Combinations of abnormal pH-impedance metrics better predicted nonresponse to proton pump inhibitor therapy, as well as benefit of treatment escalation, than individual metrics in patients with gastroesophageal reflux disease (GERD) on twice-daily PPI.

The researchers found a higher proportion of nonresponders to PPI in a group of patients that had combinations of abnormal reflux burden, characterized as acid exposure time greater than 4%, more than 80 reflux episodes, and/or mean nocturnal baseline impedance (MNBI) less than 1,500 ohms, with 85% of these patients improving following initiation of invasive GERD management such as antireflux surgery or magnetic sphincter augmentation.

Not only does the combination of metrics offer more value in identifying responders to PPI than individual metrics, but the combination also offer greater value in “subsequently predicting response to escalation of antireflux management,” study authors C. Prakash Gyawali, MD, of Washington University, St. Louis, and colleagues wrote in Gastroenterology.

Currently in question is the applicability of thresholds for metrics from pH impedance monitoring for studies performed on PPI. According to Dr. Gyawali and colleagues, thresholds from the Lyon Consensus may be too high and likewise lack optimal sensitivity for detecting refractory acid burden in patients on PPI, while thresholds based on pH-metry alone, as reported in other publications, may also lack specificity.

To determine which metrics from “on PPI” pH impedance studies predict escalation therapy needs, the researchers analyzed deidentified pH impedance studies performed in healthy volunteers (n=66; median age, 37.5 years) and patients with GERD (n = 43; median age, 57.0 years); both groups were on twice-daily PPI. The investigators compared median values for pH impedance metrics between healthy volunteers and patients with proven GERD using validated measures.

Data were included from a total of three groups: tracings from European and North American healthy volunteers who received twice-daily PPI for 5-7 days; tracings from European patients with heartburn-predominant proven GERD with prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI; and tracings from a cohort of patients with regurgitation-predominant, proven GERD and prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI.

A improvement in heartburn of at least 50%, as recorded on 4-point Likert-type scales, defined PPI responders and improvements following antireflux surgery in the European comparison group. Additionally, an improvement of at least 50% on the GERD Health-Related Quality of Life scale also characterized PPI responders and improvements following magnetic sphincter augmentation in the North American comparison group.

There was no significant difference between PPI responders and nonresponders in terms of individual conventional and novel reflux metrics. The combinations of metrics associated with abnormal reflux burden and abnormal mucosal integrity (acid exposure time >4%, >80 reflux episodes, and MNBI <1,500 ohms) were observed in 32.6% of patients with heartburn and 40.5% of patients with regurgitation-predominant GERD, but no healthy volunteers. The combinations were also observed in 57.1% and 82.4% of nonresponders, respectively.

The authors defined a borderline category (acid exposure time, >0.5% but <4%; >40 but <80 reflux episodes), which accounted for 32.6% of patients with heartburn-predominant GERD and 50% of those regurgitation-predominant GERD. Nonresponse among these borderline cases was identified in 28.6% and 81%, respectively.

“Performance characteristics of the presence of abnormal reflux burden and/or abnormal mucosal integrity in predicting PPI nonresponse consisted of sensitivity, 0.50; specificity, 0.71; and AUC, 0.59 (P = .15),” the authors explained. “Performance characteristics of abnormal and borderline reflux burden categories together in predicting PPI nonresponse consisted of sensitivity, 0.86; specificity, 0.36; and AUC, 0.62 (P = .07).”

Limitations of this study included its retrospective nature, small sample sizes for the healthy volunteer and GERD populations, and the lack of data on relevant clinical information, including body mass index, dietary patterns, and PPI types and doses. Additionally, the findings may lack generalizability because of the inclusion of only patients with GERD who underwent surgical management.

Despite these limitations, the researchers wrote that the findings and identified “thresholds will be useful in planning prospective outcome studies to conclusively determine when to escalate antireflux therapy when GERD symptoms persist despite bid PPI therapy.”

The study researchers reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study.

Combinations of abnormal pH-impedance metrics better predicted nonresponse to proton pump inhibitor therapy, as well as benefit of treatment escalation, than individual metrics in patients with gastroesophageal reflux disease (GERD) on twice-daily PPI.

The researchers found a higher proportion of nonresponders to PPI in a group of patients that had combinations of abnormal reflux burden, characterized as acid exposure time greater than 4%, more than 80 reflux episodes, and/or mean nocturnal baseline impedance (MNBI) less than 1,500 ohms, with 85% of these patients improving following initiation of invasive GERD management such as antireflux surgery or magnetic sphincter augmentation.

Not only does the combination of metrics offer more value in identifying responders to PPI than individual metrics, but the combination also offer greater value in “subsequently predicting response to escalation of antireflux management,” study authors C. Prakash Gyawali, MD, of Washington University, St. Louis, and colleagues wrote in Gastroenterology.

Currently in question is the applicability of thresholds for metrics from pH impedance monitoring for studies performed on PPI. According to Dr. Gyawali and colleagues, thresholds from the Lyon Consensus may be too high and likewise lack optimal sensitivity for detecting refractory acid burden in patients on PPI, while thresholds based on pH-metry alone, as reported in other publications, may also lack specificity.

To determine which metrics from “on PPI” pH impedance studies predict escalation therapy needs, the researchers analyzed deidentified pH impedance studies performed in healthy volunteers (n=66; median age, 37.5 years) and patients with GERD (n = 43; median age, 57.0 years); both groups were on twice-daily PPI. The investigators compared median values for pH impedance metrics between healthy volunteers and patients with proven GERD using validated measures.

Data were included from a total of three groups: tracings from European and North American healthy volunteers who received twice-daily PPI for 5-7 days; tracings from European patients with heartburn-predominant proven GERD with prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI; and tracings from a cohort of patients with regurgitation-predominant, proven GERD and prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI.

A improvement in heartburn of at least 50%, as recorded on 4-point Likert-type scales, defined PPI responders and improvements following antireflux surgery in the European comparison group. Additionally, an improvement of at least 50% on the GERD Health-Related Quality of Life scale also characterized PPI responders and improvements following magnetic sphincter augmentation in the North American comparison group.

There was no significant difference between PPI responders and nonresponders in terms of individual conventional and novel reflux metrics. The combinations of metrics associated with abnormal reflux burden and abnormal mucosal integrity (acid exposure time >4%, >80 reflux episodes, and MNBI <1,500 ohms) were observed in 32.6% of patients with heartburn and 40.5% of patients with regurgitation-predominant GERD, but no healthy volunteers. The combinations were also observed in 57.1% and 82.4% of nonresponders, respectively.

The authors defined a borderline category (acid exposure time, >0.5% but <4%; >40 but <80 reflux episodes), which accounted for 32.6% of patients with heartburn-predominant GERD and 50% of those regurgitation-predominant GERD. Nonresponse among these borderline cases was identified in 28.6% and 81%, respectively.

“Performance characteristics of the presence of abnormal reflux burden and/or abnormal mucosal integrity in predicting PPI nonresponse consisted of sensitivity, 0.50; specificity, 0.71; and AUC, 0.59 (P = .15),” the authors explained. “Performance characteristics of abnormal and borderline reflux burden categories together in predicting PPI nonresponse consisted of sensitivity, 0.86; specificity, 0.36; and AUC, 0.62 (P = .07).”

Limitations of this study included its retrospective nature, small sample sizes for the healthy volunteer and GERD populations, and the lack of data on relevant clinical information, including body mass index, dietary patterns, and PPI types and doses. Additionally, the findings may lack generalizability because of the inclusion of only patients with GERD who underwent surgical management.

Despite these limitations, the researchers wrote that the findings and identified “thresholds will be useful in planning prospective outcome studies to conclusively determine when to escalate antireflux therapy when GERD symptoms persist despite bid PPI therapy.”

The study researchers reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study.

Combinations of abnormal pH-impedance metrics better predicted nonresponse to proton pump inhibitor therapy, as well as benefit of treatment escalation, than individual metrics in patients with gastroesophageal reflux disease (GERD) on twice-daily PPI.

The researchers found a higher proportion of nonresponders to PPI in a group of patients that had combinations of abnormal reflux burden, characterized as acid exposure time greater than 4%, more than 80 reflux episodes, and/or mean nocturnal baseline impedance (MNBI) less than 1,500 ohms, with 85% of these patients improving following initiation of invasive GERD management such as antireflux surgery or magnetic sphincter augmentation.

Not only does the combination of metrics offer more value in identifying responders to PPI than individual metrics, but the combination also offer greater value in “subsequently predicting response to escalation of antireflux management,” study authors C. Prakash Gyawali, MD, of Washington University, St. Louis, and colleagues wrote in Gastroenterology.

Currently in question is the applicability of thresholds for metrics from pH impedance monitoring for studies performed on PPI. According to Dr. Gyawali and colleagues, thresholds from the Lyon Consensus may be too high and likewise lack optimal sensitivity for detecting refractory acid burden in patients on PPI, while thresholds based on pH-metry alone, as reported in other publications, may also lack specificity.

To determine which metrics from “on PPI” pH impedance studies predict escalation therapy needs, the researchers analyzed deidentified pH impedance studies performed in healthy volunteers (n=66; median age, 37.5 years) and patients with GERD (n = 43; median age, 57.0 years); both groups were on twice-daily PPI. The investigators compared median values for pH impedance metrics between healthy volunteers and patients with proven GERD using validated measures.

Data were included from a total of three groups: tracings from European and North American healthy volunteers who received twice-daily PPI for 5-7 days; tracings from European patients with heartburn-predominant proven GERD with prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI; and tracings from a cohort of patients with regurgitation-predominant, proven GERD and prior abnormal reflux monitoring off PPI who subsequently received twice-daily PPI.

A improvement in heartburn of at least 50%, as recorded on 4-point Likert-type scales, defined PPI responders and improvements following antireflux surgery in the European comparison group. Additionally, an improvement of at least 50% on the GERD Health-Related Quality of Life scale also characterized PPI responders and improvements following magnetic sphincter augmentation in the North American comparison group.

There was no significant difference between PPI responders and nonresponders in terms of individual conventional and novel reflux metrics. The combinations of metrics associated with abnormal reflux burden and abnormal mucosal integrity (acid exposure time >4%, >80 reflux episodes, and MNBI <1,500 ohms) were observed in 32.6% of patients with heartburn and 40.5% of patients with regurgitation-predominant GERD, but no healthy volunteers. The combinations were also observed in 57.1% and 82.4% of nonresponders, respectively.

The authors defined a borderline category (acid exposure time, >0.5% but <4%; >40 but <80 reflux episodes), which accounted for 32.6% of patients with heartburn-predominant GERD and 50% of those regurgitation-predominant GERD. Nonresponse among these borderline cases was identified in 28.6% and 81%, respectively.

“Performance characteristics of the presence of abnormal reflux burden and/or abnormal mucosal integrity in predicting PPI nonresponse consisted of sensitivity, 0.50; specificity, 0.71; and AUC, 0.59 (P = .15),” the authors explained. “Performance characteristics of abnormal and borderline reflux burden categories together in predicting PPI nonresponse consisted of sensitivity, 0.86; specificity, 0.36; and AUC, 0.62 (P = .07).”

Limitations of this study included its retrospective nature, small sample sizes for the healthy volunteer and GERD populations, and the lack of data on relevant clinical information, including body mass index, dietary patterns, and PPI types and doses. Additionally, the findings may lack generalizability because of the inclusion of only patients with GERD who underwent surgical management.

Despite these limitations, the researchers wrote that the findings and identified “thresholds will be useful in planning prospective outcome studies to conclusively determine when to escalate antireflux therapy when GERD symptoms persist despite bid PPI therapy.”

The study researchers reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study.

Sustained, intensive therapy with two antiglutamatergic drugs is superior to standard aggressive treatment for postanoxic super-refractory status epilepticus (SRSE), new research suggests.

In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.

The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.

“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.

Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.

If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

SUPER-CAT trial

In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.

In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.

The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.

Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.

“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.

In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.

The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).

The single-antiglutamate group was not included in the analysis of patient outcomes.

The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
 

Primary outcome met

More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.

Results showed that efficacy and safety outcomes favored DAG therapy.

The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).

For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.

The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.

The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).

There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.

Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
 

Fascinating, promising

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.

He added that his center has used “the innovative treatments” discussed in the study for a few patients.

“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.

He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”

Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”

He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.

Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”

The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.

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

Sustained, intensive therapy with two antiglutamatergic drugs is superior to standard aggressive treatment for postanoxic super-refractory status epilepticus (SRSE), new research suggests.

In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.

The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.

“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.

Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.

If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

SUPER-CAT trial

In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.

In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.

The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.

Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.

“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.

In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.

The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).

The single-antiglutamate group was not included in the analysis of patient outcomes.

The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
 

Primary outcome met

More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.

Results showed that efficacy and safety outcomes favored DAG therapy.

The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).

For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.

The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.

The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).

There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.

Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
 

Fascinating, promising

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.

He added that his center has used “the innovative treatments” discussed in the study for a few patients.

“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.

He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”

Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”

He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.

Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”

The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.

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

Sustained, intensive therapy with two antiglutamatergic drugs is superior to standard aggressive treatment for postanoxic super-refractory status epilepticus (SRSE), new research suggests.

In a retrospective cohort study of survivors of cardiac arrest with postanoxic sustained SRSE, resolution of the condition was achieved by 81% of those who received intensive treatment of ketamine plus perampanel, versus 41% of those who received standard care.

The novelty of the new treatment approach is the duration of therapy as well as the dual antiglutamate drugs, researchers note.

“So the logic is to continue treatment until resolution of refractory status epilepticus under continuous EEG [electroencephalographic] monitoring,” reported lead investigator Simone Beretta, MD, San Gerardo University Hospital, Monza, Italy.

Therapy was guided by data on brainstem reflexes, N20 cortical responses, neuronal serum enolase levels, and neuroimaging.

If all or most of these indicators are favorable, “we continue to treat without any time limit,” Dr. Beretta said. However, if the indicators become unfavorable, clinicians should consider lowering the intensity of care, he added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

SUPER-CAT trial

In SRSE, epileptic seizures occur one after another without patients recovering consciousness in between. Standard aggressive therapy for the condition does not include antiglutamatergic drugs, the researchers noted.

In the Super-Refractory Status Epilepticus After Cardiac Arrest: Aggressive Treatment Guided by Multimodal Prognostic Indicators (SUPER-CAT) study, researchers assessed the combination of two such medications.

The first was the anti-NMDA receptor drug ketamine, which was given by intravenous bolus and then continuous infusion for 3 days guided by continuous EEG to reach a ketamine EEG pattern, as evidenced by alpha and beta waves. It was combined with the anti-AMPA receptor antiepileptic perampanel via nasogastric tube for 5 days, followed by slow tapering.

Dr. Beretta noted that in the ongoing TELSTAR trial, which involved a similar patient population, a different drug combination is being used. A major difference between the two trials is that in the TELSTAR trial, aggressive therapy continues for only 2 days if there is no response.

“In the SUPER-CAT study, we continue far beyond 2 days in the majority of patients,” he said. In addition, ketamine and perampanel were not assessed in TELSTAR.

In SUPER-CAT, 489 survivors of cardiac arrest were recruited over 10 years. Of these, 101 had refractory status epilepticus. After excluding those with more than two indicators of poor prognosis (n = 31) or whose status epilepticus resolved (n = 14), 56 patients were determined to have SRSE. All had experienced relapse after undergoing one cycle of anesthetic.

The 56 participants received one of three treatment regimens: double antiglutamate (DAG) therapy of ketamine and perampanel (n = 26), single antiglutamate therapy with either agent (n = 8), or aggressive nonantiglutamate (NAG) therapy with antiepilepsy drugs and anesthetics other than ketamine or perampanel (n = 22).

The single-antiglutamate group was not included in the analysis of patient outcomes.

The DAG and NAG groups were well balanced at baseline. There were no significant differences in median age (60 years vs. 66 years), gender, low cerebral blood flow, presence of bilateral pupillary or corneal reflexes, neuron-specific enolase levels, cortical N20 somatosenory evoked potentials, moderate to severe postanoxic brain injury, and hypothermia/targeted temperature management.
 

Primary outcome met

More patients in the DAG group (42%) had moderate to severe postanoxic brain injury than in the NAG group (28%). However, the difference was not statistically significant (P = .08), possibly because of the small sample sizes. The number of antiepileptic drugs and the number of cycles of anesthetics did not differ between the groups.

Results showed that efficacy and safety outcomes favored DAG therapy.

The primary efficacy outcome was resolution of status epilepticus within 3 days after initiation of treatments. Status epilepticus resolved for 21 of 26 patients in the DAG group (81%), versus 9 of 22 patients in the NAG group (41%; odds ratio, 6.06; 95% confidence interval, 1.66-22.12; P = .005).

For secondary efficacy outcomes, there was a trend in favor of DAG, but differences from the NAG group were not statistically significant. In the groups, 46% versus 32% awakened and responded to commands before discharge from the intensive care unit, and 32% versus 23% showed good neurologic outcome at 6 months.

The primary safety outcome of all-cause mortality risk in the ICU was 90% lower for patients treated with DAG than for those treated with NAG (15% vs. 64%; OR, 0.1; 95% CI, 0.02-0.41; P < .01). Dr. Beretta explained that the high mortality rate in the NAG group was presumably a result of unresolved status epilepticus.

The secondary safety outcome of a transitory rise of gamma-glutamyl transferase greater than three times the upper limit of normal in the DAG group was expected with high-dose perampanel, the investigators noted. This outcome occurred in 77% of the DAG group versus 27% of the NAG group (OR, 9.88; 95% CI, 2.4-32.9; P < .001).

There was no statistically significant difference in incidence of recurrent cardiac arrest during therapy. This occurred in one member of the DAG group and in none in the NAG group.

Dr. Beretta reported that their investigations are still in a retrospective phase, but the researchers plan to move the work into a prospective phase and possibly a randomized trial soon.
 

Fascinating, promising

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center, Columbus, said the study provides “fascinating, very helpful data” about a condition that has responded well to current treatment options.

He added that his center has used “the innovative treatments” discussed in the study for a few patients.

“More concrete evidence will push us to use it more uniformly across all our patient population [that] has refractory status. So I’m very optimistic, and the data were very promising,” said Dr. Singh, who was not involved with the research.

He cautioned that the study was retrospective, not randomized or controlled, and that it involved a small number of patients but said that the data were “heading in the right direction.”

Although resolution of status epilepticus was better among patients in the DAG group than in the NAG group, the awakenings and neurologic outcomes were “pretty much same as standard medical therapy, which we commonly give to our patients,” said Dr. Singh. “We see this phenomenon all the time in our patients.”

He noted that other factors can determine how patients respond, such as conditions of the heart or kidneys, the presence of sepsis, and multiorgan dysfunction. These factors were not controlled for in the study.

Nonetheless, he said the study achieved its primary endpoint of better resolution of status epilepticus “because that’s the first thing you want to see: whether the treatment is taking care of that.”

The study received no outside funding. Dr. Beretta and Dr. Singh have disclosed no relevant financial relationships.

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

Baby-wearing – carrying a child against your body in a sling, soft carrier, or other device – is associated with benefits like reduced crying and increased breastfeeding, studies have shown.

But this practice also entails risks. Babies can fall out of carriers, or be injured when an adult carrying them falls, for example.

In the past decade, thousands of children were seen at EDs in the United States with injuries related to baby-wearing products, researchers estimated in a study presented at the annual meeting of the American Academy of Pediatrics.

To characterize the epidemiology of these injuries, Samantha J. Rowe, MD, chief resident physician at Walter Reed National Military Medical Center in Bethesda, Md., and colleagues analyzed data from the National Electronic Injury Surveillance System between 2011 and 2020.

They included in their analysis data from patients aged 5 years and younger who sustained an injury associated with a baby-wearing product. Baby harnesses, carriers, slings, framed baby carriers, and soft baby carriers were among the devices included in the study. The researchers used 601 cases to generate national estimates.

An estimated 14,024 patients presented to EDs because of baby-wearing injuries, and 52% of the injuries occurred when a patient fell from the product.

Most injuries (61%) occurred in children aged 5 months and younger; 19.3% of these infants required hospitalization, most often for head injuries.

The investigators found that about 22% of the injuries were associated with a caregiver falling, noted Rachel Y. Moon, MD, who was not involved in the study.

“Carrying a baby changes your center of gravity – and can also obscure your vision of where you’re walking, so adults who use these devices should be cognizant of this,” said Dr. Moon, with the University of Virginia, Charlottesville.

Dr. Rowe often practiced baby-wearing with her daughter, and found that it was beneficial. And studies have demonstrated various benefits of baby-wearing, including improved thermoregulation and glycemic control.

Still, the new analysis illustrates the potential for baby-wearing products “to cause serious injury, especially in infants 5 months and younger,” Dr. Rowe said. “We need to provide more education to caregivers on safe baby-wearing and continue to improve our safety standards for baby-wearing products.”

Study coauthor Patrick T. Reeves, MD, with the Naval Medical Center at San Diego, offered additional guidance in a news release: “Like when buying a new pair of shoes, parents must be educated on the proper sizing, selection, and wear of baby carriers to prevent injury to themselves and their child.”

Parents also need to ensure that the child’s nose and mouth are not obstructed, Dr. Moon

In a recent article discussing the possible benefits of baby-wearing in terms of helping with breastfeeding, Dr. Moon also pointed out further safety considerations: “No matter which carrier is used, for safety reasons, we need to remind parents that the baby should be positioned so that the head is upright and the nose and mouth are not obstructed.”

The researchers and Dr. Moon had no relevant financial disclosures.

[email protected]

Baby-wearing – carrying a child against your body in a sling, soft carrier, or other device – is associated with benefits like reduced crying and increased breastfeeding, studies have shown.

But this practice also entails risks. Babies can fall out of carriers, or be injured when an adult carrying them falls, for example.

In the past decade, thousands of children were seen at EDs in the United States with injuries related to baby-wearing products, researchers estimated in a study presented at the annual meeting of the American Academy of Pediatrics.

To characterize the epidemiology of these injuries, Samantha J. Rowe, MD, chief resident physician at Walter Reed National Military Medical Center in Bethesda, Md., and colleagues analyzed data from the National Electronic Injury Surveillance System between 2011 and 2020.

They included in their analysis data from patients aged 5 years and younger who sustained an injury associated with a baby-wearing product. Baby harnesses, carriers, slings, framed baby carriers, and soft baby carriers were among the devices included in the study. The researchers used 601 cases to generate national estimates.

An estimated 14,024 patients presented to EDs because of baby-wearing injuries, and 52% of the injuries occurred when a patient fell from the product.

Most injuries (61%) occurred in children aged 5 months and younger; 19.3% of these infants required hospitalization, most often for head injuries.

The investigators found that about 22% of the injuries were associated with a caregiver falling, noted Rachel Y. Moon, MD, who was not involved in the study.

“Carrying a baby changes your center of gravity – and can also obscure your vision of where you’re walking, so adults who use these devices should be cognizant of this,” said Dr. Moon, with the University of Virginia, Charlottesville.

Dr. Rowe often practiced baby-wearing with her daughter, and found that it was beneficial. And studies have demonstrated various benefits of baby-wearing, including improved thermoregulation and glycemic control.

Still, the new analysis illustrates the potential for baby-wearing products “to cause serious injury, especially in infants 5 months and younger,” Dr. Rowe said. “We need to provide more education to caregivers on safe baby-wearing and continue to improve our safety standards for baby-wearing products.”

Study coauthor Patrick T. Reeves, MD, with the Naval Medical Center at San Diego, offered additional guidance in a news release: “Like when buying a new pair of shoes, parents must be educated on the proper sizing, selection, and wear of baby carriers to prevent injury to themselves and their child.”

Parents also need to ensure that the child’s nose and mouth are not obstructed, Dr. Moon

In a recent article discussing the possible benefits of baby-wearing in terms of helping with breastfeeding, Dr. Moon also pointed out further safety considerations: “No matter which carrier is used, for safety reasons, we need to remind parents that the baby should be positioned so that the head is upright and the nose and mouth are not obstructed.”

The researchers and Dr. Moon had no relevant financial disclosures.

[email protected]

Baby-wearing – carrying a child against your body in a sling, soft carrier, or other device – is associated with benefits like reduced crying and increased breastfeeding, studies have shown.

But this practice also entails risks. Babies can fall out of carriers, or be injured when an adult carrying them falls, for example.

In the past decade, thousands of children were seen at EDs in the United States with injuries related to baby-wearing products, researchers estimated in a study presented at the annual meeting of the American Academy of Pediatrics.

To characterize the epidemiology of these injuries, Samantha J. Rowe, MD, chief resident physician at Walter Reed National Military Medical Center in Bethesda, Md., and colleagues analyzed data from the National Electronic Injury Surveillance System between 2011 and 2020.

They included in their analysis data from patients aged 5 years and younger who sustained an injury associated with a baby-wearing product. Baby harnesses, carriers, slings, framed baby carriers, and soft baby carriers were among the devices included in the study. The researchers used 601 cases to generate national estimates.

An estimated 14,024 patients presented to EDs because of baby-wearing injuries, and 52% of the injuries occurred when a patient fell from the product.

Most injuries (61%) occurred in children aged 5 months and younger; 19.3% of these infants required hospitalization, most often for head injuries.

The investigators found that about 22% of the injuries were associated with a caregiver falling, noted Rachel Y. Moon, MD, who was not involved in the study.

“Carrying a baby changes your center of gravity – and can also obscure your vision of where you’re walking, so adults who use these devices should be cognizant of this,” said Dr. Moon, with the University of Virginia, Charlottesville.

Dr. Rowe often practiced baby-wearing with her daughter, and found that it was beneficial. And studies have demonstrated various benefits of baby-wearing, including improved thermoregulation and glycemic control.

Still, the new analysis illustrates the potential for baby-wearing products “to cause serious injury, especially in infants 5 months and younger,” Dr. Rowe said. “We need to provide more education to caregivers on safe baby-wearing and continue to improve our safety standards for baby-wearing products.”

Study coauthor Patrick T. Reeves, MD, with the Naval Medical Center at San Diego, offered additional guidance in a news release: “Like when buying a new pair of shoes, parents must be educated on the proper sizing, selection, and wear of baby carriers to prevent injury to themselves and their child.”

Parents also need to ensure that the child’s nose and mouth are not obstructed, Dr. Moon

In a recent article discussing the possible benefits of baby-wearing in terms of helping with breastfeeding, Dr. Moon also pointed out further safety considerations: “No matter which carrier is used, for safety reasons, we need to remind parents that the baby should be positioned so that the head is upright and the nose and mouth are not obstructed.”

The researchers and Dr. Moon had no relevant financial disclosures.

[email protected]

Genetic testing in patients with epilepsy can yield useful information that informs treatment and improves seizure control and other outcomes, new research shows.

Results of a survey that included more than 400 patients showed that positive findings from genetic testing helped guide clinical management in 50% of cases and improved patient outcomes in 75%. In addition, the findings were applicable to both children and adults.

“Fifty percent of the time the physicians reported that, yes, receiving the genetic diagnosis did change how they managed the patients,” reported co-investigator Dianalee McKnight, PhD, director of medical affairs at Invitae, a medical genetic testing company headquartered in San Francisco. In 81.3% of cases, providers reported they changed clinical management within 3 months of receiving the genetic results, she added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

Test results can be practice-changing

Nearly 50% of positive genetic test results in epilepsy patients can help guide clinical management, Dr. McKnight noted. However, information on how physicians use genetic information in decision-making has been limited, prompting her conduct the survey.

A total of 1,567 physicians with 3,572 patients who had a definitive diagnosis of epilepsy were contacted. A total of 170 (10.8%) clinicians provided completed and eligible surveys on 429 patients with epilepsy.

The patient cohort comprised mostly children, with nearly 50 adults, which Dr. McKnight said is typical of the population receiving genetic testing in clinical practice.

She reported that genetic testing results prompted clinicians to make medication changes about 50% of the time. Other changes included specialist referral or to a clinical trial, monitoring for other neurological disease, and recommendations for dietary change or for surgery.

Growing influence of genetic testing

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center in Columbus, noted that the study highlights the value of gene testing in improving outcomes in patients with epilepsy, particularly the pediatric population.

He said the findings make him optimistic about the potential of genetic testing in adult patients – with at least one caveat.

“The limitation is that if we do find some mutation, we don’t know what to do with that. That’s definitely one challenge. And we see that more often in the adult patient population,” said Dr. Singh, who was not involved with the research.

He noted that there is a small group of genetic mutations when, found in adults, may dramatically alter treatment.

For example, he noted that if there is a gene mutation related to mTOR pathways, that could provide a future target because there are already medications that target this pathway.

Genetic testing may also be useful in cases where patients have normal brain imaging and poor response to standard treatment or in cases where patients have congenital abnormalities such as intellectual impairment or facial dysmorphic features and a co-morbid seizure disorder, he said.

Dr. Singh noted that he has often found genetic testing impractical because “if I order DNA testing right now, it will take 4 months for me to get the results. I cannot wait 4 months for the results to come back” to adjust treatment.

Dr. McKnight is an employee of and a shareholder in Invitae, which funded the study. Dr. Singh has disclosed no relevant financial relationships.

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

Genetic testing in patients with epilepsy can yield useful information that informs treatment and improves seizure control and other outcomes, new research shows.

Results of a survey that included more than 400 patients showed that positive findings from genetic testing helped guide clinical management in 50% of cases and improved patient outcomes in 75%. In addition, the findings were applicable to both children and adults.

“Fifty percent of the time the physicians reported that, yes, receiving the genetic diagnosis did change how they managed the patients,” reported co-investigator Dianalee McKnight, PhD, director of medical affairs at Invitae, a medical genetic testing company headquartered in San Francisco. In 81.3% of cases, providers reported they changed clinical management within 3 months of receiving the genetic results, she added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

Test results can be practice-changing

Nearly 50% of positive genetic test results in epilepsy patients can help guide clinical management, Dr. McKnight noted. However, information on how physicians use genetic information in decision-making has been limited, prompting her conduct the survey.

A total of 1,567 physicians with 3,572 patients who had a definitive diagnosis of epilepsy were contacted. A total of 170 (10.8%) clinicians provided completed and eligible surveys on 429 patients with epilepsy.

The patient cohort comprised mostly children, with nearly 50 adults, which Dr. McKnight said is typical of the population receiving genetic testing in clinical practice.

She reported that genetic testing results prompted clinicians to make medication changes about 50% of the time. Other changes included specialist referral or to a clinical trial, monitoring for other neurological disease, and recommendations for dietary change or for surgery.

Growing influence of genetic testing

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center in Columbus, noted that the study highlights the value of gene testing in improving outcomes in patients with epilepsy, particularly the pediatric population.

He said the findings make him optimistic about the potential of genetic testing in adult patients – with at least one caveat.

“The limitation is that if we do find some mutation, we don’t know what to do with that. That’s definitely one challenge. And we see that more often in the adult patient population,” said Dr. Singh, who was not involved with the research.

He noted that there is a small group of genetic mutations when, found in adults, may dramatically alter treatment.

For example, he noted that if there is a gene mutation related to mTOR pathways, that could provide a future target because there are already medications that target this pathway.

Genetic testing may also be useful in cases where patients have normal brain imaging and poor response to standard treatment or in cases where patients have congenital abnormalities such as intellectual impairment or facial dysmorphic features and a co-morbid seizure disorder, he said.

Dr. Singh noted that he has often found genetic testing impractical because “if I order DNA testing right now, it will take 4 months for me to get the results. I cannot wait 4 months for the results to come back” to adjust treatment.

Dr. McKnight is an employee of and a shareholder in Invitae, which funded the study. Dr. Singh has disclosed no relevant financial relationships.

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

Genetic testing in patients with epilepsy can yield useful information that informs treatment and improves seizure control and other outcomes, new research shows.

Results of a survey that included more than 400 patients showed that positive findings from genetic testing helped guide clinical management in 50% of cases and improved patient outcomes in 75%. In addition, the findings were applicable to both children and adults.

“Fifty percent of the time the physicians reported that, yes, receiving the genetic diagnosis did change how they managed the patients,” reported co-investigator Dianalee McKnight, PhD, director of medical affairs at Invitae, a medical genetic testing company headquartered in San Francisco. In 81.3% of cases, providers reported they changed clinical management within 3 months of receiving the genetic results, she added.

The findings were presented at the 2021 World Congress of Neurology (WCN).
 

Test results can be practice-changing

Nearly 50% of positive genetic test results in epilepsy patients can help guide clinical management, Dr. McKnight noted. However, information on how physicians use genetic information in decision-making has been limited, prompting her conduct the survey.

A total of 1,567 physicians with 3,572 patients who had a definitive diagnosis of epilepsy were contacted. A total of 170 (10.8%) clinicians provided completed and eligible surveys on 429 patients with epilepsy.

The patient cohort comprised mostly children, with nearly 50 adults, which Dr. McKnight said is typical of the population receiving genetic testing in clinical practice.

She reported that genetic testing results prompted clinicians to make medication changes about 50% of the time. Other changes included specialist referral or to a clinical trial, monitoring for other neurological disease, and recommendations for dietary change or for surgery.

Growing influence of genetic testing

Commenting on the findings, Jaysingh Singh, MD, co-director of the Epilepsy Surgery Center at the Ohio State University Wexner Medical Center in Columbus, noted that the study highlights the value of gene testing in improving outcomes in patients with epilepsy, particularly the pediatric population.

He said the findings make him optimistic about the potential of genetic testing in adult patients – with at least one caveat.

“The limitation is that if we do find some mutation, we don’t know what to do with that. That’s definitely one challenge. And we see that more often in the adult patient population,” said Dr. Singh, who was not involved with the research.

He noted that there is a small group of genetic mutations when, found in adults, may dramatically alter treatment.

For example, he noted that if there is a gene mutation related to mTOR pathways, that could provide a future target because there are already medications that target this pathway.

Genetic testing may also be useful in cases where patients have normal brain imaging and poor response to standard treatment or in cases where patients have congenital abnormalities such as intellectual impairment or facial dysmorphic features and a co-morbid seizure disorder, he said.

Dr. Singh noted that he has often found genetic testing impractical because “if I order DNA testing right now, it will take 4 months for me to get the results. I cannot wait 4 months for the results to come back” to adjust treatment.

Dr. McKnight is an employee of and a shareholder in Invitae, which funded the study. Dr. Singh has disclosed no relevant financial relationships.

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

New draft recommendations from the U.S. Preventive Services Task Force (USPSTF) on the use of aspirin for the primary prevention of cardiovascular disease (CVD) have been released and appear to limit the population in which it should be considered.  

David Sucsy/iStockphoto

“The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit,” the recommendation notes. They conclude that for these patients, the decision to use aspirin “should be an individual one.”

“Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit,” they note.

For older individuals, however, “The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults age 60 years or older has no net benefit,” the task force concludes.

The new recommendations were posted online Oct. 12 and will be available for public comment until November 8. Once it is finalized, the recommendation will replace the 2016 USPSTF recommendation on aspirin use to prevent CVD and colorectal cancer (CRC), they note.

In that document, the task force recommended initiating low-dose aspirin for the primary prevention of both CVD and CRC in adults 50-59 years of age who had a 10% or greater 10-year CVD risk, were not at increased risk for bleeding, had a life expectancy of at least 10 years, and were willing to take daily low-dose aspirin for at least 10 years, with the decision to start being an individual one.

For older and younger patients, they found at that time that the evidence was “insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than age 50 years or adults aged 70 years or older.”

In the new draft document, “the USPSTF has changed the age ranges and grades of its recommendation on aspirin use.” Besides the recommendations for CVD prevention, they have also changed the previous recommendation of aspirin for the prevention of CRC given evidence generated from large primary CVD prevention trials.

“Based on new analyses of the evidence from primary CVD prevention populations, longer-term follow-up data from the Women’s Health Study (WHS) (JE Buring, personal communication, November 23, 2020), and new trial evidence, the USPSTF concluded that the evidence is inadequate that low-dose aspirin use reduces CRC incidence or mortality,” it states.  
 

Optimum dose

On the optimum dose for primary CVD prevention, the task force says the benefit appears similar for a low dose (≤100 mg/d) and all doses that have been studied in CVD prevention trials (50 to 500 mg/d). “A pragmatic approach would be to use 81 mg/d, which is the most commonly prescribed dose in the United States,” it states.

The USPSTF recommends using the ACC/AHA Pooled Cohort Equations to estimate cardiovascular risk but it points out that these equations are imperfect for risk prediction at the individual level, and suggests using these risk estimates as a starting point to discuss with appropriate candidates their desire for daily aspirin use. The benefits of initiating aspirin use are greater for individuals at higher risk for CVD events (eg, those with >15% or >20% 10-year CVD risk), they note.

“Decisions about initiating aspirin use should be based on shared decision-making between clinicians and patients about the potential benefits and harms. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin use. Persons who place a higher value on the potential harms or on the burden of taking a daily preventive medication than the potential benefits may choose not to initiate low-dose aspirin use,” the task force says.

It also points out that the risk for bleeding increases modestly with advancing age. “For persons who have initiated aspirin use, the net benefits continue to accrue over time in the absence of a bleeding event. The net benefits, however, become smaller with advancing age because of an increased risk for bleeding, so modeling data suggest that it may be reasonable to consider stopping aspirin use around age 75 years,” it states.
 

Systematic review

The updated draft recommendations are based on a new systematic review commissioned by the USPSTF on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD.

The systematic review also investigated the effect of aspirin use on CRC incidence and mortality in primary CVD prevention populations, as well as the harms, particularly bleeding harms, associated with aspirin use.

In addition to the systematic evidence review, the USPSTF commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level. Modeling study parameter inputs were informed by the results of the systematic review, and the primary outcomes were net benefits expressed as quality-adjusted life-years and life-years. 

The USPSTF found 13 randomized clinical trials (RCTs) that reported on the benefits of aspirin use for the primary prevention of cardiovascular morbidity and mortality. The total number of participants was 161,680, and most trials used low-dose aspirin of 100 mg/d or less or aspirin every other day. The 13 primary prevention trials included a balanced number of male and female participants and included a broad distribution of ages, with mean age ranging from 53 years in the Physicians’ Health Study to 74 years in the ASPREE trial.

This body of evidence shows that aspirin use for primary prevention of CVD is associated with a decreased risk of myocardial infarction and stroke but not cardiovascular mortality or all-cause mortality. Results are quite similar when including studies using all doses of aspirin compared with studies using low-dose aspirin.

The USPSTF reviewed 14 RCTs in CVD primary prevention populations that reported on the bleeding harms of aspirin.

When looking at studies reporting on the harms of low-dose aspirin use (≤100 mg/d), which is most relevant to current practice, a pooled analysis of 10 trials showed that aspirin use was associated with a 58% increase in major gastrointestinal bleeding, and a pooled analysis of 11 trials showed a 31% increase in intracranial bleeds in the aspirin group compared with the control group. Low-dose aspirin use was not associated with a statistically significant increase in risk of fatal hemorrhagic stroke.

Data suggested that the increased risk of bleeding associated with aspirin use occurs relatively quickly after initiating aspirin, and data do not suggest that aspirin has a differential relative bleeding risk based on age, sex, presence of diabetes, level of CVD risk, or race or ethnicity. Although the increase in relative risk does not appear to differ based on age, the absolute risk of bleeding, and thus the magnitude of bleeding harm, does increase with age, and more so in adults age 60 years or older, they note.

The microsimulation model to estimate the magnitude of net benefit of low-dose aspirin use incorporated findings from the systematic review.

Modeling data demonstrated that aspirin use in both men and women ages 40-59 years with 10% or greater 10-year CVD risk generally provides a modest net benefit in both quality-adjusted life-years and life-years gained. Initiation of aspirin use in persons aged 60-69 years results in quality-adjusted life-years gained that range from slightly negative to slightly positive depending on CVD risk level, and life-years gained are generally negative.

In persons aged 70-79 years, initiation of aspirin use results in a loss of both quality-adjusted life-years and life-years at essentially all CVD risk levels modeled (ie, up to 20% 10-year CVD risk).

The USPSTF thus determined that aspirin use has a small net benefit in persons aged 40-59 years with 10% or greater 10-year CVD risk, and initiation of aspirin use has no net benefit in persons age 60 years or older.

When looking at net lifetime benefit of continuous aspirin use until stopping at age 65, 70, 75, 80, or 85 years, modeling data suggest that there is generally little incremental lifetime net benefit in continuing aspirin use beyond the age of 75-80 years.

The task force points out that the net benefit of continuing aspirin use by a person in their 60s or 70s is not the same as the net benefit of initiating aspirin use by a person in their 60s or 70s. This is because, in part, of the fact that CVD risk is heavily influenced by age. Persons who meet the eligibility criteria for aspirin use at a younger age (ie, ≥10% 10-year CVD risk in their 40s or 50s) typically have even higher CVD risk by their 60s or 70s compared with persons who first reach a 10% or greater 10-year CVD risk in their 60s or 70s, and may gain more benefit by continuing aspirin use than a person at lower risk might gain by initiating aspirin use, the USPSTF explains.

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

New draft recommendations from the U.S. Preventive Services Task Force (USPSTF) on the use of aspirin for the primary prevention of cardiovascular disease (CVD) have been released and appear to limit the population in which it should be considered.  

David Sucsy/iStockphoto

“The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit,” the recommendation notes. They conclude that for these patients, the decision to use aspirin “should be an individual one.”

“Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit,” they note.

For older individuals, however, “The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults age 60 years or older has no net benefit,” the task force concludes.

The new recommendations were posted online Oct. 12 and will be available for public comment until November 8. Once it is finalized, the recommendation will replace the 2016 USPSTF recommendation on aspirin use to prevent CVD and colorectal cancer (CRC), they note.

In that document, the task force recommended initiating low-dose aspirin for the primary prevention of both CVD and CRC in adults 50-59 years of age who had a 10% or greater 10-year CVD risk, were not at increased risk for bleeding, had a life expectancy of at least 10 years, and were willing to take daily low-dose aspirin for at least 10 years, with the decision to start being an individual one.

For older and younger patients, they found at that time that the evidence was “insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than age 50 years or adults aged 70 years or older.”

In the new draft document, “the USPSTF has changed the age ranges and grades of its recommendation on aspirin use.” Besides the recommendations for CVD prevention, they have also changed the previous recommendation of aspirin for the prevention of CRC given evidence generated from large primary CVD prevention trials.

“Based on new analyses of the evidence from primary CVD prevention populations, longer-term follow-up data from the Women’s Health Study (WHS) (JE Buring, personal communication, November 23, 2020), and new trial evidence, the USPSTF concluded that the evidence is inadequate that low-dose aspirin use reduces CRC incidence or mortality,” it states.  
 

Optimum dose

On the optimum dose for primary CVD prevention, the task force says the benefit appears similar for a low dose (≤100 mg/d) and all doses that have been studied in CVD prevention trials (50 to 500 mg/d). “A pragmatic approach would be to use 81 mg/d, which is the most commonly prescribed dose in the United States,” it states.

The USPSTF recommends using the ACC/AHA Pooled Cohort Equations to estimate cardiovascular risk but it points out that these equations are imperfect for risk prediction at the individual level, and suggests using these risk estimates as a starting point to discuss with appropriate candidates their desire for daily aspirin use. The benefits of initiating aspirin use are greater for individuals at higher risk for CVD events (eg, those with >15% or >20% 10-year CVD risk), they note.

“Decisions about initiating aspirin use should be based on shared decision-making between clinicians and patients about the potential benefits and harms. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin use. Persons who place a higher value on the potential harms or on the burden of taking a daily preventive medication than the potential benefits may choose not to initiate low-dose aspirin use,” the task force says.

It also points out that the risk for bleeding increases modestly with advancing age. “For persons who have initiated aspirin use, the net benefits continue to accrue over time in the absence of a bleeding event. The net benefits, however, become smaller with advancing age because of an increased risk for bleeding, so modeling data suggest that it may be reasonable to consider stopping aspirin use around age 75 years,” it states.
 

Systematic review

The updated draft recommendations are based on a new systematic review commissioned by the USPSTF on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD.

The systematic review also investigated the effect of aspirin use on CRC incidence and mortality in primary CVD prevention populations, as well as the harms, particularly bleeding harms, associated with aspirin use.

In addition to the systematic evidence review, the USPSTF commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level. Modeling study parameter inputs were informed by the results of the systematic review, and the primary outcomes were net benefits expressed as quality-adjusted life-years and life-years. 

The USPSTF found 13 randomized clinical trials (RCTs) that reported on the benefits of aspirin use for the primary prevention of cardiovascular morbidity and mortality. The total number of participants was 161,680, and most trials used low-dose aspirin of 100 mg/d or less or aspirin every other day. The 13 primary prevention trials included a balanced number of male and female participants and included a broad distribution of ages, with mean age ranging from 53 years in the Physicians’ Health Study to 74 years in the ASPREE trial.

This body of evidence shows that aspirin use for primary prevention of CVD is associated with a decreased risk of myocardial infarction and stroke but not cardiovascular mortality or all-cause mortality. Results are quite similar when including studies using all doses of aspirin compared with studies using low-dose aspirin.

The USPSTF reviewed 14 RCTs in CVD primary prevention populations that reported on the bleeding harms of aspirin.

When looking at studies reporting on the harms of low-dose aspirin use (≤100 mg/d), which is most relevant to current practice, a pooled analysis of 10 trials showed that aspirin use was associated with a 58% increase in major gastrointestinal bleeding, and a pooled analysis of 11 trials showed a 31% increase in intracranial bleeds in the aspirin group compared with the control group. Low-dose aspirin use was not associated with a statistically significant increase in risk of fatal hemorrhagic stroke.

Data suggested that the increased risk of bleeding associated with aspirin use occurs relatively quickly after initiating aspirin, and data do not suggest that aspirin has a differential relative bleeding risk based on age, sex, presence of diabetes, level of CVD risk, or race or ethnicity. Although the increase in relative risk does not appear to differ based on age, the absolute risk of bleeding, and thus the magnitude of bleeding harm, does increase with age, and more so in adults age 60 years or older, they note.

The microsimulation model to estimate the magnitude of net benefit of low-dose aspirin use incorporated findings from the systematic review.

Modeling data demonstrated that aspirin use in both men and women ages 40-59 years with 10% or greater 10-year CVD risk generally provides a modest net benefit in both quality-adjusted life-years and life-years gained. Initiation of aspirin use in persons aged 60-69 years results in quality-adjusted life-years gained that range from slightly negative to slightly positive depending on CVD risk level, and life-years gained are generally negative.

In persons aged 70-79 years, initiation of aspirin use results in a loss of both quality-adjusted life-years and life-years at essentially all CVD risk levels modeled (ie, up to 20% 10-year CVD risk).

The USPSTF thus determined that aspirin use has a small net benefit in persons aged 40-59 years with 10% or greater 10-year CVD risk, and initiation of aspirin use has no net benefit in persons age 60 years or older.

When looking at net lifetime benefit of continuous aspirin use until stopping at age 65, 70, 75, 80, or 85 years, modeling data suggest that there is generally little incremental lifetime net benefit in continuing aspirin use beyond the age of 75-80 years.

The task force points out that the net benefit of continuing aspirin use by a person in their 60s or 70s is not the same as the net benefit of initiating aspirin use by a person in their 60s or 70s. This is because, in part, of the fact that CVD risk is heavily influenced by age. Persons who meet the eligibility criteria for aspirin use at a younger age (ie, ≥10% 10-year CVD risk in their 40s or 50s) typically have even higher CVD risk by their 60s or 70s compared with persons who first reach a 10% or greater 10-year CVD risk in their 60s or 70s, and may gain more benefit by continuing aspirin use than a person at lower risk might gain by initiating aspirin use, the USPSTF explains.

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

New draft recommendations from the U.S. Preventive Services Task Force (USPSTF) on the use of aspirin for the primary prevention of cardiovascular disease (CVD) have been released and appear to limit the population in which it should be considered.  

David Sucsy/iStockphoto

“The USPSTF concludes with moderate certainty that aspirin use for the primary prevention of CVD events in adults ages 40 to 59 years who have a 10% or greater 10-year CVD risk has a small net benefit,” the recommendation notes. They conclude that for these patients, the decision to use aspirin “should be an individual one.”

“Persons who are not at increased risk for bleeding and are willing to take low-dose aspirin daily are more likely to benefit,” they note.

For older individuals, however, “The USPSTF concludes with moderate certainty that initiating aspirin use for the primary prevention of CVD events in adults age 60 years or older has no net benefit,” the task force concludes.

The new recommendations were posted online Oct. 12 and will be available for public comment until November 8. Once it is finalized, the recommendation will replace the 2016 USPSTF recommendation on aspirin use to prevent CVD and colorectal cancer (CRC), they note.

In that document, the task force recommended initiating low-dose aspirin for the primary prevention of both CVD and CRC in adults 50-59 years of age who had a 10% or greater 10-year CVD risk, were not at increased risk for bleeding, had a life expectancy of at least 10 years, and were willing to take daily low-dose aspirin for at least 10 years, with the decision to start being an individual one.

For older and younger patients, they found at that time that the evidence was “insufficient to assess the balance of benefits and harms of initiating aspirin use for the primary prevention of CVD and CRC in adults younger than age 50 years or adults aged 70 years or older.”

In the new draft document, “the USPSTF has changed the age ranges and grades of its recommendation on aspirin use.” Besides the recommendations for CVD prevention, they have also changed the previous recommendation of aspirin for the prevention of CRC given evidence generated from large primary CVD prevention trials.

“Based on new analyses of the evidence from primary CVD prevention populations, longer-term follow-up data from the Women’s Health Study (WHS) (JE Buring, personal communication, November 23, 2020), and new trial evidence, the USPSTF concluded that the evidence is inadequate that low-dose aspirin use reduces CRC incidence or mortality,” it states.  
 

Optimum dose

On the optimum dose for primary CVD prevention, the task force says the benefit appears similar for a low dose (≤100 mg/d) and all doses that have been studied in CVD prevention trials (50 to 500 mg/d). “A pragmatic approach would be to use 81 mg/d, which is the most commonly prescribed dose in the United States,” it states.

The USPSTF recommends using the ACC/AHA Pooled Cohort Equations to estimate cardiovascular risk but it points out that these equations are imperfect for risk prediction at the individual level, and suggests using these risk estimates as a starting point to discuss with appropriate candidates their desire for daily aspirin use. The benefits of initiating aspirin use are greater for individuals at higher risk for CVD events (eg, those with >15% or >20% 10-year CVD risk), they note.

“Decisions about initiating aspirin use should be based on shared decision-making between clinicians and patients about the potential benefits and harms. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin use. Persons who place a higher value on the potential harms or on the burden of taking a daily preventive medication than the potential benefits may choose not to initiate low-dose aspirin use,” the task force says.

It also points out that the risk for bleeding increases modestly with advancing age. “For persons who have initiated aspirin use, the net benefits continue to accrue over time in the absence of a bleeding event. The net benefits, however, become smaller with advancing age because of an increased risk for bleeding, so modeling data suggest that it may be reasonable to consider stopping aspirin use around age 75 years,” it states.
 

Systematic review

The updated draft recommendations are based on a new systematic review commissioned by the USPSTF on the effectiveness of aspirin to reduce the risk of CVD events (myocardial infarction and stroke), cardiovascular mortality, and all-cause mortality in persons without a history of CVD.

The systematic review also investigated the effect of aspirin use on CRC incidence and mortality in primary CVD prevention populations, as well as the harms, particularly bleeding harms, associated with aspirin use.

In addition to the systematic evidence review, the USPSTF commissioned a microsimulation modeling study to assess the net balance of benefits and harms from aspirin use for primary prevention of CVD and CRC, stratified by age, sex, and CVD risk level. Modeling study parameter inputs were informed by the results of the systematic review, and the primary outcomes were net benefits expressed as quality-adjusted life-years and life-years. 

The USPSTF found 13 randomized clinical trials (RCTs) that reported on the benefits of aspirin use for the primary prevention of cardiovascular morbidity and mortality. The total number of participants was 161,680, and most trials used low-dose aspirin of 100 mg/d or less or aspirin every other day. The 13 primary prevention trials included a balanced number of male and female participants and included a broad distribution of ages, with mean age ranging from 53 years in the Physicians’ Health Study to 74 years in the ASPREE trial.

This body of evidence shows that aspirin use for primary prevention of CVD is associated with a decreased risk of myocardial infarction and stroke but not cardiovascular mortality or all-cause mortality. Results are quite similar when including studies using all doses of aspirin compared with studies using low-dose aspirin.

The USPSTF reviewed 14 RCTs in CVD primary prevention populations that reported on the bleeding harms of aspirin.

When looking at studies reporting on the harms of low-dose aspirin use (≤100 mg/d), which is most relevant to current practice, a pooled analysis of 10 trials showed that aspirin use was associated with a 58% increase in major gastrointestinal bleeding, and a pooled analysis of 11 trials showed a 31% increase in intracranial bleeds in the aspirin group compared with the control group. Low-dose aspirin use was not associated with a statistically significant increase in risk of fatal hemorrhagic stroke.

Data suggested that the increased risk of bleeding associated with aspirin use occurs relatively quickly after initiating aspirin, and data do not suggest that aspirin has a differential relative bleeding risk based on age, sex, presence of diabetes, level of CVD risk, or race or ethnicity. Although the increase in relative risk does not appear to differ based on age, the absolute risk of bleeding, and thus the magnitude of bleeding harm, does increase with age, and more so in adults age 60 years or older, they note.

The microsimulation model to estimate the magnitude of net benefit of low-dose aspirin use incorporated findings from the systematic review.

Modeling data demonstrated that aspirin use in both men and women ages 40-59 years with 10% or greater 10-year CVD risk generally provides a modest net benefit in both quality-adjusted life-years and life-years gained. Initiation of aspirin use in persons aged 60-69 years results in quality-adjusted life-years gained that range from slightly negative to slightly positive depending on CVD risk level, and life-years gained are generally negative.

In persons aged 70-79 years, initiation of aspirin use results in a loss of both quality-adjusted life-years and life-years at essentially all CVD risk levels modeled (ie, up to 20% 10-year CVD risk).

The USPSTF thus determined that aspirin use has a small net benefit in persons aged 40-59 years with 10% or greater 10-year CVD risk, and initiation of aspirin use has no net benefit in persons age 60 years or older.

When looking at net lifetime benefit of continuous aspirin use until stopping at age 65, 70, 75, 80, or 85 years, modeling data suggest that there is generally little incremental lifetime net benefit in continuing aspirin use beyond the age of 75-80 years.

The task force points out that the net benefit of continuing aspirin use by a person in their 60s or 70s is not the same as the net benefit of initiating aspirin use by a person in their 60s or 70s. This is because, in part, of the fact that CVD risk is heavily influenced by age. Persons who meet the eligibility criteria for aspirin use at a younger age (ie, ≥10% 10-year CVD risk in their 40s or 50s) typically have even higher CVD risk by their 60s or 70s compared with persons who first reach a 10% or greater 10-year CVD risk in their 60s or 70s, and may gain more benefit by continuing aspirin use than a person at lower risk might gain by initiating aspirin use, the USPSTF explains.

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

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

The Diagnosis: Schwannoma

Schwannoma, also known as neurilemmoma, is a benign encapsulated neoplasm of the peripheral nerve sheath that presents as a subcutaneous nodule.¹ It also may present in the retroperitoneum, mediastinum, and viscera (eg, gastrointestinal tract, bone, upper respiratory tract, lymph nodes). It may occur as multiple lesions when associated with certain syndromes. It usually is an asymptomatic indolent tumor with neurologic symptoms, such as pain and tenderness, in the lesions that are deeper, larger, or closer in proximity to nearby structures.^2,3

Histologically, a schwannoma is encapsulated by the perineurium of the nerve bundle from which it originates (quiz image [top]). The tumor consists of hypercellular (Antoni type A) and hypocellular (Antoni type B) areas. Antoni type A areas consist of tightly packed, spindleshaped cells with elongated wavy nuclei and indistinct cytoplasmic borders. These nuclei tend to align into parallel rows with intervening anuclear zones forming Verocay bodies (quiz image [bottom]).⁴ Verocay bodies are not seen in all schwannomas, and similar formations may be seen in other tumors as well. Solitary circumscribed neuromas also have Verocay bodies, whereas dermatofibromas and leiomyomas have Verocay-like bodies. Antoni type B areas have scattered spindled or ovoid cells in an edematous or myxoid matrix interspersed with inflammatory cells such as lymphocytes and histiocytes. Vessels with thick hyalinized walls are a helpful feature in diagnosis.² Schwann cells of a schwannoma stain diffusely positive with S-100 protein. The capsule stains positively with epithelial membrane antigen due to the presence of perineurial cells.²

The morphologic variants of this entity include conventional (common, solitary), cellular, plexiform, ancient, melanotic, epithelioid, pseudoglandular, neuroblastomalike, and microcystic/reticular schwannomas. There are additional variants that are associated with genetic syndromes, such as multiple cutaneous plexiform schwannomas linked with neurofibromatosis type 2, psammomatous melanotic schwannoma presenting in Carney complex, schwannomatosis, and segmental schwannomatosis (a distinct form of neurofibromatosis characterized by multiple schwannomas localized to one limb). Either presentation may have alteration or deletion of the neurofibromatosis type 2 gene, NF2, on chromosome 22.^2,5

Nodular fasciitis is a benign tumor of fibroblasts and myofibroblasts that usually arises in the subcutaneous tissues. It most commonly occurs in the upper extremities, trunk, head, and neck. It presents as a single, often painful, rapidly growing, subcutaneous nodule. Histologically, lesions mostly are well circumscribed yet unencapsulated, in contrast to schwannomas. They may be hypocellular or hypercellular and are composed of uniform spindle cells with a feathery or fascicular (tissue culture–like) appearance in a loose, myxoid to collagenous stroma. There may be foci of hemorrhage and conspicuous mitoses but not atypical figures (Figure 1). Immunohistochemically, the cells stain positively for smooth muscle actin and negatively for S-100 protein, which sets it apart from a schwannoma. Most cases contain fusion genes, with myosin heavy chain 9 ubiquitin-specific peptidase 6, MYH9-USP6, being the most common fusion product.⁶

Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a benign, usually solitary dermal lesion. It most commonly occurs in middle-aged to elderly adults as a small (<1 cm), firm, flesh-colored to pink papule on the face (ie, cheeks, nose, nasolabial folds) and less commonly in the oral and acral regions and on the eyelids and penis. The lesion usually is unilobular; however, other growth patterns such as plexiform, multilobular, and fungating variants have been identified. Histologically, it is a well-circumscribed nodule with a thin capsule of perineurium that is composed of interlacing bundles of Schwann cells with a characteristic clefting artifact (Figure 2). Cells have wavy dark nuclei with scant cytoplasm that occasionally form palisades or Verocay bodies causing these lesions to be confused with schwannomas. Immunohistochemically, the Schwann cells stain positively with S-100 protein, and the perineurium stains positively with epithelial membrane antigen, Claudin-1, and Glut-1. Neurofilament protein stains axons throughout neuromas, whereas in schwannoma, the expression often is limited to entrapped axons at the periphery of the tumor.⁷

Angioleiomyoma is an uncommon, benign, smooth muscle neoplasm of the skin and subcutaneous tissue that originates from vascular smooth muscle. It most commonly presents in adult females aged 30 to 60 years, with a predilection for the lower limbs. These tumors typically are solitary, slow growing, and less than 2 cm in diameter and may be painful upon compression. Similar to schwannoma, angioleiomyoma is an encapsulated lesion composed of interlacing, uniform, smooth muscle bundles distributed around vessels (Figure 3). Smooth muscle cells have oval- or cigar-shaped nuclei with a small perinuclear vacuole of glycogen. Immunohistochemically, there is strong diffuse staining for smooth muscle actin and h-caldesmon. Recurrence after excision is rare.^2,8

Neurofibroma is a common, mostly sporadic, benign tumor of nerve sheath origin. The solitary type may be localized (well circumscribed, unencapsulated) or diffuse. The presence of multiple, deep, and plexiform lesions is associated with neurofibromatosis type 1 (von Recklinghausen disease) that is caused by germline mutations in the NF1 gene. Histologically, the tumor is composed of Schwann cells, fibroblasts, perineurial cells, and nerve axons within an extracellular myxoid to collagenous matrix (Figure 4). The diffuse type is an ill-defined proliferation that entraps adnexal structures. The plexiform type is defined by multinodular serpentine fascicles. Immunohistochemically, the Schwann cells stain positive for S-100 protein and SOX10 (SRY-Box Transcription Factor 10). Epithelial membrane antigen stains admixed perineurial cells. Neurofilament protein highlights intratumoral axons, which generally are not found throughout schwannomas. Transformation to a malignant peripheral nerve sheath tumor occurs in up to 10% of patients with neurofibromatosis type 1, usually in plexiform neurofibromas, and is characterized by increased cellularity, atypia, mitotic activity, and necrosis.⁹

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Opzelura FDA Approved for Atopic Dermatitis Incyte

Corporation announces US Food and Drug Administration (FDA) approval of Opzelura (ruxolitinib) cream 1.5% for the short-term and noncontinuous chronic treatment of mild to moderate atopic dermatitis (AD) in nonimmunocompromised patients 12 years and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Opzelura is formulated with ruxolitinib, a selective Janus kinase (JAK) 1/JAK2 inhibitor, to target key cytokine signals believed to contribute to itch and inflammation. For more information, visit www.opzelurahcp.com/.

Twyneo FDA Approved for Acne Vulgaris

Sol-Gel Technologies, Ltd, announces US Food and Drug Administration (FDA) approval of Twyneo (tretinoin 0.1% /benzoyl peroxide 3%) cream for the treatment of acne vulgaris in adult and pediatric patients 9 years and older. Tretinoin and benzoyl peroxide are widely prescribed separately for acne vulgaris; however, benzoyl peroxide causes degradation of the tretinoin molecule, thereby potentially reducing its effectiveness if used at the same time or combined in the same formulation. The formulation of Twyneo uses silica (silicon dioxide) core shell structures to separately microencapsulate tretinoin crystals and benzoyl peroxide crystals, enabling inclusion of the 2 active ingredients in the cream. For more information, visit www.sol-gel.com.

If you would like your product included in Product News, please email a press release to the Editorial Office at [email protected].

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old man with coronary artery disease (CAD) undergoes hospital treatment for diverticulitis. He receives ketorolac for abdominal pain upon arrival to the medical ward despite his known allergy to nonsteroidal anti-inflammatory drugs. Fifteen minutes after administration, he develops lightheadedness and experiences swelling of his lips. On exam, he has tachycardia and a diffuse urticarial rash across his torso. The admitting physician prescribes methylprednisolone, diphenhydramine, and a liter bolus of normal saline for suspected anaphylaxis. Epinephrine is not administered for fear of precipitating an adverse cardiovascular event given the patient’s history of CAD.

Anaphylaxis, a rapid-onset generalized immunoglobulin E (IgE)–mediated hypersensitivity reaction, can lead to significant morbidity and mortality when not managed properly. Patients can present with anaphylaxis in heterogeneous ways. Fulfilling any one of three criteria establishes the diagnosis of anaphylaxis: (1) rapid onset of skin or mucosal symptoms complicated by either respiratory compromise or hypotension; (2) two or more symptoms involving the respiratory, mucosal, cardiovascular, or gastrointestinal systems following exposure to a likely allergen; and (3) reduced blood pressure in response to a known allergen.¹ Up to 5% of the population experiences anaphylaxis in a lifetime. Medication and stinging insects account for the majority of anaphylactic reactions in adults, while food and insect stings commonly trigger it in children and adolescents.²

The majority of anaphylactic reactions, known as uniphasic or monophasic, occur rapidly as single episodes following exposure to a specific trigger and resolve within minutes to hours after treatment. Meanwhile, biphasic, or delayed-phase, anaphylaxis occurs when symptoms recur after an apparent resolution and in the absence of reexposure to the trigger. Symptoms restart within 1 to 72 hours after resolution of an initial anaphylaxis episode, with a median time to onset of 11 hours. Biphasic reactions occur in roughly 5% of patients with anaphylaxis.³

Epinephrine is the only recommended first-line medication for the treatment of anaphylaxis in all age groups.⁴ Epinephrine counteracts the cardiovascular and respiratory compromise induced by anaphylaxis through its α- and β-adrenergic activity and stabilizes mast cells.⁴ Early administration of intramuscular epinephrine decreases the need for additional interventions, reduces the likelihood of hospitalization, and is associated with reduced biphasic reactions.^5-7 Paradoxically, patients receive corticosteroids more often than epinephrine for suspected anaphylaxis, despite no robust evidence for their efficacy.^4,8,9

Corticosteroids act as potent anti-inflammatory medications that modulate mast-cell maturation, activation, and degranulation. Known to work primarily through downregulation of gene transcription responsible for cytokine, chemokine, and arachidonic acid production, their maximal anti-inflammatory effects manifest 2 to 6 hours after administration. Demonstrated efficacy in treating and preventing relapse of other inflammatory conditions, such as asthma and croup, may, in part, explain the widespread glucocorticoid use in anaphylaxis. Some believe that administration of corticosteroids may also help reduce the risk of biphasic or delayed-phase anaphylaxis.¹⁰

Based on their mechanism of action, corticosteroids do not exert any anti-inflammatory effects for several hours, regardless of their route of administration.¹⁰ In contrast, epinephrine exerts an almost immediate effect to increase cardiac output and vascular resistance, to reverse edema and bronchoconstriction, and to stabilize mast cells, preventing release of harmful chemokines and cytokines.⁴

The American Academy of Allergy, Asthma & Immunology (AAAAI) recommends early administration of epinephrine as the first-line treatment of anaphylaxis and emphasizes that evidence does not support routine corticosteroid use in the management of acute anaphylaxis or for prevention of biphasic reactions.⁹ To date, no randomized controlled trials have explored the role of corticosteroids in the treatment of acute anaphylaxis, although one is currently under way looking at whether dexamethasone has an impact on preventing biphasic reactions (Table).¹¹

The AAAAI Joint Task Force on Practice Parameters (JTFPP) conducted a pooled analysis of observational studies that did not find a reduction in biphasic reactions in adult patients receiving corticosteroids (odds ratio [OR], 0.87; 95% CI, 0.74-1.02).⁹ Further, their analysis suggests an association with administration of corticosteroids and an increased likelihood of biphasic reactions in children (OR, 1.55; 95% CI, 1.01-2.38).⁹

An observational study in children across 35 hospitals demonstrated an association with corticosteroid administration and a reduced length of hospital stay for anaphylaxis, but the same study found no reduction in repeat emergency department (ED) visits within 72 hours.¹² Similarly, a retrospective cohort study in adults did not find that corticosteroid administration reduced the 7-day risk of returning to the hospital.¹³ These studies highlight the importance of anticipatory guidance in both ED and hospital discharges for anaphylaxis since the literature does not provide data that corticosteroid administration reduces the likelihood of a biphasic course.

Long-term corticosteroids have well-known deleterious health effects. Recent evidence highlights the possible adverse events associated with even short courses of corticosteroids. A large case series from Taiwan containing 2,623,327 adults administered brief courses (<14 days) of corticosteroids demonstrated increased incidence of gastrointestinal bleeding, sepsis, and heart failure beginning 5 to 30 days after starting corticosteroid treatments for common medical conditions, with respective absolute risk increases of 10.3, 0.1, and 1 per 1000 patient-years for each condition.¹⁴ The same group of researchers found a nearly two-fold increased risk of sepsis, gastrointestinal bleeding, and pneumonia in a nearly 1 million children who had received corticosteroids within the previous year.¹⁵ Other common side effects of short-term corticosteroids include insomnia, agitation, mood disturbances, and hyperglycemia.

A growing body of evidence demonstrates that corticosteroids likely do not alter the natural disease course of anaphylaxis and carry increased risks of significant adverse events. The AAAAI recommends against the use of glucocorticoids as a first-line agent for anaphylaxis and suggests against the use of glucocorticoids to prevent biphasic reactions.⁹

The recent JTFPP analysis of observational studies demonstrated reduced hypersensitivity reactions to chemotherapeutics with corticosteroid premedication (OR, 0.49; 95% CI, 0.37-0.66). The AAAAI favors administration of corticosteroids to reduce the risk of anaphylactoid reactions—non–IgE-mediated mast cell activation—for some chemotherapeutic protocols.⁹

There is robust evidence regarding the benefits of corticosteroids in the treatment of asthma and upper-airway edema.^16,17 Allergen exposures can precipitate significant bronchospasm in individuals with asthma and trigger an exacerbation. Although routine corticosteroid use for anaphylaxis in these populations has not been directly studied, their use as an adjunctive therapy may be beneficial if there is clinical evidence of bronchospasm or significant upper-airway edema.

Rapid administration of epinephrine saves lives, reduces need for adjuvant treatments and hospitalization, and is associated with decreased risk of developing biphasic anaphylactic reactions (OR, 0.2; 95% CI, 0-0.6).^5-7 Some clinicians are apprehensive about using epinephrine owing to fears related to negative side effects, particularly adverse cardiovascular events. Kawano et al¹⁸ performed a retrospective evaluation of 492 ED visits for anaphylaxis and found that epinephrine is administered less often in older patients (age >50 years); however, when administered intramuscularly, there was no significant difference in adverse cardiovascular events in this population compared with younger individuals. The study did demonstrate an increased rate of adverse cardiac events in older patients receiving intravenous epinephrine, an observation that the authors attributed partly to dosing errors that were reported more often with intravenous use.¹⁸

• Always promptly administer intramuscular epinephrine when treating anaphylaxis.
• Routine administration of corticosteroids in the treatment of anaphylaxis is not advised owing to insufficient data supporting their efficacy and potential for adverse events. Some patient populations may derive benefit from corticosteroids, including individuals with history of asthma exhibiting bronchospastic symptoms, individuals with significant upper-airway edema, and those undergoing certain chemotherapy regimens.

In the clinical vignette, the hospitalist withheld the first-line treatment for anaphylaxis, epinephrine. Without the support of evidence in the literature, patients receive corticosteroids and antihistamines more often than epinephrine for suspected anaphylaxis. No evidence supports the routine use of corticosteroids in the management of anaphylaxis or in the prevention of biphasic reactions. Further, recent research demonstrates significant adverse events are associated with even short courses of corticosteroids.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old man with coronary artery disease (CAD) undergoes hospital treatment for diverticulitis. He receives ketorolac for abdominal pain upon arrival to the medical ward despite his known allergy to nonsteroidal anti-inflammatory drugs. Fifteen minutes after administration, he develops lightheadedness and experiences swelling of his lips. On exam, he has tachycardia and a diffuse urticarial rash across his torso. The admitting physician prescribes methylprednisolone, diphenhydramine, and a liter bolus of normal saline for suspected anaphylaxis. Epinephrine is not administered for fear of precipitating an adverse cardiovascular event given the patient’s history of CAD.

Anaphylaxis, a rapid-onset generalized immunoglobulin E (IgE)–mediated hypersensitivity reaction, can lead to significant morbidity and mortality when not managed properly. Patients can present with anaphylaxis in heterogeneous ways. Fulfilling any one of three criteria establishes the diagnosis of anaphylaxis: (1) rapid onset of skin or mucosal symptoms complicated by either respiratory compromise or hypotension; (2) two or more symptoms involving the respiratory, mucosal, cardiovascular, or gastrointestinal systems following exposure to a likely allergen; and (3) reduced blood pressure in response to a known allergen.¹ Up to 5% of the population experiences anaphylaxis in a lifetime. Medication and stinging insects account for the majority of anaphylactic reactions in adults, while food and insect stings commonly trigger it in children and adolescents.²

The majority of anaphylactic reactions, known as uniphasic or monophasic, occur rapidly as single episodes following exposure to a specific trigger and resolve within minutes to hours after treatment. Meanwhile, biphasic, or delayed-phase, anaphylaxis occurs when symptoms recur after an apparent resolution and in the absence of reexposure to the trigger. Symptoms restart within 1 to 72 hours after resolution of an initial anaphylaxis episode, with a median time to onset of 11 hours. Biphasic reactions occur in roughly 5% of patients with anaphylaxis.³

Epinephrine is the only recommended first-line medication for the treatment of anaphylaxis in all age groups.⁴ Epinephrine counteracts the cardiovascular and respiratory compromise induced by anaphylaxis through its α- and β-adrenergic activity and stabilizes mast cells.⁴ Early administration of intramuscular epinephrine decreases the need for additional interventions, reduces the likelihood of hospitalization, and is associated with reduced biphasic reactions.^5-7 Paradoxically, patients receive corticosteroids more often than epinephrine for suspected anaphylaxis, despite no robust evidence for their efficacy.^4,8,9

Corticosteroids act as potent anti-inflammatory medications that modulate mast-cell maturation, activation, and degranulation. Known to work primarily through downregulation of gene transcription responsible for cytokine, chemokine, and arachidonic acid production, their maximal anti-inflammatory effects manifest 2 to 6 hours after administration. Demonstrated efficacy in treating and preventing relapse of other inflammatory conditions, such as asthma and croup, may, in part, explain the widespread glucocorticoid use in anaphylaxis. Some believe that administration of corticosteroids may also help reduce the risk of biphasic or delayed-phase anaphylaxis.¹⁰

Based on their mechanism of action, corticosteroids do not exert any anti-inflammatory effects for several hours, regardless of their route of administration.¹⁰ In contrast, epinephrine exerts an almost immediate effect to increase cardiac output and vascular resistance, to reverse edema and bronchoconstriction, and to stabilize mast cells, preventing release of harmful chemokines and cytokines.⁴

The American Academy of Allergy, Asthma & Immunology (AAAAI) recommends early administration of epinephrine as the first-line treatment of anaphylaxis and emphasizes that evidence does not support routine corticosteroid use in the management of acute anaphylaxis or for prevention of biphasic reactions.⁹ To date, no randomized controlled trials have explored the role of corticosteroids in the treatment of acute anaphylaxis, although one is currently under way looking at whether dexamethasone has an impact on preventing biphasic reactions (Table).¹¹

The AAAAI Joint Task Force on Practice Parameters (JTFPP) conducted a pooled analysis of observational studies that did not find a reduction in biphasic reactions in adult patients receiving corticosteroids (odds ratio [OR], 0.87; 95% CI, 0.74-1.02).⁹ Further, their analysis suggests an association with administration of corticosteroids and an increased likelihood of biphasic reactions in children (OR, 1.55; 95% CI, 1.01-2.38).⁹

An observational study in children across 35 hospitals demonstrated an association with corticosteroid administration and a reduced length of hospital stay for anaphylaxis, but the same study found no reduction in repeat emergency department (ED) visits within 72 hours.¹² Similarly, a retrospective cohort study in adults did not find that corticosteroid administration reduced the 7-day risk of returning to the hospital.¹³ These studies highlight the importance of anticipatory guidance in both ED and hospital discharges for anaphylaxis since the literature does not provide data that corticosteroid administration reduces the likelihood of a biphasic course.

Long-term corticosteroids have well-known deleterious health effects. Recent evidence highlights the possible adverse events associated with even short courses of corticosteroids. A large case series from Taiwan containing 2,623,327 adults administered brief courses (<14 days) of corticosteroids demonstrated increased incidence of gastrointestinal bleeding, sepsis, and heart failure beginning 5 to 30 days after starting corticosteroid treatments for common medical conditions, with respective absolute risk increases of 10.3, 0.1, and 1 per 1000 patient-years for each condition.¹⁴ The same group of researchers found a nearly two-fold increased risk of sepsis, gastrointestinal bleeding, and pneumonia in a nearly 1 million children who had received corticosteroids within the previous year.¹⁵ Other common side effects of short-term corticosteroids include insomnia, agitation, mood disturbances, and hyperglycemia.

A growing body of evidence demonstrates that corticosteroids likely do not alter the natural disease course of anaphylaxis and carry increased risks of significant adverse events. The AAAAI recommends against the use of glucocorticoids as a first-line agent for anaphylaxis and suggests against the use of glucocorticoids to prevent biphasic reactions.⁹

The recent JTFPP analysis of observational studies demonstrated reduced hypersensitivity reactions to chemotherapeutics with corticosteroid premedication (OR, 0.49; 95% CI, 0.37-0.66). The AAAAI favors administration of corticosteroids to reduce the risk of anaphylactoid reactions—non–IgE-mediated mast cell activation—for some chemotherapeutic protocols.⁹

There is robust evidence regarding the benefits of corticosteroids in the treatment of asthma and upper-airway edema.^16,17 Allergen exposures can precipitate significant bronchospasm in individuals with asthma and trigger an exacerbation. Although routine corticosteroid use for anaphylaxis in these populations has not been directly studied, their use as an adjunctive therapy may be beneficial if there is clinical evidence of bronchospasm or significant upper-airway edema.

Rapid administration of epinephrine saves lives, reduces need for adjuvant treatments and hospitalization, and is associated with decreased risk of developing biphasic anaphylactic reactions (OR, 0.2; 95% CI, 0-0.6).^5-7 Some clinicians are apprehensive about using epinephrine owing to fears related to negative side effects, particularly adverse cardiovascular events. Kawano et al¹⁸ performed a retrospective evaluation of 492 ED visits for anaphylaxis and found that epinephrine is administered less often in older patients (age >50 years); however, when administered intramuscularly, there was no significant difference in adverse cardiovascular events in this population compared with younger individuals. The study did demonstrate an increased rate of adverse cardiac events in older patients receiving intravenous epinephrine, an observation that the authors attributed partly to dosing errors that were reported more often with intravenous use.¹⁸

• Always promptly administer intramuscular epinephrine when treating anaphylaxis.
• Routine administration of corticosteroids in the treatment of anaphylaxis is not advised owing to insufficient data supporting their efficacy and potential for adverse events. Some patient populations may derive benefit from corticosteroids, including individuals with history of asthma exhibiting bronchospastic symptoms, individuals with significant upper-airway edema, and those undergoing certain chemotherapy regimens.

In the clinical vignette, the hospitalist withheld the first-line treatment for anaphylaxis, epinephrine. Without the support of evidence in the literature, patients receive corticosteroids and antihistamines more often than epinephrine for suspected anaphylaxis. No evidence supports the routine use of corticosteroids in the management of anaphylaxis or in the prevention of biphasic reactions. Further, recent research demonstrates significant adverse events are associated with even short courses of corticosteroids.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

A 56-year-old man with coronary artery disease (CAD) undergoes hospital treatment for diverticulitis. He receives ketorolac for abdominal pain upon arrival to the medical ward despite his known allergy to nonsteroidal anti-inflammatory drugs. Fifteen minutes after administration, he develops lightheadedness and experiences swelling of his lips. On exam, he has tachycardia and a diffuse urticarial rash across his torso. The admitting physician prescribes methylprednisolone, diphenhydramine, and a liter bolus of normal saline for suspected anaphylaxis. Epinephrine is not administered for fear of precipitating an adverse cardiovascular event given the patient’s history of CAD.

Anaphylaxis, a rapid-onset generalized immunoglobulin E (IgE)–mediated hypersensitivity reaction, can lead to significant morbidity and mortality when not managed properly. Patients can present with anaphylaxis in heterogeneous ways. Fulfilling any one of three criteria establishes the diagnosis of anaphylaxis: (1) rapid onset of skin or mucosal symptoms complicated by either respiratory compromise or hypotension; (2) two or more symptoms involving the respiratory, mucosal, cardiovascular, or gastrointestinal systems following exposure to a likely allergen; and (3) reduced blood pressure in response to a known allergen.¹ Up to 5% of the population experiences anaphylaxis in a lifetime. Medication and stinging insects account for the majority of anaphylactic reactions in adults, while food and insect stings commonly trigger it in children and adolescents.²

The majority of anaphylactic reactions, known as uniphasic or monophasic, occur rapidly as single episodes following exposure to a specific trigger and resolve within minutes to hours after treatment. Meanwhile, biphasic, or delayed-phase, anaphylaxis occurs when symptoms recur after an apparent resolution and in the absence of reexposure to the trigger. Symptoms restart within 1 to 72 hours after resolution of an initial anaphylaxis episode, with a median time to onset of 11 hours. Biphasic reactions occur in roughly 5% of patients with anaphylaxis.³

Epinephrine is the only recommended first-line medication for the treatment of anaphylaxis in all age groups.⁴ Epinephrine counteracts the cardiovascular and respiratory compromise induced by anaphylaxis through its α- and β-adrenergic activity and stabilizes mast cells.⁴ Early administration of intramuscular epinephrine decreases the need for additional interventions, reduces the likelihood of hospitalization, and is associated with reduced biphasic reactions.^5-7 Paradoxically, patients receive corticosteroids more often than epinephrine for suspected anaphylaxis, despite no robust evidence for their efficacy.^4,8,9

Corticosteroids act as potent anti-inflammatory medications that modulate mast-cell maturation, activation, and degranulation. Known to work primarily through downregulation of gene transcription responsible for cytokine, chemokine, and arachidonic acid production, their maximal anti-inflammatory effects manifest 2 to 6 hours after administration. Demonstrated efficacy in treating and preventing relapse of other inflammatory conditions, such as asthma and croup, may, in part, explain the widespread glucocorticoid use in anaphylaxis. Some believe that administration of corticosteroids may also help reduce the risk of biphasic or delayed-phase anaphylaxis.¹⁰

Based on their mechanism of action, corticosteroids do not exert any anti-inflammatory effects for several hours, regardless of their route of administration.¹⁰ In contrast, epinephrine exerts an almost immediate effect to increase cardiac output and vascular resistance, to reverse edema and bronchoconstriction, and to stabilize mast cells, preventing release of harmful chemokines and cytokines.⁴

The American Academy of Allergy, Asthma & Immunology (AAAAI) recommends early administration of epinephrine as the first-line treatment of anaphylaxis and emphasizes that evidence does not support routine corticosteroid use in the management of acute anaphylaxis or for prevention of biphasic reactions.⁹ To date, no randomized controlled trials have explored the role of corticosteroids in the treatment of acute anaphylaxis, although one is currently under way looking at whether dexamethasone has an impact on preventing biphasic reactions (Table).¹¹

The AAAAI Joint Task Force on Practice Parameters (JTFPP) conducted a pooled analysis of observational studies that did not find a reduction in biphasic reactions in adult patients receiving corticosteroids (odds ratio [OR], 0.87; 95% CI, 0.74-1.02).⁹ Further, their analysis suggests an association with administration of corticosteroids and an increased likelihood of biphasic reactions in children (OR, 1.55; 95% CI, 1.01-2.38).⁹

An observational study in children across 35 hospitals demonstrated an association with corticosteroid administration and a reduced length of hospital stay for anaphylaxis, but the same study found no reduction in repeat emergency department (ED) visits within 72 hours.¹² Similarly, a retrospective cohort study in adults did not find that corticosteroid administration reduced the 7-day risk of returning to the hospital.¹³ These studies highlight the importance of anticipatory guidance in both ED and hospital discharges for anaphylaxis since the literature does not provide data that corticosteroid administration reduces the likelihood of a biphasic course.

Long-term corticosteroids have well-known deleterious health effects. Recent evidence highlights the possible adverse events associated with even short courses of corticosteroids. A large case series from Taiwan containing 2,623,327 adults administered brief courses (<14 days) of corticosteroids demonstrated increased incidence of gastrointestinal bleeding, sepsis, and heart failure beginning 5 to 30 days after starting corticosteroid treatments for common medical conditions, with respective absolute risk increases of 10.3, 0.1, and 1 per 1000 patient-years for each condition.¹⁴ The same group of researchers found a nearly two-fold increased risk of sepsis, gastrointestinal bleeding, and pneumonia in a nearly 1 million children who had received corticosteroids within the previous year.¹⁵ Other common side effects of short-term corticosteroids include insomnia, agitation, mood disturbances, and hyperglycemia.

A growing body of evidence demonstrates that corticosteroids likely do not alter the natural disease course of anaphylaxis and carry increased risks of significant adverse events. The AAAAI recommends against the use of glucocorticoids as a first-line agent for anaphylaxis and suggests against the use of glucocorticoids to prevent biphasic reactions.⁹

The recent JTFPP analysis of observational studies demonstrated reduced hypersensitivity reactions to chemotherapeutics with corticosteroid premedication (OR, 0.49; 95% CI, 0.37-0.66). The AAAAI favors administration of corticosteroids to reduce the risk of anaphylactoid reactions—non–IgE-mediated mast cell activation—for some chemotherapeutic protocols.⁹

There is robust evidence regarding the benefits of corticosteroids in the treatment of asthma and upper-airway edema.^16,17 Allergen exposures can precipitate significant bronchospasm in individuals with asthma and trigger an exacerbation. Although routine corticosteroid use for anaphylaxis in these populations has not been directly studied, their use as an adjunctive therapy may be beneficial if there is clinical evidence of bronchospasm or significant upper-airway edema.

Rapid administration of epinephrine saves lives, reduces need for adjuvant treatments and hospitalization, and is associated with decreased risk of developing biphasic anaphylactic reactions (OR, 0.2; 95% CI, 0-0.6).^5-7 Some clinicians are apprehensive about using epinephrine owing to fears related to negative side effects, particularly adverse cardiovascular events. Kawano et al¹⁸ performed a retrospective evaluation of 492 ED visits for anaphylaxis and found that epinephrine is administered less often in older patients (age >50 years); however, when administered intramuscularly, there was no significant difference in adverse cardiovascular events in this population compared with younger individuals. The study did demonstrate an increased rate of adverse cardiac events in older patients receiving intravenous epinephrine, an observation that the authors attributed partly to dosing errors that were reported more often with intravenous use.¹⁸

• Always promptly administer intramuscular epinephrine when treating anaphylaxis.
• Routine administration of corticosteroids in the treatment of anaphylaxis is not advised owing to insufficient data supporting their efficacy and potential for adverse events. Some patient populations may derive benefit from corticosteroids, including individuals with history of asthma exhibiting bronchospastic symptoms, individuals with significant upper-airway edema, and those undergoing certain chemotherapy regimens.

In the clinical vignette, the hospitalist withheld the first-line treatment for anaphylaxis, epinephrine. Without the support of evidence in the literature, patients receive corticosteroids and antihistamines more often than epinephrine for suspected anaphylaxis. No evidence supports the routine use of corticosteroids in the management of anaphylaxis or in the prevention of biphasic reactions. Further, recent research demonstrates significant adverse events are associated with even short courses of corticosteroids.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason” topics by emailing [email protected].

Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Juan, a 50-year-old man with acute myeloid leukemia (AML), sat on the edge of his bed, dejected. Juan’s leukemia had relapsed for a third time, and he was low on options and optimism. Originally from Mexico, he had made the journey to Colorado to work as a mechanic and care for his disabled son. Like millions of other individuals in the United States, he did not obtain a visa and had no affordable options for health insurance. For nearly a decade, that had seemed not to matter, until he became ill. Initially presenting to the emergency department with fatigue and night sweats, Juan was diagnosed with poor-risk AML and underwent emergent induction chemotherapy reimbursed under Emergency Medicaid (Table). Just when his bone marrow biopsy showed remission, however, Juan was told there was no chance to cure him, as his documentation status precluded him from receiving the next recommended therapy: stem cell transplant (SCT). Without transplant, Juan’s leukemia relapsed within a few months. He decided to undergo all the salvage chemotherapy that was offered, worrying about how his son would survive without his father.

For the patient with a new cancer diagnosis, a difference in immigration status may be the difference between life and death. Undocumented immigrants are excluded from federally funded benefits, including those offered under Medicare, most Medicaid programs, and the Patient Protection and Affordable Care Act (Table).¹ The nearly 11 million undocumented immigrants residing in the United States are integral to the workforce and economy. Although they pay taxes that fund Medicaid, contributing approximately $11.7 billion nationally in 2017, undocumented immigrants are ineligible to benefit from such programs.² The inequity of this policy is highlighted by Juan, an undocumented immigrant presenting with a new diagnosis of AML.

The Emergency Medical Treatment and Active Labor Act (EMTALA) is a 1986 federal law which mandates that patients who present to the hospital with an emergency medical condition receive appropriate evaluation and stabilizing treatment. An emergency condition is defined as “manifesting itself by acute symptoms of sufficient severity … such that the absence of immediate medical attention could reasonably be expected to result in (A) placing the patient’s health in serious jeopardy; (B) serious impairment to bodily functions; or (C) serious dysfunction of any bodily organ or part” (Table).^3,4 The Centers for Medicare & Medicaid manual restates the EMTALA definition and notes that services for an emergency medical condition cannot include care related to organ transplantation. Most state Emergency Medicaid programs have adopted the federal definition of what constitutes a medical emergency.⁵ As a result, undocumented individuals who qualify for Medicaid benefits but who do not meet citizenship requirements are eligible to “receive Medical Assistance benefits for emergency medical care only.”³

Similar to our patient Juan, individuals who initially present with an acute leukemia would be eligible for induction chemotherapy, as blast crisis is imminently fatal. Once in remission, however, standard-of-care therapy for patients without disqualifying comorbidities, depending on cytogenetic disease phenotypes, recommends the only current potential cure: allogeneic SCT, a treatment that was far from routine practice at the time EMTALA was enacted.⁶ When preparing for transplant, a patient is stable and no longer fits EMTALA’s “emergency” criteria, even though their health is still in “serious jeopardy,” as their cancer has been incompletely treated. Because most state Emergency Medicaid programs adopt the federal definition of an emergency medical condition, the cure is out of reach.

This policy requires clinicians to deviate from the usual standard of care and results in inferior outcomes. For AML patients in the poor-risk category, allogeneic SCT is recommended following induction chemotherapy.⁷ The risk of relapse is 30% to 40% if consolidation therapy includes SCT, vs 70% to 80% if treated with chemotherapeutic consolidation alone.⁶ AML patients in the intermediate-, and sometimes even favorable- risk categories, have been shown to benefit from allogeneic SCT as well, with risk of relapse half that of a patient who undergoes consolidation without transplant. Undocumented individuals with AML are therefore resigned to inadequate cancer treatment, including lifelong salvage chemotherapy, and have a substantially decreased chance of achieving sustained remission.⁶ Furthermore, providing inequitable care for undocumented patients with other medical conditions, such as end-stage kidney disease (ESKD), has been associated with inferior patient-reported outcomes, higher mortality and hospital costs, and clinician burnout. In many states, undocumented immigrants with ESKD rely on emergency dialysis (dialysis made available only after presenting critically ill to an emergency department). In 2019, Colorado’s Medicaid agency opted to include ESKD as a qualifying condition for Emergency Medicaid, thereby expanding access to scheduled dialysis. This led to improved patient quality of life, a decreased emotional toll on patients and clinicians, and reduced costs.^8,9

Policy discussions must consider cost. The average cost of allogeneic SCT in the United States was approximately $226,000 in 2018, which is often compared to the cost of managing a patient with refractory disease who does not receive transplant.¹⁰ This study reported a cost of active disease without transplant, including chemotherapy and hospitalizations, of approximately $69,000, plus terminal care costs of nearly $89,000; at a total of $158,000, this comes out to $68,000 less than SCT.¹⁰ This cost savings, however, results in a patient’s death rather than an up to 85% chance of long-term, relapse-free survival.⁶

To more completely capture the relationship between the healthcare value and cost-effectiveness of SCT, a second study calculated the incremental cost-effectiveness ratio (ICER) of transplantation in acute leukemias in the first 100 days post transplant, including management of complications, such as hospitalization, acute graft-versus-host disease (GVHD), infection, and blood product transfusions. ICER represents the economic value of an intervention compared to an alternative, calculated as cost per quality-adjusted life years. The ICER of SCT compared to no transplant is $16,346 to $34,360, depending on type of transplant and conditioning regimen.¹¹ An ICER of less than $50,000 is considered an acceptable expense for the value achieved—in this case, a significant opportunity for cure. This finding supports SCT, including management of complications, as an economically valuable intervention. Furthermore, if a sustained remission is achieved with SCT, this difference in expense buys the individual patient potentially decades of productivity to contribute back into society and the economy. According to the National Bureau of Economic Research, undocumented workers as a whole contribute $5 trillion to the US Gross Domestic Product over a 10-year period, or about $45,000 per worker per year.¹² According to the costs cited, curing a single undocumented worker with acute leukemia via SCT and allowing them to return to work would lead to a return on investment in less than 2 years. If the goal is high-quality, high-value, equitable care, it is logical to spend the money upfront and allow all patients the best chance for recovery.

One might suggest that patients instead receive treatment in their country of origin. This proposition, however, is often unrealistic. Latin American countries, for example, lack access to many standard-of-care cancer treatments available domestically. In Mexico, SCT is only available at a single facility in Mexico City, which is unable to track outcomes.¹³ The mortality-to-incidence ratio for cancer, a marker of availability of effective treatment, for Latin America is 0.48, substantially inferior to that of the United States (0.29).¹⁴ Importantly, almost two thirds of undocumented immigrants in the United States have lived in the country for 10 or more years, and 43% are parents of minor children, an increasing proportion of whom are American citizens.¹⁵ This highlights the impracticality of these individuals returning to their country of origin for treatment.

Medicaid laws in several states have made it possible for undocumented immigrants to receive access to standard-of-care therapies. Washington and California have included provisions that enable undocumented immigrants to receive allogeneic SCT if they are otherwise medically eligible. In the course of this policy change, legal arguments from the California Court of Appeals expressed that the language of the law was not intended to deny lifesaving treatment to an individual.¹⁶ California’s Emergency Medicaid policy is comparable to that of other states, but because the courts considered SCT a “continuation of medically necessary inpatient hospital services … directly related to the emergency” for which the patient initially presented, they concluded that it could be covered under California Medicaid. Despite covering SCT for undocumented immigrants, California maintains lower costs for those patients compared to US citizens on Medicaid while providing evidence-based cancer care.¹⁷ This exemplifies sustainable and equitable healthcare policy for the rest of the nation.

A proposed change in policy could occur at either the federal or state level. One option would be to follow the example set by the State of Washington. Under Emergency Medicaid, Washington modified qualifying conditions to include “emergency room care, inpatient admission, or outpatient surgery; a cancer treatment plan; dialysis treatment; anti-rejection medication for an organ transplant” and long-term care services.¹⁸ Federal policy reform for undocumented immigrants would also improve access to care. The US Citizenship Act of 2021, introduced to the House of Representatives in February 2021, offers a path to citizenship for undocumented immigrants, ultimately allowing for undocumented individuals to be eligible for the same programs as citizens, though after a period of up to 8 years.¹⁹ More immediate revisions of qualifying conditions under state Emergency Medicaid programs, coupled with a path to citizenship, would make significant progress towards reducing structural health inequities. Such policy change would also have broader implications. Three quarters of undocumented immigrants in the United States originate from Mexico, Central America, and South America, and the incidence rate of AML for Latinx individuals is 3.6 per 100,000, a figure which can be extrapolated to an estimated 380 cases per year in the US undocumented population.^20-22 In addition to benefiting patients with acute leukemias, the proposed policy change would also benefit numerous others who are frequently hospitalized for acute decompensations of chronic conditions, including congestive heart failure, liver disease, ESKD, and chronic lung conditions. Enabling follow-up care for these diseases under Emergency Medicaid would likewise be expected to reduce costs and improve both quality of care and patient-centered and clinical outcomes.

Hospitalists frequently care for undocumented immigrants with acute leukemias because the hospital can only be reimbursed by Emergency Medicaid when a patient is admitted to the hospital. Patients may ask about what they can expect in the course of their illness and, while details may be left to the oncologist, hospitalists will be faced with responding to many of these questions. Clinicians at our institution hold honest conversations with patients like Juan. We are compelled to provide the care that hospital and state policies allow, and can only offer the best care available to them because of the restrictions of an insurance system to which they contribute financially, yet cannot benefit from, in their time of need. We can tell our undocumented immigrant patients that we find this unacceptable and are actively advocating to change this policy.

The State of Colorado and the nation must amend its healthcare policy to include comprehensive cancer care for everyone. Offering standard-of-care therapy to all patients is not only ethical, but also an economically sound policy benefiting patients, clinicians, and the workforce.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing [email protected]

The authors thank Claire Campbell, MD, for her review of this manuscript.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing [email protected]

The authors thank Claire Campbell, MD, for her review of this manuscript.

Inspired by the ABIM Foundation’s Choosing Wisely^® campaign, the “Things We Do for No Reason^™” (TWDFNR) series reviews practices that have become common parts of hospital care but may provide little value to our patients. Practices reviewed in the TWDFNR series do not represent clear-cut conclusions or clinical practice standards but are meant as a starting place for research and active discussions among hospitalists and patients. We invite you to be part of that discussion.

An 87-year-old hospitalized man has lost 7% of his body weight in the past year. His family and the inpatient nutritionist ask about a prescription appetite stimulant.

Unintentional weight loss—the loss of more than 10 lb or 5% of usual body weight over 6 to 12 months—affects up to 27% of older adults in the community and 50% to 60% of older adults in nursing homes.^1,2 Patients who report weight loss on hospital admission have an almost four times greater risk of death in the 12 months following discharge.³ To address unintentional weight loss, clinicians may prescribe appetite stimulants.

Megestrol acetate is approved by the US Food and Drug Administration (FDA) for the treatment of weight loss in patients with AIDS.⁴ Megestrol acetate promotes weight gain through inhibition of cytokines, interleukin-6, and tumor necrosis factor-alpha, which are increased in older adults. In a randomized, placebo-controlled trial of 69 nursing home residents with ≥6 months’ life expectancy and Karnofsky score of ≥40%, patients treated with megestrol acetate for 12 weeks reported increased appetite and well-being. They achieved significant weight gain (>1.82 kg), but not until 3 months after therapy ended.⁵ No significant adverse events were reported; however, adverse event monitoring continued only for the 12-week treatment period. This follow-up duration may have been insufficient to identify some adverse events, such as venous thromboembolism.

Mirtazapine, an antidepressant and serotonin receptor antagonist, reduces levels of serotonin, a neurotransmitter that promotes early satiety.⁶ In a meta-analysis of 11 trials comparing mirtazapine to selective serotonin reuptake inhibitors for depression, patients treated with mirtazapine demonstrated an increase in the composite secondary outcome of weight gain or increased appetite.⁷ The amount of weight gain was not specified. Weight gain is more common with low-dose mirtazapine, potentially due to increased antihistamine activity at lower doses.⁸ Overall, mirtazapine is well-tolerated and efficacious in the treatment of depression and may benefit older adults with concomitant weight loss.⁶

Cyproheptadine is a first-generation antihistamine with appetite-stimulating effects. It has been found to increase weight or appetite in various disease states, particularly in the pediatric population,⁹ including cystic fibrosis¹⁰ and malignancy.¹¹ Given this evidence, there has been interest in its use in the geriatric population with unintentional weight loss.

Dronabinol is an orally active cannabinoid approved for anorexia-associated weight loss in patients with AIDS.¹² In a randomized, placebo-controlled trial in patients with AIDS-related anorexia and weight loss, participants receiving dronabinol had a statistically significant increase in appetite but no change in weight. Participants receiving dronabinol also experienced more nervous system-related adverse events, including dizziness, thinking abnormalities, and somnolence.¹³

Weight gain may not improve clinically meaningful outcomes. The absence of consistent evidence that prescription appetite stimulants improve patient-centered outcomes, such as quality of life or functional status, and the potential morbidity and mortality of these medications make prescribing appetite stimulants in older adults concerning.

Megestrol Acetate

A 2018 systematic review of randomized controlled trials studying megestrol acetate for treatment of anorexia-cachexia, primarily in adults with AIDS and cancer, found that treatment resulted in a 2.25-kg weight gain, with no improvement in quality of life and an increased risk of adverse events.¹⁴

Three prospective trials studied the effect of megestrol acetate in older adults (Appendix Table). One trial randomized 47 patients receiving skilled nursing services following an admission for acute illness to megestrol acetate vs placebo. While the investigators noted increases in appetite at higher doses of megestrol acetate, there was no change in weight or clinically relevant outcomes.¹⁵ In a second randomized controlled trial, 29 patients with illness-induced functional decline were enrolled in a strength training program in addition to being assigned to megestrol acetate or placebo. While patients receiving megestrol acetate with the exercise program had significant increases in weight and nutritional intake, they suffered a deterioration in physical function.¹⁶ In a pilot study, 17 nursing home residents who consistently ate less than 75% of their meals received megestrol acetate plus standard or optimal feeding assistance. The percentage of meals consumed increased only when patients received optimal feeding assistance in conjunction with megestrol acetate.¹⁷

The largest case-control study examining megestrol acetate for unintentional weight loss in older adults compared 709 residents in a multistate nursing home system treated with megestrol acetate to matched untreated controls. After 6 months of treatment, the median weight and change in weight did not differ significantly. Patients receiving megestrol acetate had a significant increase in mortality, surviving an average of 23.9 months, compared to 31.2 months for controls (P < .001).¹⁸

Additionally, two retrospective reviews of nursing home patients who were prescribed megestrol acetate showed incidences of venous thrombosis of 5% and 32%.^19,20 Other potentially significant adverse effects include adrenal insufficiency and fluid retention.⁶ In 2019, the American Geriatrics Society’s Beers Criteria included megestrol acetate as a medication to avoid given its “minimal effect on weight; increases [in] risk of thrombotic events and possibly death in older adults.”²¹

Mirtazapine

No studies have evaluated mirtazapine for weight gain without concomitant depression. In older adults with depression, mirtazapine has minimal impact on promoting weight gain compared to other antidepressants. In two retrospective studies of older patients with depression and weight loss, researchers found no difference in weight gain in those treated with mirtazapine vs sertraline or other nontricyclic antidepressants, excluding fluoxetine.^22,23

Cyproheptadine

There have been no controlled trials evaluating the use of cyproheptadine in older adults, in part due to anticholinergic side effects. In a trial of cancer patients, sedation and dizziness were common adverse effects.¹¹ The 2019 American Geriatrics Society’s Beers Criteria include cyproheptadine as a medication to avoid based upon the “risk of confusion, dry mouth, constipation, and other anticholinergic effects or toxicity.”²¹

Dronabinol

In a retrospective cohort study of 28 long-term care residents with anorexia and weight loss, participants receiving dronabinol for 12 weeks had no statistically significant weight gain.²⁴ The FDA cautions against prescribing dronabinol for older adults due to neurological side effects.¹² A systematic review of randomized controlled trials found that cannabinoid-based medications in patients older than 50 years were associated with a significant increase in dizziness or lightheadedness and thinking or perception disorder.²⁵

In the Choosing Wisely^® initiative, the American Geriatrics Society recommends avoiding prescription appetite stimulants for patients with anorexia or cachexia.²⁶ Instead, hospitalists should evaluate older patients for causes of unintentional weight loss, including malignancy, nonmalignant gastrointestinal disorders, depression, and dementia. Hospitalists can identify most causes based on the history, physical exam, and laboratory studies and initiate treatment for modifiable causes, such as constipation and depression.²

Hospitalists should work with an interprofessional team to develop an individualized plan to optimize caloric intake in the hospital (Table).²⁷ One in five hospitalized older adults has insufficient caloric intake during admission, which is associated with increased risk for in-hospital and 90-day mortality.²⁸ Removing dietary restrictions, increasing the variety of foods offered, and assisted eating may increase food intake.^27,29 Hospitalists should also consider discontinuing or changing medications with gastrointestinal side effects, such as metformin, cholinesterase inhibitors, bisphosphonates, and oral iron supplements. Dietitians may recommend oral nutrition supplements; if started, patients should be offered supplements after discharge.^27,29 For patients with limited access to food, social workers can help optimize social supports and identify community resources following discharge. Finally, hospitalists should coordinate with outpatient providers to monitor weight long-term.

• Recognize and address unintentional weight loss in older adults in the hospital.
• Do not prescribe appetite stimulants for unintentional weight loss in hospitalized older adults as they have no proven benefit for improving long-term outcomes and, in the case of megestrol acetate, may increase mortality.
• Work with an interprofessional team to address factors contributing to unintentional weight loss using nonpharmacologic options for improving food intake.

After discussing the lack of evidence supporting prescription appetite stimulants and the potential risks, we shifted the focus to optimizing oral intake. The team worked with the patient and the patient’s family to optimize nutrition following discharge and communicated the need for ongoing monitoring to the primary care provider.

Do you think this is a low-value practice? Is this truly a “Thing We Do for No Reason^™”? Share what you do in your practice and join in the conversation online by retweeting it on Twitter (#TWDFNR) and liking it on Facebook. We invite you to propose ideas for other “Things We Do for No Reason^™” topics by emailing [email protected]

The authors thank Claire Campbell, MD, for her review of this manuscript.