More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

Boston Scientific said it is voluntarily recalling all unused inventory of the Lotus Edge transcatheter aortic valve replacement system effective immediately.

In making the announcement today, Boston Scientific chair and CEO Mike Mahoney said the company has been increasingly challenged by the intricacies of the delivery system required to allow physicians to fully reposition and recapture the valve – key features of the system.

“The complexity of the delivery system, manufacturing challenges, the continued need for further technical enhancements, and current market adoption rates led us to the difficult decision to stop investing in the Lotus Edge platform,” Mr. Mahoney said.

Instead, the company will focus on the ACURATE neo2 aortic valve system, the Sentinel cerebral embolic protection device, and other high-growth areas, he noted.

The decision is expected to result in a $225 million to $300 million pretax charge, with $100 million to $150 million of these charges to impact the company’s adjusted results.

The Lotus device was approved in the United States in April 2019 for use in patients with severe aortic stenosis at high surgical risk based on the REPRISE 3 trial.

The Lotus Edge valve was approved in Europe in 2016, but final testing and rollout of the valve in the United States were delayed following a 2017 global recall of all Lotus valves because of reports of premature release of a pin connecting the valve to the delivery system.

Issues with the delivery system led to other Lotus valve recalls in both 2016 and 2014.

“Given the additional time and investment required to develop and reintroduce an enhanced delivery system, the company has chosen to retire the entire Lotus product platform immediately. All related commercial, clinical, research & development and manufacturing activities will also cease,” the statement said.

There is no safety issue for patients who currently have an implanted Lotus Edge valve, the company said.

This article first appeared on Medscape.com.

Boston Scientific said it is voluntarily recalling all unused inventory of the Lotus Edge transcatheter aortic valve replacement system effective immediately.

In making the announcement today, Boston Scientific chair and CEO Mike Mahoney said the company has been increasingly challenged by the intricacies of the delivery system required to allow physicians to fully reposition and recapture the valve – key features of the system.

“The complexity of the delivery system, manufacturing challenges, the continued need for further technical enhancements, and current market adoption rates led us to the difficult decision to stop investing in the Lotus Edge platform,” Mr. Mahoney said.

Instead, the company will focus on the ACURATE neo2 aortic valve system, the Sentinel cerebral embolic protection device, and other high-growth areas, he noted.

The decision is expected to result in a $225 million to $300 million pretax charge, with $100 million to $150 million of these charges to impact the company’s adjusted results.

The Lotus device was approved in the United States in April 2019 for use in patients with severe aortic stenosis at high surgical risk based on the REPRISE 3 trial.

The Lotus Edge valve was approved in Europe in 2016, but final testing and rollout of the valve in the United States were delayed following a 2017 global recall of all Lotus valves because of reports of premature release of a pin connecting the valve to the delivery system.

Issues with the delivery system led to other Lotus valve recalls in both 2016 and 2014.

“Given the additional time and investment required to develop and reintroduce an enhanced delivery system, the company has chosen to retire the entire Lotus product platform immediately. All related commercial, clinical, research & development and manufacturing activities will also cease,” the statement said.

There is no safety issue for patients who currently have an implanted Lotus Edge valve, the company said.

This article first appeared on Medscape.com.

Boston Scientific said it is voluntarily recalling all unused inventory of the Lotus Edge transcatheter aortic valve replacement system effective immediately.

In making the announcement today, Boston Scientific chair and CEO Mike Mahoney said the company has been increasingly challenged by the intricacies of the delivery system required to allow physicians to fully reposition and recapture the valve – key features of the system.

“The complexity of the delivery system, manufacturing challenges, the continued need for further technical enhancements, and current market adoption rates led us to the difficult decision to stop investing in the Lotus Edge platform,” Mr. Mahoney said.

Instead, the company will focus on the ACURATE neo2 aortic valve system, the Sentinel cerebral embolic protection device, and other high-growth areas, he noted.

The decision is expected to result in a $225 million to $300 million pretax charge, with $100 million to $150 million of these charges to impact the company’s adjusted results.

The Lotus device was approved in the United States in April 2019 for use in patients with severe aortic stenosis at high surgical risk based on the REPRISE 3 trial.

The Lotus Edge valve was approved in Europe in 2016, but final testing and rollout of the valve in the United States were delayed following a 2017 global recall of all Lotus valves because of reports of premature release of a pin connecting the valve to the delivery system.

Issues with the delivery system led to other Lotus valve recalls in both 2016 and 2014.

“Given the additional time and investment required to develop and reintroduce an enhanced delivery system, the company has chosen to retire the entire Lotus product platform immediately. All related commercial, clinical, research & development and manufacturing activities will also cease,” the statement said.

There is no safety issue for patients who currently have an implanted Lotus Edge valve, the company said.

This article first appeared on Medscape.com.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

COVID-19 patients who survive their hospitalization don’t leave the disease behind upon discharge, as a significant percentage died within 60 days of discharge, with an ICU admission heightening the risk, according to an observational study of 38 Michigan hospitals. What’s more, many of them were burdened with health and emotional challenges ranging from hospital readmission to job loss and financial problems.

“These data confirm that the toll of COVID-19 extends well beyond hospitalization, a finding consistent with long-term sequelae from sepsis and other severe respiratory viral illnesses,” wrote lead author Vineet Chopra, MBBS, of the University of Michigan, Ann Arbor, and colleagues (Ann Intern Med. 2020 Nov 11: doi: 10.7326/M20-5661)

The researchers found that 29.2% of all patients hospitalized for COVID-19 from March 16 to July 1 died. The observational cohort study included 1,648 COVID-19 patients hospitalized at 38 Michigan hospitals participating in a statewide collaborative.

The bulk of those deaths occurred during hospitalization: 24.2% of patients (n = 398). Of the 1,250 patients discharged, 78% (n = 975) went home and 12.6% (n = 158) went to a skilled nursing facility, with the remainder unaccounted for. Within 60 days of discharge, 6.7% (n = 84) of hospitalized survivors had died and 15.2% (n = 189) were readmitted. The researchers gathered 60-day postdischarge data via a telephone survey, contacting 41.8% (n = 488) of discharged patients.

Outcomes were even worse for discharged patients who spent time in the ICU. The death rate among this group was 10.4% (17 of 165) after discharge. That resulted in an overall study death rate of 63.5% (n = 257) for the 405 patients who were in the ICU.

While the study data were in the first wave of the novel coronavirus, the findings have relevance today, said Mary Jo Farmer, MD, PhD, FCCP, directory of pulmonary hypertension services at Baystate Health in Springfield, Mass.

“This is the best information we have to date,” she said. “We have to continue to have an open mind and expect that this information may change as the virus possibly mutates as it spreads, and we should continue doing these types of outcomes studies at 90 days, 120 days, etc.”

The median age of study patients was 62, with a range of 50-72. The three leading comorbidities among discharged patients were hypertension (n = 800, 64%), diabetes (34.9%, n = 436), and cardiovascular disease (24.1%, n = 301).

Poor postdischarge outcomes weren’t limited to mortality and readmission. Almost 19% (n = 92) reported new or worsening cardiopulmonary symptoms such as cough and dyspnea, 13.3% had a persistent loss of taste or smell, and 12% (n = 58) reported more difficulty with daily living tasks.

The after-effects were not only physical. Nearly half of discharged patients (48.7%, n = 238) reported emotional effects and almost 6% (n = 28) sought mental health care. Among the 40% (n = 195) employed before they were hospitalized, 36% (n = 78) couldn’t return to work because of health issues or layoffs. Sixty percent (n = 117) of the pre-employed discharged patients did return to work, but 25% (n = 30) did so with reduced hours or modified job duties because of health problems.

Financial problems were also a burden. More than a third, 36.7% (n = 179), reported some financial impact from their hospitalization. About 10% (n = 47) said they used most or all of their savings, and 7% (n = 35) said they resorted to rationing necessities such as food or medications.

The researchers noted that one in five patients had no primary care follow-up at 2 months post discharge. “Collectively, these findings suggest that better models to support COVID-19 survivors are necessary,” said Dr. Chopra and colleagues.

The postdischarge course for patients involves two humps, said Sachin Gupta, MD, FCCP a pulmonary and critical care specialist at Alameda Health System in Oakland, Calif.: Getting over the hospitalization itself and the recovery phase. “As you look at the median age of the survivors, elderly patients who survive a hospital stay are still going to have a period of recovery, and like any viral illness that leads to someone being hospitalized, when you have an elderly patient with comorbidities, not all of them can make it over that final hump.”

SOURCE: Chopra V et al. Ann Intern Med. 2020 Nov 11. doi: 10.7326/M20-5661.

As part of the 50th anniversary of Dermatology News, it is intriguing to think about where a time machine journey 5 decades back would find the field of pediatric dermatology, and to assess the changes in the specialty during the time that Dermatology News (operating then as “Skin & Allergy News”) has been reporting on innovations and changes in the practice of dermatology.

Society for Pediatric Dermatology

So, starting in 1970, we would find that pediatric dermatology did not exist as an organized specialty. It was not until 3 years later, in October 1973 in Mexico City, that the first international symposium on Pediatric Dermatology was held, and the International Society for Pediatric Dermatology was founded. I reached out to Andrew Margileth, MD, 100 years old this past July, and still active voluntary faculty in pediatric dermatology at the University of Miami, to help me “reach back” to those days. Dr. Margileth commented on how the first symposium was “brilliantly orchestrated by Ramon Ruiz-Maldonado,” from the National Institute of Paediatrics in Mexico, and that it was his “Aha moment for future practice!” That meeting spurred discussions on the development of the Society for Pediatric Dermatology the next year, with Alvin Jacobs, MD; Samuel Weinberg, MD; Nancy Esterly, MD; Sidney Hurwitz, MD; William Weston, MD; and Coleman Jacobson, MD, as some of the initial “founding mothers and fathers,” and the society was officially established in 1975.

The field of pediatric dermatology was fairly “infantile” 50 years ago, with few practitioners. But the early leaders in the field recognized that up to 30% of pediatric primary care visits included skin problems, and that there was limited training for dermatologists, as well as pediatricians, about skin diseases in children. There were clearly clinical and educational needs to establish a subspecialty of pediatric dermatology, and over the next 1-2 decades, the field expanded. The journal Pediatric Dermatology was established (in 1982), the Section on Dermatology was established by the American Academy of Pediatrics (in 1986), and fellowship programs were launched at select academic centers. And it was 30 years into our timeline before the formal subspecialty of pediatric dermatology was established through the American Board of Dermatology (2000).

The field of pediatric dermatology has evolved and matured rapidly. Standard reference textbooks have been developed in the United States and around the world (and of course, online). Pediatric dermatology is an essential part of the core curriculum for dermatologist trainees. Organizations promoting pediatric research have developed to influence basic, translational, and clinical research in conditions in neonates through adolescents, such as the Pediatric Dermatology Research Alliance (PeDRA). And meetings throughout the world now feature pediatric dermatology sessions and help to spread the advances in the diagnosis and management of pediatric skin disorders.

The practice of pediatric dermatology: How has it changed?

It is beyond the scope of this article to try to comprehensively review all of the changes in pediatric dermatology practice. But review of the evolution of a few disease states (choices influenced by my discussions with my 100-year old history guide, Dr. Margileth) displays examples of where we have been, and where we are going in our next 5, 10, or 50 years.

Hemangiomas and vascular malformations

Some of the first natural history studies on hemangiomas were done in the early 1960s, establishing that standard cutaneous hemangiomas had a typical clinical course of fairly rapid growth, plateau, and involution over time. Of interest, the hallmark article’s first author was Dr. Margileth, published in 1965 in JAMA!.This was still at a time when the identification of hemangiomas of infancy (or “HOI” as we say in the trade) was confused with vascular malformations, and no one had recognized the distinct variant tumors such as rapidly involuting and noninvoluting congenital hemangiomas (RICHs or NICHs), tufted angiomas, or hemangioendotheliomas. PHACE syndrome was not yet described (that was done in 1996 by Ilona Frieden, MD, and colleagues). And for a time, hemangiomas were treated with x-rays, before the negative impact of such radiation was acknowledged. It seems that, as a consequence of the use of x-ray therapy and as a backlash from the radiation therapy side effects and potential toxicities, even deforming and functionally significant lesions were “followed clinically” for natural involution, with a sensibility that doing nothing might be better than doing the wrong thing.

Over the next 15 years, the recognition of functionally significant hemangiomas, deformation associated with their proliferation, and the recognition of PHACE syndrome made hemangiomas of infancy an area of concern, with systemic steroids and occasionally chemotherapeutic agents (such as vincristine) being used for problematic lesions.

It has now been 12 years since the work of Christine Léauté-Labrèze, MD, et al., from the University of Bordeaux (France), led to the breakthrough of propranolol for hemangioma treatment, profoundly changing hemangioma management to an incredibly effective medical therapy extensively studied, tested in formal clinical trials, and approved by regulatory authorities. And how intriguing that this was pursued after the chance (but skilled) observation that a child who developed hypertension as a side effect of systemic steroids for nasal hemangioma treatment was prescribed propranolol for the hypertension and had his nasal hemangioma rapidly shrink, with a response superior and much quicker than that to corticosteroids.

Courtesy of Rady Children&#039;s Hospital

Inflammatory skin disorders: Acne, psoriasis, and atopic dermatitis

The care of pediatric inflammatory skin disorders has evolved, but more slowly for some diseases than others. Acne vulgaris is now recognized as much more common under age 12 than previously, presumably reflecting earlier pubertal changes in our preteens. Over the past 30 years, therapy has evolved with the use of topical retinoids (still underused by pediatricians, considered a “practice gap”), hormonal therapy with combined oral contraceptives, and oral isotretinoin, a powerful but highly effective systemic agent for severe and refractory acne. Specific pediatric guidelines came much later, with expert recommendations formulated by the American Acne and Rosacea Society and endorsed by the American Academy of Pediatrics in 2013. Over the past few years, there has been a push by experts for more judicious use of antibiotics for acne (oral and topical) to minimize the emergence of bacterial resistance. There are unanswered questions as we evolve our care: How will the new topical antiandrogens be used? Will spironolactone become part of hormonal therapy under age 18? Will the insights on certain strains of Cutibacterium acnes being associated with worse acne translate to microbiome or vaccine-based strategies?

Pediatric psoriasis has suffered, being “behind in the revolution” of biologic agents because of delayed approval of any biologic agent for treatment of pediatric psoriasis in the United States until just a few years ago, and lags behind Europe and elsewhere in the world by almost a decade. Only this year have we expanded beyond one biologic agent approved for under age 12 and two for ages 12 and older, with other approvals expected including interleukin (IL)-17 and IL-23 agents. Adult psoriasis has been recognized to be associated with a broad set of comorbidities, including obesity and early heart disease, and there is now research on how children are at risk as well, with new recommendations on how to screen children with psoriasis, supplied first by PeDRA and then in the new American Academy of Dermatology-National Psoriasis Foundation pediatric psoriasis guidelines .

Pediatric atopic dermatitis (AD) is in its early years of revolution. In the 50-year period of our thought experiment, AD has increased in prevalence from 5% or less of the pediatric population to 10%-15%. Treatment of most individuals has remained the same over the decades: Good skin care, frequent moisturizers, topical corticosteroids for flares, and management of infection if noted. The topical calcineurin inhibitors (TCIs) broadened the therapeutic approach when introduced in 2000 and 2001, but the boxed warning resulted in some practitioners minimizing their use of these useful agents. But newer studies are markedly reassuring about their safe use in children.

Steroid phobia, as well as concerns about potential side effects of the TCIs, has resulted in undertreatment of childhood AD. It is quite common to see multiple children during pediatric dermatology office hours with poorly controlled eczema, high body-surface areas of eczema, compromised sleep, secondary infections, and anxiety and depression, especially in our moderate to severe adolescents. The field is “hot” with new topical and systemic agents, including our few years’ experience with topical crisaborole, a phosphodiesterase (PDE)-4 inhibitor; and dupilumab, an IL-4-alpha blocker – the first biologic agent approved for AD and the first systemic agent (other than oral corticosteroids), just extended from 12 years to 6 years of age! As dupilumab gets studied for younger children, other biologics (including IL-13 and IL-31 blockers) are undertaking pediatric and/or adolescent trials, oral and topical JAK inhibitors are including adolescents in core clinical trials, and other novel topical agents are under study, including an aryl-hydrocarbon receptor–modulating agent and other PDE-4 inhibitors.

Procedural pediatric dermatology: From liquid nitrogen to laser, surgery, and multimodal skin care

The first generation of pediatric dermatologists were considered medical dermatologist specialists. The care of the conditions discussed above, as well as genodermatoses, diagnostic dilemmas, and management of dermatologic manifestations of systemic disease and other conditions, was the “bread and butter” of pediatric dermatology care. When I was in training, my mentor Paul Honig, MD, at the Children’s Hospital of Philadelphia had a procedure half-day each week, where he would care for a few patients who needed liquid nitrogen therapy for warts, or who needed biopsies. It was uncommon to have a large procedural/surgical part of pediatric dermatology practice. But this is now a routine part of many specialists in the field. How did this change occur?

The fundamental shift began to occur with the introduction of the pulsed dye laser for treatment of port-wine birthmarks in children with minimal scarring, and a seminal article published in the New England Journal of Medicine in 1989. Vascular lesions including port-wine stains were common, and pediatric dermatologists managed these patients for both diagnosis and medical management. Also, dermatology residencies at this time offered training in cutaneous surgery, excisions (including Mohs surgery) and repairs, and trainees in pediatric dermatology were “trained up” to high levels of expertise. As lasers were incorporated into dermatology residency work and practices, pediatric dermatologists developed the exposure and skill to do this work. An added advantage was having the knowledge of how to handle children and adolescents in an age-appropriate manner, with consideration of methods to minimize the pain and anxiety of procedures. Within a few years, pediatric dermatologists were at the forefront of the use of topical anesthetics (EMLA and liposomal lidocaine) and had general anesthesia privileges for laser and excisional surgery.

So while pediatric dermatologists still do “small procedures” every hour in most practices (cryotherapy for warts, cantharidin for molluscum, shave and punch biopsies), a subset now have extensive procedural practices, which in recent years has extended to pigment lesion lasers (to treat nevus of Ota, for example), hair laser, and combinations of lasers, including fractionated CO₂ technology, to treat hypertrophic, constrictive and/or deforming scars.
 

The future

What will pediatric dermatology be like in 10, 20, or 50 years?

I have not yet discussed some of the most challenging diseases in our field, including epidermolysis bullosa, ichthyosis, and neurocutaneous disorders and other genetic skin disorders that have an incredible impact on the lives of affected children and their families, with incredible morbidity and with many conditions that shorten lifespans. But these are the conditions where “the future is happening now,” and we are looking forward to our new gene therapy techniques helping to transform our care.

And other aspects of practice? Will we be doing a large percentage of practice over the phone (or whatever devices we have then – remember, the first iPhone was only released 13 years ago)?

Will our patients be using their own imaging systems to evaluate their nevi and skin growths, and perhaps to diagnose and manage their rashes?

Will we have prevented our inflammatory skin disorders, or “turned them off” in early life with aggressive therapy in infantile life?

I project only that all of us in dermatology will still be a resource to our pediatric patients, from neonate through young adult, through our work of preventing, caring, healing and minimizing disease impact, and hopefully enjoying the pleasures of seeing our patients healthfully develop and evolve! As will our field.
 

Dr. Eichenfield is professor of dermatology and pediatrics and vice-chair of the department of dermatology at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego. Dr. Eichenfield reports financial relationships with 20 pharmaceutical companies that manufacture dermatologic products, including products for the diseases discussed here.

As part of the 50th anniversary of Dermatology News, it is intriguing to think about where a time machine journey 5 decades back would find the field of pediatric dermatology, and to assess the changes in the specialty during the time that Dermatology News (operating then as “Skin & Allergy News”) has been reporting on innovations and changes in the practice of dermatology.

Society for Pediatric Dermatology

So, starting in 1970, we would find that pediatric dermatology did not exist as an organized specialty. It was not until 3 years later, in October 1973 in Mexico City, that the first international symposium on Pediatric Dermatology was held, and the International Society for Pediatric Dermatology was founded. I reached out to Andrew Margileth, MD, 100 years old this past July, and still active voluntary faculty in pediatric dermatology at the University of Miami, to help me “reach back” to those days. Dr. Margileth commented on how the first symposium was “brilliantly orchestrated by Ramon Ruiz-Maldonado,” from the National Institute of Paediatrics in Mexico, and that it was his “Aha moment for future practice!” That meeting spurred discussions on the development of the Society for Pediatric Dermatology the next year, with Alvin Jacobs, MD; Samuel Weinberg, MD; Nancy Esterly, MD; Sidney Hurwitz, MD; William Weston, MD; and Coleman Jacobson, MD, as some of the initial “founding mothers and fathers,” and the society was officially established in 1975.

The field of pediatric dermatology was fairly “infantile” 50 years ago, with few practitioners. But the early leaders in the field recognized that up to 30% of pediatric primary care visits included skin problems, and that there was limited training for dermatologists, as well as pediatricians, about skin diseases in children. There were clearly clinical and educational needs to establish a subspecialty of pediatric dermatology, and over the next 1-2 decades, the field expanded. The journal Pediatric Dermatology was established (in 1982), the Section on Dermatology was established by the American Academy of Pediatrics (in 1986), and fellowship programs were launched at select academic centers. And it was 30 years into our timeline before the formal subspecialty of pediatric dermatology was established through the American Board of Dermatology (2000).

The field of pediatric dermatology has evolved and matured rapidly. Standard reference textbooks have been developed in the United States and around the world (and of course, online). Pediatric dermatology is an essential part of the core curriculum for dermatologist trainees. Organizations promoting pediatric research have developed to influence basic, translational, and clinical research in conditions in neonates through adolescents, such as the Pediatric Dermatology Research Alliance (PeDRA). And meetings throughout the world now feature pediatric dermatology sessions and help to spread the advances in the diagnosis and management of pediatric skin disorders.

The practice of pediatric dermatology: How has it changed?

It is beyond the scope of this article to try to comprehensively review all of the changes in pediatric dermatology practice. But review of the evolution of a few disease states (choices influenced by my discussions with my 100-year old history guide, Dr. Margileth) displays examples of where we have been, and where we are going in our next 5, 10, or 50 years.

Hemangiomas and vascular malformations

Some of the first natural history studies on hemangiomas were done in the early 1960s, establishing that standard cutaneous hemangiomas had a typical clinical course of fairly rapid growth, plateau, and involution over time. Of interest, the hallmark article’s first author was Dr. Margileth, published in 1965 in JAMA!.This was still at a time when the identification of hemangiomas of infancy (or “HOI” as we say in the trade) was confused with vascular malformations, and no one had recognized the distinct variant tumors such as rapidly involuting and noninvoluting congenital hemangiomas (RICHs or NICHs), tufted angiomas, or hemangioendotheliomas. PHACE syndrome was not yet described (that was done in 1996 by Ilona Frieden, MD, and colleagues). And for a time, hemangiomas were treated with x-rays, before the negative impact of such radiation was acknowledged. It seems that, as a consequence of the use of x-ray therapy and as a backlash from the radiation therapy side effects and potential toxicities, even deforming and functionally significant lesions were “followed clinically” for natural involution, with a sensibility that doing nothing might be better than doing the wrong thing.

Over the next 15 years, the recognition of functionally significant hemangiomas, deformation associated with their proliferation, and the recognition of PHACE syndrome made hemangiomas of infancy an area of concern, with systemic steroids and occasionally chemotherapeutic agents (such as vincristine) being used for problematic lesions.

It has now been 12 years since the work of Christine Léauté-Labrèze, MD, et al., from the University of Bordeaux (France), led to the breakthrough of propranolol for hemangioma treatment, profoundly changing hemangioma management to an incredibly effective medical therapy extensively studied, tested in formal clinical trials, and approved by regulatory authorities. And how intriguing that this was pursued after the chance (but skilled) observation that a child who developed hypertension as a side effect of systemic steroids for nasal hemangioma treatment was prescribed propranolol for the hypertension and had his nasal hemangioma rapidly shrink, with a response superior and much quicker than that to corticosteroids.

Courtesy of Rady Children&#039;s Hospital

Inflammatory skin disorders: Acne, psoriasis, and atopic dermatitis

The care of pediatric inflammatory skin disorders has evolved, but more slowly for some diseases than others. Acne vulgaris is now recognized as much more common under age 12 than previously, presumably reflecting earlier pubertal changes in our preteens. Over the past 30 years, therapy has evolved with the use of topical retinoids (still underused by pediatricians, considered a “practice gap”), hormonal therapy with combined oral contraceptives, and oral isotretinoin, a powerful but highly effective systemic agent for severe and refractory acne. Specific pediatric guidelines came much later, with expert recommendations formulated by the American Acne and Rosacea Society and endorsed by the American Academy of Pediatrics in 2013. Over the past few years, there has been a push by experts for more judicious use of antibiotics for acne (oral and topical) to minimize the emergence of bacterial resistance. There are unanswered questions as we evolve our care: How will the new topical antiandrogens be used? Will spironolactone become part of hormonal therapy under age 18? Will the insights on certain strains of Cutibacterium acnes being associated with worse acne translate to microbiome or vaccine-based strategies?

Pediatric psoriasis has suffered, being “behind in the revolution” of biologic agents because of delayed approval of any biologic agent for treatment of pediatric psoriasis in the United States until just a few years ago, and lags behind Europe and elsewhere in the world by almost a decade. Only this year have we expanded beyond one biologic agent approved for under age 12 and two for ages 12 and older, with other approvals expected including interleukin (IL)-17 and IL-23 agents. Adult psoriasis has been recognized to be associated with a broad set of comorbidities, including obesity and early heart disease, and there is now research on how children are at risk as well, with new recommendations on how to screen children with psoriasis, supplied first by PeDRA and then in the new American Academy of Dermatology-National Psoriasis Foundation pediatric psoriasis guidelines .

Pediatric atopic dermatitis (AD) is in its early years of revolution. In the 50-year period of our thought experiment, AD has increased in prevalence from 5% or less of the pediatric population to 10%-15%. Treatment of most individuals has remained the same over the decades: Good skin care, frequent moisturizers, topical corticosteroids for flares, and management of infection if noted. The topical calcineurin inhibitors (TCIs) broadened the therapeutic approach when introduced in 2000 and 2001, but the boxed warning resulted in some practitioners minimizing their use of these useful agents. But newer studies are markedly reassuring about their safe use in children.

Steroid phobia, as well as concerns about potential side effects of the TCIs, has resulted in undertreatment of childhood AD. It is quite common to see multiple children during pediatric dermatology office hours with poorly controlled eczema, high body-surface areas of eczema, compromised sleep, secondary infections, and anxiety and depression, especially in our moderate to severe adolescents. The field is “hot” with new topical and systemic agents, including our few years’ experience with topical crisaborole, a phosphodiesterase (PDE)-4 inhibitor; and dupilumab, an IL-4-alpha blocker – the first biologic agent approved for AD and the first systemic agent (other than oral corticosteroids), just extended from 12 years to 6 years of age! As dupilumab gets studied for younger children, other biologics (including IL-13 and IL-31 blockers) are undertaking pediatric and/or adolescent trials, oral and topical JAK inhibitors are including adolescents in core clinical trials, and other novel topical agents are under study, including an aryl-hydrocarbon receptor–modulating agent and other PDE-4 inhibitors.

Procedural pediatric dermatology: From liquid nitrogen to laser, surgery, and multimodal skin care

The first generation of pediatric dermatologists were considered medical dermatologist specialists. The care of the conditions discussed above, as well as genodermatoses, diagnostic dilemmas, and management of dermatologic manifestations of systemic disease and other conditions, was the “bread and butter” of pediatric dermatology care. When I was in training, my mentor Paul Honig, MD, at the Children’s Hospital of Philadelphia had a procedure half-day each week, where he would care for a few patients who needed liquid nitrogen therapy for warts, or who needed biopsies. It was uncommon to have a large procedural/surgical part of pediatric dermatology practice. But this is now a routine part of many specialists in the field. How did this change occur?

The fundamental shift began to occur with the introduction of the pulsed dye laser for treatment of port-wine birthmarks in children with minimal scarring, and a seminal article published in the New England Journal of Medicine in 1989. Vascular lesions including port-wine stains were common, and pediatric dermatologists managed these patients for both diagnosis and medical management. Also, dermatology residencies at this time offered training in cutaneous surgery, excisions (including Mohs surgery) and repairs, and trainees in pediatric dermatology were “trained up” to high levels of expertise. As lasers were incorporated into dermatology residency work and practices, pediatric dermatologists developed the exposure and skill to do this work. An added advantage was having the knowledge of how to handle children and adolescents in an age-appropriate manner, with consideration of methods to minimize the pain and anxiety of procedures. Within a few years, pediatric dermatologists were at the forefront of the use of topical anesthetics (EMLA and liposomal lidocaine) and had general anesthesia privileges for laser and excisional surgery.

So while pediatric dermatologists still do “small procedures” every hour in most practices (cryotherapy for warts, cantharidin for molluscum, shave and punch biopsies), a subset now have extensive procedural practices, which in recent years has extended to pigment lesion lasers (to treat nevus of Ota, for example), hair laser, and combinations of lasers, including fractionated CO₂ technology, to treat hypertrophic, constrictive and/or deforming scars.
 

The future

What will pediatric dermatology be like in 10, 20, or 50 years?

I have not yet discussed some of the most challenging diseases in our field, including epidermolysis bullosa, ichthyosis, and neurocutaneous disorders and other genetic skin disorders that have an incredible impact on the lives of affected children and their families, with incredible morbidity and with many conditions that shorten lifespans. But these are the conditions where “the future is happening now,” and we are looking forward to our new gene therapy techniques helping to transform our care.

And other aspects of practice? Will we be doing a large percentage of practice over the phone (or whatever devices we have then – remember, the first iPhone was only released 13 years ago)?

Will our patients be using their own imaging systems to evaluate their nevi and skin growths, and perhaps to diagnose and manage their rashes?

Will we have prevented our inflammatory skin disorders, or “turned them off” in early life with aggressive therapy in infantile life?

I project only that all of us in dermatology will still be a resource to our pediatric patients, from neonate through young adult, through our work of preventing, caring, healing and minimizing disease impact, and hopefully enjoying the pleasures of seeing our patients healthfully develop and evolve! As will our field.
 

Dr. Eichenfield is professor of dermatology and pediatrics and vice-chair of the department of dermatology at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego. Dr. Eichenfield reports financial relationships with 20 pharmaceutical companies that manufacture dermatologic products, including products for the diseases discussed here.

As part of the 50th anniversary of Dermatology News, it is intriguing to think about where a time machine journey 5 decades back would find the field of pediatric dermatology, and to assess the changes in the specialty during the time that Dermatology News (operating then as “Skin & Allergy News”) has been reporting on innovations and changes in the practice of dermatology.

Society for Pediatric Dermatology

So, starting in 1970, we would find that pediatric dermatology did not exist as an organized specialty. It was not until 3 years later, in October 1973 in Mexico City, that the first international symposium on Pediatric Dermatology was held, and the International Society for Pediatric Dermatology was founded. I reached out to Andrew Margileth, MD, 100 years old this past July, and still active voluntary faculty in pediatric dermatology at the University of Miami, to help me “reach back” to those days. Dr. Margileth commented on how the first symposium was “brilliantly orchestrated by Ramon Ruiz-Maldonado,” from the National Institute of Paediatrics in Mexico, and that it was his “Aha moment for future practice!” That meeting spurred discussions on the development of the Society for Pediatric Dermatology the next year, with Alvin Jacobs, MD; Samuel Weinberg, MD; Nancy Esterly, MD; Sidney Hurwitz, MD; William Weston, MD; and Coleman Jacobson, MD, as some of the initial “founding mothers and fathers,” and the society was officially established in 1975.

The field of pediatric dermatology was fairly “infantile” 50 years ago, with few practitioners. But the early leaders in the field recognized that up to 30% of pediatric primary care visits included skin problems, and that there was limited training for dermatologists, as well as pediatricians, about skin diseases in children. There were clearly clinical and educational needs to establish a subspecialty of pediatric dermatology, and over the next 1-2 decades, the field expanded. The journal Pediatric Dermatology was established (in 1982), the Section on Dermatology was established by the American Academy of Pediatrics (in 1986), and fellowship programs were launched at select academic centers. And it was 30 years into our timeline before the formal subspecialty of pediatric dermatology was established through the American Board of Dermatology (2000).

The field of pediatric dermatology has evolved and matured rapidly. Standard reference textbooks have been developed in the United States and around the world (and of course, online). Pediatric dermatology is an essential part of the core curriculum for dermatologist trainees. Organizations promoting pediatric research have developed to influence basic, translational, and clinical research in conditions in neonates through adolescents, such as the Pediatric Dermatology Research Alliance (PeDRA). And meetings throughout the world now feature pediatric dermatology sessions and help to spread the advances in the diagnosis and management of pediatric skin disorders.

The practice of pediatric dermatology: How has it changed?

It is beyond the scope of this article to try to comprehensively review all of the changes in pediatric dermatology practice. But review of the evolution of a few disease states (choices influenced by my discussions with my 100-year old history guide, Dr. Margileth) displays examples of where we have been, and where we are going in our next 5, 10, or 50 years.

Hemangiomas and vascular malformations

Some of the first natural history studies on hemangiomas were done in the early 1960s, establishing that standard cutaneous hemangiomas had a typical clinical course of fairly rapid growth, plateau, and involution over time. Of interest, the hallmark article’s first author was Dr. Margileth, published in 1965 in JAMA!.This was still at a time when the identification of hemangiomas of infancy (or “HOI” as we say in the trade) was confused with vascular malformations, and no one had recognized the distinct variant tumors such as rapidly involuting and noninvoluting congenital hemangiomas (RICHs or NICHs), tufted angiomas, or hemangioendotheliomas. PHACE syndrome was not yet described (that was done in 1996 by Ilona Frieden, MD, and colleagues). And for a time, hemangiomas were treated with x-rays, before the negative impact of such radiation was acknowledged. It seems that, as a consequence of the use of x-ray therapy and as a backlash from the radiation therapy side effects and potential toxicities, even deforming and functionally significant lesions were “followed clinically” for natural involution, with a sensibility that doing nothing might be better than doing the wrong thing.

Over the next 15 years, the recognition of functionally significant hemangiomas, deformation associated with their proliferation, and the recognition of PHACE syndrome made hemangiomas of infancy an area of concern, with systemic steroids and occasionally chemotherapeutic agents (such as vincristine) being used for problematic lesions.

It has now been 12 years since the work of Christine Léauté-Labrèze, MD, et al., from the University of Bordeaux (France), led to the breakthrough of propranolol for hemangioma treatment, profoundly changing hemangioma management to an incredibly effective medical therapy extensively studied, tested in formal clinical trials, and approved by regulatory authorities. And how intriguing that this was pursued after the chance (but skilled) observation that a child who developed hypertension as a side effect of systemic steroids for nasal hemangioma treatment was prescribed propranolol for the hypertension and had his nasal hemangioma rapidly shrink, with a response superior and much quicker than that to corticosteroids.

Courtesy of Rady Children&#039;s Hospital

Inflammatory skin disorders: Acne, psoriasis, and atopic dermatitis

The care of pediatric inflammatory skin disorders has evolved, but more slowly for some diseases than others. Acne vulgaris is now recognized as much more common under age 12 than previously, presumably reflecting earlier pubertal changes in our preteens. Over the past 30 years, therapy has evolved with the use of topical retinoids (still underused by pediatricians, considered a “practice gap”), hormonal therapy with combined oral contraceptives, and oral isotretinoin, a powerful but highly effective systemic agent for severe and refractory acne. Specific pediatric guidelines came much later, with expert recommendations formulated by the American Acne and Rosacea Society and endorsed by the American Academy of Pediatrics in 2013. Over the past few years, there has been a push by experts for more judicious use of antibiotics for acne (oral and topical) to minimize the emergence of bacterial resistance. There are unanswered questions as we evolve our care: How will the new topical antiandrogens be used? Will spironolactone become part of hormonal therapy under age 18? Will the insights on certain strains of Cutibacterium acnes being associated with worse acne translate to microbiome or vaccine-based strategies?

Pediatric psoriasis has suffered, being “behind in the revolution” of biologic agents because of delayed approval of any biologic agent for treatment of pediatric psoriasis in the United States until just a few years ago, and lags behind Europe and elsewhere in the world by almost a decade. Only this year have we expanded beyond one biologic agent approved for under age 12 and two for ages 12 and older, with other approvals expected including interleukin (IL)-17 and IL-23 agents. Adult psoriasis has been recognized to be associated with a broad set of comorbidities, including obesity and early heart disease, and there is now research on how children are at risk as well, with new recommendations on how to screen children with psoriasis, supplied first by PeDRA and then in the new American Academy of Dermatology-National Psoriasis Foundation pediatric psoriasis guidelines .

Pediatric atopic dermatitis (AD) is in its early years of revolution. In the 50-year period of our thought experiment, AD has increased in prevalence from 5% or less of the pediatric population to 10%-15%. Treatment of most individuals has remained the same over the decades: Good skin care, frequent moisturizers, topical corticosteroids for flares, and management of infection if noted. The topical calcineurin inhibitors (TCIs) broadened the therapeutic approach when introduced in 2000 and 2001, but the boxed warning resulted in some practitioners minimizing their use of these useful agents. But newer studies are markedly reassuring about their safe use in children.

Steroid phobia, as well as concerns about potential side effects of the TCIs, has resulted in undertreatment of childhood AD. It is quite common to see multiple children during pediatric dermatology office hours with poorly controlled eczema, high body-surface areas of eczema, compromised sleep, secondary infections, and anxiety and depression, especially in our moderate to severe adolescents. The field is “hot” with new topical and systemic agents, including our few years’ experience with topical crisaborole, a phosphodiesterase (PDE)-4 inhibitor; and dupilumab, an IL-4-alpha blocker – the first biologic agent approved for AD and the first systemic agent (other than oral corticosteroids), just extended from 12 years to 6 years of age! As dupilumab gets studied for younger children, other biologics (including IL-13 and IL-31 blockers) are undertaking pediatric and/or adolescent trials, oral and topical JAK inhibitors are including adolescents in core clinical trials, and other novel topical agents are under study, including an aryl-hydrocarbon receptor–modulating agent and other PDE-4 inhibitors.

Procedural pediatric dermatology: From liquid nitrogen to laser, surgery, and multimodal skin care

The first generation of pediatric dermatologists were considered medical dermatologist specialists. The care of the conditions discussed above, as well as genodermatoses, diagnostic dilemmas, and management of dermatologic manifestations of systemic disease and other conditions, was the “bread and butter” of pediatric dermatology care. When I was in training, my mentor Paul Honig, MD, at the Children’s Hospital of Philadelphia had a procedure half-day each week, where he would care for a few patients who needed liquid nitrogen therapy for warts, or who needed biopsies. It was uncommon to have a large procedural/surgical part of pediatric dermatology practice. But this is now a routine part of many specialists in the field. How did this change occur?

The fundamental shift began to occur with the introduction of the pulsed dye laser for treatment of port-wine birthmarks in children with minimal scarring, and a seminal article published in the New England Journal of Medicine in 1989. Vascular lesions including port-wine stains were common, and pediatric dermatologists managed these patients for both diagnosis and medical management. Also, dermatology residencies at this time offered training in cutaneous surgery, excisions (including Mohs surgery) and repairs, and trainees in pediatric dermatology were “trained up” to high levels of expertise. As lasers were incorporated into dermatology residency work and practices, pediatric dermatologists developed the exposure and skill to do this work. An added advantage was having the knowledge of how to handle children and adolescents in an age-appropriate manner, with consideration of methods to minimize the pain and anxiety of procedures. Within a few years, pediatric dermatologists were at the forefront of the use of topical anesthetics (EMLA and liposomal lidocaine) and had general anesthesia privileges for laser and excisional surgery.

So while pediatric dermatologists still do “small procedures” every hour in most practices (cryotherapy for warts, cantharidin for molluscum, shave and punch biopsies), a subset now have extensive procedural practices, which in recent years has extended to pigment lesion lasers (to treat nevus of Ota, for example), hair laser, and combinations of lasers, including fractionated CO₂ technology, to treat hypertrophic, constrictive and/or deforming scars.
 

The future

What will pediatric dermatology be like in 10, 20, or 50 years?

I have not yet discussed some of the most challenging diseases in our field, including epidermolysis bullosa, ichthyosis, and neurocutaneous disorders and other genetic skin disorders that have an incredible impact on the lives of affected children and their families, with incredible morbidity and with many conditions that shorten lifespans. But these are the conditions where “the future is happening now,” and we are looking forward to our new gene therapy techniques helping to transform our care.

And other aspects of practice? Will we be doing a large percentage of practice over the phone (or whatever devices we have then – remember, the first iPhone was only released 13 years ago)?

Will our patients be using their own imaging systems to evaluate their nevi and skin growths, and perhaps to diagnose and manage their rashes?

Will we have prevented our inflammatory skin disorders, or “turned them off” in early life with aggressive therapy in infantile life?

I project only that all of us in dermatology will still be a resource to our pediatric patients, from neonate through young adult, through our work of preventing, caring, healing and minimizing disease impact, and hopefully enjoying the pleasures of seeing our patients healthfully develop and evolve! As will our field.
 

Dr. Eichenfield is professor of dermatology and pediatrics and vice-chair of the department of dermatology at the University of California, San Diego, and chief of pediatric and adolescent dermatology at Rady Children’s Hospital-San Diego. Dr. Eichenfield reports financial relationships with 20 pharmaceutical companies that manufacture dermatologic products, including products for the diseases discussed here.

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

Sotagliflozin, a novel type of sodium-glucose cotransporter inhibitor, showed the diverse benefits this drug class provides along some new twists in a pair of international pivotal trials that together enrolled nearly 12,000 patients with type 2 diabetes.

Unprecedented benefits were seen for the first time with a drug, sotagliflozin (Zynquista) that produces both sodium-glucose cotransporter 2 inhibition as well as SGLT1 inhibition.

They included a big reduction in both MIs and strokes; an ability to meaningfully reduce hyperglycemia in patients with severe renal dysfunction with an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73 m²; an ability to safely and effectively start in patients still hospitalized (but stable) for an acute heart failure episode; and a striking 37% relative risk reduction in cardiovascular death, heart failure hospitalizations, or an urgent outpatient visit for heart failure in 739 of the patients enrolled in both trials who had heart failure with preserved ejection fraction (HFpEF).

These studies produced for the first time evidence from controlled, prospective, randomized trials that a drug could improve the outcome of HFpEF patients.

All these novel outcomes came on top of the usual benefits clinicians have generally seen across the SGLT2 inhibitors already on the U.S. market: reductions in cardiovascular death and heart failure hospitalizations among all patients with type 2 diabetes, preservation of renal function, and hemoglobin A1c lowering among T2D patients with eGFR levels of at least 30 mL/min per 1.73 m².

“The data look spectacular,” summed up Deepak L. Bhatt, MD, who presented the results from the two trials, SOLOIST-WHF and SCORED, in talks at the virtual scientific sessions of the American Heart Association.

“I think sotagliflozin has the potential to be the best in class” based on the several added attributes shown in the two trials, he said in an interview. “We’ve shown that it is very safe, well tolerated, and effective.”

The primary results were a significant 33% relative risk reduction with sotagliflozin treatment, compared with placebo in the rate of total cardiovascular deaths, hospitalizations for heart failure, or urgent outpatient visits for heart failure during just over 9 months of median follow-up among patients with T2D recently hospitalized for heart failure in SOLOIST-WFH. And a significant 26% relative risk reduction with sotagliflozin for the same endpoint after a median follow-up of just over 14 months in SCORED, which enrolled patients with T2D and chronic kidney disease.

“Sotagliflozin adds to the SGLT2 inhibitor story,” and the SOLOIST-WHF results “may shift our focus to vulnerable, acute heart failure patients with an opportunity to treat during the transition phase,” when these patients leave the hospital, commented Jane E. Wilcox, MD, the study’s designated discussant and a heart failure cardiologist at Northwestern Medicine in Chicago.
 

A dual SGLT inhibitor

What sets sotagliflozin apart from the SGLT2 inhibitors is that it not only inhibits that protein but also SGTL1, which primarily resides in the gastrointestinal tract and is the main route for gut absorption of glucose. Dr. Bhatt said that he was unaware of any other SGLT1/2 inhibitors currently in advanced clinical testing.

The activity of sotagliflozin against the SGLT1 protein likely explains its ability to cut A1c levels in patients with severe renal dysfunction, a condition that stymies glucose lowering by SGLT2 inhibitors. In SCORED, which randomized 10,584 patients with T2D at 750 study sites in 44 countries, 813 patients (8%) had an eGFR of 25-29 mL/min per 1.73 m² at enrollment. Sotagliflozin treatment led to an average 0.6% cut in A1c in this subgroup, and by the same average amount among the patients with GFRs of 30-60 mL/min per 1.73 m2.

“This is a huge finding for endocrinologists and primary care physicians” who treat patients with T2D who have severe renal dysfunction, said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston. “It’s a good enough reason by itself to approve this drug.”

The same mechanism may also be behind another unexpected finding in SCORED. Treatment with sotagliflozin cut the rate of total episodes of cardiovascular death, nonfatal MI, or nonfatal stroke by an absolute 1.6%, compared with placebo, and by a relative 23%. This benefit was largely driven by a 32% relative risk reduction total in MIs, and a 34% relative risk reduction in total stroke, both significant differences.

“No SGLT2 inhibitor has shown a reduction in stroke, and the MI signals have been mixed. The sizable MI and stroke effects are unique to sotagliflozin,” compared with the SGLT2 inhibitors, and likely reflect one or more mechanisms that result from blocked gut SGLT1 and a cut in GI glucose uptake, said Dr. Bhatt. “Probably some novel mechanism we don’t fully understand.”
 

First-ever HFpEF benefit

In contrast to these two benefits that are probably unique to drugs that inhibit the SGLT1 protein, sotagliflozin showed two other notable and unprecedented benefits that are likely generalizable to the SGLT2 inhibitors.

First is the striking benefit for HFpEF. Neither SOLOIST, which enrolled 1,222 patients with T2D and just hospitalized for worsening heart failure, nor SCORED, which enrolled patients with T2D and chronic kidney disease based exclusively on an eGFR of 25-60 mL/min per 1.73 m², excluded patients with HFpEF, defined as heart failure patients with a left ventricular ejection fraction of at least 50%. The two studies together included a total of 739 of these patients, and they split fairly evenly between treatment with sotagliflozin or placebo.

The combined analysis showed that the incidence rate for the primary endpoint in both SOLOIST and SCORED was 59% with placebo and 39% with sotagliflozin, an absolute event reduction of 11.6 events/100 patient-years, and a significant 37% relative risk reduction, with a number needed to treat to prevent 1 event per year event of 9.

Although this observation comes from a nonprespecified combined analysis, “to me this result seems real, and I think it’s a class effect that I’m willing to extrapolate to the SGLT2 inhibitors,” Dr. Bhatt said. “It will change my practice,” he added, by spurring him to more aggressively prescribe an SGLT2 inhibitor to a patient with T2D and HFpEF.

“I think there has been some hesitation to use SGLT2 inhibitors in T2D patients with HFpEF” because of the paucity of data in this population, even though labeling and society recommendations do not rule it out. “I hope this finding will move that needle, and also generally improve SGLT2 inhibitor uptake, which has been low,” he said.
 

Also safe soon after acute heart failure decompensation

The other finding likely generalizable to SGLT2 inhibitors stems from the design of SOLOIST-WHF, which tested the efficacy and safety of starting sotagliflozin in patients with T2D as soon as they were stable after hospitalization for acute heart failure decompensation.

“Showing safety and efficacy when started in the hospital is pretty meaningful, because its tells patients that this drug is important and they should stay on it,” which should improve adherence, predicted Dr. Bhatt, who is also executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital in Boston. “That’s the ultimate treatment path to prevent patients from falling through the cracks” and failing to receive an SGLT2 inhibitor.

SOLOIST-WHF enrolled patients hospitalized for worsening heart failure who also required intravenous diuretic treatment but had become stable enough to transition to an oral diuretic and come off oxygen. During a median follow-up of just over 9 months (both SOLOIST-WHF and SCORED ended sooner than planned because of a change in drug company sponsorship), treatment with sotagliflozin cut the primary endpoint by a relative 33%, compared with placebo, and with an absolute reduction of 25 events per 100 patient-years for a number needed to treat of 4. Sotagliflozin produced a strikingly high level of treatment efficiency driven by the high event rate in these recently decompensated patients. The benefit also appeared quickly, with a significant cut in events discernible within 28 days.

Extrapolating this finding to the SGLT2 inhibitors is “not a huge leap of faith,” Dr. Bhatt said.

“There is a role for sotagliflozin in acute heart failure. It showed benefit in these high-risk, transition-phase patients,” said Dr. Wilcox.

Simultaneously with Dr. Bhatt’s presentation, results of SOLOIST-WHF and SCORED were published online in the New England Journal of Medicine.

The trials were sponsored initially by Sanofi, and more recently by Lexicon. Dr. Bhatt has received research funding from both companies, and also from several other companies. He also is an adviser to several companies. Dr. Wilcox has been a consultant to Boehringer Ingelheim and Medtronic.

mzoler@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Factor XI has emerged as a promising target for new anticoagulants, and several strategies for inhibiting the enzyme to reduce stroke, thromboembolism, and bleeding risk are under investigation, according to Jeffrey I. Weitz, MD.

These strategies could pick up where direct-acting oral anticoagulants leave off, he suggested during a presentation at the biennial summit of the Thrombosis & Hemostasis Societies of North America.

“We all know that the direct oral anticoagulants – the DOACs – are an advance over vitamin K antagonists,” said Dr. Weitz, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario.

Not only are DOACs at least as effective as vitamin K antagonists such as warfarin for stroke prevention in atrial fibrillation or for treatment of venous thromboembolism (VTE), but they also reduce intracranial bleeding and major bleeding risk in those settings, respectively, and they are more convenient to administer because they can be delivered using fixed doses without the need for coagulation monitoring, he added.

Still, new targets are needed, he said, explaining that, although DOACs moved closer to the goal of attenuating thrombosis without increasing the risk of bleeding, annual rates of major bleeding remain at 2%-3% in the atrial fibrillation population, and rates of major and clinically relevant nonmajor bleeding are about 10%.

“The fear of bleeding leads to underuse of anticoagulants for eligible patients with atrial fibrillation and inappropriate use of low-dose [non–vitamin K antagonist oral anticoagulant] regimens, which can leave patients unprotected from thrombotic complications,” he said.
 

Factor XI

That’s where Factor XI (FXI) may come in, Dr. Weitz said.

Current anticoagulants target enzymes, including FXa or thrombin, in the common pathway of coagulation, but the intrinsic pathway at the level of FXI and FXII has attracted attention in recent years.

The intrinsic pathway is activated when blood comes into contact with medical devices like stents, mechanical heart valves, or central venous catheters, but evidence also suggests that it plays a role in clot stabilization and growth, he explained, noting additional evidence of attenuation of thrombosis in mice deficient in FXI or FXII and in animals with FXI or FXII inhibitors.

“There is no bleeding with congenital FXII deficiency, and patients with FXI deficiency rarely have spontaneous bleeding, although they can bleed with surgery or trauma,” he noted. “Therefore, the promise of contact pathway inhibition is that we can attenuate thrombosis with little or no disruption of hemostasis.”

The initiators of the intrinsic pathway are naturally occurring polyphosphates that can activate FXI and FXII, promote platelet activation, and lead to thrombosis. A number of agents are being investigated to target these enzymes – particularly FXI, for which the strongest epidemiological and other evidence of its link with thrombosis exists. He noted that FXI deficiency appears protective against deep-vein thrombosis (DVT) and ischemic stroke, whereas high levels are linked with an increased risk of venous and arterial thrombosis.

Investigative strategies include the use of antisense oligonucleotides to reduce hepatic synthesis of FXI, aptamers to bind FXI and block its activity, antibodies to bind FXI and block its activation or activity, and small molecules to bind reversibly to the active site of FXI and block its activity “much like the DOACs block the activity of FXa or thrombin.”

“We have to remember that the DOACs have taken over from vitamin K antagonists, like warfarin, for many indications, and as they go generic their uptake will increase even further,” Dr. Weitz said. “When we compare the FXI inhibitors with existing anticoagulants, we don’t necessarily want to go up against the DOACs – we’re looking for indications where [DOACs] have yet to be tested or may be unsafe.”

Potential indications include the following:

Prevention of major adverse cardiovascular events in patients with end-stage renal disease with or without atrial fibrillation.

Provision of a safer platform for antiplatelet therapy in patients with acute coronary syndrome.

Secondary stroke prevention.

Prevention or treatment of cancer-associated VTE.

Prevention of thrombosis associated with central venous catheters, left ventricular assist devices, or mechanical heart valves.

Agents in development

Of the FXI inhibitors in development, ISIS-FXI_Rx, an antisense oligonucleotide against FXI, is furthest along. In a study published in Blood, ISIS-FXI_Rx produced a dose-dependent and sustained reduction in FXI levels in healthy volunteers, and in a later randomized study published in The New England Journal of Medicine, it significantly reduced the incidence of DVT in patients undergoing voluntary total knee arthroplasty (30.4% with enoxaparin vs. 4.2% with ISIS-FXI_Rx at a dose of 300 mg). Bleeding rates were 8.3% and 2.6%, respectively.

The findings showed the potential for reducing thrombosis without increasing bleeding by targeting FXI, Dr. Weitz said, adding that ISIS-FXIR_x was also evaluated in a small study of patients with end-stage renal disease undergoing hemodialysis and was shown to produce a dose-dependent reduction in FXI levels and to reduce the incidence of category 3 and 4 clotting in the air trap and dialyzer, compared with placebo, when given in addition to heparin.

This suggests that FXI knockdown can attenuate device-associated clotting to a greater extent than heparin alone, Dr. Weitz said.

The FXIa-directed inhibitory antibody osocimab has also been evaluated in both healthy volunteers and in patients undergoing total knee arthroplasty. In a 2019 study of healthy volunteers, a single IV injection showed a dose-dependent pharmacokinetic profile and produced FXI inhibition for about 1 month, and in the FOXTROT trial published in January in JAMA by Dr. Weitz and colleagues, osocimab was shown to reduce the incidence of symptomatic VTE, asymptomatic DVT, and VTE-related death up to day 10-13 after total knee arthroplasty.

Osocimab at doses ranging from 0.3-1.8 mg/kg given postoperatively or preoperatively were noninferior to enoxaparin (rates of 15.7%-23.7% vs. 26.3%), and osocimab at a preoperative dose of 1.8 mg/kg was superior to both enoxaparin and apixaban (11.5% vs. 26.3% and 14.5%, respectively), he said.

Bleeding rates ranged from 0%-5% with osocimab, compared with 6% with enoxaparin and 2% with apixaban
 

Ongoing studies

Currently ongoing studies of FXI-directed anticoagulation strategies include a study comparing ISIS-FXI_Rx with placebo in 200 patients with end-stage renal disease, a study comparing osocimab with placebo in 600 patients with end-stage renal disease, and a study comparing abelacimab – an antibody that binds to FXI and prevents its activation by either FXIIa or thrombin, with enoxaparin in 700 patients undergoing total knee arthroplasty, Dr. Weitz said.

Additionally, there is “considerable activity” with small molecule inhibitors of FXIa, including a phase 2, placebo-controlled, dose-ranging study looking at the novel JNG-7003/BMS-986177 agent for secondary stroke/transient ischemic attack prevention in 2,500 patients and a phase 2 study comparing it with enoxaparin for postoperative thromboprophylaxis in 1,200 patients undergoing total knee arthroplasty.

Parallel phase 2 studies are also underway to compare the novel BAY-2433334 small molecule inhibitor with placebo for stroke/transient ischemic attack prevention, with apixaban for atrial fibrillation, and for prevention of major adverse cardiovascular events in patients with acute MI.

These ongoing trials will help determine the risk-benefit profile of FXI inhibitors he said.

Session comoderator Anne Rose, PharmD, pharmacy coordinator at the University of Wisconsin, Madison, noted that these types of agents have been discussed “for quite some time” and asked whether they will be available for use in clinical practice in the near future.

Dr. Weitz predicted it will be at least a few years. The studies are just now moving to phase 2b and will still need to be evaluated in phase 3 trials and for appropriate new indications, he said.

Dr. Weitz reported research support from Canadian Institutes of Health research, Heart and Stroke Foundation, and Canadian Fund for Innovation, and he is a consultant and/or scientific advisory board member for Anthos, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Pfizer, Portola, Servier , and Thetherex.

sworcester@mdedge.com

Pediatric News welcomes Herschel Lessin, MD, to the editorial advisory board.

Dr. Lessin has been a practicing pediatric clinician for the past 39 years at The Children’s Medical Group. In 1997, he was a founding partner of one of the first private practice “supergroups” by merging two competing pediatric practices into one and expanding it to 25 clinicians, with eight offices in three counties in New York state’s Mid-Hudson Valley. The group provides pediatric care to more than 30,000 children and has a nearly 90-year history, across its various incarnations, providing such care.

Dr. Lessin received his medical degree from Stanford (Calif.) University and trained in pediatrics at Yale-New Haven (Conn.) Medical Center. He has been active in national policy and leadership in the American Academy of Pediatrics, having served on the executive committee of the Section of Administration and Practice Management, the national Committee on Practice and Ambulatory Medicine, and his current appointment to the national Private Payer Advocacy Advisory Committee. In those roles he has authored several national policy statements and clinical guidelines, including “Increasing Immunization Coverage,” “Immunizing Parents and Other Close Family Contacts in the Pediatric Office Setting,” “Instrument-Based Pediatric Vision Screening Policy Statement,” and most recently, “Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.” He is also the coeditor of the AAP’s ADHD toolkit for clinicians published in 2019. Dr. Lessin served as the director of clinical research for his group for 5 years and the medical director for the practice for 10 years.

He has served as a faculty member at numerous local and regional pediatric meetings. He has been a faculty member at the AAP’s annual national conference and exposition for the past decade, speaking on a variety of topics. Dr. Lessin also has been an invited speaker internationally at pediatric conferences in India and Egypt. He has participated in more than a dozen medical missions to developing countries in Latin America, the Caribbean, Africa, and Vietnam. His expertise includes practice management, the business of medicine, immunizations, ADHD, and liability topics. He has been a testifying expert witness for both defense and plaintiff in medical malpractice litigation for more than 30 years. He founded and served as president of a medical independent practice association that began with 12 physicians and grew to over 3,000 doctors. He is also a certified managed care executive. His most recent interest has been becoming a professional voice-over actor!

While performing all of the above, Dr. Lessin is a dedicated community pediatrician whose first love and primary goal has remained providing the highest quality medical care to children while helping his colleagues manage their businesses in order to be able to survive and continue to provide such care.

Pediatric News welcomes Herschel Lessin, MD, to the editorial advisory board.

Dr. Lessin has been a practicing pediatric clinician for the past 39 years at The Children’s Medical Group. In 1997, he was a founding partner of one of the first private practice “supergroups” by merging two competing pediatric practices into one and expanding it to 25 clinicians, with eight offices in three counties in New York state’s Mid-Hudson Valley. The group provides pediatric care to more than 30,000 children and has a nearly 90-year history, across its various incarnations, providing such care.

Dr. Lessin received his medical degree from Stanford (Calif.) University and trained in pediatrics at Yale-New Haven (Conn.) Medical Center. He has been active in national policy and leadership in the American Academy of Pediatrics, having served on the executive committee of the Section of Administration and Practice Management, the national Committee on Practice and Ambulatory Medicine, and his current appointment to the national Private Payer Advocacy Advisory Committee. In those roles he has authored several national policy statements and clinical guidelines, including “Increasing Immunization Coverage,” “Immunizing Parents and Other Close Family Contacts in the Pediatric Office Setting,” “Instrument-Based Pediatric Vision Screening Policy Statement,” and most recently, “Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.” He is also the coeditor of the AAP’s ADHD toolkit for clinicians published in 2019. Dr. Lessin served as the director of clinical research for his group for 5 years and the medical director for the practice for 10 years.

He has served as a faculty member at numerous local and regional pediatric meetings. He has been a faculty member at the AAP’s annual national conference and exposition for the past decade, speaking on a variety of topics. Dr. Lessin also has been an invited speaker internationally at pediatric conferences in India and Egypt. He has participated in more than a dozen medical missions to developing countries in Latin America, the Caribbean, Africa, and Vietnam. His expertise includes practice management, the business of medicine, immunizations, ADHD, and liability topics. He has been a testifying expert witness for both defense and plaintiff in medical malpractice litigation for more than 30 years. He founded and served as president of a medical independent practice association that began with 12 physicians and grew to over 3,000 doctors. He is also a certified managed care executive. His most recent interest has been becoming a professional voice-over actor!

While performing all of the above, Dr. Lessin is a dedicated community pediatrician whose first love and primary goal has remained providing the highest quality medical care to children while helping his colleagues manage their businesses in order to be able to survive and continue to provide such care.

Pediatric News welcomes Herschel Lessin, MD, to the editorial advisory board.

Dr. Lessin has been a practicing pediatric clinician for the past 39 years at The Children’s Medical Group. In 1997, he was a founding partner of one of the first private practice “supergroups” by merging two competing pediatric practices into one and expanding it to 25 clinicians, with eight offices in three counties in New York state’s Mid-Hudson Valley. The group provides pediatric care to more than 30,000 children and has a nearly 90-year history, across its various incarnations, providing such care.

Dr. Lessin received his medical degree from Stanford (Calif.) University and trained in pediatrics at Yale-New Haven (Conn.) Medical Center. He has been active in national policy and leadership in the American Academy of Pediatrics, having served on the executive committee of the Section of Administration and Practice Management, the national Committee on Practice and Ambulatory Medicine, and his current appointment to the national Private Payer Advocacy Advisory Committee. In those roles he has authored several national policy statements and clinical guidelines, including “Increasing Immunization Coverage,” “Immunizing Parents and Other Close Family Contacts in the Pediatric Office Setting,” “Instrument-Based Pediatric Vision Screening Policy Statement,” and most recently, “Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents.” He is also the coeditor of the AAP’s ADHD toolkit for clinicians published in 2019. Dr. Lessin served as the director of clinical research for his group for 5 years and the medical director for the practice for 10 years.

He has served as a faculty member at numerous local and regional pediatric meetings. He has been a faculty member at the AAP’s annual national conference and exposition for the past decade, speaking on a variety of topics. Dr. Lessin also has been an invited speaker internationally at pediatric conferences in India and Egypt. He has participated in more than a dozen medical missions to developing countries in Latin America, the Caribbean, Africa, and Vietnam. His expertise includes practice management, the business of medicine, immunizations, ADHD, and liability topics. He has been a testifying expert witness for both defense and plaintiff in medical malpractice litigation for more than 30 years. He founded and served as president of a medical independent practice association that began with 12 physicians and grew to over 3,000 doctors. He is also a certified managed care executive. His most recent interest has been becoming a professional voice-over actor!

While performing all of the above, Dr. Lessin is a dedicated community pediatrician whose first love and primary goal has remained providing the highest quality medical care to children while helping his colleagues manage their businesses in order to be able to survive and continue to provide such care.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, offers his choice of the most important and clinically relevant studies on Crohn's disease presented at the American College of Gastroenterology 2020 virtual annual scientific meeting.

First he looks at studies reflecting three medical approaches to treating the disease. He initially reports on the CELEST open-label extension study examining the safety and efficacy of 2 years of upadacitinib treatment.

Then he discusses the IM-UNITI long-term extension study, which took treatment with ustekinumab out to 5 years, the longest reported duration for an anti-IL-12/23 treatment.

Finally, he looks at a retrospective cohort study of the combination of vedolizumab and ustekinumab, which found that this may be an effective option for patients with refractory disease.

Switching gears, Dr Regueiro focuses on surgery-related studies, presenting an analysis of whether the type of surgical anastomosis influences long-term outcomes and opioid requirement.

Next up is a study of whether prior surgical history is the strongest predictor of postoperative Crohn's disease recurrence.

The last abstract he discusses examines whether preoperative medication exposure is associated with postoperative complications in patients undergoing ileocolic resection. The findings indicate that preoperative treatment should not be seen as a reason to delay surgery.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, offers his choice of the most important and clinically relevant studies on Crohn's disease presented at the American College of Gastroenterology 2020 virtual annual scientific meeting.

First he looks at studies reflecting three medical approaches to treating the disease. He initially reports on the CELEST open-label extension study examining the safety and efficacy of 2 years of upadacitinib treatment.

Then he discusses the IM-UNITI long-term extension study, which took treatment with ustekinumab out to 5 years, the longest reported duration for an anti-IL-12/23 treatment.

Finally, he looks at a retrospective cohort study of the combination of vedolizumab and ustekinumab, which found that this may be an effective option for patients with refractory disease.

Switching gears, Dr Regueiro focuses on surgery-related studies, presenting an analysis of whether the type of surgical anastomosis influences long-term outcomes and opioid requirement.

Next up is a study of whether prior surgical history is the strongest predictor of postoperative Crohn's disease recurrence.

The last abstract he discusses examines whether preoperative medication exposure is associated with postoperative complications in patients undergoing ileocolic resection. The findings indicate that preoperative treatment should not be seen as a reason to delay surgery.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

Miguel Regueiro, MD, an expert in gastroenterology at the Cleveland Clinic, offers his choice of the most important and clinically relevant studies on Crohn's disease presented at the American College of Gastroenterology 2020 virtual annual scientific meeting.

First he looks at studies reflecting three medical approaches to treating the disease. He initially reports on the CELEST open-label extension study examining the safety and efficacy of 2 years of upadacitinib treatment.

Then he discusses the IM-UNITI long-term extension study, which took treatment with ustekinumab out to 5 years, the longest reported duration for an anti-IL-12/23 treatment.

Finally, he looks at a retrospective cohort study of the combination of vedolizumab and ustekinumab, which found that this may be an effective option for patients with refractory disease.

Switching gears, Dr Regueiro focuses on surgery-related studies, presenting an analysis of whether the type of surgical anastomosis influences long-term outcomes and opioid requirement.

Next up is a study of whether prior surgical history is the strongest predictor of postoperative Crohn's disease recurrence.

The last abstract he discusses examines whether preoperative medication exposure is associated with postoperative complications in patients undergoing ileocolic resection. The findings indicate that preoperative treatment should not be seen as a reason to delay surgery.

Miguel D. Regueiro, MD, Chairman, Professor, Department of Gastroenterology, Hepatology, and Nutrition; Vice-Chair, Digestive Disease Institute, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio.

Miguel D. Regueiro, MD, has disclosed the following relevant financial relationships: Serve(d) as an advisor and/or consultant for: AbbVie; Janssen; UCB; Takeda; Pfizer; Miraca Labs; Amgen; Celgene; Seres; Allergan; Genentech; Gilead; Salix; Prometheus. Received unrestricted educational grants from: AbbVie; Janssen; UCB; Pfizer; Takeda; Salix; Shire. Received research support from AbbVie; Janssen; Takeda; Pfizer.

The Accreditation Council for Graduate Medical Education (ACGME) first mandated residency work hour restrictions in 2003.¹ In 2011, revised work hour requirements were issued, further limiting the maximum duration of a shift and extending the duration of time off between scheduled shifts.² Academic medical centers have been forced to adapt to work hour restrictions, and cuts in funding to research and educational missions have pressured institutions to restructure with a greater focus on high-quality, lower-cost care.^3,4 In response, many academic hospitals have added hospitalist teams, or incorporated advanced practice clinicians (APCs) (nurse practitioners [NPs] and physician assistants [PAs]) to accommodate resident physician duty hour restrictions on their inpatient general medicine services.^5,6 More recently, the COVID-19 pandemic has created unanticipated physician shortages forcing medical centers to rapidly expand and broaden the scope of their existing APC workforce.⁷

Several comparisons of clinical outcomes, cost, and patient satisfaction between different combinations of hospitalist-based, resident-based, or APC-based inpatient teams have been reported with conflicting observations.^6,8-14 Roy et al reported no significant differences in mortality, length of stay (LOS), or readmissions between PA and resident teams.⁶ Timmermans et al reported similar cost-effectiveness, LOS, and quality of care between PA and physician teams that included a hybrid of attending only and resident teams.^13,14 Alternatively, Singh et al and Iannuzzi et al reported increased LOS among PA teams,^10,12 whereas Chin et al observed an increased LOS and reduced 30-day readmissions among hospitalist teams.⁸ While these observed differences may be attributable to heterogeneous patient populations or institution-specific team structure, the exact reasons remain unknown. Furthermore, understanding the value of alternate staffing models is essential for medical centers to prepare for potential COVID-19 related physician shortages. To our knowledge, no study to date has directly compared outcomes between resident, APC, and hospitalist team structures within an academic medical center.

We believe our institution provides a unique environment to study the differences in inpatient general medicine team structure with respect to quality and efficiency of care delivery. The objective of our study is to directly compare clinical outcomes and resource utilization among three distinct team structures: APC, resident, and solo hospitalist. We hypothesize that clinical outcomes, cost, and utilization of consult services will be similar across all team structures and hospitalist teams will discharge patients earlier than resident and APC teams.

Study Design and Setting

We conducted a retrospective observational cohort study at the University of Utah Medical Center, a 548-bed academic medical center in Salt Lake City. An electronic database query was used to identify all patients discharged from the inpatient general internal medicine service between July 1, 2015, and July 1, 2018. Baseline patient characteristics were collected including age, gender, and Charlson comorbidity index (CCI).¹⁵ Case-mix index was determined for admissions where a Medicare Severity Diagnosis Related Group (MS-DRG) and corresponding weight was assigned.^16,17 Source of admission was collected to identify patients transferred from an outside hospital, typically due to increased medical complexity or need for specialty care not available at the referring center. Time of admission was collected to classify whether a patient was admitted during the day or at night. Length of stay was calculated as the difference between discharge date/time and admission date/time. Discharge order time was collected as a measure of clinician efficiency. The number of consults per admission was determined by the number of different medical or surgical subspecialty services that wrote at least one consultation or progress note after the time of admission and were not the primary service at the time the note was written. The project was reviewed and deemed exempt by the University of Utah Institutional Review Board (IRB 00104884).

Inpatient Care Team Structure

Patients were assigned to one of three cohorts dependent on the assigned treatment team at the time of discharge. The three inpatient team structures were as follows: (1) a “resident team” composed of a senior resident (postgraduate year [PGY] 2 or PGY3) and one to two medical students or one senior resident, two interns (PGY1), and one to two medical students supervised by a hospitalist physician; (2) an “APC team” composed of one to two APCs supervised by a hospitalist physician; and (3) a “hospitalist team” composed of one attending hospitalist independently managing all patients.

Advanced Practice Clinicians

The APC service included 10 APCs (8 PAs and 2 NPs), with a combined workforce of nine APC full-time equivalents during the study period. Their experience ranged from new graduate to 11 years of clinical experience, with an average of 4.2 years. Among the 6 APCs with prior clinical experience, the majority (86%) of their years of clinical experience were within inpatient medicine, oncology, or cardiology. Recognizing the variability in clinical experience, we employed a rigorous onboarding program that entailed an average of 80 hours of didactic sessions including 1:1 teaching of the inpatient Society of Hospital Medicine core lecture series combined with initial intense clinical oversight.¹⁸ This program ranged from 2 weeks to 6 weeks depending on the individual APC’s clinical experience, progress, and comfort working independently. This onboarding program has subsequently been formalized into a 1-year APC fellowship that began after the study period concluded.

The degree of autonomy for each APC was individualized based on their clinical experience and ability to recognize limitations such as medical decision-making, clinical knowledge, and effective use of interprofessional team members (eg, peers, nursing, ancillary staff, consultants, and support personnel). Those APCs who demonstrated a sufficient level of clinical competence functioned with a high level of autonomy. During the day, APCs were expected to be the first point of contact for interprofessional team members, to respond to acute clinical changes in a patient’s condition, and to discuss active issues with the supervising attending, all with the majority of medical decision-making, direct patient communication, documentation, and care coordination performed by the APC. An experienced subset of the APC service was responsible for overnight coverage. Nocturnist APCs independently managed all cross-cover issues on patients assigned to APC and hospitalist teams and performed admissions with very little to no direct supervision of the overnight attending physician.

Patient Admission and Redistribution Process

During the study period, resident teams performed all daytime admissions (6 am to 6 pm) on a rotating basis. On any given day, three of four resident teams performed daytime admissions with the fourth team designated as “golden” and free from admitting duties. Patients admitted during the day remained assigned to the resident team for continuity. The APC and hospitalist teams did not accept new admissions during the day. Nighttime admissions (6 pm to 6 am) were performed by a separate team composed of two senior residents, two interns, one APC, occasional APC and medical students, and one supervising attending hospitalist. This team functioned as a single unit. Nighttime admissions were performed in a sequential and rotating fashion (eg, Intern A > Intern B > Resident A > Resident B > APC > student(s) > Intern A > Intern B, etc). Patients admitted overnight were randomly redistributed the following morning, with the majority reassigned to an APC team or hospitalist team in order to offset the workload of the resident teams performing daytime admissions. Following redistribution, a patient would remain assigned to the daytime APC or hospitalist team for the duration of their hospitalization. The redistribution decisions were based on individual team census, without systematic consideration of an individual patient’s diagnosis, medical complexity, socioeconomic status, or perceived quality of learning potential (eg, good teaching case).

Study Outcomes

We divided study outcomes into two categories, clinical outcomes and resource utilization. Clinical outcomes included LOS, unplanned readmission within 30-days, and inpatient mortality and were designed to measure patient-related outcomes as a reflection of the quality of care delivered by different team structures. Resource utilization included discharge order time, discharge time, consults per admission, and total direct cost, which were designed to measure provider-related differences in efficiency and cost of care.

Statistical analysis

Baseline characteristics and unadjusted outcomes are reported as frequency and percent, normally distributed variables as mean with SD, and nonnormally distributed variables as median with interquartile range (IQR). Baseline characteristics and unadjusted outcomes were compared using the chi-square test or the t test, where appropriate. Multivariable regression analysis using generalized linear models with a log link function and gamma distribution was used for continuous outcomes. Multivariable logistic regression was used for binary outcomes.¹⁰ Covariates included in regression models were age, gender, CCI, transfer from an outside hospital, and nighttime admission. In a sensitivity analysis, we included MS-DRG weight as a covariate for 85% of hospitalizations in our cohort exclusive of observation stays, and our findings were qualitatively similar (data not reported but available on request). Adjusted continuous outcomes were estimated using marginal effects at the means.¹⁹ Due to the sensitivity of cost data and an institutional policy against disclosing cost figures, total direct costs were normalized using the unadjusted median and adjusted mean total direct cost of an admission to an APC team as the normalizing value. A P value cutoff of .05 was used to determine statistical significance. Stata/IC version 16.1 (StataCorp) was used for all analyses.

Study Population

A total of 12,716 hospital admissions were identified during the study period. Of these, 7,943 (62.5%) admissions were assigned to a resident team, 3,519 (27.7%) admissions were assigned to an APC team, and the remaining 1,254 (9.9%) were assigned to a hospitalist team. Baseline patient characteristics are reported in Table 1. Patients admitted to resident teams (mean age [SD], 56.9 [19.1] years) were younger than those admitted to an APC team (58.0 [19.3] years; P = .004) or a hospitalist team (58.2 [19.3] years; P = .026). The case-mix index (mean MS-DRG weight [SD], 1.44 [0.87]) was slightly lower for resident teams than that for APC teams (1.49 [0.90]; P = .025).Resident teams had a significantly lower proportion of night admissions than did APC teams (32.0% vs 49.5%; P < .001) and hospitalist teams (48.6%; P < .001). APC teams were assigned more patients transferred from an outside hospital (19.1%), compared with resident teams (15.0%; P < .001) and hospitalist teams (16.0%; P = .015). No other significant differences were observed in baseline characteristics between cohorts.

Clinical Outcomes

Unadjusted analysis demonstrated the LOS was similar among resident, APC, and hospitalist teams with a median (IQR) LOS of 2.90 (1.86, 4.26) days, 2.93 (1.89, 4.66) days, and 2.86 (1.84, 4.67) days, respectively. No significant differences were observed in unadjusted 30-day readmissions or inpatient mortality among the team structures (Table 2). Following multivariable adjustment for differences in baseline characteristics, no significant differences were observed in LOS, 30-day readmission, or inpatient mortality among teams (Table 3).

Resource Utilization

In unadjusted comparisons, hospitalist teams were observed to place discharge orders more than 30 minutes earlier than APC teams (median hours after midnight [IQR], 11.20 [9.63, 13.60] vs 11.73 [10.00, 13.87]; P < .001) and 54 minutes earlier than resident teams (12.10 [10.38, 13.90]; P < .001) (Table 2). Consistent with the earlier placement of discharge orders, hospitalist patients were also discharged from the hospital 26 and 32 minutes earlier than APC and resident patients, respectively. APC teams also discharged patients slightly earlier (6 minutes) than resident teams (median hours after midnight [IQR], 14.97 [13.23, 16.72] vs 15.07 [13.42, 16.73]; P = .045). Median consultation use among teams was similar, although statistically significant differences were present. Normalized total direct cost was 8% higher (P < .001) for admissions to APC teams than that for resident teams and 7% higher (P = .008) than that for hospitalist teams in unadjusted analysis (Table 2).

Following multivariable adjustment, the mean differences in discharge order time and discharge time remained significant with hospitalist teams discharging patients an average of 20 to 30 minutes earlier than APC and resident teams (Table 3). Consultant utilization remained significantly different between teams, with APC teams utilizing consultants on average 15% more than hospitalist teams (P < .001) and 7% more than resident teams (P = .001). The differences in total direct costs were not significant after adjusted analysis.

Many academic medical centers have expanded their workforce with APC or nonteaching hospitalist teams to accommodate the increasing volume of hospital admissions, resident work hour restrictions,^1,2 and medical complexity of an aging population. Several hospitals have reported comparative outcomes between different care delivery models, with conflicting results.^6,8,10-12 In our study, we directly evaluated three inpatient care delivery models and found that hospitalist teams discharged patients more efficiently and utilized fewer consultants, compared with APC and resident teams. In spite of this improved efficiency, no significant differences were observed in cost or other clinical outcomes.

Our findings are important and further strengthen the evidence supporting the use of APCs on inpatient general medicine services and are of particular interest to academic centers struggling to expand staffing in order to offset the growth in patient volume and reduction in resident workforce. We believe several findings from our study warrant further discussion.

First, although hospitalist teams were able to discharge patients more efficiently, this observation may be influenced by factors of workflow rather than caused by significant disparities in efficiency between provider types (ie, APC vs hospitalist vs resident physician). As with most academic centers, patients assigned to resident teams are presented by house staff to an attending physician who is ultimately responsible for patient care decisions. Therefore, it is conceivable that delays in the discharge process are in part related to the convention of bedside rounding and discussing the care plan prior to discharge.²⁰ In fact, we recognized this as a bottleneck and changed our discharge process for resident teams in June 2017, with a measurable improvement in discharge times. In the absence of this intervention, our observed differences in discharge times among teams may have been even greater.

Second, no significant differences in clinical outcomes were observed in our adjusted analyses, which suggests that a similar quality of care is delivered to patients regardless of team structure, an important observation when considering different staffing models.

Third, we observed a significant increase in consultation use among resident and APC teams, compared with hospitalists. While we are not able to precisely identify the basis for this variation, we believe it could reflect differences in clinical experience, comfort with diagnostic uncertainty, or the unequal distribution of patients transferred from outside hospitals for tertiary care. Interestingly, the greater consultation use did not correlate with higher healthcare costs, a finding recently reported by Stevens et al.²¹

Fourth, we believe the lack of differences in cost and clinical outcomes among team structures may be of particular interest to academic centers when considering physician burnout, salaries, and clinical education. The relationship between clerical burden, such as completing clinical documentation and computerized physician order entry, has been implicated as a risk factor for physician burnout.²² Incorporating APCs into roles similar to those performed by resident physicians may reduce the clerical burden on hospitalists, thereby reducing the risk of physician burnout. The addition of APCs may also represent opportunities for cost savings for healthcare centers when comparing the median salary of an APC to that of an internal medicine hospitalist.^23,24 Moreover, academic hospitalists have been shown to be excellent medical educators and report increased job satisfaction with a variety of duties beyond direct patient care.^24,25 Unforeseen benefits of adding APC teams within our institution has been the added teaching opportunities for APCs and APC students, increased collegiality with the APCs, and the creation of an APC fellowship program with a focus on inpatient medicine. Similar postgraduate training programs have been reported and serve as effective models to train APCs for hospital-based practice.²⁶

Lastly, although this project was conceived and completed prior to the COVID-19 pandemic, our observations may be informative for medical centers experiencing a workforce shortage caused by a surge of COVID-19 patients. During a physician shortage we believe our APC team model could be rapidly expanded to accommodate a large influx of patients. This expansion could be accomplished through a single attending physician overseeing multiple APC teams. In this model, the supervising physician would only evaluate the most complex patients with most patients being managed solely by an APC from admission to discharge. Such changes may require temporary suspension of state laws restricting APC independent practice.^27,28

Our findings contrast those of previous reports in that we did not observe significant differences in clinical outcomes (ie, LOS, inpatient mortality, and 30-day readmissions) or total direct cost.^8,10,21 Other institutions have noted an increased LOS among APC teams and hospitalist teams, compared with resident teams.^8,10 Furthermore, Chin et al and Iannuzzi et al reported reductions in healthcare cost for resident teams, whereas our study did not identify significant cost differences among team structures. Although we cannot pinpoint the exact reason(s) for these dissimilarities, it is plausible that unmeasured factors such as institutional differences in APC training, direct physician supervision, admission processes, or inpatient team census may play a role.

Several study limitations should be recognized. First, the retrospective, nonrandomized design is one of the largest limitations of our study. Administrative data was obtained via an electronic query of our data warehouse, and although we aimed to identify as many patient characteristics as possible to adjust for cofounding effects, undetected differences among cohorts may exist. Second, our inpatient admission process may have placed undue burden on resident teams to perform all daytime admissions, inadvertently affecting study outcomes. It is possible the observed benefits of a solo hospitalist team are attributable to the lack of admitting duties rather than inherent advantages of the team structure. If this were the case, we would expect similar benefits among APC teams, which we did not note. Third, the study was performed at a single academic center, which may limit the generalizability of our results. Fourth, it is possible the outcomes are similar among teams because our hospitalist faculty rotate proportionately between the different teams. Lastly, the study was underpowered to detect a significant difference in mortality between hospitalist and APC teams. A post hoc power calculation based on our observed sample and effect sizes estimated 75% power to detect a mortality difference between hospitalists and APCs; other mortality comparisons were adequately powered.

We observed similar total direct costs, LOS, 30-day readmission, and inpatient mortality between hospitalist, APC, and resident teams. APC and resident teams utilized more consultants and discharged patient later than hospitalists. Our analysis suggests clinical outcomes are not significantly affected by inpatient team structure, and the addition of general medicine inpatient APC or hospitalist teams represent safe and efficient alternatives to traditional resident teams within an academic medical center.

All authors declare they have no conflicts of interest.

The Accreditation Council for Graduate Medical Education (ACGME) first mandated residency work hour restrictions in 2003.¹ In 2011, revised work hour requirements were issued, further limiting the maximum duration of a shift and extending the duration of time off between scheduled shifts.² Academic medical centers have been forced to adapt to work hour restrictions, and cuts in funding to research and educational missions have pressured institutions to restructure with a greater focus on high-quality, lower-cost care.^3,4 In response, many academic hospitals have added hospitalist teams, or incorporated advanced practice clinicians (APCs) (nurse practitioners [NPs] and physician assistants [PAs]) to accommodate resident physician duty hour restrictions on their inpatient general medicine services.^5,6 More recently, the COVID-19 pandemic has created unanticipated physician shortages forcing medical centers to rapidly expand and broaden the scope of their existing APC workforce.⁷

Several comparisons of clinical outcomes, cost, and patient satisfaction between different combinations of hospitalist-based, resident-based, or APC-based inpatient teams have been reported with conflicting observations.^6,8-14 Roy et al reported no significant differences in mortality, length of stay (LOS), or readmissions between PA and resident teams.⁶ Timmermans et al reported similar cost-effectiveness, LOS, and quality of care between PA and physician teams that included a hybrid of attending only and resident teams.^13,14 Alternatively, Singh et al and Iannuzzi et al reported increased LOS among PA teams,^10,12 whereas Chin et al observed an increased LOS and reduced 30-day readmissions among hospitalist teams.⁸ While these observed differences may be attributable to heterogeneous patient populations or institution-specific team structure, the exact reasons remain unknown. Furthermore, understanding the value of alternate staffing models is essential for medical centers to prepare for potential COVID-19 related physician shortages. To our knowledge, no study to date has directly compared outcomes between resident, APC, and hospitalist team structures within an academic medical center.

We believe our institution provides a unique environment to study the differences in inpatient general medicine team structure with respect to quality and efficiency of care delivery. The objective of our study is to directly compare clinical outcomes and resource utilization among three distinct team structures: APC, resident, and solo hospitalist. We hypothesize that clinical outcomes, cost, and utilization of consult services will be similar across all team structures and hospitalist teams will discharge patients earlier than resident and APC teams.

Study Design and Setting

We conducted a retrospective observational cohort study at the University of Utah Medical Center, a 548-bed academic medical center in Salt Lake City. An electronic database query was used to identify all patients discharged from the inpatient general internal medicine service between July 1, 2015, and July 1, 2018. Baseline patient characteristics were collected including age, gender, and Charlson comorbidity index (CCI).¹⁵ Case-mix index was determined for admissions where a Medicare Severity Diagnosis Related Group (MS-DRG) and corresponding weight was assigned.^16,17 Source of admission was collected to identify patients transferred from an outside hospital, typically due to increased medical complexity or need for specialty care not available at the referring center. Time of admission was collected to classify whether a patient was admitted during the day or at night. Length of stay was calculated as the difference between discharge date/time and admission date/time. Discharge order time was collected as a measure of clinician efficiency. The number of consults per admission was determined by the number of different medical or surgical subspecialty services that wrote at least one consultation or progress note after the time of admission and were not the primary service at the time the note was written. The project was reviewed and deemed exempt by the University of Utah Institutional Review Board (IRB 00104884).

Inpatient Care Team Structure

Patients were assigned to one of three cohorts dependent on the assigned treatment team at the time of discharge. The three inpatient team structures were as follows: (1) a “resident team” composed of a senior resident (postgraduate year [PGY] 2 or PGY3) and one to two medical students or one senior resident, two interns (PGY1), and one to two medical students supervised by a hospitalist physician; (2) an “APC team” composed of one to two APCs supervised by a hospitalist physician; and (3) a “hospitalist team” composed of one attending hospitalist independently managing all patients.

Advanced Practice Clinicians

The APC service included 10 APCs (8 PAs and 2 NPs), with a combined workforce of nine APC full-time equivalents during the study period. Their experience ranged from new graduate to 11 years of clinical experience, with an average of 4.2 years. Among the 6 APCs with prior clinical experience, the majority (86%) of their years of clinical experience were within inpatient medicine, oncology, or cardiology. Recognizing the variability in clinical experience, we employed a rigorous onboarding program that entailed an average of 80 hours of didactic sessions including 1:1 teaching of the inpatient Society of Hospital Medicine core lecture series combined with initial intense clinical oversight.¹⁸ This program ranged from 2 weeks to 6 weeks depending on the individual APC’s clinical experience, progress, and comfort working independently. This onboarding program has subsequently been formalized into a 1-year APC fellowship that began after the study period concluded.

The degree of autonomy for each APC was individualized based on their clinical experience and ability to recognize limitations such as medical decision-making, clinical knowledge, and effective use of interprofessional team members (eg, peers, nursing, ancillary staff, consultants, and support personnel). Those APCs who demonstrated a sufficient level of clinical competence functioned with a high level of autonomy. During the day, APCs were expected to be the first point of contact for interprofessional team members, to respond to acute clinical changes in a patient’s condition, and to discuss active issues with the supervising attending, all with the majority of medical decision-making, direct patient communication, documentation, and care coordination performed by the APC. An experienced subset of the APC service was responsible for overnight coverage. Nocturnist APCs independently managed all cross-cover issues on patients assigned to APC and hospitalist teams and performed admissions with very little to no direct supervision of the overnight attending physician.

Patient Admission and Redistribution Process

During the study period, resident teams performed all daytime admissions (6 am to 6 pm) on a rotating basis. On any given day, three of four resident teams performed daytime admissions with the fourth team designated as “golden” and free from admitting duties. Patients admitted during the day remained assigned to the resident team for continuity. The APC and hospitalist teams did not accept new admissions during the day. Nighttime admissions (6 pm to 6 am) were performed by a separate team composed of two senior residents, two interns, one APC, occasional APC and medical students, and one supervising attending hospitalist. This team functioned as a single unit. Nighttime admissions were performed in a sequential and rotating fashion (eg, Intern A > Intern B > Resident A > Resident B > APC > student(s) > Intern A > Intern B, etc). Patients admitted overnight were randomly redistributed the following morning, with the majority reassigned to an APC team or hospitalist team in order to offset the workload of the resident teams performing daytime admissions. Following redistribution, a patient would remain assigned to the daytime APC or hospitalist team for the duration of their hospitalization. The redistribution decisions were based on individual team census, without systematic consideration of an individual patient’s diagnosis, medical complexity, socioeconomic status, or perceived quality of learning potential (eg, good teaching case).

Study Outcomes

We divided study outcomes into two categories, clinical outcomes and resource utilization. Clinical outcomes included LOS, unplanned readmission within 30-days, and inpatient mortality and were designed to measure patient-related outcomes as a reflection of the quality of care delivered by different team structures. Resource utilization included discharge order time, discharge time, consults per admission, and total direct cost, which were designed to measure provider-related differences in efficiency and cost of care.

Statistical analysis

Baseline characteristics and unadjusted outcomes are reported as frequency and percent, normally distributed variables as mean with SD, and nonnormally distributed variables as median with interquartile range (IQR). Baseline characteristics and unadjusted outcomes were compared using the chi-square test or the t test, where appropriate. Multivariable regression analysis using generalized linear models with a log link function and gamma distribution was used for continuous outcomes. Multivariable logistic regression was used for binary outcomes.¹⁰ Covariates included in regression models were age, gender, CCI, transfer from an outside hospital, and nighttime admission. In a sensitivity analysis, we included MS-DRG weight as a covariate for 85% of hospitalizations in our cohort exclusive of observation stays, and our findings were qualitatively similar (data not reported but available on request). Adjusted continuous outcomes were estimated using marginal effects at the means.¹⁹ Due to the sensitivity of cost data and an institutional policy against disclosing cost figures, total direct costs were normalized using the unadjusted median and adjusted mean total direct cost of an admission to an APC team as the normalizing value. A P value cutoff of .05 was used to determine statistical significance. Stata/IC version 16.1 (StataCorp) was used for all analyses.

Study Population

A total of 12,716 hospital admissions were identified during the study period. Of these, 7,943 (62.5%) admissions were assigned to a resident team, 3,519 (27.7%) admissions were assigned to an APC team, and the remaining 1,254 (9.9%) were assigned to a hospitalist team. Baseline patient characteristics are reported in Table 1. Patients admitted to resident teams (mean age [SD], 56.9 [19.1] years) were younger than those admitted to an APC team (58.0 [19.3] years; P = .004) or a hospitalist team (58.2 [19.3] years; P = .026). The case-mix index (mean MS-DRG weight [SD], 1.44 [0.87]) was slightly lower for resident teams than that for APC teams (1.49 [0.90]; P = .025).Resident teams had a significantly lower proportion of night admissions than did APC teams (32.0% vs 49.5%; P < .001) and hospitalist teams (48.6%; P < .001). APC teams were assigned more patients transferred from an outside hospital (19.1%), compared with resident teams (15.0%; P < .001) and hospitalist teams (16.0%; P = .015). No other significant differences were observed in baseline characteristics between cohorts.

Clinical Outcomes

Unadjusted analysis demonstrated the LOS was similar among resident, APC, and hospitalist teams with a median (IQR) LOS of 2.90 (1.86, 4.26) days, 2.93 (1.89, 4.66) days, and 2.86 (1.84, 4.67) days, respectively. No significant differences were observed in unadjusted 30-day readmissions or inpatient mortality among the team structures (Table 2). Following multivariable adjustment for differences in baseline characteristics, no significant differences were observed in LOS, 30-day readmission, or inpatient mortality among teams (Table 3).

Resource Utilization

In unadjusted comparisons, hospitalist teams were observed to place discharge orders more than 30 minutes earlier than APC teams (median hours after midnight [IQR], 11.20 [9.63, 13.60] vs 11.73 [10.00, 13.87]; P < .001) and 54 minutes earlier than resident teams (12.10 [10.38, 13.90]; P < .001) (Table 2). Consistent with the earlier placement of discharge orders, hospitalist patients were also discharged from the hospital 26 and 32 minutes earlier than APC and resident patients, respectively. APC teams also discharged patients slightly earlier (6 minutes) than resident teams (median hours after midnight [IQR], 14.97 [13.23, 16.72] vs 15.07 [13.42, 16.73]; P = .045). Median consultation use among teams was similar, although statistically significant differences were present. Normalized total direct cost was 8% higher (P < .001) for admissions to APC teams than that for resident teams and 7% higher (P = .008) than that for hospitalist teams in unadjusted analysis (Table 2).

Following multivariable adjustment, the mean differences in discharge order time and discharge time remained significant with hospitalist teams discharging patients an average of 20 to 30 minutes earlier than APC and resident teams (Table 3). Consultant utilization remained significantly different between teams, with APC teams utilizing consultants on average 15% more than hospitalist teams (P < .001) and 7% more than resident teams (P = .001). The differences in total direct costs were not significant after adjusted analysis.

Many academic medical centers have expanded their workforce with APC or nonteaching hospitalist teams to accommodate the increasing volume of hospital admissions, resident work hour restrictions,^1,2 and medical complexity of an aging population. Several hospitals have reported comparative outcomes between different care delivery models, with conflicting results.^6,8,10-12 In our study, we directly evaluated three inpatient care delivery models and found that hospitalist teams discharged patients more efficiently and utilized fewer consultants, compared with APC and resident teams. In spite of this improved efficiency, no significant differences were observed in cost or other clinical outcomes.

Our findings are important and further strengthen the evidence supporting the use of APCs on inpatient general medicine services and are of particular interest to academic centers struggling to expand staffing in order to offset the growth in patient volume and reduction in resident workforce. We believe several findings from our study warrant further discussion.

First, although hospitalist teams were able to discharge patients more efficiently, this observation may be influenced by factors of workflow rather than caused by significant disparities in efficiency between provider types (ie, APC vs hospitalist vs resident physician). As with most academic centers, patients assigned to resident teams are presented by house staff to an attending physician who is ultimately responsible for patient care decisions. Therefore, it is conceivable that delays in the discharge process are in part related to the convention of bedside rounding and discussing the care plan prior to discharge.²⁰ In fact, we recognized this as a bottleneck and changed our discharge process for resident teams in June 2017, with a measurable improvement in discharge times. In the absence of this intervention, our observed differences in discharge times among teams may have been even greater.

Second, no significant differences in clinical outcomes were observed in our adjusted analyses, which suggests that a similar quality of care is delivered to patients regardless of team structure, an important observation when considering different staffing models.

Third, we observed a significant increase in consultation use among resident and APC teams, compared with hospitalists. While we are not able to precisely identify the basis for this variation, we believe it could reflect differences in clinical experience, comfort with diagnostic uncertainty, or the unequal distribution of patients transferred from outside hospitals for tertiary care. Interestingly, the greater consultation use did not correlate with higher healthcare costs, a finding recently reported by Stevens et al.²¹

Fourth, we believe the lack of differences in cost and clinical outcomes among team structures may be of particular interest to academic centers when considering physician burnout, salaries, and clinical education. The relationship between clerical burden, such as completing clinical documentation and computerized physician order entry, has been implicated as a risk factor for physician burnout.²² Incorporating APCs into roles similar to those performed by resident physicians may reduce the clerical burden on hospitalists, thereby reducing the risk of physician burnout. The addition of APCs may also represent opportunities for cost savings for healthcare centers when comparing the median salary of an APC to that of an internal medicine hospitalist.^23,24 Moreover, academic hospitalists have been shown to be excellent medical educators and report increased job satisfaction with a variety of duties beyond direct patient care.^24,25 Unforeseen benefits of adding APC teams within our institution has been the added teaching opportunities for APCs and APC students, increased collegiality with the APCs, and the creation of an APC fellowship program with a focus on inpatient medicine. Similar postgraduate training programs have been reported and serve as effective models to train APCs for hospital-based practice.²⁶

Lastly, although this project was conceived and completed prior to the COVID-19 pandemic, our observations may be informative for medical centers experiencing a workforce shortage caused by a surge of COVID-19 patients. During a physician shortage we believe our APC team model could be rapidly expanded to accommodate a large influx of patients. This expansion could be accomplished through a single attending physician overseeing multiple APC teams. In this model, the supervising physician would only evaluate the most complex patients with most patients being managed solely by an APC from admission to discharge. Such changes may require temporary suspension of state laws restricting APC independent practice.^27,28

Our findings contrast those of previous reports in that we did not observe significant differences in clinical outcomes (ie, LOS, inpatient mortality, and 30-day readmissions) or total direct cost.^8,10,21 Other institutions have noted an increased LOS among APC teams and hospitalist teams, compared with resident teams.^8,10 Furthermore, Chin et al and Iannuzzi et al reported reductions in healthcare cost for resident teams, whereas our study did not identify significant cost differences among team structures. Although we cannot pinpoint the exact reason(s) for these dissimilarities, it is plausible that unmeasured factors such as institutional differences in APC training, direct physician supervision, admission processes, or inpatient team census may play a role.

Several study limitations should be recognized. First, the retrospective, nonrandomized design is one of the largest limitations of our study. Administrative data was obtained via an electronic query of our data warehouse, and although we aimed to identify as many patient characteristics as possible to adjust for cofounding effects, undetected differences among cohorts may exist. Second, our inpatient admission process may have placed undue burden on resident teams to perform all daytime admissions, inadvertently affecting study outcomes. It is possible the observed benefits of a solo hospitalist team are attributable to the lack of admitting duties rather than inherent advantages of the team structure. If this were the case, we would expect similar benefits among APC teams, which we did not note. Third, the study was performed at a single academic center, which may limit the generalizability of our results. Fourth, it is possible the outcomes are similar among teams because our hospitalist faculty rotate proportionately between the different teams. Lastly, the study was underpowered to detect a significant difference in mortality between hospitalist and APC teams. A post hoc power calculation based on our observed sample and effect sizes estimated 75% power to detect a mortality difference between hospitalists and APCs; other mortality comparisons were adequately powered.

We observed similar total direct costs, LOS, 30-day readmission, and inpatient mortality between hospitalist, APC, and resident teams. APC and resident teams utilized more consultants and discharged patient later than hospitalists. Our analysis suggests clinical outcomes are not significantly affected by inpatient team structure, and the addition of general medicine inpatient APC or hospitalist teams represent safe and efficient alternatives to traditional resident teams within an academic medical center.

All authors declare they have no conflicts of interest.

The Accreditation Council for Graduate Medical Education (ACGME) first mandated residency work hour restrictions in 2003.¹ In 2011, revised work hour requirements were issued, further limiting the maximum duration of a shift and extending the duration of time off between scheduled shifts.² Academic medical centers have been forced to adapt to work hour restrictions, and cuts in funding to research and educational missions have pressured institutions to restructure with a greater focus on high-quality, lower-cost care.^3,4 In response, many academic hospitals have added hospitalist teams, or incorporated advanced practice clinicians (APCs) (nurse practitioners [NPs] and physician assistants [PAs]) to accommodate resident physician duty hour restrictions on their inpatient general medicine services.^5,6 More recently, the COVID-19 pandemic has created unanticipated physician shortages forcing medical centers to rapidly expand and broaden the scope of their existing APC workforce.⁷

Several comparisons of clinical outcomes, cost, and patient satisfaction between different combinations of hospitalist-based, resident-based, or APC-based inpatient teams have been reported with conflicting observations.^6,8-14 Roy et al reported no significant differences in mortality, length of stay (LOS), or readmissions between PA and resident teams.⁶ Timmermans et al reported similar cost-effectiveness, LOS, and quality of care between PA and physician teams that included a hybrid of attending only and resident teams.^13,14 Alternatively, Singh et al and Iannuzzi et al reported increased LOS among PA teams,^10,12 whereas Chin et al observed an increased LOS and reduced 30-day readmissions among hospitalist teams.⁸ While these observed differences may be attributable to heterogeneous patient populations or institution-specific team structure, the exact reasons remain unknown. Furthermore, understanding the value of alternate staffing models is essential for medical centers to prepare for potential COVID-19 related physician shortages. To our knowledge, no study to date has directly compared outcomes between resident, APC, and hospitalist team structures within an academic medical center.

We believe our institution provides a unique environment to study the differences in inpatient general medicine team structure with respect to quality and efficiency of care delivery. The objective of our study is to directly compare clinical outcomes and resource utilization among three distinct team structures: APC, resident, and solo hospitalist. We hypothesize that clinical outcomes, cost, and utilization of consult services will be similar across all team structures and hospitalist teams will discharge patients earlier than resident and APC teams.

Study Design and Setting

We conducted a retrospective observational cohort study at the University of Utah Medical Center, a 548-bed academic medical center in Salt Lake City. An electronic database query was used to identify all patients discharged from the inpatient general internal medicine service between July 1, 2015, and July 1, 2018. Baseline patient characteristics were collected including age, gender, and Charlson comorbidity index (CCI).¹⁵ Case-mix index was determined for admissions where a Medicare Severity Diagnosis Related Group (MS-DRG) and corresponding weight was assigned.^16,17 Source of admission was collected to identify patients transferred from an outside hospital, typically due to increased medical complexity or need for specialty care not available at the referring center. Time of admission was collected to classify whether a patient was admitted during the day or at night. Length of stay was calculated as the difference between discharge date/time and admission date/time. Discharge order time was collected as a measure of clinician efficiency. The number of consults per admission was determined by the number of different medical or surgical subspecialty services that wrote at least one consultation or progress note after the time of admission and were not the primary service at the time the note was written. The project was reviewed and deemed exempt by the University of Utah Institutional Review Board (IRB 00104884).

Inpatient Care Team Structure

Patients were assigned to one of three cohorts dependent on the assigned treatment team at the time of discharge. The three inpatient team structures were as follows: (1) a “resident team” composed of a senior resident (postgraduate year [PGY] 2 or PGY3) and one to two medical students or one senior resident, two interns (PGY1), and one to two medical students supervised by a hospitalist physician; (2) an “APC team” composed of one to two APCs supervised by a hospitalist physician; and (3) a “hospitalist team” composed of one attending hospitalist independently managing all patients.

Advanced Practice Clinicians

The APC service included 10 APCs (8 PAs and 2 NPs), with a combined workforce of nine APC full-time equivalents during the study period. Their experience ranged from new graduate to 11 years of clinical experience, with an average of 4.2 years. Among the 6 APCs with prior clinical experience, the majority (86%) of their years of clinical experience were within inpatient medicine, oncology, or cardiology. Recognizing the variability in clinical experience, we employed a rigorous onboarding program that entailed an average of 80 hours of didactic sessions including 1:1 teaching of the inpatient Society of Hospital Medicine core lecture series combined with initial intense clinical oversight.¹⁸ This program ranged from 2 weeks to 6 weeks depending on the individual APC’s clinical experience, progress, and comfort working independently. This onboarding program has subsequently been formalized into a 1-year APC fellowship that began after the study period concluded.

The degree of autonomy for each APC was individualized based on their clinical experience and ability to recognize limitations such as medical decision-making, clinical knowledge, and effective use of interprofessional team members (eg, peers, nursing, ancillary staff, consultants, and support personnel). Those APCs who demonstrated a sufficient level of clinical competence functioned with a high level of autonomy. During the day, APCs were expected to be the first point of contact for interprofessional team members, to respond to acute clinical changes in a patient’s condition, and to discuss active issues with the supervising attending, all with the majority of medical decision-making, direct patient communication, documentation, and care coordination performed by the APC. An experienced subset of the APC service was responsible for overnight coverage. Nocturnist APCs independently managed all cross-cover issues on patients assigned to APC and hospitalist teams and performed admissions with very little to no direct supervision of the overnight attending physician.

Patient Admission and Redistribution Process

During the study period, resident teams performed all daytime admissions (6 am to 6 pm) on a rotating basis. On any given day, three of four resident teams performed daytime admissions with the fourth team designated as “golden” and free from admitting duties. Patients admitted during the day remained assigned to the resident team for continuity. The APC and hospitalist teams did not accept new admissions during the day. Nighttime admissions (6 pm to 6 am) were performed by a separate team composed of two senior residents, two interns, one APC, occasional APC and medical students, and one supervising attending hospitalist. This team functioned as a single unit. Nighttime admissions were performed in a sequential and rotating fashion (eg, Intern A > Intern B > Resident A > Resident B > APC > student(s) > Intern A > Intern B, etc). Patients admitted overnight were randomly redistributed the following morning, with the majority reassigned to an APC team or hospitalist team in order to offset the workload of the resident teams performing daytime admissions. Following redistribution, a patient would remain assigned to the daytime APC or hospitalist team for the duration of their hospitalization. The redistribution decisions were based on individual team census, without systematic consideration of an individual patient’s diagnosis, medical complexity, socioeconomic status, or perceived quality of learning potential (eg, good teaching case).

Study Outcomes

We divided study outcomes into two categories, clinical outcomes and resource utilization. Clinical outcomes included LOS, unplanned readmission within 30-days, and inpatient mortality and were designed to measure patient-related outcomes as a reflection of the quality of care delivered by different team structures. Resource utilization included discharge order time, discharge time, consults per admission, and total direct cost, which were designed to measure provider-related differences in efficiency and cost of care.

Statistical analysis

Baseline characteristics and unadjusted outcomes are reported as frequency and percent, normally distributed variables as mean with SD, and nonnormally distributed variables as median with interquartile range (IQR). Baseline characteristics and unadjusted outcomes were compared using the chi-square test or the t test, where appropriate. Multivariable regression analysis using generalized linear models with a log link function and gamma distribution was used for continuous outcomes. Multivariable logistic regression was used for binary outcomes.¹⁰ Covariates included in regression models were age, gender, CCI, transfer from an outside hospital, and nighttime admission. In a sensitivity analysis, we included MS-DRG weight as a covariate for 85% of hospitalizations in our cohort exclusive of observation stays, and our findings were qualitatively similar (data not reported but available on request). Adjusted continuous outcomes were estimated using marginal effects at the means.¹⁹ Due to the sensitivity of cost data and an institutional policy against disclosing cost figures, total direct costs were normalized using the unadjusted median and adjusted mean total direct cost of an admission to an APC team as the normalizing value. A P value cutoff of .05 was used to determine statistical significance. Stata/IC version 16.1 (StataCorp) was used for all analyses.

Study Population

A total of 12,716 hospital admissions were identified during the study period. Of these, 7,943 (62.5%) admissions were assigned to a resident team, 3,519 (27.7%) admissions were assigned to an APC team, and the remaining 1,254 (9.9%) were assigned to a hospitalist team. Baseline patient characteristics are reported in Table 1. Patients admitted to resident teams (mean age [SD], 56.9 [19.1] years) were younger than those admitted to an APC team (58.0 [19.3] years; P = .004) or a hospitalist team (58.2 [19.3] years; P = .026). The case-mix index (mean MS-DRG weight [SD], 1.44 [0.87]) was slightly lower for resident teams than that for APC teams (1.49 [0.90]; P = .025).Resident teams had a significantly lower proportion of night admissions than did APC teams (32.0% vs 49.5%; P < .001) and hospitalist teams (48.6%; P < .001). APC teams were assigned more patients transferred from an outside hospital (19.1%), compared with resident teams (15.0%; P < .001) and hospitalist teams (16.0%; P = .015). No other significant differences were observed in baseline characteristics between cohorts.

Clinical Outcomes

Unadjusted analysis demonstrated the LOS was similar among resident, APC, and hospitalist teams with a median (IQR) LOS of 2.90 (1.86, 4.26) days, 2.93 (1.89, 4.66) days, and 2.86 (1.84, 4.67) days, respectively. No significant differences were observed in unadjusted 30-day readmissions or inpatient mortality among the team structures (Table 2). Following multivariable adjustment for differences in baseline characteristics, no significant differences were observed in LOS, 30-day readmission, or inpatient mortality among teams (Table 3).

Resource Utilization

In unadjusted comparisons, hospitalist teams were observed to place discharge orders more than 30 minutes earlier than APC teams (median hours after midnight [IQR], 11.20 [9.63, 13.60] vs 11.73 [10.00, 13.87]; P < .001) and 54 minutes earlier than resident teams (12.10 [10.38, 13.90]; P < .001) (Table 2). Consistent with the earlier placement of discharge orders, hospitalist patients were also discharged from the hospital 26 and 32 minutes earlier than APC and resident patients, respectively. APC teams also discharged patients slightly earlier (6 minutes) than resident teams (median hours after midnight [IQR], 14.97 [13.23, 16.72] vs 15.07 [13.42, 16.73]; P = .045). Median consultation use among teams was similar, although statistically significant differences were present. Normalized total direct cost was 8% higher (P < .001) for admissions to APC teams than that for resident teams and 7% higher (P = .008) than that for hospitalist teams in unadjusted analysis (Table 2).

Following multivariable adjustment, the mean differences in discharge order time and discharge time remained significant with hospitalist teams discharging patients an average of 20 to 30 minutes earlier than APC and resident teams (Table 3). Consultant utilization remained significantly different between teams, with APC teams utilizing consultants on average 15% more than hospitalist teams (P < .001) and 7% more than resident teams (P = .001). The differences in total direct costs were not significant after adjusted analysis.

Many academic medical centers have expanded their workforce with APC or nonteaching hospitalist teams to accommodate the increasing volume of hospital admissions, resident work hour restrictions,^1,2 and medical complexity of an aging population. Several hospitals have reported comparative outcomes between different care delivery models, with conflicting results.^6,8,10-12 In our study, we directly evaluated three inpatient care delivery models and found that hospitalist teams discharged patients more efficiently and utilized fewer consultants, compared with APC and resident teams. In spite of this improved efficiency, no significant differences were observed in cost or other clinical outcomes.

Our findings are important and further strengthen the evidence supporting the use of APCs on inpatient general medicine services and are of particular interest to academic centers struggling to expand staffing in order to offset the growth in patient volume and reduction in resident workforce. We believe several findings from our study warrant further discussion.

First, although hospitalist teams were able to discharge patients more efficiently, this observation may be influenced by factors of workflow rather than caused by significant disparities in efficiency between provider types (ie, APC vs hospitalist vs resident physician). As with most academic centers, patients assigned to resident teams are presented by house staff to an attending physician who is ultimately responsible for patient care decisions. Therefore, it is conceivable that delays in the discharge process are in part related to the convention of bedside rounding and discussing the care plan prior to discharge.²⁰ In fact, we recognized this as a bottleneck and changed our discharge process for resident teams in June 2017, with a measurable improvement in discharge times. In the absence of this intervention, our observed differences in discharge times among teams may have been even greater.

Second, no significant differences in clinical outcomes were observed in our adjusted analyses, which suggests that a similar quality of care is delivered to patients regardless of team structure, an important observation when considering different staffing models.

Third, we observed a significant increase in consultation use among resident and APC teams, compared with hospitalists. While we are not able to precisely identify the basis for this variation, we believe it could reflect differences in clinical experience, comfort with diagnostic uncertainty, or the unequal distribution of patients transferred from outside hospitals for tertiary care. Interestingly, the greater consultation use did not correlate with higher healthcare costs, a finding recently reported by Stevens et al.²¹

Fourth, we believe the lack of differences in cost and clinical outcomes among team structures may be of particular interest to academic centers when considering physician burnout, salaries, and clinical education. The relationship between clerical burden, such as completing clinical documentation and computerized physician order entry, has been implicated as a risk factor for physician burnout.²² Incorporating APCs into roles similar to those performed by resident physicians may reduce the clerical burden on hospitalists, thereby reducing the risk of physician burnout. The addition of APCs may also represent opportunities for cost savings for healthcare centers when comparing the median salary of an APC to that of an internal medicine hospitalist.^23,24 Moreover, academic hospitalists have been shown to be excellent medical educators and report increased job satisfaction with a variety of duties beyond direct patient care.^24,25 Unforeseen benefits of adding APC teams within our institution has been the added teaching opportunities for APCs and APC students, increased collegiality with the APCs, and the creation of an APC fellowship program with a focus on inpatient medicine. Similar postgraduate training programs have been reported and serve as effective models to train APCs for hospital-based practice.²⁶

Lastly, although this project was conceived and completed prior to the COVID-19 pandemic, our observations may be informative for medical centers experiencing a workforce shortage caused by a surge of COVID-19 patients. During a physician shortage we believe our APC team model could be rapidly expanded to accommodate a large influx of patients. This expansion could be accomplished through a single attending physician overseeing multiple APC teams. In this model, the supervising physician would only evaluate the most complex patients with most patients being managed solely by an APC from admission to discharge. Such changes may require temporary suspension of state laws restricting APC independent practice.^27,28

Our findings contrast those of previous reports in that we did not observe significant differences in clinical outcomes (ie, LOS, inpatient mortality, and 30-day readmissions) or total direct cost.^8,10,21 Other institutions have noted an increased LOS among APC teams and hospitalist teams, compared with resident teams.^8,10 Furthermore, Chin et al and Iannuzzi et al reported reductions in healthcare cost for resident teams, whereas our study did not identify significant cost differences among team structures. Although we cannot pinpoint the exact reason(s) for these dissimilarities, it is plausible that unmeasured factors such as institutional differences in APC training, direct physician supervision, admission processes, or inpatient team census may play a role.

Several study limitations should be recognized. First, the retrospective, nonrandomized design is one of the largest limitations of our study. Administrative data was obtained via an electronic query of our data warehouse, and although we aimed to identify as many patient characteristics as possible to adjust for cofounding effects, undetected differences among cohorts may exist. Second, our inpatient admission process may have placed undue burden on resident teams to perform all daytime admissions, inadvertently affecting study outcomes. It is possible the observed benefits of a solo hospitalist team are attributable to the lack of admitting duties rather than inherent advantages of the team structure. If this were the case, we would expect similar benefits among APC teams, which we did not note. Third, the study was performed at a single academic center, which may limit the generalizability of our results. Fourth, it is possible the outcomes are similar among teams because our hospitalist faculty rotate proportionately between the different teams. Lastly, the study was underpowered to detect a significant difference in mortality between hospitalist and APC teams. A post hoc power calculation based on our observed sample and effect sizes estimated 75% power to detect a mortality difference between hospitalists and APCs; other mortality comparisons were adequately powered.

We observed similar total direct costs, LOS, 30-day readmission, and inpatient mortality between hospitalist, APC, and resident teams. APC and resident teams utilized more consultants and discharged patient later than hospitalists. Our analysis suggests clinical outcomes are not significantly affected by inpatient team structure, and the addition of general medicine inpatient APC or hospitalist teams represent safe and efficient alternatives to traditional resident teams within an academic medical center.

All authors declare they have no conflicts of interest.

Readmission rates are frequently used as a hospital quality metric, with use including payment incentive at the hospital level,¹ specific condition quality measurement,² balancing measures for quality improvement projects,^3-5 transition success,^6,7 and use in public hospital rankings.⁸ Currently, four methods are commonly used to evaluate pediatric readmissions, each with strengths and limitations, including the following (Appendix Table 1):

1. All-cause readmissions: A measure of any readmission within a given time period regardless of the reason for readmission.⁹

2. Unplanned readmission/time flag: A measure intended to identify unplanned readmissions. This measure relies on time designations within the electronic health record. The time between hospital registration and admission is calculated, and if the readmission is registered more than 24 hours prior to admission, the readmission is considered planned.¹⁰ Hereafter, this measure will be referred to as the time flag measure.

3. Pediatric all-condition readmission (PACR): A measure intended to identify unplanned readmission through the exclusion of certain procedures and diagnoses.¹¹

4. Potentially preventable readmission (PPR): A method to identify preventable readmissions based on a proprietary algorithm developed by 3M Health Information Systems.^12,13

While all four of these measures are used to assess quality, there is little known about these measures’ ability to exclude planned readmissions and identify only preventable pediatric readmission, which conceptually is most relevant to the quality of care. However, many of these measures were not intended to capture preventability, but instead capture the related issue of whether the readmission was planned. Therefore, we sought to evaluate the four readmission measures as they relate to both preventability and unplanned status as determined through medical record review with multidisciplinary care provider input.

As part of a hospital-wide readmission reduction quality improvement collaborative at a free-standing tertiary care children’s hospital, clinicians from hospital medicine, cardiology, neonatology, and neurology teams reviewed 30-day readmissions using a standardized abstraction tool. All readmission events (observation or inpatient encounter) after any discharge (observation or inpatient encounter) from eligible units were reviewed; therefore, each hospitalization was a potential index hospitalization. We classified the preventability of each readmission with use of a previously described Likert scale with high interrater reliability.¹⁴ For these analyses, readmissions were considered preventable if the reviewing team rated them as either “more likely preventable” or “preventable in most circumstances.” Each readmission was also evaluated as planned or unplanned. Methods for readmission review and classification are in the Appendix.

We included all readmissions between July 2014 and June 2016. We compared the medical record review classifications with the assessments from each of the four measures of pediatric readmission. We calculated sensitivity and specificity for both outcomes (planned/unplanned and preventable/not preventable) for all four measures. For standardization of discussion, we categorized description of measure performance as “very poor” as less than 50%, “poor” between 50%-75%, “fair” as 75%-85%, “good” as 85%-90%, “very good” as 90%-95% and excellent as greater than 95%. We also calculated positive and negative predictive value (PPV and NPV) over plausible ranges of prevalence using the sensitivity and specificity of each comparison (Appendix).

Of note, certain exclusions are outlined by the PACR and PPR algorithms. The PACR evaluates only readmission events that occur in children younger than 18 years. The PPR algorithm does not assign preventability if either the index or readmission event is classified as an observation stay or if it is part of a larger chain of readmissions.

Among 30-day readmissions considered, 1,643 were eligible for medical record review; 1,125 reviews were completed by the clinical teams (68.5%). The median time to readmission was 7 days (interquartile range [IQR], 4-18). Most children were non-Hispanic White (71%) or Black (20%). The median age at hospitalization was 2.3 years (IQR 0.4-12.1). Most children had Medicaid (56%) or private (41%) insurance. Most of the reviews were performed in cardiology (43%) and hospital medicine (37%) with patients in neurology (13%) and neonatology (7%) constituting the remaining reviews. Uncontrolled advancement of chronic disease was the most common readmission category on medical record review (25.1%), followed by unrelated readmission (20.7%), scheduled readmission (20.4%), and progression of acute disease (16.6%) (Appendix Table 2).

Assessment of Preventable and Unplanned Readmissions

On multidisciplinary medical record review, most readmissions were classified as not preventable (84.5%). Specifically, 64% were not preventable and unplanned; 20% were deemed not preventable and planned. Only 15% were classified as unplanned and preventable and 1% as planned and preventable (Appendix Figure: Population A/B).

Matching Chart Review to the Four Algorithms

All 1,125 readmissions were assessed by the all-cause and time flag readmission measures (Appendix Figure: Population A/B). After applying algorithm exclusions (details in Appendix), only 804 of the 1,125 (71.5%) reviewed readmissions matched for PACR readmission comparison (Appendix Figure: Population C); 487 of the 1,125 (43.3%) of the reviewed readmissions matched for PPR comparison (Appendix Figure: Population D).

All-Cause

Because all-cause determines only if a readmission occurs, the measure is by definition 100% sensitive and 0% specific in both assessment of preventability and unplanned readmission (Table: Section A).

Time Flag

The time flag measure identified 80% (866/1,112) of the readmissions as unplanned. This measure had very good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and good to excellent NPV. In terms of identifying unplanned readmissions, the time flag measure had excellent sensitivity and very good specificity, which corresponded to very good to excellent PPV and good to very good NPV (Table: Section B).

PACR

The PACR algorithm identified 75% (599/796) of readmissions as unplanned. The PACR has good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PACR had fair sensitivity but poor specificity, which corresponded to fair PPV and poor NPV (Table: Section C).

PPR

The PPR algorithm identified 53% (257/487) of admissions as potentially preventable. The PPR algorithm had poor sensitivity and specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PPR algorithm had poor sensitivity and fair specificity in identifying unplanned readmissions, which corresponded to fair to good PPV and very poor to poor NPV (Table: Section D).

Evaluation of Excluded Readmission Events

Because both the PACR and PPR had large numbers of algorithm exclusions, we describe the preventability and unplanned assessment of the excluded readmission events. Both algorithms excluded preventable events. Of the 321 readmissions excluded by the PACR algorithm, 13.4% were classified as preventable by chart review. Likewise, 14.9% of 638 readmissions excluded by PPR were classified as preventable by chart review.

The ability to accurately capture preventable pediatric readmission is a goal for hospital quality experts and health policymakers alike. Of the four commonly used readmission measures to assess readmission, only PPR is designed to focus on preventability. Unfortunately, none of these four measures is adequately sensitive or specific to identify preventable readmissions; all measures had very poor PPV for preventability. Of the four measures, the time flag measure had the best sensitivity, specificity, PPV, and NPV for identifying unplanned readmissions.

The overall percentage of unplanned readmissions identified by both the time flag and by PACR measures match the overall percentage of unplanned readmissions identified in chart review: The time flag measure identified 80% of admissions as unplanned versus 79% identified by chart review (Appendix Figure: Population A/B); PACR classified 75% as unplanned versus 81% identified by chart review for PACR-eligible readmissions (Appendix Figure: Population C). In contrast, the PPR algorithm classified many more readmissions as potentially preventable (53%) than were identified by chart review at only 16% (Appendix Figure: Population D). The PACR and PPR algorithms also exclude a significant number of readmissions that are unplanned and a smaller, but not trivial, number of readmissions that are preventable; these exclusions limit their accuracy.

The ability to apply these four measures in real time during a hospitalization varies by metric. Two of the measures, the all-cause and time flag, can be applied during a readmission event, which is appealing for quality improvement initiatives. These measures allow for notification of providers that a current hospitalization is a readmission event, which allows providers the opportunity to learn from these events as they occur (Appendix Table 1). While “unplanned” is not the same as “potentially preventable,” almost all potentially preventable readmissions are unplanned; therefore, accurately identifying unplanned readmissions is more beneficial than all-cause. Additionally, a low all-cause readmission rate can be indicative of poor access to scheduled procedures. Nevertheless, all-cause readmission is sometimes used to measure quality.^1,8 While the time flag measure may be more useful for quality improvement initiatives and hospital providers, it relies on hospital registration time, which is not widely available in administrative data sources and, therefore, has limited usefulness to policymakers.

Both PACR and PPR require administrative claims analysis, which is appealing from a policy standpoint. However, the reliance on claims data means the inclusion/exclusion of events can occur only retrospectively, which limits the usefulness of these measures in learning and intervening in real time. When the two measures are compared, PACR offers better sensitivity and PPR offers better specificity with regard to identifying unplanned readmission. The PPR software overcalls preventable readmissions, identifying more readmissions as preventable than there actually are. Nevertheless, Medicaid in several states uses PPR for payment incentive.^1,15-17 Given the poor performance of PPR in assessing both preventable and unplanned pediatric readmission, the use of this measure as a quality metric should be limited.

This study should be considered in the context of several limitations. Because the assessment of preventability was determined as part of a learning quality improvement collaborative and not as a planned research endeavor, not all readmission reviews were completed nor were other existent tools¹⁸ that allow for preventability assessment via more structured medical record review used. Second, we reviewed cases only from certain clinical services, which would limit generalizability of these findings to all pediatric admissions. However, given the low sensitivity and specificity of some of the metrics, we would not anticipate that the addition of other types of admissions would improve the sensitivity and specificity enough to ensure reliability. Third, while we relied on an established method to determine preventability, prior work has demonstrated that additional information gathered from families may change preventability.¹⁹ Finally, due to the exclusions required by the PPR and PACR algorithms, not all readmission events were reviewed. However, these exclusions reflect the actual specifications of use for both measures.

The PPR software has poor fidelity in identifying preventable and unplanned pediatric readmission; this finding has broad policy implications given how widely it is used by state Medicaid offices to assess financial penalties. Among the four pediatric readmission measures used, the time flag metric best identifies unplanned readmissions.

The authors have no conflicts of interest or financial relationships relevant to this article to disclose.

Dr Auger’s research is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1). The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Readmission rates are frequently used as a hospital quality metric, with use including payment incentive at the hospital level,¹ specific condition quality measurement,² balancing measures for quality improvement projects,^3-5 transition success,^6,7 and use in public hospital rankings.⁸ Currently, four methods are commonly used to evaluate pediatric readmissions, each with strengths and limitations, including the following (Appendix Table 1):

1. All-cause readmissions: A measure of any readmission within a given time period regardless of the reason for readmission.⁹

2. Unplanned readmission/time flag: A measure intended to identify unplanned readmissions. This measure relies on time designations within the electronic health record. The time between hospital registration and admission is calculated, and if the readmission is registered more than 24 hours prior to admission, the readmission is considered planned.¹⁰ Hereafter, this measure will be referred to as the time flag measure.

3. Pediatric all-condition readmission (PACR): A measure intended to identify unplanned readmission through the exclusion of certain procedures and diagnoses.¹¹

4. Potentially preventable readmission (PPR): A method to identify preventable readmissions based on a proprietary algorithm developed by 3M Health Information Systems.^12,13

While all four of these measures are used to assess quality, there is little known about these measures’ ability to exclude planned readmissions and identify only preventable pediatric readmission, which conceptually is most relevant to the quality of care. However, many of these measures were not intended to capture preventability, but instead capture the related issue of whether the readmission was planned. Therefore, we sought to evaluate the four readmission measures as they relate to both preventability and unplanned status as determined through medical record review with multidisciplinary care provider input.

As part of a hospital-wide readmission reduction quality improvement collaborative at a free-standing tertiary care children’s hospital, clinicians from hospital medicine, cardiology, neonatology, and neurology teams reviewed 30-day readmissions using a standardized abstraction tool. All readmission events (observation or inpatient encounter) after any discharge (observation or inpatient encounter) from eligible units were reviewed; therefore, each hospitalization was a potential index hospitalization. We classified the preventability of each readmission with use of a previously described Likert scale with high interrater reliability.¹⁴ For these analyses, readmissions were considered preventable if the reviewing team rated them as either “more likely preventable” or “preventable in most circumstances.” Each readmission was also evaluated as planned or unplanned. Methods for readmission review and classification are in the Appendix.

We included all readmissions between July 2014 and June 2016. We compared the medical record review classifications with the assessments from each of the four measures of pediatric readmission. We calculated sensitivity and specificity for both outcomes (planned/unplanned and preventable/not preventable) for all four measures. For standardization of discussion, we categorized description of measure performance as “very poor” as less than 50%, “poor” between 50%-75%, “fair” as 75%-85%, “good” as 85%-90%, “very good” as 90%-95% and excellent as greater than 95%. We also calculated positive and negative predictive value (PPV and NPV) over plausible ranges of prevalence using the sensitivity and specificity of each comparison (Appendix).

Of note, certain exclusions are outlined by the PACR and PPR algorithms. The PACR evaluates only readmission events that occur in children younger than 18 years. The PPR algorithm does not assign preventability if either the index or readmission event is classified as an observation stay or if it is part of a larger chain of readmissions.

Among 30-day readmissions considered, 1,643 were eligible for medical record review; 1,125 reviews were completed by the clinical teams (68.5%). The median time to readmission was 7 days (interquartile range [IQR], 4-18). Most children were non-Hispanic White (71%) or Black (20%). The median age at hospitalization was 2.3 years (IQR 0.4-12.1). Most children had Medicaid (56%) or private (41%) insurance. Most of the reviews were performed in cardiology (43%) and hospital medicine (37%) with patients in neurology (13%) and neonatology (7%) constituting the remaining reviews. Uncontrolled advancement of chronic disease was the most common readmission category on medical record review (25.1%), followed by unrelated readmission (20.7%), scheduled readmission (20.4%), and progression of acute disease (16.6%) (Appendix Table 2).

Assessment of Preventable and Unplanned Readmissions

On multidisciplinary medical record review, most readmissions were classified as not preventable (84.5%). Specifically, 64% were not preventable and unplanned; 20% were deemed not preventable and planned. Only 15% were classified as unplanned and preventable and 1% as planned and preventable (Appendix Figure: Population A/B).

Matching Chart Review to the Four Algorithms

All 1,125 readmissions were assessed by the all-cause and time flag readmission measures (Appendix Figure: Population A/B). After applying algorithm exclusions (details in Appendix), only 804 of the 1,125 (71.5%) reviewed readmissions matched for PACR readmission comparison (Appendix Figure: Population C); 487 of the 1,125 (43.3%) of the reviewed readmissions matched for PPR comparison (Appendix Figure: Population D).

All-Cause

Because all-cause determines only if a readmission occurs, the measure is by definition 100% sensitive and 0% specific in both assessment of preventability and unplanned readmission (Table: Section A).

Time Flag

The time flag measure identified 80% (866/1,112) of the readmissions as unplanned. This measure had very good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and good to excellent NPV. In terms of identifying unplanned readmissions, the time flag measure had excellent sensitivity and very good specificity, which corresponded to very good to excellent PPV and good to very good NPV (Table: Section B).

PACR

The PACR algorithm identified 75% (599/796) of readmissions as unplanned. The PACR has good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PACR had fair sensitivity but poor specificity, which corresponded to fair PPV and poor NPV (Table: Section C).

PPR

The PPR algorithm identified 53% (257/487) of admissions as potentially preventable. The PPR algorithm had poor sensitivity and specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PPR algorithm had poor sensitivity and fair specificity in identifying unplanned readmissions, which corresponded to fair to good PPV and very poor to poor NPV (Table: Section D).

Evaluation of Excluded Readmission Events

Because both the PACR and PPR had large numbers of algorithm exclusions, we describe the preventability and unplanned assessment of the excluded readmission events. Both algorithms excluded preventable events. Of the 321 readmissions excluded by the PACR algorithm, 13.4% were classified as preventable by chart review. Likewise, 14.9% of 638 readmissions excluded by PPR were classified as preventable by chart review.

The ability to accurately capture preventable pediatric readmission is a goal for hospital quality experts and health policymakers alike. Of the four commonly used readmission measures to assess readmission, only PPR is designed to focus on preventability. Unfortunately, none of these four measures is adequately sensitive or specific to identify preventable readmissions; all measures had very poor PPV for preventability. Of the four measures, the time flag measure had the best sensitivity, specificity, PPV, and NPV for identifying unplanned readmissions.

The overall percentage of unplanned readmissions identified by both the time flag and by PACR measures match the overall percentage of unplanned readmissions identified in chart review: The time flag measure identified 80% of admissions as unplanned versus 79% identified by chart review (Appendix Figure: Population A/B); PACR classified 75% as unplanned versus 81% identified by chart review for PACR-eligible readmissions (Appendix Figure: Population C). In contrast, the PPR algorithm classified many more readmissions as potentially preventable (53%) than were identified by chart review at only 16% (Appendix Figure: Population D). The PACR and PPR algorithms also exclude a significant number of readmissions that are unplanned and a smaller, but not trivial, number of readmissions that are preventable; these exclusions limit their accuracy.

The ability to apply these four measures in real time during a hospitalization varies by metric. Two of the measures, the all-cause and time flag, can be applied during a readmission event, which is appealing for quality improvement initiatives. These measures allow for notification of providers that a current hospitalization is a readmission event, which allows providers the opportunity to learn from these events as they occur (Appendix Table 1). While “unplanned” is not the same as “potentially preventable,” almost all potentially preventable readmissions are unplanned; therefore, accurately identifying unplanned readmissions is more beneficial than all-cause. Additionally, a low all-cause readmission rate can be indicative of poor access to scheduled procedures. Nevertheless, all-cause readmission is sometimes used to measure quality.^1,8 While the time flag measure may be more useful for quality improvement initiatives and hospital providers, it relies on hospital registration time, which is not widely available in administrative data sources and, therefore, has limited usefulness to policymakers.

Both PACR and PPR require administrative claims analysis, which is appealing from a policy standpoint. However, the reliance on claims data means the inclusion/exclusion of events can occur only retrospectively, which limits the usefulness of these measures in learning and intervening in real time. When the two measures are compared, PACR offers better sensitivity and PPR offers better specificity with regard to identifying unplanned readmission. The PPR software overcalls preventable readmissions, identifying more readmissions as preventable than there actually are. Nevertheless, Medicaid in several states uses PPR for payment incentive.^1,15-17 Given the poor performance of PPR in assessing both preventable and unplanned pediatric readmission, the use of this measure as a quality metric should be limited.

This study should be considered in the context of several limitations. Because the assessment of preventability was determined as part of a learning quality improvement collaborative and not as a planned research endeavor, not all readmission reviews were completed nor were other existent tools¹⁸ that allow for preventability assessment via more structured medical record review used. Second, we reviewed cases only from certain clinical services, which would limit generalizability of these findings to all pediatric admissions. However, given the low sensitivity and specificity of some of the metrics, we would not anticipate that the addition of other types of admissions would improve the sensitivity and specificity enough to ensure reliability. Third, while we relied on an established method to determine preventability, prior work has demonstrated that additional information gathered from families may change preventability.¹⁹ Finally, due to the exclusions required by the PPR and PACR algorithms, not all readmission events were reviewed. However, these exclusions reflect the actual specifications of use for both measures.

The PPR software has poor fidelity in identifying preventable and unplanned pediatric readmission; this finding has broad policy implications given how widely it is used by state Medicaid offices to assess financial penalties. Among the four pediatric readmission measures used, the time flag metric best identifies unplanned readmissions.

The authors have no conflicts of interest or financial relationships relevant to this article to disclose.

Dr Auger’s research is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1). The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Readmission rates are frequently used as a hospital quality metric, with use including payment incentive at the hospital level,¹ specific condition quality measurement,² balancing measures for quality improvement projects,^3-5 transition success,^6,7 and use in public hospital rankings.⁸ Currently, four methods are commonly used to evaluate pediatric readmissions, each with strengths and limitations, including the following (Appendix Table 1):

1. All-cause readmissions: A measure of any readmission within a given time period regardless of the reason for readmission.⁹

2. Unplanned readmission/time flag: A measure intended to identify unplanned readmissions. This measure relies on time designations within the electronic health record. The time between hospital registration and admission is calculated, and if the readmission is registered more than 24 hours prior to admission, the readmission is considered planned.¹⁰ Hereafter, this measure will be referred to as the time flag measure.

3. Pediatric all-condition readmission (PACR): A measure intended to identify unplanned readmission through the exclusion of certain procedures and diagnoses.¹¹

4. Potentially preventable readmission (PPR): A method to identify preventable readmissions based on a proprietary algorithm developed by 3M Health Information Systems.^12,13

While all four of these measures are used to assess quality, there is little known about these measures’ ability to exclude planned readmissions and identify only preventable pediatric readmission, which conceptually is most relevant to the quality of care. However, many of these measures were not intended to capture preventability, but instead capture the related issue of whether the readmission was planned. Therefore, we sought to evaluate the four readmission measures as they relate to both preventability and unplanned status as determined through medical record review with multidisciplinary care provider input.

As part of a hospital-wide readmission reduction quality improvement collaborative at a free-standing tertiary care children’s hospital, clinicians from hospital medicine, cardiology, neonatology, and neurology teams reviewed 30-day readmissions using a standardized abstraction tool. All readmission events (observation or inpatient encounter) after any discharge (observation or inpatient encounter) from eligible units were reviewed; therefore, each hospitalization was a potential index hospitalization. We classified the preventability of each readmission with use of a previously described Likert scale with high interrater reliability.¹⁴ For these analyses, readmissions were considered preventable if the reviewing team rated them as either “more likely preventable” or “preventable in most circumstances.” Each readmission was also evaluated as planned or unplanned. Methods for readmission review and classification are in the Appendix.

We included all readmissions between July 2014 and June 2016. We compared the medical record review classifications with the assessments from each of the four measures of pediatric readmission. We calculated sensitivity and specificity for both outcomes (planned/unplanned and preventable/not preventable) for all four measures. For standardization of discussion, we categorized description of measure performance as “very poor” as less than 50%, “poor” between 50%-75%, “fair” as 75%-85%, “good” as 85%-90%, “very good” as 90%-95% and excellent as greater than 95%. We also calculated positive and negative predictive value (PPV and NPV) over plausible ranges of prevalence using the sensitivity and specificity of each comparison (Appendix).

Of note, certain exclusions are outlined by the PACR and PPR algorithms. The PACR evaluates only readmission events that occur in children younger than 18 years. The PPR algorithm does not assign preventability if either the index or readmission event is classified as an observation stay or if it is part of a larger chain of readmissions.

Among 30-day readmissions considered, 1,643 were eligible for medical record review; 1,125 reviews were completed by the clinical teams (68.5%). The median time to readmission was 7 days (interquartile range [IQR], 4-18). Most children were non-Hispanic White (71%) or Black (20%). The median age at hospitalization was 2.3 years (IQR 0.4-12.1). Most children had Medicaid (56%) or private (41%) insurance. Most of the reviews were performed in cardiology (43%) and hospital medicine (37%) with patients in neurology (13%) and neonatology (7%) constituting the remaining reviews. Uncontrolled advancement of chronic disease was the most common readmission category on medical record review (25.1%), followed by unrelated readmission (20.7%), scheduled readmission (20.4%), and progression of acute disease (16.6%) (Appendix Table 2).

Assessment of Preventable and Unplanned Readmissions

On multidisciplinary medical record review, most readmissions were classified as not preventable (84.5%). Specifically, 64% were not preventable and unplanned; 20% were deemed not preventable and planned. Only 15% were classified as unplanned and preventable and 1% as planned and preventable (Appendix Figure: Population A/B).

Matching Chart Review to the Four Algorithms

All 1,125 readmissions were assessed by the all-cause and time flag readmission measures (Appendix Figure: Population A/B). After applying algorithm exclusions (details in Appendix), only 804 of the 1,125 (71.5%) reviewed readmissions matched for PACR readmission comparison (Appendix Figure: Population C); 487 of the 1,125 (43.3%) of the reviewed readmissions matched for PPR comparison (Appendix Figure: Population D).

All-Cause

Because all-cause determines only if a readmission occurs, the measure is by definition 100% sensitive and 0% specific in both assessment of preventability and unplanned readmission (Table: Section A).

Time Flag

The time flag measure identified 80% (866/1,112) of the readmissions as unplanned. This measure had very good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and good to excellent NPV. In terms of identifying unplanned readmissions, the time flag measure had excellent sensitivity and very good specificity, which corresponded to very good to excellent PPV and good to very good NPV (Table: Section B).

PACR

The PACR algorithm identified 75% (599/796) of readmissions as unplanned. The PACR has good sensitivity but very poor specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PACR had fair sensitivity but poor specificity, which corresponded to fair PPV and poor NPV (Table: Section C).

PPR

The PPR algorithm identified 53% (257/487) of admissions as potentially preventable. The PPR algorithm had poor sensitivity and specificity in identifying preventable readmissions, which corresponded to very poor PPV and fair to very good NPV. In terms of identifying unplanned readmissions, the PPR algorithm had poor sensitivity and fair specificity in identifying unplanned readmissions, which corresponded to fair to good PPV and very poor to poor NPV (Table: Section D).

Evaluation of Excluded Readmission Events

Because both the PACR and PPR had large numbers of algorithm exclusions, we describe the preventability and unplanned assessment of the excluded readmission events. Both algorithms excluded preventable events. Of the 321 readmissions excluded by the PACR algorithm, 13.4% were classified as preventable by chart review. Likewise, 14.9% of 638 readmissions excluded by PPR were classified as preventable by chart review.

The ability to accurately capture preventable pediatric readmission is a goal for hospital quality experts and health policymakers alike. Of the four commonly used readmission measures to assess readmission, only PPR is designed to focus on preventability. Unfortunately, none of these four measures is adequately sensitive or specific to identify preventable readmissions; all measures had very poor PPV for preventability. Of the four measures, the time flag measure had the best sensitivity, specificity, PPV, and NPV for identifying unplanned readmissions.

The overall percentage of unplanned readmissions identified by both the time flag and by PACR measures match the overall percentage of unplanned readmissions identified in chart review: The time flag measure identified 80% of admissions as unplanned versus 79% identified by chart review (Appendix Figure: Population A/B); PACR classified 75% as unplanned versus 81% identified by chart review for PACR-eligible readmissions (Appendix Figure: Population C). In contrast, the PPR algorithm classified many more readmissions as potentially preventable (53%) than were identified by chart review at only 16% (Appendix Figure: Population D). The PACR and PPR algorithms also exclude a significant number of readmissions that are unplanned and a smaller, but not trivial, number of readmissions that are preventable; these exclusions limit their accuracy.

The ability to apply these four measures in real time during a hospitalization varies by metric. Two of the measures, the all-cause and time flag, can be applied during a readmission event, which is appealing for quality improvement initiatives. These measures allow for notification of providers that a current hospitalization is a readmission event, which allows providers the opportunity to learn from these events as they occur (Appendix Table 1). While “unplanned” is not the same as “potentially preventable,” almost all potentially preventable readmissions are unplanned; therefore, accurately identifying unplanned readmissions is more beneficial than all-cause. Additionally, a low all-cause readmission rate can be indicative of poor access to scheduled procedures. Nevertheless, all-cause readmission is sometimes used to measure quality.^1,8 While the time flag measure may be more useful for quality improvement initiatives and hospital providers, it relies on hospital registration time, which is not widely available in administrative data sources and, therefore, has limited usefulness to policymakers.

Both PACR and PPR require administrative claims analysis, which is appealing from a policy standpoint. However, the reliance on claims data means the inclusion/exclusion of events can occur only retrospectively, which limits the usefulness of these measures in learning and intervening in real time. When the two measures are compared, PACR offers better sensitivity and PPR offers better specificity with regard to identifying unplanned readmission. The PPR software overcalls preventable readmissions, identifying more readmissions as preventable than there actually are. Nevertheless, Medicaid in several states uses PPR for payment incentive.^1,15-17 Given the poor performance of PPR in assessing both preventable and unplanned pediatric readmission, the use of this measure as a quality metric should be limited.

This study should be considered in the context of several limitations. Because the assessment of preventability was determined as part of a learning quality improvement collaborative and not as a planned research endeavor, not all readmission reviews were completed nor were other existent tools¹⁸ that allow for preventability assessment via more structured medical record review used. Second, we reviewed cases only from certain clinical services, which would limit generalizability of these findings to all pediatric admissions. However, given the low sensitivity and specificity of some of the metrics, we would not anticipate that the addition of other types of admissions would improve the sensitivity and specificity enough to ensure reliability. Third, while we relied on an established method to determine preventability, prior work has demonstrated that additional information gathered from families may change preventability.¹⁹ Finally, due to the exclusions required by the PPR and PACR algorithms, not all readmission events were reviewed. However, these exclusions reflect the actual specifications of use for both measures.

The PPR software has poor fidelity in identifying preventable and unplanned pediatric readmission; this finding has broad policy implications given how widely it is used by state Medicaid offices to assess financial penalties. Among the four pediatric readmission measures used, the time flag metric best identifies unplanned readmissions.

The authors have no conflicts of interest or financial relationships relevant to this article to disclose.

Dr Auger’s research is supported by a grant from the Agency for Healthcare Research and Quality (1K08HS204735-01A1). The project described was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number 5UL1TR001425-04. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.