPC, the addition of darolutamide to docetaxel and ADT improves overall survival. This combination appeared to be well tolerated, with no evidence of increased toxicity noted. Certainly, this combination represents a potential new standard treatment option in this population; however, further understanding of which subgroups of men benefit from enhanced therapy is needed to aid in proper patient selection. 

—Santosh Kagathur, MD, and Daniel Isaac, DO, MS
Michigan State University, East Lansing, MI

Study 1 Overview (SCOT-HEART Investigators)

Objective: To assess cardiovascular mortality and nonfatal myocardial infarction at 5 years in patients with stable chest pain referred to cardiology clinic for management with either standard care plus computed tomography angiography (CTA) or standard care alone.

Design: Multicenter, randomized, open-label prospective study.

Setting and participants: A total of 4146 patients with stable chest pain were randomized to standard care or standard care plus CTA at 12 centers across Scotland and were followed for 5 years.

Main outcome measures: The primary end point was a composite of death from coronary heart disease or nonfatal myocardial infarction. Main secondary end points were nonfatal myocardial infarction, nonfatal stroke, and frequency of invasive coronary angiography (ICA) and coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting.

Main results: The primary outcome including the composite of cardiovascular death or nonfatal myocardial infarction was lower in the CTA group than in the standard-care group at 2.3% (48 of 2073 patients) vs 3.9% (81 of 2073 patients), respectively (hazard ratio, 0.59; 95% CI, 0.41-0.84; P = .004). Although there was a higher rate of ICA and coronary revascularization in the CTA group than in the standard-care group in the first few months of follow-up, the overall rates were similar at 5 years, with ICA performed in 491 patients and 502 patients in the CTA vs standard-care groups, respectively (hazard ratio, 1.00; 95% CI, 0.88-1.13). Similarly, coronary revascularization was performed in 279 patients in the CTA group and in 267 patients in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91-1.27). There were, however, more preventive therapies initiated in patients in the CTA group than in the standard-care group (odds ratio, 1.40; 95% CI, 1.19-1.65).

Conclusion: In patients with stable chest pain, the use of CTA in addition to standard care resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years; the main contributor to this outcome was a reduced nonfatal myocardial infarction rate. There was no difference in the rate of coronary angiography or coronary revascularization between the 2 groups at 5 years.

Study 2 Overview (DISCHARGE Trial Group)

Objective: To compare the effectiveness of computed tomography (CT) with ICA as a diagnostic tool in patients with stable chest pain and intermediate pretest probability of coronary artery disease (CAD).

Design: Multicenter, randomized, assessor-blinded pragmatic prospective study.

Setting and participants: A total of 3667 patients with stable chest pain and intermediate pretest probability of CAD were enrolled at 26 centers and randomized into CT or ICA groups. Only 3561 patients were included in the modified intention-to-treat analysis, with 1808 patients and 1753 patients in the CT and ICA groups, respectively.

Main outcome measures: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke over 3.5 years. The main secondary outcomes were major procedure-related complications and patient-reported angina pectoris during the last 4 weeks of follow up.

Main results: The primary outcome occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 patients (3.0%) in the ICA group (hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). The secondary outcomes showed that major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 patients (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13-0.55). Rates of patient-reported angina in the final 4 weeks of follow-up were 8.8% in the CT group and 7.5% in the ICA group (odds ratio, 1.17; 95% CI, 0.92-1.48).

Conclusion: Risk of major adverse cardiovascular events from the primary outcome were similar in both the CT and ICA groups among patients with stable chest pain and intermediate pretest probability of CAD. Patients referred for CT had a lower rate of coronary angiography leading to fewer major procedure-related complications in these patients than in those referred for ICA.

Evaluation and treatment of obstructive atherosclerosis is an important part of clinical care in patients presenting with angina symptoms.¹ Thus, the initial investigation for patients with suspected obstructive CAD includes ruling out acute coronary syndrome and assessing quality of life.¹ The diagnostic test should be tailored to the pretest probability for the diagnosis of obstructive CAD.²

In the United States, stress testing traditionally has been used for the initial assessment in patients with suspected CAD,³ but recently CTA has been utilized more frequently for this purpose. Compared to a stress test, which often helps identify and assess ischemia, CTA can provide anatomical assessment, with higher sensitivity to identify CAD.⁴ Furthermore, it can distinguish nonobstructive plaques that can be challenging to identify with stress test alone.

Whether CTA is superior to stress testing as the initial assessment for CAD has been debated. The randomized PROMISE trial compared patients with stable angina who underwent functional stress testing or CTA as an initial strategy.⁵ They reported a similar outcome between the 2 groups at a median follow-up of 2 years. However, in the original SCOT-HEART trial (CT coronary angiography in patients with suspected angina due to coronary heart disease), which was published in the same year as the PROMISE trial, the patients who underwent initial assessment with CTA had a numerically lower composite end point of cardiac death and myocardial infarction at a median follow-up of 1.7 years (1.3% vs 2.0%, P = .053).⁶

Given this result, the SCOT-HEART investigators extended the follow-up to evaluate the composite end point of death from coronary heart disease or nonfatal myocardial infarction at 5 years.⁷ This trial enrolled patients who were initially referred to a cardiology clinic for evaluation of chest pain, and they were randomized to standard care plus CTA or standard care alone. At a median duration of 4.8 years, the primary outcome was lower in the CTA group (2.3%, 48 patients) than in the standard-care group (3.9%, 81 patients) (hazard ratio, 0.58; 95% CI, 0.41-0.84; P = .004). Both groups had similar rates of invasive coronary angiography and had similar coronary revascularization rates.

It is hypothesized that this lower rate of nonfatal myocardial infarction in patients with CTA plus standard care is associated with a higher rate of preventive therapies initiated in patients in the CTA-plus-standard-care group compared to standard care alone. However, the difference in the standard-care group should be noted when compared to the PROMISE trial. In the PROMISE trial, the comparator group had predominantly stress imaging (either nuclear stress test or echocardiography), while in the SCOT-HEART trial, the group had predominantly stress electrocardiogram (ECG), and only 10% of the patients underwent stress imaging. It is possible the difference seen in the rate of nonfatal myocardial infarction was due to suboptimal diagnosis of CAD with stress ECG, which has lower sensitivity compared to stress imaging.

The DISCHARGE trial investigated the effectiveness of CTA vs ICA as the initial diagnostic test in the management of patients with stable chest pain and an intermediate pretest probability of obstructive CAD.⁸ At 3.5 years of follow-up, the primary composite of cardiovascular death, myocardial infarction, or stroke was similar in both groups (2.1% vs 3.0; hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). Importantly, as fewer patients underwent ICA, the risk of procedure-related complication was lower in the CTA group than in the ICA group. However, it is important to note that only 25% of the patients diagnosed with obstructive CAD had greater than 50% vessel stenosis, which raises the question of whether an initial invasive strategy is appropriate for this population.

The strengths of these 2 studies include the large number of patients enrolled along with adequate follow-up, 5 years in the SCOT-HEART trial and 3.5 years in the DISCHARGE trial. The 2 studies overall suggest the usefulness of CTA for assessment of CAD. However, the control groups were very different in these 2 trials. In the SCOT-HEART study, the comparator group was primarily assessed by stress ECG, while in the DISCHARGE study, the comparator group was primary assessed by ICA. In the PROMISE trial, the composite end point of death, myocardial infarction, hospitalization for unstable angina, or major procedural complication was similar when the strategy of initial CTA was compared to functional testing with imaging (exercise ECG, nuclear stress testing, or echocardiography).⁵ Thus, clinical assessment is still needed when clinicians are selecting the appropriate diagnostic test for patients with suspected CAD. The most recent guidelines give similar recommendations for CTA compared to stress imaging.⁹ Whether further improvement in CTA acquisition or the addition of CT fractional flow reserve can further improve outcomes requires additional study.

Applications for Clinical Practice and System Implementation

In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful in diagnosis compared to stress ECG and in reducing utilization of low-yield ICA. Whether CTA is more useful compared to the other noninvasive stress imaging modalities in this population requires further study.

Practice Points

• In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful compared to stress ECG.
• Use of CTA can potentially reduce the use of low-yield coronary angiography.

–Thai Nguyen, MD, Albert Chan, MD, Taishi Hirai, MD
University of Missouri, Columbia, MO

Study 1 Overview (SCOT-HEART Investigators)

Objective: To assess cardiovascular mortality and nonfatal myocardial infarction at 5 years in patients with stable chest pain referred to cardiology clinic for management with either standard care plus computed tomography angiography (CTA) or standard care alone.

Design: Multicenter, randomized, open-label prospective study.

Setting and participants: A total of 4146 patients with stable chest pain were randomized to standard care or standard care plus CTA at 12 centers across Scotland and were followed for 5 years.

Main outcome measures: The primary end point was a composite of death from coronary heart disease or nonfatal myocardial infarction. Main secondary end points were nonfatal myocardial infarction, nonfatal stroke, and frequency of invasive coronary angiography (ICA) and coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting.

Main results: The primary outcome including the composite of cardiovascular death or nonfatal myocardial infarction was lower in the CTA group than in the standard-care group at 2.3% (48 of 2073 patients) vs 3.9% (81 of 2073 patients), respectively (hazard ratio, 0.59; 95% CI, 0.41-0.84; P = .004). Although there was a higher rate of ICA and coronary revascularization in the CTA group than in the standard-care group in the first few months of follow-up, the overall rates were similar at 5 years, with ICA performed in 491 patients and 502 patients in the CTA vs standard-care groups, respectively (hazard ratio, 1.00; 95% CI, 0.88-1.13). Similarly, coronary revascularization was performed in 279 patients in the CTA group and in 267 patients in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91-1.27). There were, however, more preventive therapies initiated in patients in the CTA group than in the standard-care group (odds ratio, 1.40; 95% CI, 1.19-1.65).

Conclusion: In patients with stable chest pain, the use of CTA in addition to standard care resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years; the main contributor to this outcome was a reduced nonfatal myocardial infarction rate. There was no difference in the rate of coronary angiography or coronary revascularization between the 2 groups at 5 years.

Study 2 Overview (DISCHARGE Trial Group)

Objective: To compare the effectiveness of computed tomography (CT) with ICA as a diagnostic tool in patients with stable chest pain and intermediate pretest probability of coronary artery disease (CAD).

Design: Multicenter, randomized, assessor-blinded pragmatic prospective study.

Setting and participants: A total of 3667 patients with stable chest pain and intermediate pretest probability of CAD were enrolled at 26 centers and randomized into CT or ICA groups. Only 3561 patients were included in the modified intention-to-treat analysis, with 1808 patients and 1753 patients in the CT and ICA groups, respectively.

Main outcome measures: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke over 3.5 years. The main secondary outcomes were major procedure-related complications and patient-reported angina pectoris during the last 4 weeks of follow up.

Main results: The primary outcome occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 patients (3.0%) in the ICA group (hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). The secondary outcomes showed that major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 patients (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13-0.55). Rates of patient-reported angina in the final 4 weeks of follow-up were 8.8% in the CT group and 7.5% in the ICA group (odds ratio, 1.17; 95% CI, 0.92-1.48).

Conclusion: Risk of major adverse cardiovascular events from the primary outcome were similar in both the CT and ICA groups among patients with stable chest pain and intermediate pretest probability of CAD. Patients referred for CT had a lower rate of coronary angiography leading to fewer major procedure-related complications in these patients than in those referred for ICA.

Evaluation and treatment of obstructive atherosclerosis is an important part of clinical care in patients presenting with angina symptoms.¹ Thus, the initial investigation for patients with suspected obstructive CAD includes ruling out acute coronary syndrome and assessing quality of life.¹ The diagnostic test should be tailored to the pretest probability for the diagnosis of obstructive CAD.²

In the United States, stress testing traditionally has been used for the initial assessment in patients with suspected CAD,³ but recently CTA has been utilized more frequently for this purpose. Compared to a stress test, which often helps identify and assess ischemia, CTA can provide anatomical assessment, with higher sensitivity to identify CAD.⁴ Furthermore, it can distinguish nonobstructive plaques that can be challenging to identify with stress test alone.

Whether CTA is superior to stress testing as the initial assessment for CAD has been debated. The randomized PROMISE trial compared patients with stable angina who underwent functional stress testing or CTA as an initial strategy.⁵ They reported a similar outcome between the 2 groups at a median follow-up of 2 years. However, in the original SCOT-HEART trial (CT coronary angiography in patients with suspected angina due to coronary heart disease), which was published in the same year as the PROMISE trial, the patients who underwent initial assessment with CTA had a numerically lower composite end point of cardiac death and myocardial infarction at a median follow-up of 1.7 years (1.3% vs 2.0%, P = .053).⁶

Given this result, the SCOT-HEART investigators extended the follow-up to evaluate the composite end point of death from coronary heart disease or nonfatal myocardial infarction at 5 years.⁷ This trial enrolled patients who were initially referred to a cardiology clinic for evaluation of chest pain, and they were randomized to standard care plus CTA or standard care alone. At a median duration of 4.8 years, the primary outcome was lower in the CTA group (2.3%, 48 patients) than in the standard-care group (3.9%, 81 patients) (hazard ratio, 0.58; 95% CI, 0.41-0.84; P = .004). Both groups had similar rates of invasive coronary angiography and had similar coronary revascularization rates.

It is hypothesized that this lower rate of nonfatal myocardial infarction in patients with CTA plus standard care is associated with a higher rate of preventive therapies initiated in patients in the CTA-plus-standard-care group compared to standard care alone. However, the difference in the standard-care group should be noted when compared to the PROMISE trial. In the PROMISE trial, the comparator group had predominantly stress imaging (either nuclear stress test or echocardiography), while in the SCOT-HEART trial, the group had predominantly stress electrocardiogram (ECG), and only 10% of the patients underwent stress imaging. It is possible the difference seen in the rate of nonfatal myocardial infarction was due to suboptimal diagnosis of CAD with stress ECG, which has lower sensitivity compared to stress imaging.

The DISCHARGE trial investigated the effectiveness of CTA vs ICA as the initial diagnostic test in the management of patients with stable chest pain and an intermediate pretest probability of obstructive CAD.⁸ At 3.5 years of follow-up, the primary composite of cardiovascular death, myocardial infarction, or stroke was similar in both groups (2.1% vs 3.0; hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). Importantly, as fewer patients underwent ICA, the risk of procedure-related complication was lower in the CTA group than in the ICA group. However, it is important to note that only 25% of the patients diagnosed with obstructive CAD had greater than 50% vessel stenosis, which raises the question of whether an initial invasive strategy is appropriate for this population.

The strengths of these 2 studies include the large number of patients enrolled along with adequate follow-up, 5 years in the SCOT-HEART trial and 3.5 years in the DISCHARGE trial. The 2 studies overall suggest the usefulness of CTA for assessment of CAD. However, the control groups were very different in these 2 trials. In the SCOT-HEART study, the comparator group was primarily assessed by stress ECG, while in the DISCHARGE study, the comparator group was primary assessed by ICA. In the PROMISE trial, the composite end point of death, myocardial infarction, hospitalization for unstable angina, or major procedural complication was similar when the strategy of initial CTA was compared to functional testing with imaging (exercise ECG, nuclear stress testing, or echocardiography).⁵ Thus, clinical assessment is still needed when clinicians are selecting the appropriate diagnostic test for patients with suspected CAD. The most recent guidelines give similar recommendations for CTA compared to stress imaging.⁹ Whether further improvement in CTA acquisition or the addition of CT fractional flow reserve can further improve outcomes requires additional study.

Applications for Clinical Practice and System Implementation

In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful in diagnosis compared to stress ECG and in reducing utilization of low-yield ICA. Whether CTA is more useful compared to the other noninvasive stress imaging modalities in this population requires further study.

Practice Points

• In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful compared to stress ECG.
• Use of CTA can potentially reduce the use of low-yield coronary angiography.

–Thai Nguyen, MD, Albert Chan, MD, Taishi Hirai, MD
University of Missouri, Columbia, MO

Study 1 Overview (SCOT-HEART Investigators)

Objective: To assess cardiovascular mortality and nonfatal myocardial infarction at 5 years in patients with stable chest pain referred to cardiology clinic for management with either standard care plus computed tomography angiography (CTA) or standard care alone.

Design: Multicenter, randomized, open-label prospective study.

Setting and participants: A total of 4146 patients with stable chest pain were randomized to standard care or standard care plus CTA at 12 centers across Scotland and were followed for 5 years.

Main outcome measures: The primary end point was a composite of death from coronary heart disease or nonfatal myocardial infarction. Main secondary end points were nonfatal myocardial infarction, nonfatal stroke, and frequency of invasive coronary angiography (ICA) and coronary revascularization with percutaneous coronary intervention or coronary artery bypass grafting.

Main results: The primary outcome including the composite of cardiovascular death or nonfatal myocardial infarction was lower in the CTA group than in the standard-care group at 2.3% (48 of 2073 patients) vs 3.9% (81 of 2073 patients), respectively (hazard ratio, 0.59; 95% CI, 0.41-0.84; P = .004). Although there was a higher rate of ICA and coronary revascularization in the CTA group than in the standard-care group in the first few months of follow-up, the overall rates were similar at 5 years, with ICA performed in 491 patients and 502 patients in the CTA vs standard-care groups, respectively (hazard ratio, 1.00; 95% CI, 0.88-1.13). Similarly, coronary revascularization was performed in 279 patients in the CTA group and in 267 patients in the standard-care group (hazard ratio, 1.07; 95% CI, 0.91-1.27). There were, however, more preventive therapies initiated in patients in the CTA group than in the standard-care group (odds ratio, 1.40; 95% CI, 1.19-1.65).

Conclusion: In patients with stable chest pain, the use of CTA in addition to standard care resulted in a significantly lower rate of death from coronary heart disease or nonfatal myocardial infarction at 5 years; the main contributor to this outcome was a reduced nonfatal myocardial infarction rate. There was no difference in the rate of coronary angiography or coronary revascularization between the 2 groups at 5 years.

Study 2 Overview (DISCHARGE Trial Group)

Objective: To compare the effectiveness of computed tomography (CT) with ICA as a diagnostic tool in patients with stable chest pain and intermediate pretest probability of coronary artery disease (CAD).

Design: Multicenter, randomized, assessor-blinded pragmatic prospective study.

Setting and participants: A total of 3667 patients with stable chest pain and intermediate pretest probability of CAD were enrolled at 26 centers and randomized into CT or ICA groups. Only 3561 patients were included in the modified intention-to-treat analysis, with 1808 patients and 1753 patients in the CT and ICA groups, respectively.

Main outcome measures: The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke over 3.5 years. The main secondary outcomes were major procedure-related complications and patient-reported angina pectoris during the last 4 weeks of follow up.

Main results: The primary outcome occurred in 38 of 1808 patients (2.1%) in the CT group and in 52 of 1753 patients (3.0%) in the ICA group (hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). The secondary outcomes showed that major procedure-related complications occurred in 9 patients (0.5%) in the CT group and in 33 patients (1.9%) in the ICA group (hazard ratio, 0.26; 95% CI, 0.13-0.55). Rates of patient-reported angina in the final 4 weeks of follow-up were 8.8% in the CT group and 7.5% in the ICA group (odds ratio, 1.17; 95% CI, 0.92-1.48).

Conclusion: Risk of major adverse cardiovascular events from the primary outcome were similar in both the CT and ICA groups among patients with stable chest pain and intermediate pretest probability of CAD. Patients referred for CT had a lower rate of coronary angiography leading to fewer major procedure-related complications in these patients than in those referred for ICA.

Evaluation and treatment of obstructive atherosclerosis is an important part of clinical care in patients presenting with angina symptoms.¹ Thus, the initial investigation for patients with suspected obstructive CAD includes ruling out acute coronary syndrome and assessing quality of life.¹ The diagnostic test should be tailored to the pretest probability for the diagnosis of obstructive CAD.²

In the United States, stress testing traditionally has been used for the initial assessment in patients with suspected CAD,³ but recently CTA has been utilized more frequently for this purpose. Compared to a stress test, which often helps identify and assess ischemia, CTA can provide anatomical assessment, with higher sensitivity to identify CAD.⁴ Furthermore, it can distinguish nonobstructive plaques that can be challenging to identify with stress test alone.

Whether CTA is superior to stress testing as the initial assessment for CAD has been debated. The randomized PROMISE trial compared patients with stable angina who underwent functional stress testing or CTA as an initial strategy.⁵ They reported a similar outcome between the 2 groups at a median follow-up of 2 years. However, in the original SCOT-HEART trial (CT coronary angiography in patients with suspected angina due to coronary heart disease), which was published in the same year as the PROMISE trial, the patients who underwent initial assessment with CTA had a numerically lower composite end point of cardiac death and myocardial infarction at a median follow-up of 1.7 years (1.3% vs 2.0%, P = .053).⁶

Given this result, the SCOT-HEART investigators extended the follow-up to evaluate the composite end point of death from coronary heart disease or nonfatal myocardial infarction at 5 years.⁷ This trial enrolled patients who were initially referred to a cardiology clinic for evaluation of chest pain, and they were randomized to standard care plus CTA or standard care alone. At a median duration of 4.8 years, the primary outcome was lower in the CTA group (2.3%, 48 patients) than in the standard-care group (3.9%, 81 patients) (hazard ratio, 0.58; 95% CI, 0.41-0.84; P = .004). Both groups had similar rates of invasive coronary angiography and had similar coronary revascularization rates.

It is hypothesized that this lower rate of nonfatal myocardial infarction in patients with CTA plus standard care is associated with a higher rate of preventive therapies initiated in patients in the CTA-plus-standard-care group compared to standard care alone. However, the difference in the standard-care group should be noted when compared to the PROMISE trial. In the PROMISE trial, the comparator group had predominantly stress imaging (either nuclear stress test or echocardiography), while in the SCOT-HEART trial, the group had predominantly stress electrocardiogram (ECG), and only 10% of the patients underwent stress imaging. It is possible the difference seen in the rate of nonfatal myocardial infarction was due to suboptimal diagnosis of CAD with stress ECG, which has lower sensitivity compared to stress imaging.

The DISCHARGE trial investigated the effectiveness of CTA vs ICA as the initial diagnostic test in the management of patients with stable chest pain and an intermediate pretest probability of obstructive CAD.⁸ At 3.5 years of follow-up, the primary composite of cardiovascular death, myocardial infarction, or stroke was similar in both groups (2.1% vs 3.0; hazard ratio, 0.70; 95% CI, 0.46-1.07; P = .10). Importantly, as fewer patients underwent ICA, the risk of procedure-related complication was lower in the CTA group than in the ICA group. However, it is important to note that only 25% of the patients diagnosed with obstructive CAD had greater than 50% vessel stenosis, which raises the question of whether an initial invasive strategy is appropriate for this population.

The strengths of these 2 studies include the large number of patients enrolled along with adequate follow-up, 5 years in the SCOT-HEART trial and 3.5 years in the DISCHARGE trial. The 2 studies overall suggest the usefulness of CTA for assessment of CAD. However, the control groups were very different in these 2 trials. In the SCOT-HEART study, the comparator group was primarily assessed by stress ECG, while in the DISCHARGE study, the comparator group was primary assessed by ICA. In the PROMISE trial, the composite end point of death, myocardial infarction, hospitalization for unstable angina, or major procedural complication was similar when the strategy of initial CTA was compared to functional testing with imaging (exercise ECG, nuclear stress testing, or echocardiography).⁵ Thus, clinical assessment is still needed when clinicians are selecting the appropriate diagnostic test for patients with suspected CAD. The most recent guidelines give similar recommendations for CTA compared to stress imaging.⁹ Whether further improvement in CTA acquisition or the addition of CT fractional flow reserve can further improve outcomes requires additional study.

Applications for Clinical Practice and System Implementation

In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful in diagnosis compared to stress ECG and in reducing utilization of low-yield ICA. Whether CTA is more useful compared to the other noninvasive stress imaging modalities in this population requires further study.

Practice Points

• In patients with stable chest pain and intermediate pretest probability of CAD, CTA is useful compared to stress ECG.
• Use of CTA can potentially reduce the use of low-yield coronary angiography.

–Thai Nguyen, MD, Albert Chan, MD, Taishi Hirai, MD
University of Missouri, Columbia, MO

Study 1 Overview (Bhasin et al)

Objective: To examine the effect of a multifactorial intervention for fall prevention on fall injury in community-dwelling older adults.

Design: This was a pragmatic, cluster randomized trial conducted in 86 primary care practices across 10 health care systems.

Setting and participants: The primary care sites were selected based on the prespecified criteria of size, ability to implement the intervention, proximity to other practices, accessibility to electronic health records, and access to community-based exercise programs. The primary care practices were randomly assigned to intervention or control.

Eligibility criteria for participants at those practices included age 70 years or older, dwelling in the community, and having an increased risk of falls, as determined by a history of fall-related injury in the past year, 2 or more falls in the past year, or being afraid of falling because of problems with balance or walking. Exclusion criteria were inability to provide consent or lack of proxy consent for participants who were determined to have cognitive impairment based on screening, and inability to speak English or Spanish. A total of 2802 participants were enrolled in the intervention group, and 2649 participants were enrolled in the control group.

Intervention: The intervention contained 5 components: a standardized assessment of 7 modifiable risk factors for fall injuries; standardized protocol-driven recommendations for management of risk factors; an individualized care plan focused on 1 to 3 risk factors; implementation of care plans, including referrals to community-based programs; and follow-up care conducted by telephone or in person. The modifiable risk factors included impairment of strength, gait, or balance; use of medications related to falls; postural hypotension; problems with feet or footwear; visual impairment; osteoporosis or vitamin D deficiency; and home safety hazards. The intervention was delivered by nurses who had completed online training modules and face-to-face training sessions focused on the intervention and motivational interviewing along with continuing education, in partnership with participants and their primary care providers. In the control group, participants received enhanced usual care, including an informational pamphlet, and were encouraged to discuss fall prevention with their primary care provider, including the results of their screening evaluation.

Main outcome measures: The primary outcome of the study was the first serious fall injury in a time-to-event analysis, defined as a fall resulting in a fracture (other than thoracic or lumbar vertebral fracture), joint dislocation, cut requiring closure, head injury requiring hospitalization, sprain or strain, bruising or swelling, or other serious injury. The secondary outcome was first patient-reported fall injury, also in a time-to-event analysis, ascertained by telephone interviews conducted every 4 months. Other outcomes included hospital admissions, emergency department visits, and other health care utilization. Adjudication of fall events and injuries was conducted by a team blinded to treatment assignment and verified using administrative claims data, encounter data, or electronic health record review.

Main results: The intervention and control groups were similar in terms of sex and age: 62.5% vs 61.5% of participants were women, and mean (SD) age was 79.9 (5.7) years and 79.5 (5.8) years, respectively. Other demographic characteristics were similar between groups. For the primary outcome, the rate of first serious injury was 4.9 per 100 person-years in the intervention group and 5.3 per 100 person-years in the control group, with a hazard ratio of 0.92 (95% CI, 0.80-1.06; P = .25). For the secondary outcome of patient-reported fall injury, there were 25.6 events per 100 person-years in the intervention group and 28.6 in the control group, with a hazard ratio of 0.90 (95% CI, 0.83-0.99; P =0.004). Rates of hospitalization and other secondary outcomes were similar between groups.

Conclusion: The multifactorial STRIDE intervention did not reduce the rate of serious fall injury when compared to enhanced usual care. The intervention did result in lower rates of fall injury by patient report, but no other significant outcomes were seen.

Study 2 Overview (Stark et al)

Objective: To examine the effect of a behavioral home hazard removal intervention for fall prevention on risk of fall in community-dwelling older adults.

Design: This randomized clinical trial was conducted at a single site in St. Louis, Missouri. Participants were community-dwelling older adults who received services from the Area Agency on Aging (AAA). Inclusion criteria included age 65 years and older, having 1 or more falls in the previous 12 months or being worried about falling by self report, and currently receiving services from an AAA. Exclusion criteria included living in an institution or being severely cognitively impaired and unable to follow directions or report falls. Participants who met the criteria were contacted by phone and invited to participate. A total of 310 participants were enrolled in the study, with an equal number of participants assigned to the intervention and control groups.

Intervention: The intervention included hazard identification and removal after a comprehensive assessment of participants, their behaviors, and the environment; this assessment took place during the first visit, which lasted approximately 80 minutes. A home hazard removal plan was developed, and in the second session, which lasted approximately 40 minutes, remediation of hazards was carried out. A third session for home modification that lasted approximately 30 minutes was conducted, if needed. At 6 months after the intervention, a booster session to identify and remediate any new home hazards and address issues was conducted. Specific interventions, as identified by the assessment, included minor home repair such as grab bars, adaptive equipment, task modification, and education. Shared decision making that enabled older adults to control changes in their homes, self-management strategies to improve awareness, and motivational enhancement strategies to improve acceptance were employed. Scripted algorithms and checklists were used to deliver the intervention. For usual care, an annual assessment and referrals to community services, if needed, were conducted in the AAA.

Main outcome measures: The primary outcome of the study was the number of days to first fall in 12 months. Falls were defined as unintentional movements to the floor, ground, or object below knee level, and falls were recorded through a daily journal for 12 months. Participants were contacted by phone if they did not return the journal or reported a fall. Participants were interviewed to verify falls and determine whether a fall was injurious. Secondary outcomes included rate of falls per person per 12 months; daily activity performance measured using the Older Americans Resources and Services Activities of Daily Living scale; falls self-efficacy, which measures confidence performing daily activities without falling; and quality of life using the SF-36 at 12 months.

Main results: Most of the study participants were women (74%), and mean (SD) age was 75 (7.4) years. Study retention was similar between the intervention and control groups, with 82% completing the study in the intervention group compared with 81% in the control group. Fidelity to the intervention, as measured by a checklist by the interventionist, was 99%, and adherence to home modification, as measured by number of home modifications in use by self report, was high at 92% at 6 months and 91% at 12 months. For the primary outcome, fall hazard was not different between the intervention and control groups (hazard ratio, 0.9; 95% CI, 0.66-1.27). For the secondary outcomes, the rate of falling was lower in the intervention group compared with the control group, with a relative risk of 0.62 (95% CI, 0.40-0.95). There was no difference in other secondary outcomes of daily activity performance, falls self-efficacy, or quality of life.

Conclusion: Despite high adherence to home modifications and fidelity to the intervention, this home hazard removal program did not reduce the risk of falling when compared to usual care. It did reduce the rate of falls, although no other effects were observed.

Commentary

Observational studies have identified factors that contribute to falls,¹ and over the past 30 years a number of intervention trials designed to reduce the risk of falling have been conducted. A recent Cochrane review, published prior to the Bhasin et al and Stark et al trials, looked at the effect of multifactorial interventions for fall prevention across 62 trials that included 19,935 older adults living in the community. The review concluded that multifactorial interventions may reduce the rate of falls, but this conclusion was based on low-quality evidence and there was significant heterogeneity across the studies.²

The STRIDE randomized trial represents the latest effort to address the evidence gap around fall prevention, with the STRIDE investigators hoping this would be the definitive trial that leads to practice change in fall prevention. Smaller trials that have demonstrated effectiveness were brought to scale in this large randomized trial that included 86 practices and more than 5000 participants. The investigators used risk of injurious falls as the primary outcome, as this outcome is considered the most clinically meaningful for the study population. The results, however, were disappointing: the multifactorial intervention in STRIDE did not result in a reduction of risk of injurious falls. Challenges in the implementation of this large trial may have contributed to its results; falls care managers, key to this multifactorial intervention, reported difficulties in navigating complex relationships with patients, families, study staff, and primary care practices during the study. Barriers reported included clinical space limitations, variable buy-in from providers, and turnover of practice staff and providers.³ Such implementation factors may have resulted in the divergent results between smaller clinical trials and this large-scale trial conducted across multiple settings.

The second study, by Stark et al, examined a home modification program and its effect on risk of falls. A prior Cochrane review examining the effect of home safety assessment and modification indicates that these strategies are effective in reducing the rate of falls as well as the risk of falling.⁴ The results of the current trial showed a reduction in the rate of falls but not in the risk of falling; however, this study did not examine outcomes of serious injurious falls, which may be more clinically meaningful. The Stark et al study adds to the existing literature showing that home modification may have an impact on fall rates. One noteworthy aspect of the Stark et al trial is the high adherence rate to home modification in a community-based approach; perhaps the investigators’ approach can be translated to real-world use.

Applications for Clinical Practice and System Implementation

The role of exercise programs in reducing fall rates is well established,⁵ but neither of these studies focused on exercise interventions. STRIDE offered community-based exercise program referral, but there is variability in such programs and study staff reported challenges in matching participants with appropriate exercise programs.³ Further studies that examine combinations of multifactorial falls risk reduction, exercise, and home safety, with careful consideration of implementation challenges to assure fidelity and adherence to the intervention, are needed to ascertain the best strategy for fall prevention for older adults at risk.

Given the results of these trials, it is difficult to recommend one falls prevention intervention over another. Clinicians should continue to identify falls risk factors using standardized assessments and determine which factors are modifiable.

Practice Points

• Incorporating assessments of falls risk in primary care is feasible, and such assessments can identify important risk factors.
• Clinicians and health systems should identify avenues, such as developing programmatic approaches, to providing home safety assessment and intervention, exercise options, medication review, and modification of other risk factors.
• Ensuring delivery of these elements reliably through programmatic approaches with adequate follow-up is key to preventing falls in this population.

—William W. Hung, MD, MPH

Study 1 Overview (Bhasin et al)

Objective: To examine the effect of a multifactorial intervention for fall prevention on fall injury in community-dwelling older adults.

Design: This was a pragmatic, cluster randomized trial conducted in 86 primary care practices across 10 health care systems.

Setting and participants: The primary care sites were selected based on the prespecified criteria of size, ability to implement the intervention, proximity to other practices, accessibility to electronic health records, and access to community-based exercise programs. The primary care practices were randomly assigned to intervention or control.

Eligibility criteria for participants at those practices included age 70 years or older, dwelling in the community, and having an increased risk of falls, as determined by a history of fall-related injury in the past year, 2 or more falls in the past year, or being afraid of falling because of problems with balance or walking. Exclusion criteria were inability to provide consent or lack of proxy consent for participants who were determined to have cognitive impairment based on screening, and inability to speak English or Spanish. A total of 2802 participants were enrolled in the intervention group, and 2649 participants were enrolled in the control group.

Intervention: The intervention contained 5 components: a standardized assessment of 7 modifiable risk factors for fall injuries; standardized protocol-driven recommendations for management of risk factors; an individualized care plan focused on 1 to 3 risk factors; implementation of care plans, including referrals to community-based programs; and follow-up care conducted by telephone or in person. The modifiable risk factors included impairment of strength, gait, or balance; use of medications related to falls; postural hypotension; problems with feet or footwear; visual impairment; osteoporosis or vitamin D deficiency; and home safety hazards. The intervention was delivered by nurses who had completed online training modules and face-to-face training sessions focused on the intervention and motivational interviewing along with continuing education, in partnership with participants and their primary care providers. In the control group, participants received enhanced usual care, including an informational pamphlet, and were encouraged to discuss fall prevention with their primary care provider, including the results of their screening evaluation.

Main outcome measures: The primary outcome of the study was the first serious fall injury in a time-to-event analysis, defined as a fall resulting in a fracture (other than thoracic or lumbar vertebral fracture), joint dislocation, cut requiring closure, head injury requiring hospitalization, sprain or strain, bruising or swelling, or other serious injury. The secondary outcome was first patient-reported fall injury, also in a time-to-event analysis, ascertained by telephone interviews conducted every 4 months. Other outcomes included hospital admissions, emergency department visits, and other health care utilization. Adjudication of fall events and injuries was conducted by a team blinded to treatment assignment and verified using administrative claims data, encounter data, or electronic health record review.

Main results: The intervention and control groups were similar in terms of sex and age: 62.5% vs 61.5% of participants were women, and mean (SD) age was 79.9 (5.7) years and 79.5 (5.8) years, respectively. Other demographic characteristics were similar between groups. For the primary outcome, the rate of first serious injury was 4.9 per 100 person-years in the intervention group and 5.3 per 100 person-years in the control group, with a hazard ratio of 0.92 (95% CI, 0.80-1.06; P = .25). For the secondary outcome of patient-reported fall injury, there were 25.6 events per 100 person-years in the intervention group and 28.6 in the control group, with a hazard ratio of 0.90 (95% CI, 0.83-0.99; P =0.004). Rates of hospitalization and other secondary outcomes were similar between groups.

Conclusion: The multifactorial STRIDE intervention did not reduce the rate of serious fall injury when compared to enhanced usual care. The intervention did result in lower rates of fall injury by patient report, but no other significant outcomes were seen.

Study 2 Overview (Stark et al)

Objective: To examine the effect of a behavioral home hazard removal intervention for fall prevention on risk of fall in community-dwelling older adults.

Design: This randomized clinical trial was conducted at a single site in St. Louis, Missouri. Participants were community-dwelling older adults who received services from the Area Agency on Aging (AAA). Inclusion criteria included age 65 years and older, having 1 or more falls in the previous 12 months or being worried about falling by self report, and currently receiving services from an AAA. Exclusion criteria included living in an institution or being severely cognitively impaired and unable to follow directions or report falls. Participants who met the criteria were contacted by phone and invited to participate. A total of 310 participants were enrolled in the study, with an equal number of participants assigned to the intervention and control groups.

Intervention: The intervention included hazard identification and removal after a comprehensive assessment of participants, their behaviors, and the environment; this assessment took place during the first visit, which lasted approximately 80 minutes. A home hazard removal plan was developed, and in the second session, which lasted approximately 40 minutes, remediation of hazards was carried out. A third session for home modification that lasted approximately 30 minutes was conducted, if needed. At 6 months after the intervention, a booster session to identify and remediate any new home hazards and address issues was conducted. Specific interventions, as identified by the assessment, included minor home repair such as grab bars, adaptive equipment, task modification, and education. Shared decision making that enabled older adults to control changes in their homes, self-management strategies to improve awareness, and motivational enhancement strategies to improve acceptance were employed. Scripted algorithms and checklists were used to deliver the intervention. For usual care, an annual assessment and referrals to community services, if needed, were conducted in the AAA.

Main outcome measures: The primary outcome of the study was the number of days to first fall in 12 months. Falls were defined as unintentional movements to the floor, ground, or object below knee level, and falls were recorded through a daily journal for 12 months. Participants were contacted by phone if they did not return the journal or reported a fall. Participants were interviewed to verify falls and determine whether a fall was injurious. Secondary outcomes included rate of falls per person per 12 months; daily activity performance measured using the Older Americans Resources and Services Activities of Daily Living scale; falls self-efficacy, which measures confidence performing daily activities without falling; and quality of life using the SF-36 at 12 months.

Main results: Most of the study participants were women (74%), and mean (SD) age was 75 (7.4) years. Study retention was similar between the intervention and control groups, with 82% completing the study in the intervention group compared with 81% in the control group. Fidelity to the intervention, as measured by a checklist by the interventionist, was 99%, and adherence to home modification, as measured by number of home modifications in use by self report, was high at 92% at 6 months and 91% at 12 months. For the primary outcome, fall hazard was not different between the intervention and control groups (hazard ratio, 0.9; 95% CI, 0.66-1.27). For the secondary outcomes, the rate of falling was lower in the intervention group compared with the control group, with a relative risk of 0.62 (95% CI, 0.40-0.95). There was no difference in other secondary outcomes of daily activity performance, falls self-efficacy, or quality of life.

Conclusion: Despite high adherence to home modifications and fidelity to the intervention, this home hazard removal program did not reduce the risk of falling when compared to usual care. It did reduce the rate of falls, although no other effects were observed.

Commentary

Observational studies have identified factors that contribute to falls,¹ and over the past 30 years a number of intervention trials designed to reduce the risk of falling have been conducted. A recent Cochrane review, published prior to the Bhasin et al and Stark et al trials, looked at the effect of multifactorial interventions for fall prevention across 62 trials that included 19,935 older adults living in the community. The review concluded that multifactorial interventions may reduce the rate of falls, but this conclusion was based on low-quality evidence and there was significant heterogeneity across the studies.²

The STRIDE randomized trial represents the latest effort to address the evidence gap around fall prevention, with the STRIDE investigators hoping this would be the definitive trial that leads to practice change in fall prevention. Smaller trials that have demonstrated effectiveness were brought to scale in this large randomized trial that included 86 practices and more than 5000 participants. The investigators used risk of injurious falls as the primary outcome, as this outcome is considered the most clinically meaningful for the study population. The results, however, were disappointing: the multifactorial intervention in STRIDE did not result in a reduction of risk of injurious falls. Challenges in the implementation of this large trial may have contributed to its results; falls care managers, key to this multifactorial intervention, reported difficulties in navigating complex relationships with patients, families, study staff, and primary care practices during the study. Barriers reported included clinical space limitations, variable buy-in from providers, and turnover of practice staff and providers.³ Such implementation factors may have resulted in the divergent results between smaller clinical trials and this large-scale trial conducted across multiple settings.

The second study, by Stark et al, examined a home modification program and its effect on risk of falls. A prior Cochrane review examining the effect of home safety assessment and modification indicates that these strategies are effective in reducing the rate of falls as well as the risk of falling.⁴ The results of the current trial showed a reduction in the rate of falls but not in the risk of falling; however, this study did not examine outcomes of serious injurious falls, which may be more clinically meaningful. The Stark et al study adds to the existing literature showing that home modification may have an impact on fall rates. One noteworthy aspect of the Stark et al trial is the high adherence rate to home modification in a community-based approach; perhaps the investigators’ approach can be translated to real-world use.

Applications for Clinical Practice and System Implementation

The role of exercise programs in reducing fall rates is well established,⁵ but neither of these studies focused on exercise interventions. STRIDE offered community-based exercise program referral, but there is variability in such programs and study staff reported challenges in matching participants with appropriate exercise programs.³ Further studies that examine combinations of multifactorial falls risk reduction, exercise, and home safety, with careful consideration of implementation challenges to assure fidelity and adherence to the intervention, are needed to ascertain the best strategy for fall prevention for older adults at risk.

Given the results of these trials, it is difficult to recommend one falls prevention intervention over another. Clinicians should continue to identify falls risk factors using standardized assessments and determine which factors are modifiable.

Practice Points

• Incorporating assessments of falls risk in primary care is feasible, and such assessments can identify important risk factors.
• Clinicians and health systems should identify avenues, such as developing programmatic approaches, to providing home safety assessment and intervention, exercise options, medication review, and modification of other risk factors.
• Ensuring delivery of these elements reliably through programmatic approaches with adequate follow-up is key to preventing falls in this population.

—William W. Hung, MD, MPH

Study 1 Overview (Bhasin et al)

Objective: To examine the effect of a multifactorial intervention for fall prevention on fall injury in community-dwelling older adults.

Design: This was a pragmatic, cluster randomized trial conducted in 86 primary care practices across 10 health care systems.

Setting and participants: The primary care sites were selected based on the prespecified criteria of size, ability to implement the intervention, proximity to other practices, accessibility to electronic health records, and access to community-based exercise programs. The primary care practices were randomly assigned to intervention or control.

Eligibility criteria for participants at those practices included age 70 years or older, dwelling in the community, and having an increased risk of falls, as determined by a history of fall-related injury in the past year, 2 or more falls in the past year, or being afraid of falling because of problems with balance or walking. Exclusion criteria were inability to provide consent or lack of proxy consent for participants who were determined to have cognitive impairment based on screening, and inability to speak English or Spanish. A total of 2802 participants were enrolled in the intervention group, and 2649 participants were enrolled in the control group.

Intervention: The intervention contained 5 components: a standardized assessment of 7 modifiable risk factors for fall injuries; standardized protocol-driven recommendations for management of risk factors; an individualized care plan focused on 1 to 3 risk factors; implementation of care plans, including referrals to community-based programs; and follow-up care conducted by telephone or in person. The modifiable risk factors included impairment of strength, gait, or balance; use of medications related to falls; postural hypotension; problems with feet or footwear; visual impairment; osteoporosis or vitamin D deficiency; and home safety hazards. The intervention was delivered by nurses who had completed online training modules and face-to-face training sessions focused on the intervention and motivational interviewing along with continuing education, in partnership with participants and their primary care providers. In the control group, participants received enhanced usual care, including an informational pamphlet, and were encouraged to discuss fall prevention with their primary care provider, including the results of their screening evaluation.

Main outcome measures: The primary outcome of the study was the first serious fall injury in a time-to-event analysis, defined as a fall resulting in a fracture (other than thoracic or lumbar vertebral fracture), joint dislocation, cut requiring closure, head injury requiring hospitalization, sprain or strain, bruising or swelling, or other serious injury. The secondary outcome was first patient-reported fall injury, also in a time-to-event analysis, ascertained by telephone interviews conducted every 4 months. Other outcomes included hospital admissions, emergency department visits, and other health care utilization. Adjudication of fall events and injuries was conducted by a team blinded to treatment assignment and verified using administrative claims data, encounter data, or electronic health record review.

Main results: The intervention and control groups were similar in terms of sex and age: 62.5% vs 61.5% of participants were women, and mean (SD) age was 79.9 (5.7) years and 79.5 (5.8) years, respectively. Other demographic characteristics were similar between groups. For the primary outcome, the rate of first serious injury was 4.9 per 100 person-years in the intervention group and 5.3 per 100 person-years in the control group, with a hazard ratio of 0.92 (95% CI, 0.80-1.06; P = .25). For the secondary outcome of patient-reported fall injury, there were 25.6 events per 100 person-years in the intervention group and 28.6 in the control group, with a hazard ratio of 0.90 (95% CI, 0.83-0.99; P =0.004). Rates of hospitalization and other secondary outcomes were similar between groups.

Conclusion: The multifactorial STRIDE intervention did not reduce the rate of serious fall injury when compared to enhanced usual care. The intervention did result in lower rates of fall injury by patient report, but no other significant outcomes were seen.

Study 2 Overview (Stark et al)

Objective: To examine the effect of a behavioral home hazard removal intervention for fall prevention on risk of fall in community-dwelling older adults.

Design: This randomized clinical trial was conducted at a single site in St. Louis, Missouri. Participants were community-dwelling older adults who received services from the Area Agency on Aging (AAA). Inclusion criteria included age 65 years and older, having 1 or more falls in the previous 12 months or being worried about falling by self report, and currently receiving services from an AAA. Exclusion criteria included living in an institution or being severely cognitively impaired and unable to follow directions or report falls. Participants who met the criteria were contacted by phone and invited to participate. A total of 310 participants were enrolled in the study, with an equal number of participants assigned to the intervention and control groups.

Intervention: The intervention included hazard identification and removal after a comprehensive assessment of participants, their behaviors, and the environment; this assessment took place during the first visit, which lasted approximately 80 minutes. A home hazard removal plan was developed, and in the second session, which lasted approximately 40 minutes, remediation of hazards was carried out. A third session for home modification that lasted approximately 30 minutes was conducted, if needed. At 6 months after the intervention, a booster session to identify and remediate any new home hazards and address issues was conducted. Specific interventions, as identified by the assessment, included minor home repair such as grab bars, adaptive equipment, task modification, and education. Shared decision making that enabled older adults to control changes in their homes, self-management strategies to improve awareness, and motivational enhancement strategies to improve acceptance were employed. Scripted algorithms and checklists were used to deliver the intervention. For usual care, an annual assessment and referrals to community services, if needed, were conducted in the AAA.

Main outcome measures: The primary outcome of the study was the number of days to first fall in 12 months. Falls were defined as unintentional movements to the floor, ground, or object below knee level, and falls were recorded through a daily journal for 12 months. Participants were contacted by phone if they did not return the journal or reported a fall. Participants were interviewed to verify falls and determine whether a fall was injurious. Secondary outcomes included rate of falls per person per 12 months; daily activity performance measured using the Older Americans Resources and Services Activities of Daily Living scale; falls self-efficacy, which measures confidence performing daily activities without falling; and quality of life using the SF-36 at 12 months.

Main results: Most of the study participants were women (74%), and mean (SD) age was 75 (7.4) years. Study retention was similar between the intervention and control groups, with 82% completing the study in the intervention group compared with 81% in the control group. Fidelity to the intervention, as measured by a checklist by the interventionist, was 99%, and adherence to home modification, as measured by number of home modifications in use by self report, was high at 92% at 6 months and 91% at 12 months. For the primary outcome, fall hazard was not different between the intervention and control groups (hazard ratio, 0.9; 95% CI, 0.66-1.27). For the secondary outcomes, the rate of falling was lower in the intervention group compared with the control group, with a relative risk of 0.62 (95% CI, 0.40-0.95). There was no difference in other secondary outcomes of daily activity performance, falls self-efficacy, or quality of life.

Conclusion: Despite high adherence to home modifications and fidelity to the intervention, this home hazard removal program did not reduce the risk of falling when compared to usual care. It did reduce the rate of falls, although no other effects were observed.

Commentary

Observational studies have identified factors that contribute to falls,¹ and over the past 30 years a number of intervention trials designed to reduce the risk of falling have been conducted. A recent Cochrane review, published prior to the Bhasin et al and Stark et al trials, looked at the effect of multifactorial interventions for fall prevention across 62 trials that included 19,935 older adults living in the community. The review concluded that multifactorial interventions may reduce the rate of falls, but this conclusion was based on low-quality evidence and there was significant heterogeneity across the studies.²

The STRIDE randomized trial represents the latest effort to address the evidence gap around fall prevention, with the STRIDE investigators hoping this would be the definitive trial that leads to practice change in fall prevention. Smaller trials that have demonstrated effectiveness were brought to scale in this large randomized trial that included 86 practices and more than 5000 participants. The investigators used risk of injurious falls as the primary outcome, as this outcome is considered the most clinically meaningful for the study population. The results, however, were disappointing: the multifactorial intervention in STRIDE did not result in a reduction of risk of injurious falls. Challenges in the implementation of this large trial may have contributed to its results; falls care managers, key to this multifactorial intervention, reported difficulties in navigating complex relationships with patients, families, study staff, and primary care practices during the study. Barriers reported included clinical space limitations, variable buy-in from providers, and turnover of practice staff and providers.³ Such implementation factors may have resulted in the divergent results between smaller clinical trials and this large-scale trial conducted across multiple settings.

The second study, by Stark et al, examined a home modification program and its effect on risk of falls. A prior Cochrane review examining the effect of home safety assessment and modification indicates that these strategies are effective in reducing the rate of falls as well as the risk of falling.⁴ The results of the current trial showed a reduction in the rate of falls but not in the risk of falling; however, this study did not examine outcomes of serious injurious falls, which may be more clinically meaningful. The Stark et al study adds to the existing literature showing that home modification may have an impact on fall rates. One noteworthy aspect of the Stark et al trial is the high adherence rate to home modification in a community-based approach; perhaps the investigators’ approach can be translated to real-world use.

Applications for Clinical Practice and System Implementation

The role of exercise programs in reducing fall rates is well established,⁵ but neither of these studies focused on exercise interventions. STRIDE offered community-based exercise program referral, but there is variability in such programs and study staff reported challenges in matching participants with appropriate exercise programs.³ Further studies that examine combinations of multifactorial falls risk reduction, exercise, and home safety, with careful consideration of implementation challenges to assure fidelity and adherence to the intervention, are needed to ascertain the best strategy for fall prevention for older adults at risk.

Given the results of these trials, it is difficult to recommend one falls prevention intervention over another. Clinicians should continue to identify falls risk factors using standardized assessments and determine which factors are modifiable.

Practice Points

• Incorporating assessments of falls risk in primary care is feasible, and such assessments can identify important risk factors.
• Clinicians and health systems should identify avenues, such as developing programmatic approaches, to providing home safety assessment and intervention, exercise options, medication review, and modification of other risk factors.
• Ensuring delivery of these elements reliably through programmatic approaches with adequate follow-up is key to preventing falls in this population.

—William W. Hung, MD, MPH

SAN DIEGO – Patients with acute cholangitis are twice as likely to be readmitted within 30 days if they don’t get a cholecystectomy in the same hospital admission for which they get biliary decompression, researchers say.

The readmissions result mostly from sepsis and recurrence of the acute cholangitis, said Ahmad Khan, MD, MS, a gastroenterology fellow at Case Western Reserve University in Cleveland, at Digestive Diseases Week^® (DDW) 2022. “These added readmissions can cause a significant burden in terms of costs and extra days of hospitalization in these patients.”

Acute cholangitis in patients without bile duct stents is most often caused by biliary calculi, benign biliary stricture, or malignancy. A gastrointestinal emergency, it requires treatment with biliary decompression followed by cholecystectomy, but the cholecystectomy is considered an elective procedure.

Surgeons may delay it if the patient is very sick, or simply for scheduling reasons, Dr. Khan said. “There are some areas where the surgeons may be too busy,” he said. Or if the patient first presents at the end of the week, some surgeons will send the patient home so they don’t have to operate on the weekend, he said.

To understand the consequences of these decisions, Dr. Khan and his colleagues analyzed data from 2016 to 2018 from the National Readmission Database of the U.S. Agency for Healthcare Research and Quality.

They found that 11% of patients who went home before returning for a cholecystectomy had to be readmitted versus only 5.5% of those who got a cholecystectomy during the same (index) admission as their biliary decompression.

Patients who got cholecystectomies during their index admissions were slightly younger and healthier: Their mean age was 67.29 years and 20.59% had three or more comorbidities at index admission versus 70.77 years of age and 39.80% with three or more comorbidities at index admission for those who got their cholecystectomies later.

The researchers did not find any significant differences in the hospitals’ characteristics, such as being urban or academic, between the two groups.

Mortality was higher for those who received their cholecystectomy after returning home, but they spent less time in the hospital at lower total cost. The differences in outcomes between the index admission and readmission were all statistically significant (P < .01).

This observational study could not determine cause and effect, but it justifies a prospective trial that could more definitely determine which approach results in better outcomes, Dr. Khan said.

That patients are less likely to need readmission if they return home without a gall bladder after treatment for acute cholangitis “makes sense,” said session comoderator Richard Sterling, MD, MSc, chief of hepatology at Virginia Commonwealth University in Richmond.

“Should you do it immediately or can you wait a day or 2? They didn’t really address when during that admission, so we still don’t know the optimal sequence of events.”

If a patient has so many comorbidities that the surgeon and anesthesiologist don’t think the patient could survive a cholecystectomy, then the surgeon might do a cholecystostomy instead, he said.

Dr. Khan said he hopes to delve deeper into the data to determine what factors might have influenced the surgeons’ decisions to delay the cholecystectomy. “I want to see, of the patients who did not get same-admission cholecystectomies, how many had diabetes, how many had coronary artery disease, how many were on blood thinners, and things like that.”

Neither Dr. Khan nor Dr. Sterling reported any relevant financial interests.

SAN DIEGO – Patients with acute cholangitis are twice as likely to be readmitted within 30 days if they don’t get a cholecystectomy in the same hospital admission for which they get biliary decompression, researchers say.

The readmissions result mostly from sepsis and recurrence of the acute cholangitis, said Ahmad Khan, MD, MS, a gastroenterology fellow at Case Western Reserve University in Cleveland, at Digestive Diseases Week^® (DDW) 2022. “These added readmissions can cause a significant burden in terms of costs and extra days of hospitalization in these patients.”

Acute cholangitis in patients without bile duct stents is most often caused by biliary calculi, benign biliary stricture, or malignancy. A gastrointestinal emergency, it requires treatment with biliary decompression followed by cholecystectomy, but the cholecystectomy is considered an elective procedure.

Surgeons may delay it if the patient is very sick, or simply for scheduling reasons, Dr. Khan said. “There are some areas where the surgeons may be too busy,” he said. Or if the patient first presents at the end of the week, some surgeons will send the patient home so they don’t have to operate on the weekend, he said.

To understand the consequences of these decisions, Dr. Khan and his colleagues analyzed data from 2016 to 2018 from the National Readmission Database of the U.S. Agency for Healthcare Research and Quality.

They found that 11% of patients who went home before returning for a cholecystectomy had to be readmitted versus only 5.5% of those who got a cholecystectomy during the same (index) admission as their biliary decompression.

Patients who got cholecystectomies during their index admissions were slightly younger and healthier: Their mean age was 67.29 years and 20.59% had three or more comorbidities at index admission versus 70.77 years of age and 39.80% with three or more comorbidities at index admission for those who got their cholecystectomies later.

The researchers did not find any significant differences in the hospitals’ characteristics, such as being urban or academic, between the two groups.

Mortality was higher for those who received their cholecystectomy after returning home, but they spent less time in the hospital at lower total cost. The differences in outcomes between the index admission and readmission were all statistically significant (P < .01).

This observational study could not determine cause and effect, but it justifies a prospective trial that could more definitely determine which approach results in better outcomes, Dr. Khan said.

That patients are less likely to need readmission if they return home without a gall bladder after treatment for acute cholangitis “makes sense,” said session comoderator Richard Sterling, MD, MSc, chief of hepatology at Virginia Commonwealth University in Richmond.

“Should you do it immediately or can you wait a day or 2? They didn’t really address when during that admission, so we still don’t know the optimal sequence of events.”

If a patient has so many comorbidities that the surgeon and anesthesiologist don’t think the patient could survive a cholecystectomy, then the surgeon might do a cholecystostomy instead, he said.

Dr. Khan said he hopes to delve deeper into the data to determine what factors might have influenced the surgeons’ decisions to delay the cholecystectomy. “I want to see, of the patients who did not get same-admission cholecystectomies, how many had diabetes, how many had coronary artery disease, how many were on blood thinners, and things like that.”

Neither Dr. Khan nor Dr. Sterling reported any relevant financial interests.

SAN DIEGO – Patients with acute cholangitis are twice as likely to be readmitted within 30 days if they don’t get a cholecystectomy in the same hospital admission for which they get biliary decompression, researchers say.

The readmissions result mostly from sepsis and recurrence of the acute cholangitis, said Ahmad Khan, MD, MS, a gastroenterology fellow at Case Western Reserve University in Cleveland, at Digestive Diseases Week^® (DDW) 2022. “These added readmissions can cause a significant burden in terms of costs and extra days of hospitalization in these patients.”

Acute cholangitis in patients without bile duct stents is most often caused by biliary calculi, benign biliary stricture, or malignancy. A gastrointestinal emergency, it requires treatment with biliary decompression followed by cholecystectomy, but the cholecystectomy is considered an elective procedure.

Surgeons may delay it if the patient is very sick, or simply for scheduling reasons, Dr. Khan said. “There are some areas where the surgeons may be too busy,” he said. Or if the patient first presents at the end of the week, some surgeons will send the patient home so they don’t have to operate on the weekend, he said.

To understand the consequences of these decisions, Dr. Khan and his colleagues analyzed data from 2016 to 2018 from the National Readmission Database of the U.S. Agency for Healthcare Research and Quality.

They found that 11% of patients who went home before returning for a cholecystectomy had to be readmitted versus only 5.5% of those who got a cholecystectomy during the same (index) admission as their biliary decompression.

Patients who got cholecystectomies during their index admissions were slightly younger and healthier: Their mean age was 67.29 years and 20.59% had three or more comorbidities at index admission versus 70.77 years of age and 39.80% with three or more comorbidities at index admission for those who got their cholecystectomies later.

The researchers did not find any significant differences in the hospitals’ characteristics, such as being urban or academic, between the two groups.

Mortality was higher for those who received their cholecystectomy after returning home, but they spent less time in the hospital at lower total cost. The differences in outcomes between the index admission and readmission were all statistically significant (P < .01).

This observational study could not determine cause and effect, but it justifies a prospective trial that could more definitely determine which approach results in better outcomes, Dr. Khan said.

That patients are less likely to need readmission if they return home without a gall bladder after treatment for acute cholangitis “makes sense,” said session comoderator Richard Sterling, MD, MSc, chief of hepatology at Virginia Commonwealth University in Richmond.

“Should you do it immediately or can you wait a day or 2? They didn’t really address when during that admission, so we still don’t know the optimal sequence of events.”

If a patient has so many comorbidities that the surgeon and anesthesiologist don’t think the patient could survive a cholecystectomy, then the surgeon might do a cholecystostomy instead, he said.

Dr. Khan said he hopes to delve deeper into the data to determine what factors might have influenced the surgeons’ decisions to delay the cholecystectomy. “I want to see, of the patients who did not get same-admission cholecystectomies, how many had diabetes, how many had coronary artery disease, how many were on blood thinners, and things like that.”

Neither Dr. Khan nor Dr. Sterling reported any relevant financial interests.

Sparring among professional mixed martial arts (MMA) practitioners may have both positive and negative effects on the brain, early research suggests.

Investigators found sparring, defined as strategically hitting opponents with kicks, punches, and other strikes during practice sessions, is linked to increased white matter hyperintensities in the brain, pointing to possible vascular damage from repeated head trauma. However, the study results also show sparring was associated with a larger bilateral caudate which, in theory, is neuroprotective.

“From our preliminary study, sparring practice in MMA fighters may have a ‘double-edged sword’ effect on the brain,” study investigator Aaron Esagoff, a second-year medical student at Johns Hopkins University School of Medicine, Baltimore, told this news organization.

Growing popularity

MMA is a full-contact combat sport that has become increasingly popular over the past 15 years. It combines techniques from boxing, wrestling, karate, judo, and jujitsu.

To prepare for fights, MMA practitioners incorporate sparring and grappling, which use techniques such as chokes and locks to submit an opponent. Head protection is sometimes incorporated during practice, but is not the norm during a fight, said Mr. Esagoff.

The study investigated sparring during practice rather than fights because, he said, MMA competitors only fight a few times a year but spend hundreds of hours training. “So the health effects of training are going to be really important,” he said.

As with other combat sports, MMA involves hits to the head. Previous research has shown repetitive head trauma can lead to neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease, Mr. Esagoff noted.

Previous studies have also linked more professional fights and years of fighting to a decrease in brain volume among MMA fighters, he added.

The new analysis was conducted as part of the Professional Fighters Brain Health Study, a longitudinal cohort study of MMA professional fighters. It included 92 fighters with data available on MRI and habits regarding practicing. The mean age of the participants was 30 years, 62% were White, and 85% were men.

The study examined sparring but did not include grappling because of “several challenges” with the current data analysis, Mr. Esagoff said. Researchers adjusted for age, sex, education, race, number of fights, total intracranial volume, and type of MRI scanner used.
 

A ‘highly strategic’ sport

Results showed a strong association between the number of sparring rounds per week and increased white matter hyperintensity volume (mcL) on MRI (P = .039).

This suggests white matter damage, possibly a result of direct neuronal injury, vascular damage, or immune modulation, said Mr. Esagoff. However, another mechanism may be involved, he added.

There was also a significant association between sparring and increased size of the caudate nucleus, an area of the brain involved in movement, learning, and memory (P = .014 for right caudate volume, P = .012 for left caudate volume).

There are some theories that might explain this finding, said Mr. Esagoff. For example, individuals who spar more may get better at avoiding impacts and injuries during a fight, which might in turn affect the size of the caudate.

The controlled movements and techniques used during sparring could also affect the caudate. “Some research has shown that behavior, learning, and/or exercise may increase the size of certain brain regions,” Mr. Esagoff said.

He noted the “highly strategic” nature of combat sports – and used the example of Brazilian jiu-jitsu. That sport “is known as human chess because it takes a thoughtful approach to defeat a larger opponent with base, leverage, and technique,” he said.

However, Mr. Esagoff stressed that while it is possible movements involved in MMA increase caudate size, this is just a theory at this point.

A study limitation was that fighters volunteered to participate and may not represent all fighters. As well, the study was cross-sectional and looked at only one point in time, so it cannot infer causation.

Overall, the new findings should help inform fighters, governing bodies, and the public about the potential risks and benefits of different styles of MMA fighting and practice, although more research is needed, said Mr. Esagoff.

He and his team now plan to conduct a longer-term study and investigate effects of grappling on brain structure and function in addition to sparring.
 

Jury still out

Commenting on the study, Howard Liu, MD, chair of the University of Nebraska Medical Center department of psychiatry and incoming chair of the APA’s Council on Communications, said the jury “is clearly still out” when it comes to the investigation of brain impacts.

“We don’t know quite what these changes fully correlate to,” said Dr. Liu, who moderated a press briefing highlighting the study.

He underlined the importance of protecting athletes vulnerable to head trauma, be they professionals or those involved at the youth sports level.

Dr. Liu also noted the “extreme popularity” and rapid growth of MMA around the world, which he said provides an opportunity for researchers to study these professional fighters.

“This is a unique population that signed up in the midst of hundreds of hours of sparring to advance neuroscience, and that’s quite amazing,” he said.

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

Sparring among professional mixed martial arts (MMA) practitioners may have both positive and negative effects on the brain, early research suggests.

Investigators found sparring, defined as strategically hitting opponents with kicks, punches, and other strikes during practice sessions, is linked to increased white matter hyperintensities in the brain, pointing to possible vascular damage from repeated head trauma. However, the study results also show sparring was associated with a larger bilateral caudate which, in theory, is neuroprotective.

“From our preliminary study, sparring practice in MMA fighters may have a ‘double-edged sword’ effect on the brain,” study investigator Aaron Esagoff, a second-year medical student at Johns Hopkins University School of Medicine, Baltimore, told this news organization.

Growing popularity

MMA is a full-contact combat sport that has become increasingly popular over the past 15 years. It combines techniques from boxing, wrestling, karate, judo, and jujitsu.

To prepare for fights, MMA practitioners incorporate sparring and grappling, which use techniques such as chokes and locks to submit an opponent. Head protection is sometimes incorporated during practice, but is not the norm during a fight, said Mr. Esagoff.

The study investigated sparring during practice rather than fights because, he said, MMA competitors only fight a few times a year but spend hundreds of hours training. “So the health effects of training are going to be really important,” he said.

As with other combat sports, MMA involves hits to the head. Previous research has shown repetitive head trauma can lead to neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease, Mr. Esagoff noted.

Previous studies have also linked more professional fights and years of fighting to a decrease in brain volume among MMA fighters, he added.

The new analysis was conducted as part of the Professional Fighters Brain Health Study, a longitudinal cohort study of MMA professional fighters. It included 92 fighters with data available on MRI and habits regarding practicing. The mean age of the participants was 30 years, 62% were White, and 85% were men.

The study examined sparring but did not include grappling because of “several challenges” with the current data analysis, Mr. Esagoff said. Researchers adjusted for age, sex, education, race, number of fights, total intracranial volume, and type of MRI scanner used.
 

A ‘highly strategic’ sport

Results showed a strong association between the number of sparring rounds per week and increased white matter hyperintensity volume (mcL) on MRI (P = .039).

This suggests white matter damage, possibly a result of direct neuronal injury, vascular damage, or immune modulation, said Mr. Esagoff. However, another mechanism may be involved, he added.

There was also a significant association between sparring and increased size of the caudate nucleus, an area of the brain involved in movement, learning, and memory (P = .014 for right caudate volume, P = .012 for left caudate volume).

There are some theories that might explain this finding, said Mr. Esagoff. For example, individuals who spar more may get better at avoiding impacts and injuries during a fight, which might in turn affect the size of the caudate.

The controlled movements and techniques used during sparring could also affect the caudate. “Some research has shown that behavior, learning, and/or exercise may increase the size of certain brain regions,” Mr. Esagoff said.

He noted the “highly strategic” nature of combat sports – and used the example of Brazilian jiu-jitsu. That sport “is known as human chess because it takes a thoughtful approach to defeat a larger opponent with base, leverage, and technique,” he said.

However, Mr. Esagoff stressed that while it is possible movements involved in MMA increase caudate size, this is just a theory at this point.

A study limitation was that fighters volunteered to participate and may not represent all fighters. As well, the study was cross-sectional and looked at only one point in time, so it cannot infer causation.

Overall, the new findings should help inform fighters, governing bodies, and the public about the potential risks and benefits of different styles of MMA fighting and practice, although more research is needed, said Mr. Esagoff.

He and his team now plan to conduct a longer-term study and investigate effects of grappling on brain structure and function in addition to sparring.
 

Jury still out

Commenting on the study, Howard Liu, MD, chair of the University of Nebraska Medical Center department of psychiatry and incoming chair of the APA’s Council on Communications, said the jury “is clearly still out” when it comes to the investigation of brain impacts.

“We don’t know quite what these changes fully correlate to,” said Dr. Liu, who moderated a press briefing highlighting the study.

He underlined the importance of protecting athletes vulnerable to head trauma, be they professionals or those involved at the youth sports level.

Dr. Liu also noted the “extreme popularity” and rapid growth of MMA around the world, which he said provides an opportunity for researchers to study these professional fighters.

“This is a unique population that signed up in the midst of hundreds of hours of sparring to advance neuroscience, and that’s quite amazing,” he said.

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

Sparring among professional mixed martial arts (MMA) practitioners may have both positive and negative effects on the brain, early research suggests.

Investigators found sparring, defined as strategically hitting opponents with kicks, punches, and other strikes during practice sessions, is linked to increased white matter hyperintensities in the brain, pointing to possible vascular damage from repeated head trauma. However, the study results also show sparring was associated with a larger bilateral caudate which, in theory, is neuroprotective.

“From our preliminary study, sparring practice in MMA fighters may have a ‘double-edged sword’ effect on the brain,” study investigator Aaron Esagoff, a second-year medical student at Johns Hopkins University School of Medicine, Baltimore, told this news organization.

Growing popularity

MMA is a full-contact combat sport that has become increasingly popular over the past 15 years. It combines techniques from boxing, wrestling, karate, judo, and jujitsu.

To prepare for fights, MMA practitioners incorporate sparring and grappling, which use techniques such as chokes and locks to submit an opponent. Head protection is sometimes incorporated during practice, but is not the norm during a fight, said Mr. Esagoff.

The study investigated sparring during practice rather than fights because, he said, MMA competitors only fight a few times a year but spend hundreds of hours training. “So the health effects of training are going to be really important,” he said.

As with other combat sports, MMA involves hits to the head. Previous research has shown repetitive head trauma can lead to neurodegenerative diseases, including chronic traumatic encephalopathy (CTE) and Alzheimer’s disease, Mr. Esagoff noted.

Previous studies have also linked more professional fights and years of fighting to a decrease in brain volume among MMA fighters, he added.

The new analysis was conducted as part of the Professional Fighters Brain Health Study, a longitudinal cohort study of MMA professional fighters. It included 92 fighters with data available on MRI and habits regarding practicing. The mean age of the participants was 30 years, 62% were White, and 85% were men.

The study examined sparring but did not include grappling because of “several challenges” with the current data analysis, Mr. Esagoff said. Researchers adjusted for age, sex, education, race, number of fights, total intracranial volume, and type of MRI scanner used.
 

A ‘highly strategic’ sport

Results showed a strong association between the number of sparring rounds per week and increased white matter hyperintensity volume (mcL) on MRI (P = .039).

This suggests white matter damage, possibly a result of direct neuronal injury, vascular damage, or immune modulation, said Mr. Esagoff. However, another mechanism may be involved, he added.

There was also a significant association between sparring and increased size of the caudate nucleus, an area of the brain involved in movement, learning, and memory (P = .014 for right caudate volume, P = .012 for left caudate volume).

There are some theories that might explain this finding, said Mr. Esagoff. For example, individuals who spar more may get better at avoiding impacts and injuries during a fight, which might in turn affect the size of the caudate.

The controlled movements and techniques used during sparring could also affect the caudate. “Some research has shown that behavior, learning, and/or exercise may increase the size of certain brain regions,” Mr. Esagoff said.

He noted the “highly strategic” nature of combat sports – and used the example of Brazilian jiu-jitsu. That sport “is known as human chess because it takes a thoughtful approach to defeat a larger opponent with base, leverage, and technique,” he said.

However, Mr. Esagoff stressed that while it is possible movements involved in MMA increase caudate size, this is just a theory at this point.

A study limitation was that fighters volunteered to participate and may not represent all fighters. As well, the study was cross-sectional and looked at only one point in time, so it cannot infer causation.

Overall, the new findings should help inform fighters, governing bodies, and the public about the potential risks and benefits of different styles of MMA fighting and practice, although more research is needed, said Mr. Esagoff.

He and his team now plan to conduct a longer-term study and investigate effects of grappling on brain structure and function in addition to sparring.
 

Jury still out

Commenting on the study, Howard Liu, MD, chair of the University of Nebraska Medical Center department of psychiatry and incoming chair of the APA’s Council on Communications, said the jury “is clearly still out” when it comes to the investigation of brain impacts.

“We don’t know quite what these changes fully correlate to,” said Dr. Liu, who moderated a press briefing highlighting the study.

He underlined the importance of protecting athletes vulnerable to head trauma, be they professionals or those involved at the youth sports level.

Dr. Liu also noted the “extreme popularity” and rapid growth of MMA around the world, which he said provides an opportunity for researchers to study these professional fighters.

“This is a unique population that signed up in the midst of hundreds of hours of sparring to advance neuroscience, and that’s quite amazing,” he said.

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

The U.S. Food and Drug Administration is easing rules to allow infant formula imports from the United Kingdom, which would bring about 2 million cans to the U.S. in coming weeks.

Kendal Nutricare will be able to offer certain infant formula products under the Kendamil brand to ease the nationwide formula shortage.

“Importantly, we anticipate additional infant formula products may be safely and quickly imported in the U.S. in the near-term, based on ongoing discussions with manufacturers and suppliers worldwide,” Robert Califf, MD, the FDA commissioner, said in a statement.

Kendal Nutricare has more than 40,000 cans in stock for immediate dispatch, the FDA said, and the U.S. Department of Health and Human Services is talking to the company about the best ways to get the products to the U.S. as quickly as possible.

Kendamil has set up a website for consumers to receive updates and find products once they arrive in the U.S.

After an evaluation, the FDA said it had no safety or nutrition concerns about the products. The evaluation reviewed the company’s microbiological testing, labeling, and information about facility production and inspection history.

On May 24, the FDA announced that Abbott Nutrition will release about 300,000 cans of its EleCare specialty amino acid-based formula to families that need urgent, life-sustaining supplies. The products had more tests for microbes before release.

Although some EleCare products were included in Abbott’s infant formula recall earlier this year, the cans that will be released were in different lots, have never been released, and have been maintained in storage, the FDA said.

“These EleCare product lots were not part of the recall but have been on hold due to concerns that they were produced under unsanitary conditions observed at Abbott Nutrition’s Sturgis, Michigan, facility,” the FDA wrote.

The FDA encourages parents and caregivers to talk with their health care providers to weigh the potential risk of bacterial infection with the critical need for the product, based on its special dietary formulation for infants with severe food allergies or gut disorders.

The FDA also said that Abbott confirmed the EleCare products will be the first formula produced at the Sturgis facility when it restarts production soon. Other specialty metabolic formulas will follow.

Abbott plans to restart production at the Sturgis facility on June 4, the company said in a statement, noting that the early batches of EleCare would be available to consumers around June 20.

The products being released now are EleCare (for infants under 1 year) and EleCare Jr. (for ages 1 and older). Those who want to request products should contact their health care providers or call Abbott directly at 800-881-0876.

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

The U.S. Food and Drug Administration is easing rules to allow infant formula imports from the United Kingdom, which would bring about 2 million cans to the U.S. in coming weeks.

Kendal Nutricare will be able to offer certain infant formula products under the Kendamil brand to ease the nationwide formula shortage.

“Importantly, we anticipate additional infant formula products may be safely and quickly imported in the U.S. in the near-term, based on ongoing discussions with manufacturers and suppliers worldwide,” Robert Califf, MD, the FDA commissioner, said in a statement.

Kendal Nutricare has more than 40,000 cans in stock for immediate dispatch, the FDA said, and the U.S. Department of Health and Human Services is talking to the company about the best ways to get the products to the U.S. as quickly as possible.

Kendamil has set up a website for consumers to receive updates and find products once they arrive in the U.S.

After an evaluation, the FDA said it had no safety or nutrition concerns about the products. The evaluation reviewed the company’s microbiological testing, labeling, and information about facility production and inspection history.

On May 24, the FDA announced that Abbott Nutrition will release about 300,000 cans of its EleCare specialty amino acid-based formula to families that need urgent, life-sustaining supplies. The products had more tests for microbes before release.

Although some EleCare products were included in Abbott’s infant formula recall earlier this year, the cans that will be released were in different lots, have never been released, and have been maintained in storage, the FDA said.

“These EleCare product lots were not part of the recall but have been on hold due to concerns that they were produced under unsanitary conditions observed at Abbott Nutrition’s Sturgis, Michigan, facility,” the FDA wrote.

The FDA encourages parents and caregivers to talk with their health care providers to weigh the potential risk of bacterial infection with the critical need for the product, based on its special dietary formulation for infants with severe food allergies or gut disorders.

The FDA also said that Abbott confirmed the EleCare products will be the first formula produced at the Sturgis facility when it restarts production soon. Other specialty metabolic formulas will follow.

Abbott plans to restart production at the Sturgis facility on June 4, the company said in a statement, noting that the early batches of EleCare would be available to consumers around June 20.

The products being released now are EleCare (for infants under 1 year) and EleCare Jr. (for ages 1 and older). Those who want to request products should contact their health care providers or call Abbott directly at 800-881-0876.

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

The U.S. Food and Drug Administration is easing rules to allow infant formula imports from the United Kingdom, which would bring about 2 million cans to the U.S. in coming weeks.

Kendal Nutricare will be able to offer certain infant formula products under the Kendamil brand to ease the nationwide formula shortage.

“Importantly, we anticipate additional infant formula products may be safely and quickly imported in the U.S. in the near-term, based on ongoing discussions with manufacturers and suppliers worldwide,” Robert Califf, MD, the FDA commissioner, said in a statement.

Kendal Nutricare has more than 40,000 cans in stock for immediate dispatch, the FDA said, and the U.S. Department of Health and Human Services is talking to the company about the best ways to get the products to the U.S. as quickly as possible.

Kendamil has set up a website for consumers to receive updates and find products once they arrive in the U.S.

After an evaluation, the FDA said it had no safety or nutrition concerns about the products. The evaluation reviewed the company’s microbiological testing, labeling, and information about facility production and inspection history.

On May 24, the FDA announced that Abbott Nutrition will release about 300,000 cans of its EleCare specialty amino acid-based formula to families that need urgent, life-sustaining supplies. The products had more tests for microbes before release.

Although some EleCare products were included in Abbott’s infant formula recall earlier this year, the cans that will be released were in different lots, have never been released, and have been maintained in storage, the FDA said.

“These EleCare product lots were not part of the recall but have been on hold due to concerns that they were produced under unsanitary conditions observed at Abbott Nutrition’s Sturgis, Michigan, facility,” the FDA wrote.

The FDA encourages parents and caregivers to talk with their health care providers to weigh the potential risk of bacterial infection with the critical need for the product, based on its special dietary formulation for infants with severe food allergies or gut disorders.

The FDA also said that Abbott confirmed the EleCare products will be the first formula produced at the Sturgis facility when it restarts production soon. Other specialty metabolic formulas will follow.

Abbott plans to restart production at the Sturgis facility on June 4, the company said in a statement, noting that the early batches of EleCare would be available to consumers around June 20.

The products being released now are EleCare (for infants under 1 year) and EleCare Jr. (for ages 1 and older). Those who want to request products should contact their health care providers or call Abbott directly at 800-881-0876.

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