BOSTON — Patients who have had a stroke are thought to be at a higher risk for another one, but oral anticoagulation with edoxaban led to no discernible reduction in the risk for a second stroke, and the risk for major bleeding was more than quadruple the risk with no anticoagulation, a subanalysis of a major European trial has shown.

“There is no interaction between prior stroke or TIA [transient ischemic attack] and the treatment effect, and this is true for the primary outcome and the safety outcome,” Paulus Kirchoff, MD, director of cardiology at the University Heart and Vascular Center in Hamburg, Germany, said during his presentation of a subanalysis of the NOAH-AFNET 6 trial at the annual meeting of the Heart Rhythm Society (HRS) 2024. However, “there is a signal for more safety events in patients randomized to anticoagulation with a prior stroke.”

The subanalysis involved 253 patients who had had a stroke or TIA and who had device-detected atrial fibrillation (AF) from the overall NOAH-AFNET 6 population of 2536 patients, which enrolled patients 65 years and older with at least one additional CHA2DS-VASc risk factor and patients 75 years and older with device-detected subclinical AF episodes of at least 6 minutes. Patients were randomized to either edoxaban or no anticoagulation, but 53.9% of the no-anticoagulation group was taking aspirin at trial enrollment. Anticoagulation with edoxaban was shown to have no significant impact on stroke rates or other cardiovascular outcomes.
 

Subanalysis Results

In the subanalysis, a composite of stroke, systemic embolism, and cardiovascular death — the primary outcome — was similar in the edoxaban and no-anticoagulation groups (14/122 patients [11.5%] vs 16/131 patients [12.2%]; 5.7% vs 6.3% per patient-year).

The rate of recurrent stroke was also similar in the edoxaban and no-anticoagulation groups (4 of 122 patients [3.3%] vs 6 of 131 patients [4.6%]; 1.6% vs 2.3% per patient-year). And there were eight cardiovascular deaths in each group.

However, edoxaban patients had significantly higher rates of major bleeding.

“This is a subanalysis, so what we see in terms of the number of patients with events is not powered for a definitive answer, but we do see that there were 10 major bleeds in the group of patients with a prior stroke or TIA in NOAH,” Dr. Kirchoff reported. “Eight of those 10 major bleeds occurred in patients randomized to edoxaban.”

Results from the NOAH-AFNET 6 trial have been compared with those from the ARTESiA trial, which compared apixaban anticoagulation with aspirin in patients with subclinical AF and was also presented at HRS 2024. ARTESiA showed that apixaban significantly lowered the risk for stroke and systemic embolism.

“In ARTESiA, everyone was on aspirin when they were randomized to no anticoagulation; in NOAH, only about half were on aspirin,” Dr. Kirchoff said.

Both studies had similar outcomes for cardiovascular death in the anticoagulation and no-anticoagulation groups. “It’s not significant; it may be chance, but it’s definitely not the reduction in death that we have seen in the anticoagulant trials,” Dr. Kirchoff said. “When you look at the meta-analyses of the early anticoagulation trials, there’s a one third reduction in death, and here we’re talking about a smaller reduction.”

This research points to a need for a better way to evaluate stroke risk. “We need new markers,” Dr. Kirchoff said. “Some of them may be in the blood or imaging, genetics maybe, and one thing that really emerges from my perspective is that we now have the first evidence to suggest that patients with a very low atrial fibrillation burden have a low stroke rate.”

More research is needed to better understand AF characteristics and stroke risk, he said.
 

AF Care Enters a ‘Gray Zone’

The NOAH-AFNET 6 results, coupled with those from ARTESiA, are changing the paradigm for anticoagulation in patients with stroke, said Taya Glotzer, MD, an electrophysiologist at the Hackensack University Medical Center in Hackensack, New Jersey, who compiled her own analysis of the studies’ outcomes.

“In ARTESiA, the stroke reduction was only 0.44% a year, with a number needed to treat of 250,” she said. “In the NOAH-AFNET 6 main trial, the stroke reduction was 0.2%, with the number needed to treat of 500, and in the NOAH prior stroke patients, there was a 0.7% reduction, with a number needed to treat of 143.”

None of these trials would meet the standard for a class 1 recommendation for anticoagulation with a reduction of even 1%-2% per year, she noted, but they do show that the stroke rate “is very, very low” in prior patients with stroke.

“Prior to 2024, we knew what was black and white; we knew who to anticoagulate and who not to anticoagulate. And now we are in a gray zone, trying to balance the risk of stroke and bleeding. We have to individualize or hope for substudies, perhaps using the CHA2DS-VASc score or other information about the left atrium, to help us make decisions in these patients. It’s not just going to be black and white,” she said.

Dr. Kirchoff had no relevant financial relationships to disclose. Dr. Glotzer disclosed financial relationships with Medtronic, Abbott, Boston Scientific, and MediaSphere Medical.

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

BOSTON — Patients who have had a stroke are thought to be at a higher risk for another one, but oral anticoagulation with edoxaban led to no discernible reduction in the risk for a second stroke, and the risk for major bleeding was more than quadruple the risk with no anticoagulation, a subanalysis of a major European trial has shown.

“There is no interaction between prior stroke or TIA [transient ischemic attack] and the treatment effect, and this is true for the primary outcome and the safety outcome,” Paulus Kirchoff, MD, director of cardiology at the University Heart and Vascular Center in Hamburg, Germany, said during his presentation of a subanalysis of the NOAH-AFNET 6 trial at the annual meeting of the Heart Rhythm Society (HRS) 2024. However, “there is a signal for more safety events in patients randomized to anticoagulation with a prior stroke.”

The subanalysis involved 253 patients who had had a stroke or TIA and who had device-detected atrial fibrillation (AF) from the overall NOAH-AFNET 6 population of 2536 patients, which enrolled patients 65 years and older with at least one additional CHA2DS-VASc risk factor and patients 75 years and older with device-detected subclinical AF episodes of at least 6 minutes. Patients were randomized to either edoxaban or no anticoagulation, but 53.9% of the no-anticoagulation group was taking aspirin at trial enrollment. Anticoagulation with edoxaban was shown to have no significant impact on stroke rates or other cardiovascular outcomes.
 

Subanalysis Results

In the subanalysis, a composite of stroke, systemic embolism, and cardiovascular death — the primary outcome — was similar in the edoxaban and no-anticoagulation groups (14/122 patients [11.5%] vs 16/131 patients [12.2%]; 5.7% vs 6.3% per patient-year).

The rate of recurrent stroke was also similar in the edoxaban and no-anticoagulation groups (4 of 122 patients [3.3%] vs 6 of 131 patients [4.6%]; 1.6% vs 2.3% per patient-year). And there were eight cardiovascular deaths in each group.

However, edoxaban patients had significantly higher rates of major bleeding.

“This is a subanalysis, so what we see in terms of the number of patients with events is not powered for a definitive answer, but we do see that there were 10 major bleeds in the group of patients with a prior stroke or TIA in NOAH,” Dr. Kirchoff reported. “Eight of those 10 major bleeds occurred in patients randomized to edoxaban.”

Results from the NOAH-AFNET 6 trial have been compared with those from the ARTESiA trial, which compared apixaban anticoagulation with aspirin in patients with subclinical AF and was also presented at HRS 2024. ARTESiA showed that apixaban significantly lowered the risk for stroke and systemic embolism.

“In ARTESiA, everyone was on aspirin when they were randomized to no anticoagulation; in NOAH, only about half were on aspirin,” Dr. Kirchoff said.

Both studies had similar outcomes for cardiovascular death in the anticoagulation and no-anticoagulation groups. “It’s not significant; it may be chance, but it’s definitely not the reduction in death that we have seen in the anticoagulant trials,” Dr. Kirchoff said. “When you look at the meta-analyses of the early anticoagulation trials, there’s a one third reduction in death, and here we’re talking about a smaller reduction.”

This research points to a need for a better way to evaluate stroke risk. “We need new markers,” Dr. Kirchoff said. “Some of them may be in the blood or imaging, genetics maybe, and one thing that really emerges from my perspective is that we now have the first evidence to suggest that patients with a very low atrial fibrillation burden have a low stroke rate.”

More research is needed to better understand AF characteristics and stroke risk, he said.
 

AF Care Enters a ‘Gray Zone’

The NOAH-AFNET 6 results, coupled with those from ARTESiA, are changing the paradigm for anticoagulation in patients with stroke, said Taya Glotzer, MD, an electrophysiologist at the Hackensack University Medical Center in Hackensack, New Jersey, who compiled her own analysis of the studies’ outcomes.

“In ARTESiA, the stroke reduction was only 0.44% a year, with a number needed to treat of 250,” she said. “In the NOAH-AFNET 6 main trial, the stroke reduction was 0.2%, with the number needed to treat of 500, and in the NOAH prior stroke patients, there was a 0.7% reduction, with a number needed to treat of 143.”

None of these trials would meet the standard for a class 1 recommendation for anticoagulation with a reduction of even 1%-2% per year, she noted, but they do show that the stroke rate “is very, very low” in prior patients with stroke.

“Prior to 2024, we knew what was black and white; we knew who to anticoagulate and who not to anticoagulate. And now we are in a gray zone, trying to balance the risk of stroke and bleeding. We have to individualize or hope for substudies, perhaps using the CHA2DS-VASc score or other information about the left atrium, to help us make decisions in these patients. It’s not just going to be black and white,” she said.

Dr. Kirchoff had no relevant financial relationships to disclose. Dr. Glotzer disclosed financial relationships with Medtronic, Abbott, Boston Scientific, and MediaSphere Medical.

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

BOSTON — Patients who have had a stroke are thought to be at a higher risk for another one, but oral anticoagulation with edoxaban led to no discernible reduction in the risk for a second stroke, and the risk for major bleeding was more than quadruple the risk with no anticoagulation, a subanalysis of a major European trial has shown.

“There is no interaction between prior stroke or TIA [transient ischemic attack] and the treatment effect, and this is true for the primary outcome and the safety outcome,” Paulus Kirchoff, MD, director of cardiology at the University Heart and Vascular Center in Hamburg, Germany, said during his presentation of a subanalysis of the NOAH-AFNET 6 trial at the annual meeting of the Heart Rhythm Society (HRS) 2024. However, “there is a signal for more safety events in patients randomized to anticoagulation with a prior stroke.”

The subanalysis involved 253 patients who had had a stroke or TIA and who had device-detected atrial fibrillation (AF) from the overall NOAH-AFNET 6 population of 2536 patients, which enrolled patients 65 years and older with at least one additional CHA2DS-VASc risk factor and patients 75 years and older with device-detected subclinical AF episodes of at least 6 minutes. Patients were randomized to either edoxaban or no anticoagulation, but 53.9% of the no-anticoagulation group was taking aspirin at trial enrollment. Anticoagulation with edoxaban was shown to have no significant impact on stroke rates or other cardiovascular outcomes.
 

Subanalysis Results

In the subanalysis, a composite of stroke, systemic embolism, and cardiovascular death — the primary outcome — was similar in the edoxaban and no-anticoagulation groups (14/122 patients [11.5%] vs 16/131 patients [12.2%]; 5.7% vs 6.3% per patient-year).

The rate of recurrent stroke was also similar in the edoxaban and no-anticoagulation groups (4 of 122 patients [3.3%] vs 6 of 131 patients [4.6%]; 1.6% vs 2.3% per patient-year). And there were eight cardiovascular deaths in each group.

However, edoxaban patients had significantly higher rates of major bleeding.

“This is a subanalysis, so what we see in terms of the number of patients with events is not powered for a definitive answer, but we do see that there were 10 major bleeds in the group of patients with a prior stroke or TIA in NOAH,” Dr. Kirchoff reported. “Eight of those 10 major bleeds occurred in patients randomized to edoxaban.”

Results from the NOAH-AFNET 6 trial have been compared with those from the ARTESiA trial, which compared apixaban anticoagulation with aspirin in patients with subclinical AF and was also presented at HRS 2024. ARTESiA showed that apixaban significantly lowered the risk for stroke and systemic embolism.

“In ARTESiA, everyone was on aspirin when they were randomized to no anticoagulation; in NOAH, only about half were on aspirin,” Dr. Kirchoff said.

Both studies had similar outcomes for cardiovascular death in the anticoagulation and no-anticoagulation groups. “It’s not significant; it may be chance, but it’s definitely not the reduction in death that we have seen in the anticoagulant trials,” Dr. Kirchoff said. “When you look at the meta-analyses of the early anticoagulation trials, there’s a one third reduction in death, and here we’re talking about a smaller reduction.”

This research points to a need for a better way to evaluate stroke risk. “We need new markers,” Dr. Kirchoff said. “Some of them may be in the blood or imaging, genetics maybe, and one thing that really emerges from my perspective is that we now have the first evidence to suggest that patients with a very low atrial fibrillation burden have a low stroke rate.”

More research is needed to better understand AF characteristics and stroke risk, he said.
 

AF Care Enters a ‘Gray Zone’

The NOAH-AFNET 6 results, coupled with those from ARTESiA, are changing the paradigm for anticoagulation in patients with stroke, said Taya Glotzer, MD, an electrophysiologist at the Hackensack University Medical Center in Hackensack, New Jersey, who compiled her own analysis of the studies’ outcomes.

“In ARTESiA, the stroke reduction was only 0.44% a year, with a number needed to treat of 250,” she said. “In the NOAH-AFNET 6 main trial, the stroke reduction was 0.2%, with the number needed to treat of 500, and in the NOAH prior stroke patients, there was a 0.7% reduction, with a number needed to treat of 143.”

None of these trials would meet the standard for a class 1 recommendation for anticoagulation with a reduction of even 1%-2% per year, she noted, but they do show that the stroke rate “is very, very low” in prior patients with stroke.

“Prior to 2024, we knew what was black and white; we knew who to anticoagulate and who not to anticoagulate. And now we are in a gray zone, trying to balance the risk of stroke and bleeding. We have to individualize or hope for substudies, perhaps using the CHA2DS-VASc score or other information about the left atrium, to help us make decisions in these patients. It’s not just going to be black and white,” she said.

Dr. Kirchoff had no relevant financial relationships to disclose. Dr. Glotzer disclosed financial relationships with Medtronic, Abbott, Boston Scientific, and MediaSphere Medical.

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

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects approximately 0.1% of the US population.^1,2 Severe disease or HS flares can lead patients to seek care through the emergency department (ED), with some requiring inpatient admission. ³ Inpatient hospitalization of patients with HS has increased over the last 2 decades, and patients with HS utilize emergency and inpatient care more frequently than those with other dermatologic conditions.^4,5 Minority patients and those of lower socioeconomic status are more likely to present to the ED for HS management due to limited access to care and other existing comorbid conditions. ⁴ In a 2022 study of the Nationwide Readmissions Database, the authors looked at hospital readmission rates of patients with HS compared with those with heart failure—both patient populations with chronic debilitating conditions. Results indicated that the hospital readmission rates for patients with HS surpassed those of patients with heart failure for that year, highlighting the need for improved inpatient management of HS.⁶

Patients with HS present to the ED with severe pain, fever, wound care, or the need for surgical intervention. The ED and inpatient hospital setting are locations in which physicians may not be as familiar with the diagnosis or treatment of HS, specifically flares or severe disease. ⁷ The inpatient care setting provides access to certain resources that can be challenging to obtain in the outpatient clinical setting, such as social workers and pain specialists, but also can prove challenging in obtaining other resources for HS management, such as advanced medical therapies. Given the increase in hospital- based care for HS and lack of widespread inpatient access to dermatology and HS experts, consensus recommendations for management of HS in the acute hospital setting would be beneficial. In our study, we sought to generate a collection of expert consensus statements providers can refer to when managing patients with HS in the inpatient setting.

Methods

The study team at the Wake Forest University School of Medicine (Winston-Salem, North Carolina)(M.N., R.P., L.C.S.) developed an initial set of consensus statements based on current published HS treatment guidelines,^8,9 publications on management of inpatient HS,³ published supportive care guidelines for Stevens-Johnson syndrome, 10 and personal clinical experience in managing inpatient HS, which resulted in 50 statements organized into the following categories: overall care, wound care, genital care, pain management, infection control, medical management, surgical management, nutrition, and transitional care guidelines. This study was approved by the Wake Forest University institutional review board (IRB00084257).

Participant Recruitment—Dermatologists were identified for participation in the study based on membership in the Society of Dermatology Hospitalists and the Hidradenitis Suppurativa Foundation or authorship of publications relevant to HS or inpatient dermatology. Dermatologists from larger academic institutions with HS specialty clinics and inpatient dermatology services also were identified. Participants were invited via email and could suggest other experts for inclusion. A total of 31 dermatologists were invited to participate in the study, with 26 agreeing to participate. All participating dermatologists were practicing in the United States.

Delphi Study—In the first round of the Delphi study, the participants were sent an online survey via REDCap in which they were asked to rank the appropriateness of each of the proposed 50 guideline statements on a scale of 1 (very inappropriate) to 9 (very appropriate). Participants also were able to provide commentary and feedback on each of the statements. Survey results were analyzed using the RAND/ UCLA Appropriateness Method.¹¹ For each statement, the median rating for appropriateness, interpercentile range (IPR), IPR adjusted for symmetry, and disagreement index (DI) were calculated (DI=IPR/IPR adjusted for symmetry). The 30th and 70th percentiles were used in the DI calculation as the upper and lower limits, respectively. A median rating for appropriateness of 1.0 to 3.9 was considered “inappropriate,” 4.0 to 6.9 was considered “uncertain appropriateness,” and 7.0 to 9.0 was “appropriate.” A DI value greater than or equal to 1 indicated a lack of consensus regarding the appropriateness of the statement. Following each round, participants received a copy of their responses along with the group median rank of each statement. Statements that did not reach consensus in the first Delphi round were revised based on feedback received by the participants, and a second survey with 14 statements was sent via REDCap 2 weeks later. The RAND/UCLA Appropriateness Method also was applied to this second Delphi round. After the second survey, participants received a copy of anonymized comments regarding the consensus statements and were allowed to provide additional final commentary to be included in the discussion of these recommendations.

Results

Twenty-six dermatologists completed the first-round survey, and 24 participants completed the second-round survey. All participants self-identified as having expertise in either HS (n=22 [85%]) or inpatient dermatology (n=17 [65%]), and 13 (50%) participants self-identified as experts in both HS and inpatient dermatology. All participants, except 1, were affiliated with an academic health system with inpatient dermatology services. The average length of time in practice as a dermatologist was 10 years (median, 9 years [range, 3–27 years]).

Of the 50 initial proposed consensus statements, 26 (52%) achieved consensus after the first round; 21 statements revealed DI calculations that did not achieve consensus. Two statements achieved consensus but received median ratings for appropriateness, indicating uncertain appropriateness; because of this, 1 statement was removed and 1 was revised based on participant feedback, resulting in 13 revised statements (eTable 1). Controversial topics in the consensus process included obtaining wound cultures and meaningful culture data interpretation, use of specific biologic medications in the inpatient setting, and use of intravenous ertapenem. Participant responses to these topics are discussed in detail below. Of these secondround statements, all achieved consensus. The final set of consensus statements can be found in eTable 2.

Comment

Our Delphi consensus study combined the expertise of both dermatologists who care for patients with HS and those with inpatient dermatology experience to produce a set of recommendations for the management of HS in the hospital care setting. A strength of this study is inclusion of many national leaders in both HS and inpatient dermatology, with some participants having developed the previously published HS treatment guidelines and others having participated in inpatient dermatology Delphi studies.8-10 The expertise is further strengthened by the geographically diverse institutional representation within the United States.

The final consensus recommendations included 40 statements covering a range of patient care issues, including use of appropriate inpatient subspecialists (care team), supportive care measures (wound care, pain control, genital care), disease-oriented treatment (medical management, surgical management), inpatient complications (infection control, nutrition), and successful transition back to outpatient management (transitional care). These recommendations are meant to serve as a resource for providers to consider when taking care of inpatient HS flares, recognizing that the complexity and individual circumstances of each patient are unique.

Delphi Consensus Recommendations Compared to Prior Guidelines—Several recommendations in the current study align with the previously published North American clinical management guidelines for HS.^8,9 Our recommendations agree with prior guidelines on the importance of disease staging and pain assessment using validated assessment tools as well as screening for HS comorbidities. There also is agreement in the potential benefit of involving pain specialists in the development of a comprehensive pain management plan. The inpatient care setting provides a unique opportunity to engage multiple specialists and collaborate on patient care in a timely manner. Our recommendations regarding surgical care also align with established guidelines in recommending incision and drainage as an acute bedside procedure best utilized for symptom relief in inflamed abscesses and relegating most other surgical management to the outpatient setting. Wound care recommendations also are similar, with our expert participants agreeing on individualizing dressing choices based on wound characteristics. A benefit of inpatient wound care is access to skilled nursing for dressing changes and potentially improved access to more sophisticated dressing materials. Our recommendations differ from the prior guidelines in our focus on severe HS, HS flares, and HS complications, which constitute the majority of inpatient disease management. We provide additional guidance on management of secondary infections, perianal fistulous disease, and importantly transitional care to optimize discharge planning.

Differing Opinions in Our Analysis—Despite the success of our Delphi consensus process, there were some differing opinions regarding certain aspects of inpatient HS management, which is to be expected given the lack of strong evidence-based research to support some of the recommended practices. There were differing opinions on the utility of wound culture data, with some participants feeling culture data could help with antibiotic susceptibility and resistance patterns, while others felt wound cultures represent bacterial colonization or biofilm formation.

Initial consensus statements in the first Delphi round were created for individual biologic medications but did not achieve consensus, and feedback on the use of biologics in the inpatient environment was mixed, largely due to logistic and insurance issues. Many participants felt biologic medication cost, difficulty obtaining inpatient reimbursement, health care resource utilization, and availability of biologics in different hospital systems prevented recommending the use of specific biologics during hospitalization. The one exception was in the case of a hospitalized patient who was already receiving infliximab for HS: there was consensus on ensuring the patient dosing was maximized, if appropriate, to 10 mg/kg.12 Ertapenem use also was controversial, with some participants using it as a bridge therapy to either outpatient biologic use or surgery, while others felt it was onerous and difficult to establish reliable access to secure intravenous administration and regular dosing once the patient left the inpatient setting.¹³ Others said they have experienced objections from infectious disease colleagues on the use of intravenous antibiotics, citing antibiotic stewardship concerns.

Patient Care in the Inpatient Setting—Prior literature suggests patients admitted as inpatients for HS tend to be of lower socioeconomic status and are admitted to larger urban teaching hospitals.^14,15 Patients with lower socioeconomic status have increased difficulty accessing health care resources; therefore, inpatient admission serves as an opportunity to provide a holistic HS assessment and coordinate resources for chronic outpatient management.

Study Limitations—This Delphi consensus study has some limitations. The existing literature on inpatient management of HS is limited, challenging our ability to assess the extent to which these published recommendations are already being implemented. Additionally, the study included HS and inpatient dermatology experts from the United States, which means the recommendations may not be generalizable to other countries. Most participants practiced dermatology at large tertiary care academic medical centers, which may limit the ability to implement recommendations in all US inpatient care settings such as small community-based hospitals; however, many of the supportive care guidelines such as pain control, wound care, nutritional support, and social work should be achievable in most inpatient care settings.

Conclusion

Given the increase in inpatient and ED health care utilization for HS, there is an urgent need for expert consensus recommendations on inpatient management of this unique patient population, which requires complex multidisciplinary care. Our recommendations are a resource for providers to utilize and potentially improve the standard of care we provide these patients.

Acknowledgment—We thank the Wake Forest University Clinical and Translational Science Institute (Winston- Salem, North Carolina) for providing statistical help.

LISBON, PORTUGAL — Few people with suspected heart failure and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are receiving a diagnosis after a year, reported investigators, who say high rates of hospitalization are common.

Presenting here at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024, researchers shared results from the REVOLUTION-HF study involving almost 8000 people who consulted outpatient primary and secondary care over a 5-year period.

About two thirds of the patients had suspected heart failure; however, less than 30% of the people received a diagnosis within a year.

Yet hospitalization was eight times higher in the suspected heart failure group than in the control group, and all-cause mortality was nearly doubled. The outcomes were even worse in patients with high NT-proBNP levels.

Patients with suspected heart failure are “waiting far too long to see a specialist, and that results in a delay to guideline-directed medical therapy, despite the fact that we’re perfectly happy to slap them all on diuretics,” said study presenter Lisa Anderson, MD, PhD, Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George’s Hospital, University of London, England.

“We need to rethink our management of heart failure patients presenting in the community,” she said.

A big gap exists internationally between presentation with heart failure, an elevated NT-proBNP, and confirmatory specialist assessment, she explained.

“It’s a scandal that patients are coming to the GP with signs and symptoms of heart failure, they get tested for natriuretic peptides, and nothing happens,” said co-author Antoni Bayés-Genís, MD, PhD, Heart Institute director, Hospital Universitari Germans Trias i Pujol Catedràtic, Barcelona, Spain.

“These patients may receive an echo, or not, in the coming 12 months,” and “during these 12 months, there is a huge number of heart failure hospitalizations and deaths that could probably be prevented.”
 

Why the Reluctance to Diagnose?

Many issues get in the way of early diagnosis, Dr. Bayés-Genís said. “Inertia, comorbidities, ageism.”

A lot of patients with heart failure are elderly women with some degree of weight gain, he said. “And they come to the clinic with fatigue, so we tell them, ‘Well, that’s normal.”

But “it may not be normal,” he added. “This is a very important topic that we, as a society, need to address.”

There are several “misconceptions” about heart failure, said Ileana L. Piña, MD, MPH, the Robert Stein Chair for Quality and Safety, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, who was not involved in the study.

For example, “we’re all convinced that guideline-directed medical therapy works,” but the evidence is only for patients “with a diagnosis.” In addition, “millions of patients get tested” for heart failure, but they already have a “known diagnosis.”

“When we study these drugs, we’re studying them on patients with manifest disease,” who are only then randomized, Dr. Piña said. “But we seldom see them while they’re developing heart failure. And it’s a process; it doesn’t happen overnight.”

Patients initially often think they may have asthma, and so what follows is an extended period of “uncertainty” and “important time lost” before they finally undergo the assessments that show that they have heart failure, she said.

However, “uncertainty” often lands a patient “in the emergency room or with an unscheduled office visit, where NT-proBNP might get ordered and there’s a long lineup for an echo.”

There are several strengths of the current study, Dr. Piña said, including the fact that 50% of the study population were women, and they were older than a typical trial population. Nevertheless, the results were “eye-opening but not surprising” and, in the end, “disappointing.”

“I agree, we need a revolution, Dr. Anderson,” Dr. Piña said. “The revolution of paying attention to the NT-proBNP when you get it and it’s elevated” and then following through with echocardiography and starting “guideline-directed medical therapy early.”

The diagnosis of heart failure “relies on the presentation of patients with nonspecific signs and symptoms,” such as dyspnea and peripheral edema, “but initiation of guideline-directed medical therapy — life-saving treatment — has to wait until we have a formal echocardiography and specialist clinician assessment,” Dr. Anderson said.

The latest clinical consensus statement from the Heart Failure Association “proposes both rule-in and rule-out NT-proBNP levels for heart failure diagnosis, and obviously we all recognize that it’s important to treat patients as soon as they’re diagnosed,” she explained.
 

REVOLUTION-HF

To examine the risk profile for patients presenting to outpatient care with suspected heart failure, the researchers conducted REVOLUTION-HF, which leveraged nationwide Swedish linked data from general practices, specialists, pharmacies, hospitals, and cause of death registers.

“Really impressively, most of these NT-proBNP tests were coming back within a day,” Dr. Anderson said, “so a really, really good turnaround.”

Individuals were excluded if they had an inpatient admission, echocardiography, or heart failure diagnosis between presentation and the NT-proBNP measurement.

These people were then compared with those presenting to primary or secondary outpatient care for any reason and matched for age, sex, care level, and index year. Both groups were followed up for 1 year.

“Despite this really impressive, almost immediate NT-proBNP testing,” the waiting times to undergo echocardiography were “really disappointing,” Dr. Anderson said.

The median time to first registered echocardiography was 40 days, and only 29% of patients with suspected heart failure received a diagnosis within a year of the index presentation date, which she described as “inadequately slow.”

“And how does this translate to medical therapy?” she asked.
 

Heart Failure Drugs

After the index presentation, the rate of loop diuretic use quadrupled among individuals suspected of having heart failure, but there was a “muted response” when it came to the prescribing of beta-blockers and the other pillars of heart failure therapy, which Dr. Anderson called “very disappointing.”

For outcomes after the index presentation, the rate of hospitalization was much higher in the group with suspected heart failure than in the control group (16.1 vs 2.2 events per 100 person-years). And all-cause mortality occurred more often in the group with suspected heart failure than in the control group (10.3 vs 6.5 events per 100 person-years).

Among patients with NT-proBNP levels of 2000 ng/L, there was a “rapid” onset of hospitalization “within the first few days” of the index presentation, which was tracked by a more linear rise in all-cause deaths, Dr. Anderson reported.

In the United Kingdom, “we are very proud of our 2- and 6-week pathways,” which stipulate that suspected heart failure patients with NT-proBNP levels between 400 and 2000 ng/L are to have a specialist assessment and transthoracic echocardiography within 6 weeks; for those with levels > 2000 ng/L, that interval is accelerated to 2 weeks, she said.

The current results show that “2 weeks is too slow.” And looking at the rest of the cohort with lower NT-proBNP levels, “patients have already been admitted and died” by 6 weeks, she said.

When patients are stratified by age, “you get exactly what you would expect,” Dr. Anderson said. “The older patients are the most at risk” for both hospitalization and all-cause mortality.
 

A version of this article appeared on Medscape.com.

LISBON, PORTUGAL — Few people with suspected heart failure and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are receiving a diagnosis after a year, reported investigators, who say high rates of hospitalization are common.

Presenting here at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024, researchers shared results from the REVOLUTION-HF study involving almost 8000 people who consulted outpatient primary and secondary care over a 5-year period.

About two thirds of the patients had suspected heart failure; however, less than 30% of the people received a diagnosis within a year.

Yet hospitalization was eight times higher in the suspected heart failure group than in the control group, and all-cause mortality was nearly doubled. The outcomes were even worse in patients with high NT-proBNP levels.

Patients with suspected heart failure are “waiting far too long to see a specialist, and that results in a delay to guideline-directed medical therapy, despite the fact that we’re perfectly happy to slap them all on diuretics,” said study presenter Lisa Anderson, MD, PhD, Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George’s Hospital, University of London, England.

“We need to rethink our management of heart failure patients presenting in the community,” she said.

A big gap exists internationally between presentation with heart failure, an elevated NT-proBNP, and confirmatory specialist assessment, she explained.

“It’s a scandal that patients are coming to the GP with signs and symptoms of heart failure, they get tested for natriuretic peptides, and nothing happens,” said co-author Antoni Bayés-Genís, MD, PhD, Heart Institute director, Hospital Universitari Germans Trias i Pujol Catedràtic, Barcelona, Spain.

“These patients may receive an echo, or not, in the coming 12 months,” and “during these 12 months, there is a huge number of heart failure hospitalizations and deaths that could probably be prevented.”
 

Why the Reluctance to Diagnose?

Many issues get in the way of early diagnosis, Dr. Bayés-Genís said. “Inertia, comorbidities, ageism.”

A lot of patients with heart failure are elderly women with some degree of weight gain, he said. “And they come to the clinic with fatigue, so we tell them, ‘Well, that’s normal.”

But “it may not be normal,” he added. “This is a very important topic that we, as a society, need to address.”

There are several “misconceptions” about heart failure, said Ileana L. Piña, MD, MPH, the Robert Stein Chair for Quality and Safety, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, who was not involved in the study.

For example, “we’re all convinced that guideline-directed medical therapy works,” but the evidence is only for patients “with a diagnosis.” In addition, “millions of patients get tested” for heart failure, but they already have a “known diagnosis.”

“When we study these drugs, we’re studying them on patients with manifest disease,” who are only then randomized, Dr. Piña said. “But we seldom see them while they’re developing heart failure. And it’s a process; it doesn’t happen overnight.”

Patients initially often think they may have asthma, and so what follows is an extended period of “uncertainty” and “important time lost” before they finally undergo the assessments that show that they have heart failure, she said.

However, “uncertainty” often lands a patient “in the emergency room or with an unscheduled office visit, where NT-proBNP might get ordered and there’s a long lineup for an echo.”

There are several strengths of the current study, Dr. Piña said, including the fact that 50% of the study population were women, and they were older than a typical trial population. Nevertheless, the results were “eye-opening but not surprising” and, in the end, “disappointing.”

“I agree, we need a revolution, Dr. Anderson,” Dr. Piña said. “The revolution of paying attention to the NT-proBNP when you get it and it’s elevated” and then following through with echocardiography and starting “guideline-directed medical therapy early.”

The diagnosis of heart failure “relies on the presentation of patients with nonspecific signs and symptoms,” such as dyspnea and peripheral edema, “but initiation of guideline-directed medical therapy — life-saving treatment — has to wait until we have a formal echocardiography and specialist clinician assessment,” Dr. Anderson said.

The latest clinical consensus statement from the Heart Failure Association “proposes both rule-in and rule-out NT-proBNP levels for heart failure diagnosis, and obviously we all recognize that it’s important to treat patients as soon as they’re diagnosed,” she explained.
 

REVOLUTION-HF

To examine the risk profile for patients presenting to outpatient care with suspected heart failure, the researchers conducted REVOLUTION-HF, which leveraged nationwide Swedish linked data from general practices, specialists, pharmacies, hospitals, and cause of death registers.

“Really impressively, most of these NT-proBNP tests were coming back within a day,” Dr. Anderson said, “so a really, really good turnaround.”

Individuals were excluded if they had an inpatient admission, echocardiography, or heart failure diagnosis between presentation and the NT-proBNP measurement.

These people were then compared with those presenting to primary or secondary outpatient care for any reason and matched for age, sex, care level, and index year. Both groups were followed up for 1 year.

“Despite this really impressive, almost immediate NT-proBNP testing,” the waiting times to undergo echocardiography were “really disappointing,” Dr. Anderson said.

The median time to first registered echocardiography was 40 days, and only 29% of patients with suspected heart failure received a diagnosis within a year of the index presentation date, which she described as “inadequately slow.”

“And how does this translate to medical therapy?” she asked.
 

Heart Failure Drugs

After the index presentation, the rate of loop diuretic use quadrupled among individuals suspected of having heart failure, but there was a “muted response” when it came to the prescribing of beta-blockers and the other pillars of heart failure therapy, which Dr. Anderson called “very disappointing.”

For outcomes after the index presentation, the rate of hospitalization was much higher in the group with suspected heart failure than in the control group (16.1 vs 2.2 events per 100 person-years). And all-cause mortality occurred more often in the group with suspected heart failure than in the control group (10.3 vs 6.5 events per 100 person-years).

Among patients with NT-proBNP levels of 2000 ng/L, there was a “rapid” onset of hospitalization “within the first few days” of the index presentation, which was tracked by a more linear rise in all-cause deaths, Dr. Anderson reported.

In the United Kingdom, “we are very proud of our 2- and 6-week pathways,” which stipulate that suspected heart failure patients with NT-proBNP levels between 400 and 2000 ng/L are to have a specialist assessment and transthoracic echocardiography within 6 weeks; for those with levels > 2000 ng/L, that interval is accelerated to 2 weeks, she said.

The current results show that “2 weeks is too slow.” And looking at the rest of the cohort with lower NT-proBNP levels, “patients have already been admitted and died” by 6 weeks, she said.

When patients are stratified by age, “you get exactly what you would expect,” Dr. Anderson said. “The older patients are the most at risk” for both hospitalization and all-cause mortality.
 

A version of this article appeared on Medscape.com.

LISBON, PORTUGAL — Few people with suspected heart failure and elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are receiving a diagnosis after a year, reported investigators, who say high rates of hospitalization are common.

Presenting here at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) 2024, researchers shared results from the REVOLUTION-HF study involving almost 8000 people who consulted outpatient primary and secondary care over a 5-year period.

About two thirds of the patients had suspected heart failure; however, less than 30% of the people received a diagnosis within a year.

Yet hospitalization was eight times higher in the suspected heart failure group than in the control group, and all-cause mortality was nearly doubled. The outcomes were even worse in patients with high NT-proBNP levels.

Patients with suspected heart failure are “waiting far too long to see a specialist, and that results in a delay to guideline-directed medical therapy, despite the fact that we’re perfectly happy to slap them all on diuretics,” said study presenter Lisa Anderson, MD, PhD, Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Research Institute, St George’s Hospital, University of London, England.

“We need to rethink our management of heart failure patients presenting in the community,” she said.

A big gap exists internationally between presentation with heart failure, an elevated NT-proBNP, and confirmatory specialist assessment, she explained.

“It’s a scandal that patients are coming to the GP with signs and symptoms of heart failure, they get tested for natriuretic peptides, and nothing happens,” said co-author Antoni Bayés-Genís, MD, PhD, Heart Institute director, Hospital Universitari Germans Trias i Pujol Catedràtic, Barcelona, Spain.

“These patients may receive an echo, or not, in the coming 12 months,” and “during these 12 months, there is a huge number of heart failure hospitalizations and deaths that could probably be prevented.”
 

Why the Reluctance to Diagnose?

Many issues get in the way of early diagnosis, Dr. Bayés-Genís said. “Inertia, comorbidities, ageism.”

A lot of patients with heart failure are elderly women with some degree of weight gain, he said. “And they come to the clinic with fatigue, so we tell them, ‘Well, that’s normal.”

But “it may not be normal,” he added. “This is a very important topic that we, as a society, need to address.”

There are several “misconceptions” about heart failure, said Ileana L. Piña, MD, MPH, the Robert Stein Chair for Quality and Safety, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, who was not involved in the study.

For example, “we’re all convinced that guideline-directed medical therapy works,” but the evidence is only for patients “with a diagnosis.” In addition, “millions of patients get tested” for heart failure, but they already have a “known diagnosis.”

“When we study these drugs, we’re studying them on patients with manifest disease,” who are only then randomized, Dr. Piña said. “But we seldom see them while they’re developing heart failure. And it’s a process; it doesn’t happen overnight.”

Patients initially often think they may have asthma, and so what follows is an extended period of “uncertainty” and “important time lost” before they finally undergo the assessments that show that they have heart failure, she said.

However, “uncertainty” often lands a patient “in the emergency room or with an unscheduled office visit, where NT-proBNP might get ordered and there’s a long lineup for an echo.”

There are several strengths of the current study, Dr. Piña said, including the fact that 50% of the study population were women, and they were older than a typical trial population. Nevertheless, the results were “eye-opening but not surprising” and, in the end, “disappointing.”

“I agree, we need a revolution, Dr. Anderson,” Dr. Piña said. “The revolution of paying attention to the NT-proBNP when you get it and it’s elevated” and then following through with echocardiography and starting “guideline-directed medical therapy early.”

The diagnosis of heart failure “relies on the presentation of patients with nonspecific signs and symptoms,” such as dyspnea and peripheral edema, “but initiation of guideline-directed medical therapy — life-saving treatment — has to wait until we have a formal echocardiography and specialist clinician assessment,” Dr. Anderson said.

The latest clinical consensus statement from the Heart Failure Association “proposes both rule-in and rule-out NT-proBNP levels for heart failure diagnosis, and obviously we all recognize that it’s important to treat patients as soon as they’re diagnosed,” she explained.
 

REVOLUTION-HF

To examine the risk profile for patients presenting to outpatient care with suspected heart failure, the researchers conducted REVOLUTION-HF, which leveraged nationwide Swedish linked data from general practices, specialists, pharmacies, hospitals, and cause of death registers.

“Really impressively, most of these NT-proBNP tests were coming back within a day,” Dr. Anderson said, “so a really, really good turnaround.”

Individuals were excluded if they had an inpatient admission, echocardiography, or heart failure diagnosis between presentation and the NT-proBNP measurement.

These people were then compared with those presenting to primary or secondary outpatient care for any reason and matched for age, sex, care level, and index year. Both groups were followed up for 1 year.

“Despite this really impressive, almost immediate NT-proBNP testing,” the waiting times to undergo echocardiography were “really disappointing,” Dr. Anderson said.

The median time to first registered echocardiography was 40 days, and only 29% of patients with suspected heart failure received a diagnosis within a year of the index presentation date, which she described as “inadequately slow.”

“And how does this translate to medical therapy?” she asked.
 

Heart Failure Drugs

After the index presentation, the rate of loop diuretic use quadrupled among individuals suspected of having heart failure, but there was a “muted response” when it came to the prescribing of beta-blockers and the other pillars of heart failure therapy, which Dr. Anderson called “very disappointing.”

For outcomes after the index presentation, the rate of hospitalization was much higher in the group with suspected heart failure than in the control group (16.1 vs 2.2 events per 100 person-years). And all-cause mortality occurred more often in the group with suspected heart failure than in the control group (10.3 vs 6.5 events per 100 person-years).

Among patients with NT-proBNP levels of 2000 ng/L, there was a “rapid” onset of hospitalization “within the first few days” of the index presentation, which was tracked by a more linear rise in all-cause deaths, Dr. Anderson reported.

In the United Kingdom, “we are very proud of our 2- and 6-week pathways,” which stipulate that suspected heart failure patients with NT-proBNP levels between 400 and 2000 ng/L are to have a specialist assessment and transthoracic echocardiography within 6 weeks; for those with levels > 2000 ng/L, that interval is accelerated to 2 weeks, she said.

The current results show that “2 weeks is too slow.” And looking at the rest of the cohort with lower NT-proBNP levels, “patients have already been admitted and died” by 6 weeks, she said.

When patients are stratified by age, “you get exactly what you would expect,” Dr. Anderson said. “The older patients are the most at risk” for both hospitalization and all-cause mortality.
 

A version of this article appeared on Medscape.com.

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

After 26 years in practice, there are still things about the brain that amaze me, often that I first notice on myself.

Filtering (I guess “selective attention” sounds better) is one of them. We don’t notice it, but it’s definitely there.

Working at a jigsaw puzzle, I find myself looking for a specific piece, say, a white tab with a dark background and yellow stripe in the center. There may be several hundred pieces spread around me at the table, but the brain quickly starts filtering them out. In a fraction of a second I only notice ones with a white tab, then mentally those are broken down by the other characteristics. If it looks promising, I’ll look back at the space I’m trying to fit it in, mentally rotate the piece (another tricky thing if you think about it) and, if that seems to match, will pick up the piece to try. If it doesn’t fit the process repeats.

It’s a remarkable ability to see a relationship between two separate objects that isn’t always apparent.

But it’s not just sight. Although I’ve always loved music, it wasn’t until my own kids were in a band that I found the ability to break it down, removing the other instruments. It brings a remarkable clarity to suddenly hearing my daughter on the marimba, or son on the flute. Even with 70 other instrument playing around them.

You can try it yourself, listening to Keith Moon’s amazing drums on The Who’s “5:15.” Or in Bob Seger’s “Fire Lake.” Take out Seger and the instruments and you suddenly realize it’s the Eagles doing the background singing.

In Carly Simon’s “You’re So Vain,” a song you generally don’t attribute to the Rolling Stones, a little bit of focus will reveal Mick Jagger’s distinctive voice in the background chorus of “Don’t you, don’t you, don’t you?”

The ability isn’t something we created. It was there from our ancestors in the trees and caves. They used this ability to identify friend from foe, find the right path home, and pick out what was edible from what was poisonous. Like with so many other things, and without realizing it, our brains have retooled it for the world we now face, even if it’s just to find our car in the parking lot.

Sodium, calcium, potassium, and other ions flow in and out of nerve cells, an electrical impulse propagates though a network, matching incoming sounds and images to ones previously stored. That’s all it is, but the results are remarkable.

We take the everyday for granted, but should stop and think how amazing it really is.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.¹ The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.

UNC Chapel Hill

In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
 

PD-1 inhibitors

Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.

Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.²

Additionally, in 2022, Makker et al. published results from a phase 3 trial³ evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.

With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,⁴ comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.

In the similar randomized, international, phase 3 RUBY trial,⁵ Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.

The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
 

Takeaway

Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.

Anti-HER2 therapies

HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.⁷ These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.

Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,⁸ which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.

The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
 

Takeaway

Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.

Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.

References

1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.

2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.

3. Makker V et al. N Engl J Med. 2022;386(5):437-48.

4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.

5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.

6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.

7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.

8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.

While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.¹ The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.

UNC Chapel Hill

In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
 

PD-1 inhibitors

Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.

Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.²

Additionally, in 2022, Makker et al. published results from a phase 3 trial³ evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.

With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,⁴ comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.

In the similar randomized, international, phase 3 RUBY trial,⁵ Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.

The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
 

Takeaway

Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.

Anti-HER2 therapies

HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.⁷ These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.

Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,⁸ which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.

The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
 

Takeaway

Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.

Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.

References

1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.

2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.

3. Makker V et al. N Engl J Med. 2022;386(5):437-48.

4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.

5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.

6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.

7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.

8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.

While rates of most other cancers have declined or plateaued, the incidence and mortality rate of endometrial cancer continue to rise.¹ The landscape of endometrial cancer treatment has evolved quickly over the past 2-3 years. While surgery and radiation therapy remain the mainstay of treatment for early-stage disease, the development of multiple targeted therapeutics has led to additional treatment options in advanced-stage disease and more aggressive tumor types, which are both associated with a poorer prognosis.

UNC Chapel Hill

In this update, we highlight the recent advances in these targeted therapies in endometrial cancer. We review the landmark NRG-GY018 and RUBY trials, which demonstrated that checkpoint inhibitors improve outcomes in women with advanced endometrial cancer. We discuss an immunotherapy and antivascular endothelial growth factor (VEGF) combination useful in certain tumors lacking biomarker expression. We also highlight progress against endometrial cancers that overexpress human epidermal growth factor receptor 2 (HER2), demonstrated in the DESTINY PanTumor-02 trial.
 

PD-1 inhibitors

Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells that binds to programmed cell death ligand 1 (PD-L1). PD-L1 is expressed on many immune cells but can also be expressed on tumor cells. The interaction of PD-L1 expressed on the surface of endometrial cancer cells with the PD-1 receptor on T cells results in diminished T-cell function, eliminating the immune system’s ability to attack the tumor cells. Treatment with a PD-1 inhibitor prevents this ligand-receptor interaction and restores cancer-fighting function to T cells.

Pembrolizumab, an antibody against the PD-1 receptor, has been used as single-agent treatment for recurrent endometrial cancer since the KEYNOTE-158 study demonstrated clinical benefit in patients with mismatch repair deficient (dMMR) tumors.²

Additionally, in 2022, Makker et al. published results from a phase 3 trial³ evaluating immunotherapy in the treatment of recurrent endometrial cancer, specifically in patients with mismatch repair proficient (pMMR) tumors. They compared the combination of pembrolizumab and lenvatinib, an oral inhibitor of VEGF, to physician’s choice next-line chemotherapy in over 800 patients with advanced or recurrent endometrial cancer. They found that progression-free survival (PFS) was significantly improved from a median of 3.8 months with chemotherapy to a median of 6.6 months with pembrolizumab and lenvatinib in the pMMR population. Overall survival was also improved from 12 months to 17.4 months in the pMMR population.

With the clear benefit of immunotherapy in the recurrent setting established, Eskander and colleagues were the first to evaluate treatment with pembrolizumab as upfront treatment in the NRG-GY018 trial,⁴ comparing standard first-line chemotherapy (carboplatin and paclitaxel) with or without the addition of pembrolizumab. This randomized, international, phase 3 trial included over 800 patients with advanced or recurrent endometrial cancer of any histology except carcinosarcoma. Patients received carboplatin and paclitaxel with either pembrolizumab or placebo, followed by maintenance pembrolizumab or placebo. The results showed an improvement in PFS with the addition of immunotherapy, with a risk of disease progression or death with pembrolizumab 70% lower than with placebo in patients with dMMR tumors and 46% lower than with placebo in patients with pMMR tumors.

In the similar randomized, international, phase 3 RUBY trial,⁵ Mirza and colleagues compared standard chemotherapy with or without the addition of another PD-1 inhibitor, dostarlimab, in almost 500 patients with advanced or recurrent endometrial cancer of any histology. They found that the addition of dostarlimab to standard chemotherapy significantly improved PFS. Unpublished data presented at the Society of Gynecologic Oncology annual meeting in March also demonstrated an improvement in overall survival.6 As in NRG-GY018, they found a substantial benefit again in the dMMR population.

The results of these three landmark trials demonstrate the increasing role for immunotherapy in endometrial cancer, especially at the time of initial treatment, and how biomarkers can help direct treatment options.
 

Takeaway

Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.

Anti-HER2 therapies

HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.⁷ These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.

Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,⁸ which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.

The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
 

Takeaway

Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.

Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.

References

1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.

2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.

3. Makker V et al. N Engl J Med. 2022;386(5):437-48.

4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.

5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.

6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.

7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.

8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.

The US Food and Drug Administration has expanded the indication for durvalumab (Imfinzi, AstraZeneca) to include mismatch repair deficient (dMMR) newly diagnosed advanced or recurrent endometrial cancer in combination with carboplatin and paclitaxel followed by single-agent use for maintenance.

Originally approved in 2017, the programmed death ligand 1 inhibitor caries previously approved indications for non–small cell lung cancer, biliary tract cancer, and hepatocellular carcinoma.

Approval of the new indication was based on the phase 3 DUO-E trial, which included 95 women with newly diagnosed advanced or recurrent dMMR endometrial cancer. Patients were randomized to durvalumab 1120 mg or placebo with carboplatin plus paclitaxel every 3 weeks for a maximum of six cycles followed by durvalumab 1500 mg every 4 weeks until disease progression.

Median progression-free survival (PFS) was 7 months in the placebo arm but not reached in the durvalumab group. Overall survival outcomes were immature at the PFS analysis.

A quarter or more of durvalumab patients experienced peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.

The recommended treatment regimen for dMMR endometrial cancer in women who weigh ≥ 30 kg is 1120 mg with carboplatin plus paclitaxel every 3 weeks for six cycles, followed by single-agent durvalumab 1500 mg every 4 weeks.

The price of 2.4 mL of durvalumab at a concentration of 50 mg/mL is $1027, according to drugs.com.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has expanded the indication for durvalumab (Imfinzi, AstraZeneca) to include mismatch repair deficient (dMMR) newly diagnosed advanced or recurrent endometrial cancer in combination with carboplatin and paclitaxel followed by single-agent use for maintenance.

Originally approved in 2017, the programmed death ligand 1 inhibitor caries previously approved indications for non–small cell lung cancer, biliary tract cancer, and hepatocellular carcinoma.

Approval of the new indication was based on the phase 3 DUO-E trial, which included 95 women with newly diagnosed advanced or recurrent dMMR endometrial cancer. Patients were randomized to durvalumab 1120 mg or placebo with carboplatin plus paclitaxel every 3 weeks for a maximum of six cycles followed by durvalumab 1500 mg every 4 weeks until disease progression.

Median progression-free survival (PFS) was 7 months in the placebo arm but not reached in the durvalumab group. Overall survival outcomes were immature at the PFS analysis.

A quarter or more of durvalumab patients experienced peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.

The recommended treatment regimen for dMMR endometrial cancer in women who weigh ≥ 30 kg is 1120 mg with carboplatin plus paclitaxel every 3 weeks for six cycles, followed by single-agent durvalumab 1500 mg every 4 weeks.

The price of 2.4 mL of durvalumab at a concentration of 50 mg/mL is $1027, according to drugs.com.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has expanded the indication for durvalumab (Imfinzi, AstraZeneca) to include mismatch repair deficient (dMMR) newly diagnosed advanced or recurrent endometrial cancer in combination with carboplatin and paclitaxel followed by single-agent use for maintenance.

Originally approved in 2017, the programmed death ligand 1 inhibitor caries previously approved indications for non–small cell lung cancer, biliary tract cancer, and hepatocellular carcinoma.

Approval of the new indication was based on the phase 3 DUO-E trial, which included 95 women with newly diagnosed advanced or recurrent dMMR endometrial cancer. Patients were randomized to durvalumab 1120 mg or placebo with carboplatin plus paclitaxel every 3 weeks for a maximum of six cycles followed by durvalumab 1500 mg every 4 weeks until disease progression.

Median progression-free survival (PFS) was 7 months in the placebo arm but not reached in the durvalumab group. Overall survival outcomes were immature at the PFS analysis.

A quarter or more of durvalumab patients experienced peripheral neuropathy, musculoskeletal pain, nausea, alopecia, fatigue, abdominal pain, constipation, rash, diarrhea, vomiting, and cough.

The recommended treatment regimen for dMMR endometrial cancer in women who weigh ≥ 30 kg is 1120 mg with carboplatin plus paclitaxel every 3 weeks for six cycles, followed by single-agent durvalumab 1500 mg every 4 weeks.

The price of 2.4 mL of durvalumab at a concentration of 50 mg/mL is $1027, according to drugs.com.

A version of this article appeared on Medscape.com.

Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.

The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.

Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.

The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
 

Why Surgeons?

The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.

Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.

“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
 

Types of Unprofessional Behaviors

The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.

In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”

The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
 

Impact of Unprofessional Behavior

Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.

Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.

However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.

“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.

The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
 

Study Limitations

The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
 

A version of this article appeared on Medscape.com.

Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.

The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.

Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.

The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
 

Why Surgeons?

The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.

Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.

“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
 

Types of Unprofessional Behaviors

The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.

In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”

The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
 

Impact of Unprofessional Behavior

Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.

Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.

However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.

“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.

The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
 

Study Limitations

The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
 

A version of this article appeared on Medscape.com.

Most doctors mind their manners. But surgeons are the most likely to be reported for unprofessional behavior, while physicians practicing in pediatric settings are the least likely, according to a recent study of more than 35,000 physicians.

The research, published on June 6 in JAMA Network Open, found that fewer than 10% of physicians were reported by their coworkers for at least one instance of unprofessional behavior, and only 1% showed a pattern of such reports.

Data were gathered from the Center for Patient and Professional Advocacy’s (CPPA’s) Coworker Observation Reporting System (CORS) program, a national collaborative in which 193 participating hospitals and practice sites file safety-event reports involving medical workers’ unprofessional behaviors. An algorithm that weights CORS reports based on recency and severity was used to analyze the data. The study was spearheaded by William O. Cooper, MD, MPH, director of the CPPA at Vanderbilt University Medical Center, Nashville, Tennessee.

The retrospective cohort study included deidentified data on credentialed physicians, not including residents or fellows, who practiced at a CORS site between 2018 and 2022.
 

Why Surgeons?

The authors speculated that the reason surgeons were reported for unprofessional behavior more often than their colleagues in nonsurgical specialties was because surgery is a more stressful environment than other specialties and requires more teamwork, resulting in more interactions during high-stakes events.

Daniel Katz, MD, professor and vice chair of education for the Department of Anesthesiology, Perioperative and Pain Medicine at the Icahn School of Medicine at Mount Sinai, New York City, added that part of the problem is that surgeons are expected to perform at very high levels all the time.

“When things that are outside the control of the surgeon don’t go well,” Dr. Katz said, “that can lead to increased frustration and negative emotions, which will then bring out these kinds of behaviors.”
 

Types of Unprofessional Behaviors

The most common out-of-bounds behaviors reported involved disrespectful communication or lack of professional responsibility. In one example, a physician called a coworker a “bossy cow” when the coworker reminded the physician of the need to do a timeout before beginning a bronchoscopy.

In another case involving professional responsibility, a coworker asked a physician if the team should wait for a disoriented patient’s spouse to arrive. The doctor’s response: “We’ll be here all night if we do that. If you won’t sign as a witness, I’ll get someone else who will.”

The least common reports involved unprofessionalism related to medical care or professional integrity. One cited a physician removing a Foley catheter without wearing gloves and having visible urine on his hands and not washing them before touching other things in the room. In a reported lapse of professional integrity, a physician billed at level five after spending only 4 minutes with a patient.
 

Impact of Unprofessional Behavior

Unprofessional behavior among physicians is more than just unpleasant. It can threaten the functioning of teams and increase patient complications. In addition, individuals who model unprofessional behaviors are associated with increased malpractice claims, the study’s authors wrote.

Dr. Katz agreed that unprofessional behavior is damaging to both patients and the profession as a whole.

However, this doesn’t happen because some doctors are bad, he said. Physicians today are working in a pressure cooker. The current healthcare environment, with its increased administrative burdens, lack of staffing, and other problems, has increased the overall level of stress and led to burnout among healthcare personnel.

“You have to fix the system to create a working environment that doesn’t cause somebody to explode,” Dr. Katz said.

The goal of the CORS program and this study, Dr. Cooper said, is to help physicians better weather these stresses.
 

Study Limitations

The authors noted some weaknesses in the study. Some unprofessional behavior may go unreported because of fear of retaliation or for other reasons victims or witnesses did not feel safe to report their colleagues. Also, reports were not evaluated to ensure the truth of the accusations. The records reviewed did not include the gender of the physician, though the researchers pointed out that previous studies have shown that women are less likely than men to receive CORS reports.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A clinically significant association exists between fructose and fructan malabsorption in certain patients with irritable bowel syndrome (IBS), indicating that some may benefit from eliminating both carbohydrates.

METHODOLOGY:

• Previous research has focused on fructose or fructan malabsorption separately in patients with IBS, rather than together in the same cohort.
• Researchers conducted a retrospective review of electronic medical records obtained from January 2017 to June 2022 at a single US medical clinic from patients with IBS who had undergone fructose and fructan hydrogen breath tests (HBTs).
• Patients were advised to have a low-carbohydrate dinner the day before, and fast for at least 12 hours prior to the HBT.
• Separate fructose and fructan HBTs were performed at baseline and again on separate days (minimum 1 day between HBTs) by administering a 25-g fructose or 10-g insulin solution and noting the breath hydrogen readings every 30 minutes for 3 hours. Breath hydrogen levels ≥ 20 ppm indicated a positive malabsorption result for either of the carbohydrates.
• The HBT results were compared to study the association between fructose and fructan malabsorption.

TAKEAWAY:

• Among 186 patients (median age, 36.7 years; 37.6% men), 38.2% tested positive for fructose malabsorption, 48.9% for fructan malabsorption, and 22.6% for both.
• There was a significant association between positive fructose and positive fructan HBT readings (P = .0283).
• Patients who tested positive for fructose or fructan malabsorption had a 1.951 times higher likelihood of testing positive for the other carbohydrate (95% CI, 1.072-3.476).

IN PRACTICE:

“The positive association between fructose and fructan malabsorption in patients with IBS suggests that fructan malabsorption should be suspected in a patient who tests positive for fructose malabsorption, and vice versa,” the authors wrote.

SOURCE:

The study, led by Twan Sia, MD, Boston Specialists, Boston, was published online in BMC Gastroenterology.

LIMITATIONS:

The findings may have limited generalizability, as it included patients primarily from the northeastern region of the United States. The study limited HBT to 3 hours, beyond which rises in hydrogen gas might have been missed. Moreover, the use of an absolute hydrogen threshold of 20 ppm differs from that used in most other studies.

DISCLOSURES:

This study did not receive any specific grant from any funding agencies. One of the authors declared being a consultant for various pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A clinically significant association exists between fructose and fructan malabsorption in certain patients with irritable bowel syndrome (IBS), indicating that some may benefit from eliminating both carbohydrates.

METHODOLOGY:

• Previous research has focused on fructose or fructan malabsorption separately in patients with IBS, rather than together in the same cohort.
• Researchers conducted a retrospective review of electronic medical records obtained from January 2017 to June 2022 at a single US medical clinic from patients with IBS who had undergone fructose and fructan hydrogen breath tests (HBTs).
• Patients were advised to have a low-carbohydrate dinner the day before, and fast for at least 12 hours prior to the HBT.
• Separate fructose and fructan HBTs were performed at baseline and again on separate days (minimum 1 day between HBTs) by administering a 25-g fructose or 10-g insulin solution and noting the breath hydrogen readings every 30 minutes for 3 hours. Breath hydrogen levels ≥ 20 ppm indicated a positive malabsorption result for either of the carbohydrates.
• The HBT results were compared to study the association between fructose and fructan malabsorption.

TAKEAWAY:

• Among 186 patients (median age, 36.7 years; 37.6% men), 38.2% tested positive for fructose malabsorption, 48.9% for fructan malabsorption, and 22.6% for both.
• There was a significant association between positive fructose and positive fructan HBT readings (P = .0283).
• Patients who tested positive for fructose or fructan malabsorption had a 1.951 times higher likelihood of testing positive for the other carbohydrate (95% CI, 1.072-3.476).

IN PRACTICE:

“The positive association between fructose and fructan malabsorption in patients with IBS suggests that fructan malabsorption should be suspected in a patient who tests positive for fructose malabsorption, and vice versa,” the authors wrote.

SOURCE:

The study, led by Twan Sia, MD, Boston Specialists, Boston, was published online in BMC Gastroenterology.

LIMITATIONS:

The findings may have limited generalizability, as it included patients primarily from the northeastern region of the United States. The study limited HBT to 3 hours, beyond which rises in hydrogen gas might have been missed. Moreover, the use of an absolute hydrogen threshold of 20 ppm differs from that used in most other studies.

DISCLOSURES:

This study did not receive any specific grant from any funding agencies. One of the authors declared being a consultant for various pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A clinically significant association exists between fructose and fructan malabsorption in certain patients with irritable bowel syndrome (IBS), indicating that some may benefit from eliminating both carbohydrates.

METHODOLOGY:

• Previous research has focused on fructose or fructan malabsorption separately in patients with IBS, rather than together in the same cohort.
• Researchers conducted a retrospective review of electronic medical records obtained from January 2017 to June 2022 at a single US medical clinic from patients with IBS who had undergone fructose and fructan hydrogen breath tests (HBTs).
• Patients were advised to have a low-carbohydrate dinner the day before, and fast for at least 12 hours prior to the HBT.
• Separate fructose and fructan HBTs were performed at baseline and again on separate days (minimum 1 day between HBTs) by administering a 25-g fructose or 10-g insulin solution and noting the breath hydrogen readings every 30 minutes for 3 hours. Breath hydrogen levels ≥ 20 ppm indicated a positive malabsorption result for either of the carbohydrates.
• The HBT results were compared to study the association between fructose and fructan malabsorption.

TAKEAWAY:

• Among 186 patients (median age, 36.7 years; 37.6% men), 38.2% tested positive for fructose malabsorption, 48.9% for fructan malabsorption, and 22.6% for both.
• There was a significant association between positive fructose and positive fructan HBT readings (P = .0283).
• Patients who tested positive for fructose or fructan malabsorption had a 1.951 times higher likelihood of testing positive for the other carbohydrate (95% CI, 1.072-3.476).

IN PRACTICE:

“The positive association between fructose and fructan malabsorption in patients with IBS suggests that fructan malabsorption should be suspected in a patient who tests positive for fructose malabsorption, and vice versa,” the authors wrote.

SOURCE:

The study, led by Twan Sia, MD, Boston Specialists, Boston, was published online in BMC Gastroenterology.

LIMITATIONS:

The findings may have limited generalizability, as it included patients primarily from the northeastern region of the United States. The study limited HBT to 3 hours, beyond which rises in hydrogen gas might have been missed. Moreover, the use of an absolute hydrogen threshold of 20 ppm differs from that used in most other studies.

DISCLOSURES:

This study did not receive any specific grant from any funding agencies. One of the authors declared being a consultant for various pharmaceutical companies.
 

A version of this article appeared on Medscape.com.

Almost all primary care providers (PCPs) have taken on diagnosing and managing ADHD. With about 12% of school aged children affected, typical PCPs can expect about 240 children with ADHD under their care. Adopting this primary care function has been helped by having clear diagnostic criteria for the three DMS 5 “presentations” of ADHD, open source tools (e.g. Vanderbilts), expectation of collaboration by educators, American Academy of Pediatrics (AAP) guidelines for diagnosis and management, Society for Developmental–Behavioral Pediatrics guidelines for “complex ADHD,” and access to effective medication treatments PCPs can provide (although less so for behavioral ones), cultural acceptance of individuals with ADHD, and especially reliable payment by insurers.

Screening

But what about PCP management of autism spectrum disorder (ASD), now affecting 2.8%, for an expected 60 children under care for each of us? PCP detection and care for children with ASD is more complex than ADHD, but even more essential, so we need to learn the skills. It is more essential because very early detection and entry into evidence-based intervention has long-term benefits for the child and family that are not as crucial for ADHD. While ADHD symptoms may not impact functioning until age 7 or even 12 years of age, signs of ASD usually emerge earlier (by 18 months) but gradually and about 30% after apparently normal development even to age 2 years.

Screening is crucial, but unfortunately not perfect. Recent AAP surveys show that most PCPs screen for autism at the recommended 18 and 24 months. But what happens after that? How many offices are tracking referrals for positive screens for needed evaluations and early intervention? Our data shows that tracking is rarely done and children do not start to get the benefit of early intervention until 4.5 years of age, on average.
 

Diagnostic Testing

And screening is the easiest part of addressing ASD. Wait times for diagnostic testing can be agonizing months to years. Multiple programs are training PCPs to perform hands-on 10- to 30-minute secondary screening with considerable success. You can become proficient on tools such as STAT (Screening Tool for Autism in Two-Year-Olds), RITA-T (Rapid Interactive Screening Test for Autism in Toddlers), BISCUIT (Baby and Infant Screen for Children with Autism Traits), SORF (Systematic Observation of Red Flags), ADEC (Autism Detection in Early Childhood) or CARS (Childhood Autism Rating Scale) with a few hours of training. Even secondary assessments done virtually by PCPs such as TELE-ASD-PEDS quite accurately predict a verifiable ASD diagnosis for those referred by concerns. Some problems of the reported accuracy of these secondary screening processes have to do with validation in samples of children for whom parents or clinicians already had concern and generally not including many younger children in whom it is so important to detect. Level of confidence of developmental and behavioral pediatricians of the presence of ASD is highly related to ultimate diagnosis. But success with PCPs’ mastering secondary screening has not yet been reported to convince insurers to approve payment for intervention services such as Applied Behavior Analysis (ABA).

Comorbidity

Co-existing conditions affect the majority of patients with ASD (70%), compared with ADHD, but with a broader range and more debilitating and difficult to manage conditions. More medical co-existing issues such as intellectual disability (25%-75%), seizures (12%-26%), motor incoordination (51%), GI conditions (9%-91%), sleep difficulty (50%-80%), sleep apnea, congenital heart disease, avoidant-restrictive food intake disorder, autoimmune disorders, and genetic syndromes (e.g. Fragile X, tuberous sclerosis, Down, Angelman’s, untreated PKU, neurofibromatosis, Klinefelter syndrome) reflect the range of underpinnings of ASD. The need to detect and manage these co-existing issues, besides assessing hearing and vision, makes our skilled involvement and vigilance in ASD care essential. Referring for help from OTs, PTs, speech pathologists, neurologists, psychologists, and special educators as issues in their domains are prioritized is also our responsibility. We must also help families balance utilizing these resources so as to avoid overwhelm.

Anxiety (50%), ADHD (37%-85%), depression (54%), bipolar (7.3%), suicidal ideation (40% starting < 8 years), and emotion dysregulation, familiar to us from our management of ADHD, may develop but are often less well defined and more intractable in ASD, making use of screening tools essential. Using a system like CHADIS that has online pre-visit and monitoring screens delivered based on algorithms for the numerous co-existing conditions, automated handouts, and functions to make and track referral success can facilitate care for this complex chronic condition. Identifying mental health providers with ASD expertise is more difficult, so more management is on us. While medications for these conditions can be beneficial, we need to learn to use lower doses, slower dose increases, and employ problem-solving of side effects with more parent collaboration than for ADHD as children with ASD often cannot self-report effectively. We need to ask about the common ad hoc use of complementary medications and substances (32%-87%) that may be complicating. Of course, these conditions and the caveats of management require more of our time with the patient and family as well as communication with the many other professionals involved. It is important to set our own and our families’ expectations (and schedules) for much more frequent contact and also to bill appropriately with chronic care (99487,89,90) and collaborative care CPT codes (99492,3,4 or G2214).
 

Behavioral Manifestations

During our care, the often extreme behavioral manifestations of ASD may be the most pressing issues. We need new understanding and skills to sort out and counsel on inflexible, explosive, and sensory triggered behaviors. Just as for ADHD, using the approach of Functional Behavioral Assessment and plans for home as well as school behavior can be key. More difficult in ASD is looking for physical causes, since the child may not provide clear cues because of communication and sensory differences. Conditions common in children with ASD such as constipation, dental caries, otitis, dietary intolerances, allergies, migraine, sleep deficits, menstrual cramps, or fears and changes from puberty manifesting behaviorally are often tricky to sort out.

While the diagnosis of ASD, as for ADHD, does not require any laboratory testing, looking for possible causes is important information for the family and someday may also lead to genetic or other therapies. We need to know that recommendations include screening for Ferritin, Pb, chromosomal microarray and FMR I testing as well as checking that PKU was normal; MECP 2 is indicated in females and symptomatic males; and PTENS testing for children with head circumference greater than 2.5-3 SD. Metabolic and mitochondrial assays are indicated only when symptoms suggest. We need to develop confidence to reserve MRIs or EEGs for cases with abnormal neuro. exams, regression, or history of seizures. It is demanding to keep up with AAP recommendations in this very active area of research.
 

Interventions

The interventions for ADHD are generally school accommodations and therapies for comorbidities. In contrast, since core social communication skills are the main deficit in ASD, all children screened positive for ASD should be referred for early intervention while awaiting, as well as after, diagnosis. While all states have no or low-cost early intervention, quality and quantity (of hours offered) varies. We should also recommend and try to determine if evidence-based intervention is being provided, such as pivotal response training, UCLA discrete trial therapy, Carbone’s verbal behavior, applied behavior analysis (ABA), Early Start Denver Model, and sometimes music and social skills trainings (effect size 0.42-0.76). Such professional interventions have best evidence with more than 25 hours/week but 15 hours has benefit for higher functioning children. CBT can help anxiety even in younger children. One way for families to provide more hours and more generalizable intervention is coaching by the PLAY Project or DIRFloortime, parent mediated interventions with evidence, some with training both in person or online. Alternative communication training and other condition specific assistance are often needed (e.g. Picture Exchange Communication System for nonverbal children).

While we should already be familiar with writing 504 plan and IEP requests to schools, which also apply to children with ASD, in addition we need to be ready to advise about other legal rights including autism waivers, wraparound services, guardianship, and trust accounts. We can share quality educational materials available online (e.g. from Autism Speaks, SPARK, and Autism Navigator). Social media groups may be supportive, but also may contain disinformation we need to dispel.

Unfortunately, templates, questionnaires, and lack of interdisciplinary referral and communication functions of EHRs don’t support the complexities of care for ASD. While the AAP has guidelines for diagnosis and management and an online toolkit, consider adding a system with an autism-specific module like CHADIS and joining the Autism Care Network or ECHO Autism sessions to get both information and support to take on the evolving critical role of autism care.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

Almost all primary care providers (PCPs) have taken on diagnosing and managing ADHD. With about 12% of school aged children affected, typical PCPs can expect about 240 children with ADHD under their care. Adopting this primary care function has been helped by having clear diagnostic criteria for the three DMS 5 “presentations” of ADHD, open source tools (e.g. Vanderbilts), expectation of collaboration by educators, American Academy of Pediatrics (AAP) guidelines for diagnosis and management, Society for Developmental–Behavioral Pediatrics guidelines for “complex ADHD,” and access to effective medication treatments PCPs can provide (although less so for behavioral ones), cultural acceptance of individuals with ADHD, and especially reliable payment by insurers.

Screening

But what about PCP management of autism spectrum disorder (ASD), now affecting 2.8%, for an expected 60 children under care for each of us? PCP detection and care for children with ASD is more complex than ADHD, but even more essential, so we need to learn the skills. It is more essential because very early detection and entry into evidence-based intervention has long-term benefits for the child and family that are not as crucial for ADHD. While ADHD symptoms may not impact functioning until age 7 or even 12 years of age, signs of ASD usually emerge earlier (by 18 months) but gradually and about 30% after apparently normal development even to age 2 years.

Screening is crucial, but unfortunately not perfect. Recent AAP surveys show that most PCPs screen for autism at the recommended 18 and 24 months. But what happens after that? How many offices are tracking referrals for positive screens for needed evaluations and early intervention? Our data shows that tracking is rarely done and children do not start to get the benefit of early intervention until 4.5 years of age, on average.
 

Diagnostic Testing

And screening is the easiest part of addressing ASD. Wait times for diagnostic testing can be agonizing months to years. Multiple programs are training PCPs to perform hands-on 10- to 30-minute secondary screening with considerable success. You can become proficient on tools such as STAT (Screening Tool for Autism in Two-Year-Olds), RITA-T (Rapid Interactive Screening Test for Autism in Toddlers), BISCUIT (Baby and Infant Screen for Children with Autism Traits), SORF (Systematic Observation of Red Flags), ADEC (Autism Detection in Early Childhood) or CARS (Childhood Autism Rating Scale) with a few hours of training. Even secondary assessments done virtually by PCPs such as TELE-ASD-PEDS quite accurately predict a verifiable ASD diagnosis for those referred by concerns. Some problems of the reported accuracy of these secondary screening processes have to do with validation in samples of children for whom parents or clinicians already had concern and generally not including many younger children in whom it is so important to detect. Level of confidence of developmental and behavioral pediatricians of the presence of ASD is highly related to ultimate diagnosis. But success with PCPs’ mastering secondary screening has not yet been reported to convince insurers to approve payment for intervention services such as Applied Behavior Analysis (ABA).

Comorbidity

Co-existing conditions affect the majority of patients with ASD (70%), compared with ADHD, but with a broader range and more debilitating and difficult to manage conditions. More medical co-existing issues such as intellectual disability (25%-75%), seizures (12%-26%), motor incoordination (51%), GI conditions (9%-91%), sleep difficulty (50%-80%), sleep apnea, congenital heart disease, avoidant-restrictive food intake disorder, autoimmune disorders, and genetic syndromes (e.g. Fragile X, tuberous sclerosis, Down, Angelman’s, untreated PKU, neurofibromatosis, Klinefelter syndrome) reflect the range of underpinnings of ASD. The need to detect and manage these co-existing issues, besides assessing hearing and vision, makes our skilled involvement and vigilance in ASD care essential. Referring for help from OTs, PTs, speech pathologists, neurologists, psychologists, and special educators as issues in their domains are prioritized is also our responsibility. We must also help families balance utilizing these resources so as to avoid overwhelm.

Anxiety (50%), ADHD (37%-85%), depression (54%), bipolar (7.3%), suicidal ideation (40% starting < 8 years), and emotion dysregulation, familiar to us from our management of ADHD, may develop but are often less well defined and more intractable in ASD, making use of screening tools essential. Using a system like CHADIS that has online pre-visit and monitoring screens delivered based on algorithms for the numerous co-existing conditions, automated handouts, and functions to make and track referral success can facilitate care for this complex chronic condition. Identifying mental health providers with ASD expertise is more difficult, so more management is on us. While medications for these conditions can be beneficial, we need to learn to use lower doses, slower dose increases, and employ problem-solving of side effects with more parent collaboration than for ADHD as children with ASD often cannot self-report effectively. We need to ask about the common ad hoc use of complementary medications and substances (32%-87%) that may be complicating. Of course, these conditions and the caveats of management require more of our time with the patient and family as well as communication with the many other professionals involved. It is important to set our own and our families’ expectations (and schedules) for much more frequent contact and also to bill appropriately with chronic care (99487,89,90) and collaborative care CPT codes (99492,3,4 or G2214).
 

Behavioral Manifestations

During our care, the often extreme behavioral manifestations of ASD may be the most pressing issues. We need new understanding and skills to sort out and counsel on inflexible, explosive, and sensory triggered behaviors. Just as for ADHD, using the approach of Functional Behavioral Assessment and plans for home as well as school behavior can be key. More difficult in ASD is looking for physical causes, since the child may not provide clear cues because of communication and sensory differences. Conditions common in children with ASD such as constipation, dental caries, otitis, dietary intolerances, allergies, migraine, sleep deficits, menstrual cramps, or fears and changes from puberty manifesting behaviorally are often tricky to sort out.

While the diagnosis of ASD, as for ADHD, does not require any laboratory testing, looking for possible causes is important information for the family and someday may also lead to genetic or other therapies. We need to know that recommendations include screening for Ferritin, Pb, chromosomal microarray and FMR I testing as well as checking that PKU was normal; MECP 2 is indicated in females and symptomatic males; and PTENS testing for children with head circumference greater than 2.5-3 SD. Metabolic and mitochondrial assays are indicated only when symptoms suggest. We need to develop confidence to reserve MRIs or EEGs for cases with abnormal neuro. exams, regression, or history of seizures. It is demanding to keep up with AAP recommendations in this very active area of research.
 

Interventions

The interventions for ADHD are generally school accommodations and therapies for comorbidities. In contrast, since core social communication skills are the main deficit in ASD, all children screened positive for ASD should be referred for early intervention while awaiting, as well as after, diagnosis. While all states have no or low-cost early intervention, quality and quantity (of hours offered) varies. We should also recommend and try to determine if evidence-based intervention is being provided, such as pivotal response training, UCLA discrete trial therapy, Carbone’s verbal behavior, applied behavior analysis (ABA), Early Start Denver Model, and sometimes music and social skills trainings (effect size 0.42-0.76). Such professional interventions have best evidence with more than 25 hours/week but 15 hours has benefit for higher functioning children. CBT can help anxiety even in younger children. One way for families to provide more hours and more generalizable intervention is coaching by the PLAY Project or DIRFloortime, parent mediated interventions with evidence, some with training both in person or online. Alternative communication training and other condition specific assistance are often needed (e.g. Picture Exchange Communication System for nonverbal children).

While we should already be familiar with writing 504 plan and IEP requests to schools, which also apply to children with ASD, in addition we need to be ready to advise about other legal rights including autism waivers, wraparound services, guardianship, and trust accounts. We can share quality educational materials available online (e.g. from Autism Speaks, SPARK, and Autism Navigator). Social media groups may be supportive, but also may contain disinformation we need to dispel.

Unfortunately, templates, questionnaires, and lack of interdisciplinary referral and communication functions of EHRs don’t support the complexities of care for ASD. While the AAP has guidelines for diagnosis and management and an online toolkit, consider adding a system with an autism-specific module like CHADIS and joining the Autism Care Network or ECHO Autism sessions to get both information and support to take on the evolving critical role of autism care.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

Almost all primary care providers (PCPs) have taken on diagnosing and managing ADHD. With about 12% of school aged children affected, typical PCPs can expect about 240 children with ADHD under their care. Adopting this primary care function has been helped by having clear diagnostic criteria for the three DMS 5 “presentations” of ADHD, open source tools (e.g. Vanderbilts), expectation of collaboration by educators, American Academy of Pediatrics (AAP) guidelines for diagnosis and management, Society for Developmental–Behavioral Pediatrics guidelines for “complex ADHD,” and access to effective medication treatments PCPs can provide (although less so for behavioral ones), cultural acceptance of individuals with ADHD, and especially reliable payment by insurers.

Screening

But what about PCP management of autism spectrum disorder (ASD), now affecting 2.8%, for an expected 60 children under care for each of us? PCP detection and care for children with ASD is more complex than ADHD, but even more essential, so we need to learn the skills. It is more essential because very early detection and entry into evidence-based intervention has long-term benefits for the child and family that are not as crucial for ADHD. While ADHD symptoms may not impact functioning until age 7 or even 12 years of age, signs of ASD usually emerge earlier (by 18 months) but gradually and about 30% after apparently normal development even to age 2 years.

Screening is crucial, but unfortunately not perfect. Recent AAP surveys show that most PCPs screen for autism at the recommended 18 and 24 months. But what happens after that? How many offices are tracking referrals for positive screens for needed evaluations and early intervention? Our data shows that tracking is rarely done and children do not start to get the benefit of early intervention until 4.5 years of age, on average.
 

Diagnostic Testing

And screening is the easiest part of addressing ASD. Wait times for diagnostic testing can be agonizing months to years. Multiple programs are training PCPs to perform hands-on 10- to 30-minute secondary screening with considerable success. You can become proficient on tools such as STAT (Screening Tool for Autism in Two-Year-Olds), RITA-T (Rapid Interactive Screening Test for Autism in Toddlers), BISCUIT (Baby and Infant Screen for Children with Autism Traits), SORF (Systematic Observation of Red Flags), ADEC (Autism Detection in Early Childhood) or CARS (Childhood Autism Rating Scale) with a few hours of training. Even secondary assessments done virtually by PCPs such as TELE-ASD-PEDS quite accurately predict a verifiable ASD diagnosis for those referred by concerns. Some problems of the reported accuracy of these secondary screening processes have to do with validation in samples of children for whom parents or clinicians already had concern and generally not including many younger children in whom it is so important to detect. Level of confidence of developmental and behavioral pediatricians of the presence of ASD is highly related to ultimate diagnosis. But success with PCPs’ mastering secondary screening has not yet been reported to convince insurers to approve payment for intervention services such as Applied Behavior Analysis (ABA).

Comorbidity

Co-existing conditions affect the majority of patients with ASD (70%), compared with ADHD, but with a broader range and more debilitating and difficult to manage conditions. More medical co-existing issues such as intellectual disability (25%-75%), seizures (12%-26%), motor incoordination (51%), GI conditions (9%-91%), sleep difficulty (50%-80%), sleep apnea, congenital heart disease, avoidant-restrictive food intake disorder, autoimmune disorders, and genetic syndromes (e.g. Fragile X, tuberous sclerosis, Down, Angelman’s, untreated PKU, neurofibromatosis, Klinefelter syndrome) reflect the range of underpinnings of ASD. The need to detect and manage these co-existing issues, besides assessing hearing and vision, makes our skilled involvement and vigilance in ASD care essential. Referring for help from OTs, PTs, speech pathologists, neurologists, psychologists, and special educators as issues in their domains are prioritized is also our responsibility. We must also help families balance utilizing these resources so as to avoid overwhelm.

Anxiety (50%), ADHD (37%-85%), depression (54%), bipolar (7.3%), suicidal ideation (40% starting < 8 years), and emotion dysregulation, familiar to us from our management of ADHD, may develop but are often less well defined and more intractable in ASD, making use of screening tools essential. Using a system like CHADIS that has online pre-visit and monitoring screens delivered based on algorithms for the numerous co-existing conditions, automated handouts, and functions to make and track referral success can facilitate care for this complex chronic condition. Identifying mental health providers with ASD expertise is more difficult, so more management is on us. While medications for these conditions can be beneficial, we need to learn to use lower doses, slower dose increases, and employ problem-solving of side effects with more parent collaboration than for ADHD as children with ASD often cannot self-report effectively. We need to ask about the common ad hoc use of complementary medications and substances (32%-87%) that may be complicating. Of course, these conditions and the caveats of management require more of our time with the patient and family as well as communication with the many other professionals involved. It is important to set our own and our families’ expectations (and schedules) for much more frequent contact and also to bill appropriately with chronic care (99487,89,90) and collaborative care CPT codes (99492,3,4 or G2214).
 

Behavioral Manifestations

During our care, the often extreme behavioral manifestations of ASD may be the most pressing issues. We need new understanding and skills to sort out and counsel on inflexible, explosive, and sensory triggered behaviors. Just as for ADHD, using the approach of Functional Behavioral Assessment and plans for home as well as school behavior can be key. More difficult in ASD is looking for physical causes, since the child may not provide clear cues because of communication and sensory differences. Conditions common in children with ASD such as constipation, dental caries, otitis, dietary intolerances, allergies, migraine, sleep deficits, menstrual cramps, or fears and changes from puberty manifesting behaviorally are often tricky to sort out.

While the diagnosis of ASD, as for ADHD, does not require any laboratory testing, looking for possible causes is important information for the family and someday may also lead to genetic or other therapies. We need to know that recommendations include screening for Ferritin, Pb, chromosomal microarray and FMR I testing as well as checking that PKU was normal; MECP 2 is indicated in females and symptomatic males; and PTENS testing for children with head circumference greater than 2.5-3 SD. Metabolic and mitochondrial assays are indicated only when symptoms suggest. We need to develop confidence to reserve MRIs or EEGs for cases with abnormal neuro. exams, regression, or history of seizures. It is demanding to keep up with AAP recommendations in this very active area of research.
 

Interventions

The interventions for ADHD are generally school accommodations and therapies for comorbidities. In contrast, since core social communication skills are the main deficit in ASD, all children screened positive for ASD should be referred for early intervention while awaiting, as well as after, diagnosis. While all states have no or low-cost early intervention, quality and quantity (of hours offered) varies. We should also recommend and try to determine if evidence-based intervention is being provided, such as pivotal response training, UCLA discrete trial therapy, Carbone’s verbal behavior, applied behavior analysis (ABA), Early Start Denver Model, and sometimes music and social skills trainings (effect size 0.42-0.76). Such professional interventions have best evidence with more than 25 hours/week but 15 hours has benefit for higher functioning children. CBT can help anxiety even in younger children. One way for families to provide more hours and more generalizable intervention is coaching by the PLAY Project or DIRFloortime, parent mediated interventions with evidence, some with training both in person or online. Alternative communication training and other condition specific assistance are often needed (e.g. Picture Exchange Communication System for nonverbal children).

While we should already be familiar with writing 504 plan and IEP requests to schools, which also apply to children with ASD, in addition we need to be ready to advise about other legal rights including autism waivers, wraparound services, guardianship, and trust accounts. We can share quality educational materials available online (e.g. from Autism Speaks, SPARK, and Autism Navigator). Social media groups may be supportive, but also may contain disinformation we need to dispel.

Unfortunately, templates, questionnaires, and lack of interdisciplinary referral and communication functions of EHRs don’t support the complexities of care for ASD. While the AAP has guidelines for diagnosis and management and an online toolkit, consider adding a system with an autism-specific module like CHADIS and joining the Autism Care Network or ECHO Autism sessions to get both information and support to take on the evolving critical role of autism care.
 

Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS. She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.

SAN DIEGO — Susceptibility to post-traumatic headache could be linked to mutations in ion channel and ion transporter genes, according to results from a preliminary study.

Post-traumatic headache is a common symptom of traumatic brain injury (TBI).

There is evidence that genetic mutations could play a role in both TBI development and response. In particular, the S213L mutation for familial hemiplegic migraine-1 (FHM1), found in the CACNA1A gene, can cause individuals carrying it to be highly sensitive to otherwise trivial head impacts, according to Lyn Griffiths, PhD.

The consequences can be post-traumatic headache, but also seizures, cerebral edema, coma, or worse. Another form of FHM is associated with mutations in ATP1A2.

“This stimulated our interest in looking at genes that relate to TBI with a particular focus on ion channel genes,” said Dr. Griffiths, during a presentation of the study at the annual meeting of the American Headache Society.

The researchers analyzed data from 117 participants who had at least one concussion with a post-traumatic headache, and recruited family members when possible. There were 15 participants who developed severe reactions to trivial head trauma, 13 who had been diagnosed with concussion and underwent imaging related to TBI-associated symptoms, 54 who had been recruited through local sporting groups campuses, and 35 recruited through a medical research foundation. Blood or saliva samples were used to perform whole exome sequencing.

The researchers looked for gene candidates within different tiers. Tier 1 included genes that had already been implicated in severe migraine. The second tier included 353 ion channel and iron transporter genes. Tier 3 comprised neurotransmission-related genes.

After sequencing, the researchers filtered genetic mutations to include only those that affected amino acid composition of the protein, were predicted by two or more in silico analysis tools to be damaging, and were identified in multiple, unrelated patients.

In tier 2, the greatest number of potential damaging variants were found in the SCN9A gene, which is involved in pain perception and processing. There were six variants found in eight cases. Of these eight individuals, three had suffered severe reactions to relatively minor head trauma.

In tier 3, the researchers identified mutations in eight neurotransmitter-related genes.

Through comparison with a general population control group, the researchers identified 43 different rare, amino acid–changing variants that occurred within 16 ion channel and ion channel transporter genes. These mutations were found in 53 individuals, at an approximately fivefold higher frequency than the control group (odds ratio, 5.6; P < .0001).

“We identified a number of rare genetic variants implicated in migraine — ion channel and other neurologically associated genes — in those suffering from post-traumatic headache,” said Dr. Griffiths. She also noted that the whole genomes they collected will allow for further analysis of other gene candidates in the future.

During the Q&A period, Dr. Griffiths was asked if the research group tracked the severity of the TBIs suffered by participants. She responded that they had not, and this was a limitation of the study.

Another questioner asked if parents should consider genetic testing for susceptibility mutations when considering whether to allow a child to participate in sports or activities with elevated risk of TBI. “I don’t necessarily think this is a bad thing,” she said, though she conceded that the work is still immature. “It’s probably a bit early because we haven’t identified all the genes that are involved or all the specific mutations ... but I think down the track, that makes perfect sense. Why would you not do some sensible preventive screening to aid with things like maybe you wear more headgear or you consider what’s the appropriate sport for that person?”

Laine Green, MD, assistant professor of neurology at Mayo Clinic Arizona, Phoenix, who moderated the session, was asked for comment. “I think the idea of potentially identifying people that have more genetic susceptibility to injuries is very intriguing, because post-traumatic headache and symptoms is always a difficult area to treat, potentially identifying those that with more genetic susceptibility might be helpful. It may also potentially allow us to target specific treatments, especially in this case, looking at different ion channels. There are medications that may work better at ion channel targets than other targets,” said Dr. Green.

He also endorsed the potential value of screening. “Speaking as a parent, I might like to know my child is at higher risk if they’re going to participate in contact sports or other high risk activities,” he said.

Dr. Griffiths and Dr. Green have no relevant financial disclosures.