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Topical options for acne patients continue to expand
yet they are likely underused in today’s clinical practice.
A study of prescribing practices from 2012 to 2014 indicated that dermatologists prescribed retinoids for just 58.8% of acne cases, while nondermatologists prescribed them for only 32.4% of cases. “If the guidelines are telling us that we should use topical retinoids for almost all of our acne patients, why are we using them for half of the patients?” Emmy Graber, MD, MBA, asked during MedscapeLive’s annual Las Vegas Dermatology Seminar. “We have a lot of options today for topical retinoids,” she added, noting that, in the past few years, trifarotene cream 0.005% and new formulations of tazarotene lotion (0.045%) and tretinoin lotion (0.05%) have become available.
According to Dr. Graber, president of The Dermatology Institute of Boston, tazarotene has been considered the most efficacious topical retinoid but is generally the least well tolerated, while adapalene has often been considered to be one of the better-tolerated topical retinoids. “This is a broad generalization,” she said. “One should also take into account the concentration and formulation of the retinoid. Cutaneous adverse events increase in severity as the concentration increases regardless of the vehicle.” There are no studies comparing trifarotene with other topical retinoids, she added.
In two phase 2, double-blind, vehicle-controlled studies (PERFECT 1 and PERFECT 2), researchers randomized more than 2,400 patients with moderate facial or truncal acne to receive trifarotene cream or a vehicle for 12 weeks. The mean percent change from baseline in facial inflammatory lesions in the trifarotene-treated group was –54.4% and –66.2% in PERFECT 1, and PERFECT 2, respectively, while the mean percent change from baseline in facial noninflammatory lesions was –49.7% and –57.7%, respectively.
In addition, the mean percent change from baseline in truncal inflammatory lesions in the trifarotene-treated groups was –57.4% and –65.4%, respectively, while the mean percent change from baseline in truncal noninflammatory lesions was –49.1% and –55.2%, respectively.
The choice of vehicle may affect absorption of topical retinoids, and some formulations may increase skin hydration and decrease transepidermal water loss, “which is a good thing,” Dr. Graber said. “Also, vehicles aim to slow drug delivery over time while also making sure that the drug penetrates into the pilosebaceous unit.”
One recent advance is the honeycomb-like polymeric emulsion technology found in tretinoin 0.05% lotion and tazarotene 0.045% lotion. These formulations contain droplets of the tretinoin and tazarotene embedded in a honeycomb matrix with hydrating agents. “I think this is exciting and could enhance our patient compliance and tolerability,” she said. Another unique feature about these two products, especially the tretinoin product, is the very small particle size with this new formulation. “It’s small enough that it can penetrate down into the pilosebaceous unit,” which is different than with older formulations, in which the tretinoin “largely just sat on the surface of the skin and didn’t penetrate into the pilosebaceous unit.” In addition, she said, “there’s only 9% degradation of the tretinoin in UV light, compared to 72% degradation of standard tretinoin 0.025% gel, and with the new tretinoin formulation, there’s no degradation when used with benzoyl peroxide.”
Another new topical retinoid to consider is a fixed-dose combination of encapsulated benzoyl peroxide 3% and encapsulated tretinoin 0.1% cream (Twyneo), which was approved by the Food and Drug Administration in July 2021 for the treatment of acne in adults and children aged 9 years and older. “Typically, benzoyl peroxide and tretinoin cannot be mixed in the same tube to stability issues,” she said. “Here, each product is individually encapsulated in a silica shell so that they can be applied together.”
The approval was supported by positive results from two phase 3, randomized, double-blind, vehicle-controlled, multicenter studies (NCT03761784 and NCT03761810), in which Twyneo demonstrated efficacy and a favorable tolerability profile in patients aged 9 years and older with facial acne.
Another topical treatment option, dapsone, is now FDA approved for ages 9 and up, expanded from its initial indication for ages 12 and up. The new indication is based on a phase 4, multicenter, open-label study in which acne patients aged 9-11 years applied dapsone 7.5% gel once daily to the face and acne-affected areas on the upper chest, upper back, and shoulders for 12 weeks. After 12 weeks, facial acne was clear or almost clear in about 47% of patients. “Inflammatory, noninflammatory, and total lesions decreased from baseline, but there was a greater reduction in noninflammatory lesions, so if you have a very young patient with acne, now you can consider dapsone gel,” Dr. Graber said.
In August 2020, clascoterone cream became the first topical androgen receptor inhibitor approved for the treatment of acne in patients 12 years of age and older. It is a drug believed to address sebum and inflammation directly in the sebaceous gland and is structurally similar to dihydrotestosterone and spironolactone.
“This is a completely new drug category in acne,” she said. “Unlike all oral antiandrogen therapies, clascoterone cream can be used in both males and females with acne. It’s the first acne drug to have a new mechanism of action in almost 40 years, since isotretinoin was approved in 1982.”
In vitro, she continued, clascoterone competes with dihydrotestosterone for binding to the androgen receptor, inhibiting downstream signaling and leading to inhibited sebum production, reduced secretion of inflammatory cytokines, and inhibition of inflammatory pathways. Two phase 3 studies that led to its approval involved 1,440 patients with moderate to severe facial acne aged 9-58 years. The cream was applied twice a day for 12 weeks and treatment adherence was approximately 90%. The researchers found that clascoterone cream was significantly more effective than vehicle cream at achieving Investigator’s Global Assessment scores of 0 (clear) or 1 (almost clear), the definition of treatment success in the study, and reducing noninflammatory lesion and inflammatory lesion counts at week 12. “There were no safety issues noted during these studies, and clascoterone cream was well tolerated,” Dr. Graber said.
Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.
MedscapeLive and this news organization are owned by the same parent company.
Commentary by Lawrence W. Eichenfield, MD
Acne vulgaris remains an issue of tremendous importance to preteens, teens, and young adults, with approximately 85% of individuals aged 12-24 being affected. Expanding options for topical treatments may help bring effective disease control. Dr. Graber pointed out that historically, pediatricians and other primary care practitioners utilize topical retinoids less often for acne care as compared with dermatologists or guidelines recommendations (either the AAP’s or AAD’s). There are now expanded options, including over-the-counter retinoids (adapalene 0.1% gel), generic and trade brand topical tretinoin products, prescription adapalene medications, older and recently approved tazarotene products, and a newer type of topical retinoid, trifarotene. Novel formulations and emulsion technology, as well as retinoid developed in combination products, give more options in patients down to 9 years of age. A novel topical anti-androgen, clascoterone, is in its own category, as the first topical “hormonal agent,” allowing hormonal therapy to be used for males as well as females (aged 12 years and up). A recent review in JAMA (2021 Nov 23;326[20]:2055-67) incorporates many of these newer medications into management suggestions, emphasizing that first-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals, whereas in more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.
Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.
A version of this article first appeared on Medscape.com.
This article was updated 6/18/22.
yet they are likely underused in today’s clinical practice.
A study of prescribing practices from 2012 to 2014 indicated that dermatologists prescribed retinoids for just 58.8% of acne cases, while nondermatologists prescribed them for only 32.4% of cases. “If the guidelines are telling us that we should use topical retinoids for almost all of our acne patients, why are we using them for half of the patients?” Emmy Graber, MD, MBA, asked during MedscapeLive’s annual Las Vegas Dermatology Seminar. “We have a lot of options today for topical retinoids,” she added, noting that, in the past few years, trifarotene cream 0.005% and new formulations of tazarotene lotion (0.045%) and tretinoin lotion (0.05%) have become available.
According to Dr. Graber, president of The Dermatology Institute of Boston, tazarotene has been considered the most efficacious topical retinoid but is generally the least well tolerated, while adapalene has often been considered to be one of the better-tolerated topical retinoids. “This is a broad generalization,” she said. “One should also take into account the concentration and formulation of the retinoid. Cutaneous adverse events increase in severity as the concentration increases regardless of the vehicle.” There are no studies comparing trifarotene with other topical retinoids, she added.
In two phase 2, double-blind, vehicle-controlled studies (PERFECT 1 and PERFECT 2), researchers randomized more than 2,400 patients with moderate facial or truncal acne to receive trifarotene cream or a vehicle for 12 weeks. The mean percent change from baseline in facial inflammatory lesions in the trifarotene-treated group was –54.4% and –66.2% in PERFECT 1, and PERFECT 2, respectively, while the mean percent change from baseline in facial noninflammatory lesions was –49.7% and –57.7%, respectively.
In addition, the mean percent change from baseline in truncal inflammatory lesions in the trifarotene-treated groups was –57.4% and –65.4%, respectively, while the mean percent change from baseline in truncal noninflammatory lesions was –49.1% and –55.2%, respectively.
The choice of vehicle may affect absorption of topical retinoids, and some formulations may increase skin hydration and decrease transepidermal water loss, “which is a good thing,” Dr. Graber said. “Also, vehicles aim to slow drug delivery over time while also making sure that the drug penetrates into the pilosebaceous unit.”
One recent advance is the honeycomb-like polymeric emulsion technology found in tretinoin 0.05% lotion and tazarotene 0.045% lotion. These formulations contain droplets of the tretinoin and tazarotene embedded in a honeycomb matrix with hydrating agents. “I think this is exciting and could enhance our patient compliance and tolerability,” she said. Another unique feature about these two products, especially the tretinoin product, is the very small particle size with this new formulation. “It’s small enough that it can penetrate down into the pilosebaceous unit,” which is different than with older formulations, in which the tretinoin “largely just sat on the surface of the skin and didn’t penetrate into the pilosebaceous unit.” In addition, she said, “there’s only 9% degradation of the tretinoin in UV light, compared to 72% degradation of standard tretinoin 0.025% gel, and with the new tretinoin formulation, there’s no degradation when used with benzoyl peroxide.”
Another new topical retinoid to consider is a fixed-dose combination of encapsulated benzoyl peroxide 3% and encapsulated tretinoin 0.1% cream (Twyneo), which was approved by the Food and Drug Administration in July 2021 for the treatment of acne in adults and children aged 9 years and older. “Typically, benzoyl peroxide and tretinoin cannot be mixed in the same tube to stability issues,” she said. “Here, each product is individually encapsulated in a silica shell so that they can be applied together.”
The approval was supported by positive results from two phase 3, randomized, double-blind, vehicle-controlled, multicenter studies (NCT03761784 and NCT03761810), in which Twyneo demonstrated efficacy and a favorable tolerability profile in patients aged 9 years and older with facial acne.
Another topical treatment option, dapsone, is now FDA approved for ages 9 and up, expanded from its initial indication for ages 12 and up. The new indication is based on a phase 4, multicenter, open-label study in which acne patients aged 9-11 years applied dapsone 7.5% gel once daily to the face and acne-affected areas on the upper chest, upper back, and shoulders for 12 weeks. After 12 weeks, facial acne was clear or almost clear in about 47% of patients. “Inflammatory, noninflammatory, and total lesions decreased from baseline, but there was a greater reduction in noninflammatory lesions, so if you have a very young patient with acne, now you can consider dapsone gel,” Dr. Graber said.
In August 2020, clascoterone cream became the first topical androgen receptor inhibitor approved for the treatment of acne in patients 12 years of age and older. It is a drug believed to address sebum and inflammation directly in the sebaceous gland and is structurally similar to dihydrotestosterone and spironolactone.
“This is a completely new drug category in acne,” she said. “Unlike all oral antiandrogen therapies, clascoterone cream can be used in both males and females with acne. It’s the first acne drug to have a new mechanism of action in almost 40 years, since isotretinoin was approved in 1982.”
In vitro, she continued, clascoterone competes with dihydrotestosterone for binding to the androgen receptor, inhibiting downstream signaling and leading to inhibited sebum production, reduced secretion of inflammatory cytokines, and inhibition of inflammatory pathways. Two phase 3 studies that led to its approval involved 1,440 patients with moderate to severe facial acne aged 9-58 years. The cream was applied twice a day for 12 weeks and treatment adherence was approximately 90%. The researchers found that clascoterone cream was significantly more effective than vehicle cream at achieving Investigator’s Global Assessment scores of 0 (clear) or 1 (almost clear), the definition of treatment success in the study, and reducing noninflammatory lesion and inflammatory lesion counts at week 12. “There were no safety issues noted during these studies, and clascoterone cream was well tolerated,” Dr. Graber said.
Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.
MedscapeLive and this news organization are owned by the same parent company.
Commentary by Lawrence W. Eichenfield, MD
Acne vulgaris remains an issue of tremendous importance to preteens, teens, and young adults, with approximately 85% of individuals aged 12-24 being affected. Expanding options for topical treatments may help bring effective disease control. Dr. Graber pointed out that historically, pediatricians and other primary care practitioners utilize topical retinoids less often for acne care as compared with dermatologists or guidelines recommendations (either the AAP’s or AAD’s). There are now expanded options, including over-the-counter retinoids (adapalene 0.1% gel), generic and trade brand topical tretinoin products, prescription adapalene medications, older and recently approved tazarotene products, and a newer type of topical retinoid, trifarotene. Novel formulations and emulsion technology, as well as retinoid developed in combination products, give more options in patients down to 9 years of age. A novel topical anti-androgen, clascoterone, is in its own category, as the first topical “hormonal agent,” allowing hormonal therapy to be used for males as well as females (aged 12 years and up). A recent review in JAMA (2021 Nov 23;326[20]:2055-67) incorporates many of these newer medications into management suggestions, emphasizing that first-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals, whereas in more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.
Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.
A version of this article first appeared on Medscape.com.
This article was updated 6/18/22.
yet they are likely underused in today’s clinical practice.
A study of prescribing practices from 2012 to 2014 indicated that dermatologists prescribed retinoids for just 58.8% of acne cases, while nondermatologists prescribed them for only 32.4% of cases. “If the guidelines are telling us that we should use topical retinoids for almost all of our acne patients, why are we using them for half of the patients?” Emmy Graber, MD, MBA, asked during MedscapeLive’s annual Las Vegas Dermatology Seminar. “We have a lot of options today for topical retinoids,” she added, noting that, in the past few years, trifarotene cream 0.005% and new formulations of tazarotene lotion (0.045%) and tretinoin lotion (0.05%) have become available.
According to Dr. Graber, president of The Dermatology Institute of Boston, tazarotene has been considered the most efficacious topical retinoid but is generally the least well tolerated, while adapalene has often been considered to be one of the better-tolerated topical retinoids. “This is a broad generalization,” she said. “One should also take into account the concentration and formulation of the retinoid. Cutaneous adverse events increase in severity as the concentration increases regardless of the vehicle.” There are no studies comparing trifarotene with other topical retinoids, she added.
In two phase 2, double-blind, vehicle-controlled studies (PERFECT 1 and PERFECT 2), researchers randomized more than 2,400 patients with moderate facial or truncal acne to receive trifarotene cream or a vehicle for 12 weeks. The mean percent change from baseline in facial inflammatory lesions in the trifarotene-treated group was –54.4% and –66.2% in PERFECT 1, and PERFECT 2, respectively, while the mean percent change from baseline in facial noninflammatory lesions was –49.7% and –57.7%, respectively.
In addition, the mean percent change from baseline in truncal inflammatory lesions in the trifarotene-treated groups was –57.4% and –65.4%, respectively, while the mean percent change from baseline in truncal noninflammatory lesions was –49.1% and –55.2%, respectively.
The choice of vehicle may affect absorption of topical retinoids, and some formulations may increase skin hydration and decrease transepidermal water loss, “which is a good thing,” Dr. Graber said. “Also, vehicles aim to slow drug delivery over time while also making sure that the drug penetrates into the pilosebaceous unit.”
One recent advance is the honeycomb-like polymeric emulsion technology found in tretinoin 0.05% lotion and tazarotene 0.045% lotion. These formulations contain droplets of the tretinoin and tazarotene embedded in a honeycomb matrix with hydrating agents. “I think this is exciting and could enhance our patient compliance and tolerability,” she said. Another unique feature about these two products, especially the tretinoin product, is the very small particle size with this new formulation. “It’s small enough that it can penetrate down into the pilosebaceous unit,” which is different than with older formulations, in which the tretinoin “largely just sat on the surface of the skin and didn’t penetrate into the pilosebaceous unit.” In addition, she said, “there’s only 9% degradation of the tretinoin in UV light, compared to 72% degradation of standard tretinoin 0.025% gel, and with the new tretinoin formulation, there’s no degradation when used with benzoyl peroxide.”
Another new topical retinoid to consider is a fixed-dose combination of encapsulated benzoyl peroxide 3% and encapsulated tretinoin 0.1% cream (Twyneo), which was approved by the Food and Drug Administration in July 2021 for the treatment of acne in adults and children aged 9 years and older. “Typically, benzoyl peroxide and tretinoin cannot be mixed in the same tube to stability issues,” she said. “Here, each product is individually encapsulated in a silica shell so that they can be applied together.”
The approval was supported by positive results from two phase 3, randomized, double-blind, vehicle-controlled, multicenter studies (NCT03761784 and NCT03761810), in which Twyneo demonstrated efficacy and a favorable tolerability profile in patients aged 9 years and older with facial acne.
Another topical treatment option, dapsone, is now FDA approved for ages 9 and up, expanded from its initial indication for ages 12 and up. The new indication is based on a phase 4, multicenter, open-label study in which acne patients aged 9-11 years applied dapsone 7.5% gel once daily to the face and acne-affected areas on the upper chest, upper back, and shoulders for 12 weeks. After 12 weeks, facial acne was clear or almost clear in about 47% of patients. “Inflammatory, noninflammatory, and total lesions decreased from baseline, but there was a greater reduction in noninflammatory lesions, so if you have a very young patient with acne, now you can consider dapsone gel,” Dr. Graber said.
In August 2020, clascoterone cream became the first topical androgen receptor inhibitor approved for the treatment of acne in patients 12 years of age and older. It is a drug believed to address sebum and inflammation directly in the sebaceous gland and is structurally similar to dihydrotestosterone and spironolactone.
“This is a completely new drug category in acne,” she said. “Unlike all oral antiandrogen therapies, clascoterone cream can be used in both males and females with acne. It’s the first acne drug to have a new mechanism of action in almost 40 years, since isotretinoin was approved in 1982.”
In vitro, she continued, clascoterone competes with dihydrotestosterone for binding to the androgen receptor, inhibiting downstream signaling and leading to inhibited sebum production, reduced secretion of inflammatory cytokines, and inhibition of inflammatory pathways. Two phase 3 studies that led to its approval involved 1,440 patients with moderate to severe facial acne aged 9-58 years. The cream was applied twice a day for 12 weeks and treatment adherence was approximately 90%. The researchers found that clascoterone cream was significantly more effective than vehicle cream at achieving Investigator’s Global Assessment scores of 0 (clear) or 1 (almost clear), the definition of treatment success in the study, and reducing noninflammatory lesion and inflammatory lesion counts at week 12. “There were no safety issues noted during these studies, and clascoterone cream was well tolerated,” Dr. Graber said.
Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.
MedscapeLive and this news organization are owned by the same parent company.
Commentary by Lawrence W. Eichenfield, MD
Acne vulgaris remains an issue of tremendous importance to preteens, teens, and young adults, with approximately 85% of individuals aged 12-24 being affected. Expanding options for topical treatments may help bring effective disease control. Dr. Graber pointed out that historically, pediatricians and other primary care practitioners utilize topical retinoids less often for acne care as compared with dermatologists or guidelines recommendations (either the AAP’s or AAD’s). There are now expanded options, including over-the-counter retinoids (adapalene 0.1% gel), generic and trade brand topical tretinoin products, prescription adapalene medications, older and recently approved tazarotene products, and a newer type of topical retinoid, trifarotene. Novel formulations and emulsion technology, as well as retinoid developed in combination products, give more options in patients down to 9 years of age. A novel topical anti-androgen, clascoterone, is in its own category, as the first topical “hormonal agent,” allowing hormonal therapy to be used for males as well as females (aged 12 years and up). A recent review in JAMA (2021 Nov 23;326[20]:2055-67) incorporates many of these newer medications into management suggestions, emphasizing that first-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals, whereas in more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.
Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.
A version of this article first appeared on Medscape.com.
This article was updated 6/18/22.
FROM THE MEDSCAPELIVE LAS VEGAS DERMATOLOGY SEMINAR
Cirrhosis comorbidities tied to worse outcomes
Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.
“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.
A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.
The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).
Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).
The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.
The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.
“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.
The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.
A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.
Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.
Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.
“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.
A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.
The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).
Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).
The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.
The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.
“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.
The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.
A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.
Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.
Multiple comorbidities appear to worsen mortality outcomes in patients with cirrhosis: Those with compensated cirrhosis and three comorbid conditions have a mortality rate similar to patients with decompensated cirrhosis, according to a new analysis of a population-based cohort in the Dallas-Fort Worth metroplex.
“I think it’s a pretty strong message that just the presence of these chronic diseases has such a strong effect in the long run. They at least contribute to mortality to some extent. It’s really important to focus on these chronic diseases as targets early during the care that we provide to these to cirrhotic patients to make sure that we control them so that, in the long run, we can decrease the premature death and mortality in these patients,” said Mohammad Amin Fallahzadeh, MD, MPH, who presented the results at the annual meeting of the American Association for the Study of Liver Diseases.
The study included 35,361 patients with cirrhosis. The mean age of participants was 59.5 years, 41.8% were female, 29.7% were non-White, and 17.5% were Hispanic. Comorbidities were common, occurring in about 25% of patients. Forty-five percent of comorbidities were cardiovascular diseases (CVD); 28.9% of subjects had one comorbidity, 17.5% had two comorbidities, and 12.6% had three comorbidities.
A Kaplan-Meier curve showed that patients with compensated cirrhosis and no comorbidities had the highest survival over time, while decompensated patients with comorbidities had the lowest survival (P = .01). The curve showed similar survival between patients with compensated cirrhosis and three comorbidities and decompensated patients with no comorbidities.
The risk of death increased with one comorbidity (hazard ratio, 2.5; 95% confidence interval, 2.23-2.8), two comorbidities (HR, 3.27; 95% CI, 2.9-3.69), and three comorbidities (HR, 4.52; 95% CI, 3.99-5.12).
Mortality increased with the number of comorbidities in both compensated and decompensated patients; patients with hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease; by race (White, Black, and other); and in different age groups. A stronger effect of comorbidities was seen in compensated patients (HR, 6.4 vs. 4.1), female patients (HR, 5.2 vs. 4.1), and in patients older than age 65 years (HR, 7.2 vs. 3.7 in those aged 45-64 years and 5.0 in those younger than age 45 years).
The researchers also found an apparent synergistic effect of chronic kidney disease (CKD) and CVD. Both conditions were associated with increased risk on their own, but when a patient had both CVD and CKD, mortality was higher than just the added risk of the two conditions.
The findings confirm that patients with cirrhosis and comorbidities seem to have worse quality of life and higher mortality. “I didn’t expect that it would have such a major effect, to make a compensated patient as if they are decompensated, but we definitely see that in our daily practice,” said Dr. Fallahzadeh, who is a 2nd-year internal medicine resident at Baylor University Medical Center, Dallas.
“When a hepatologist or an internist has a visit with a patient who is diagnosed with cirrhosis, they need to screen them for the other chronic diseases like diabetes, CKD, and cardiovascular disease to make sure that if they have any of these conditions, they’ll be under control, or if they need any referral for better management. For example, if they need a nephrology referral, it [should] be done as early as possible so that we can minimize the burden of these diseases in the long run for these patients. And we need to educate the patients as well about controlling these chronic problems,” said Dr. Fallahzadeh.
The findings might make researchers reconsider how to classify compensated and decompensated cirrhosis. “When we talk about decompensated liver disease, we’re talking about variceal hemorrhage, ascites, and encephalopathy. In this case, they’re saying that if you’re compensated and you [have] three of these associated medical conditions, that you could be worse off than decompensated cirrhosis. It’s really challenging the status quo and how we think about these two disease entities. They’re thought of a lot differently in terms of the mortality. That needs to be further elucidated,” said Mayur Brahmania, MD, assistant professor of medicine at Western University, London, Ont., who moderated the session.
A key limitation to the study was that the researchers did not have access to data about medication use, so it could not be determined if comorbidities were being controlled. Body mass index and most lifestyle factors were also uncontrolled.
Dr. Fallahzadeh and Dr. Brahmania have no relevant financial disclosures.
FROM THE LIVER MEETING
Serious infection hospitalizations have declined in patients with PsA
The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.
Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.
“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.
The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.
Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.
Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).
A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.
Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.
“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”
Dr. Kavanaugh said the question is worth investigating further with data from other sources.
The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.
The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.
Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.
“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.
The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.
Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.
Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).
A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.
Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.
“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”
Dr. Kavanaugh said the question is worth investigating further with data from other sources.
The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.
The rate of U.S. hospitalizations for three types of serious infections in patients with psoriatic arthritis (PsA) appears to have declined from 2012 to 2017, according to research presented at the virtual annual meeting of the American College of Rheumatology.
Several of the standard treatments for PsA have an increased risk of infections, but the rates vary amongst conventional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, biologics, and other therapies.
“Given the uptake of biological therapies has increased over recent years, we sought to investigate the national trends in serious infections in patients with psoriatic arthritis from the years 2012 to 2017,” Vagishwari Murugesan, MBBS, a psoriatic arthritis clinical fellow at the University of Toronto, told attendees in a prerecorded poster presentation. Dr. Murugesan was a fellow at Boston University when she conducted the research.
The researchers analyzed data from 2012 to 2017 in the U.S. National Inpatient Sample (NIS), which includes approximately 20% of all discharges from U.S. community hospitals except rehabilitation and long-term acute care institutions. Using ICD-9 and ICD-10 codes, the researchers identified all discharge records containing a diagnosis of PsA as well as pneumonia, sepsis, urinary tract infection (UTI), and skin and soft-tissue infections. After making adjustments to match U.S. population age distributions over the years, they examined trends in serious infections among patients with PsA for that 6-year period.
Demographics over those years changed little: The average age of discharged patients was 59.5 in 2012 and 60.8 in 2017. Similarly, the patient population was 56% women and 88.5% Whites in 2012 and 57.7% women and 88.4% Whites in 2017. The average length of stay was also similar: 4.7 days in 2012, compared with 4.9 days in 2017.
Among 50,700 discharges of patients with PsA in 2012, the researchers identified 125 with pneumonia, 230 with sepsis, 312 with skin and soft-tissue infections, and 174 with a UTI. Among the 179,400 discharges in 2017 of patients with PsA, 344 had pneumonia, 374 had sepsis, 681 had skin and soft-tissue infections, and 348 had a UTI. After statistical analysis, the researchers found no significant differences in pneumonia diagnoses during the years studied, but they did find a statistically significant decline in sepsis, skin and soft tissue infections, and UTI discharges (P < .001).
A notable limitation of the study is the NIS database’s lack of data on treatments or outpatient data, making it impossible to determine if more infections were occurring but simply being treated in outpatient settings, although it’s not clear why such a substantial shift would occur in just 5 years. It’s also possible that coding practices differ across hospital, but, presumably, the ways they might differ in 2012 would be similar to any differences in 2017.
Arthur Kavanaugh, MD, a professor of medicine and director of the Center for Innovative Therapy at the University of California, San Diego, found the results interesting for what he considers an important topic.
“What makes these data interesting is the same thing that limits their reliability: The authors note that infections decreased ‘despite the increase in use of biologics over this time,’ ” Dr. Kavanaugh said in an interview. “These are claims data, so there is no way to support any association between those serious infections and biologic use. Indeed, multiple factors could have also impacted these data. It is not possible to tell from claims data.”
Dr. Kavanaugh said the question is worth investigating further with data from other sources.
The research was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. One study coauthor reported ties to UCB; Dr. Murugesan and her other coauthors reported no disclosures. Dr. Kavanaugh had no disclosures.
FROM ACR 2021
How to deal with offensive or impaired doctors
Knowing what to say and do can lead to a positive outcome for the physician involved and the organization.
Misbehaving and impaired physicians put their organizations at risk, which can lead to malpractice/patient injury lawsuits, labor law and harassment claims, and a damaged reputation through negative social media reviews, said Debra Phairas, MBA, president of Practice and Liability Consultants LLC, at the annual meeting of the Medical Group Management Association (MGMA) .
“Verbal harassment or bullying claims can result in large dollar awards against the organizations that knew about the behavior and did nothing to stop it. Organizations can be sued for that,” says Ms. Phairas.
She recalls a doctor who called a female doctor “an entitled bitch” and the administrator “incompetent” in front of other staff. “He would pick on one department manager at every meeting and humiliate them in front of the others,” says Ms. Phairas.
After working with a human resources (HR) attorney and conducting independent reviews, they used a strategy Ms. Phairas calls her “3 C’s” for dealing with disruptive doctors.
Confront, correct, and/or counsel
The three C’s can work individually or together, depending on the doctor’s situation. Confronting a physician can start with an informal discussion; correcting can involve seeking a written apology that directly addresses the problem or sending a letter of admonition; and coaching or counseling can be offered. If the doctor resists those efforts, practice administrators can issue a final letter of warning and then suspend or terminate the physician, says Ms. Phairas.
Sometimes having a conversation with a disruptive doctor about the risks and consequences is enough to change the offending behavior, says Ms. Phairas.
She recalled being asked by a medical group to meet with a physician who she says was “snapping the bra straps of medical assistants in the hall — everyone there was horrified. I told him that’s not appropriate, that he was placing everyone at risk and they will terminate him if he didn’t stop. I asked for his commitment to stop, and he agreed,” says Ms. Phairas.
She also recommends implementing these strategies to prevent and deal with disruptive physicians:
- Implement a code of conduct and share it during interviews;
- Have zero tolerance policies and procedures for documenting behavior;
- Get advice from a good employment attorney;
- Implement written performance improvement plans;
- Provide resources to change the behavior;
- Follow through with suspension and termination; and
- Add to shareholder agreements a clause stating that partners/shareholders can gently ask or insist that the physician obtain counseling or help.
Getting impaired doctors help
Doctors can be impaired through substance abuse, a serious medical illness, mental illness, or age-related deterioration.
Life events such as divorce or the death of a spouse, child, or a physician partner can affect a doctor’s mental health. “In those cases, you need to have the courage to say you’re really depressed and we all agree you need to get help,” says Ms. Phairas.
She recalls one occasion in which a practice administration staff member could not locate a doctor whose patients were waiting to be seen. “He was so devastated from his divorce that he had crawled into a ball beneath his desk. She had to coax him out and tell him that they were worried about him and he needed to get help.”
Another reason doctors may not be performing well may be because of an undiagnosed medical illness. Doctors in an orthopedic group were mad at another partner who had slowed down and couldn’t help pay the expenses. “They were ready to terminate him when he went to the doctor and learned he had colon cancer,” says Ms. Phairas.
Ms. Phairas recommends that practices update their partner shareholder agreements regularly with the following:
- Include “fit for duty” examinations, especially after age 65.
- Insist that a physician be evaluated by a doctor outside the practice. The doctor may be one that they agree upon or one chosen by the local medical society president.
- Include in the agreement the clause, “Partners and employees will be subject to review for impairment due to matters including but not limited to age-related, physical, or mental conditions.”
- Establish a voting mechanism for terminating a physician.
Aging doctors who won’t retire
Some doctors have retired early because of COVID, whereas others are staying on because they are feeling financial pressures — they lost a lot of money last year and need to make up for it, says Ms. Phairas.
She warned that administrators have to be careful in dealing with older doctors because of age discrimination laws.
Doctors may not notice they are declining mentally until it becomes a problem. Ms. Phairas recalls an internist senior partner who started behaving erratically when he was 78 years old. “He wrote himself a $25,000 check from the organization’s funds without telling his partners, left a patient he should have been watching and she fell over and sued the practice, and the staff started noticing that he was forgetting or not doing things,” says Ms. Phairas.
She sought guidance from a good HR attorney and involved a malpractice attorney. She then met with the senior partner. “I reminded him of his Hippocratic Oath that he took when he became a doctor and told him that his actions were harming patients. I pleaded with him that it was time to retire. He didn’t.”
Because this physician wouldn’t retire, the practice referred to their updated shareholder agreement, which stated that they could insist that the physician undergo a neuropsychiatric assessment from a certified specialist. He didn’t pass the evaluation, which then provided evidence of his declining cognitive skills.
“All the doctors, myself, and the HR attorney talked to him about this and laid out all the facts. It was hard to say these things, but he listened and left. We went through the termination process to protect the practice and avoid litigation. The malpractice insurer also refused to renew his policy,” says Ms. Phairas.
A version of this article first appeared on Medscape.com.
Knowing what to say and do can lead to a positive outcome for the physician involved and the organization.
Misbehaving and impaired physicians put their organizations at risk, which can lead to malpractice/patient injury lawsuits, labor law and harassment claims, and a damaged reputation through negative social media reviews, said Debra Phairas, MBA, president of Practice and Liability Consultants LLC, at the annual meeting of the Medical Group Management Association (MGMA) .
“Verbal harassment or bullying claims can result in large dollar awards against the organizations that knew about the behavior and did nothing to stop it. Organizations can be sued for that,” says Ms. Phairas.
She recalls a doctor who called a female doctor “an entitled bitch” and the administrator “incompetent” in front of other staff. “He would pick on one department manager at every meeting and humiliate them in front of the others,” says Ms. Phairas.
After working with a human resources (HR) attorney and conducting independent reviews, they used a strategy Ms. Phairas calls her “3 C’s” for dealing with disruptive doctors.
Confront, correct, and/or counsel
The three C’s can work individually or together, depending on the doctor’s situation. Confronting a physician can start with an informal discussion; correcting can involve seeking a written apology that directly addresses the problem or sending a letter of admonition; and coaching or counseling can be offered. If the doctor resists those efforts, practice administrators can issue a final letter of warning and then suspend or terminate the physician, says Ms. Phairas.
Sometimes having a conversation with a disruptive doctor about the risks and consequences is enough to change the offending behavior, says Ms. Phairas.
She recalled being asked by a medical group to meet with a physician who she says was “snapping the bra straps of medical assistants in the hall — everyone there was horrified. I told him that’s not appropriate, that he was placing everyone at risk and they will terminate him if he didn’t stop. I asked for his commitment to stop, and he agreed,” says Ms. Phairas.
She also recommends implementing these strategies to prevent and deal with disruptive physicians:
- Implement a code of conduct and share it during interviews;
- Have zero tolerance policies and procedures for documenting behavior;
- Get advice from a good employment attorney;
- Implement written performance improvement plans;
- Provide resources to change the behavior;
- Follow through with suspension and termination; and
- Add to shareholder agreements a clause stating that partners/shareholders can gently ask or insist that the physician obtain counseling or help.
Getting impaired doctors help
Doctors can be impaired through substance abuse, a serious medical illness, mental illness, or age-related deterioration.
Life events such as divorce or the death of a spouse, child, or a physician partner can affect a doctor’s mental health. “In those cases, you need to have the courage to say you’re really depressed and we all agree you need to get help,” says Ms. Phairas.
She recalls one occasion in which a practice administration staff member could not locate a doctor whose patients were waiting to be seen. “He was so devastated from his divorce that he had crawled into a ball beneath his desk. She had to coax him out and tell him that they were worried about him and he needed to get help.”
Another reason doctors may not be performing well may be because of an undiagnosed medical illness. Doctors in an orthopedic group were mad at another partner who had slowed down and couldn’t help pay the expenses. “They were ready to terminate him when he went to the doctor and learned he had colon cancer,” says Ms. Phairas.
Ms. Phairas recommends that practices update their partner shareholder agreements regularly with the following:
- Include “fit for duty” examinations, especially after age 65.
- Insist that a physician be evaluated by a doctor outside the practice. The doctor may be one that they agree upon or one chosen by the local medical society president.
- Include in the agreement the clause, “Partners and employees will be subject to review for impairment due to matters including but not limited to age-related, physical, or mental conditions.”
- Establish a voting mechanism for terminating a physician.
Aging doctors who won’t retire
Some doctors have retired early because of COVID, whereas others are staying on because they are feeling financial pressures — they lost a lot of money last year and need to make up for it, says Ms. Phairas.
She warned that administrators have to be careful in dealing with older doctors because of age discrimination laws.
Doctors may not notice they are declining mentally until it becomes a problem. Ms. Phairas recalls an internist senior partner who started behaving erratically when he was 78 years old. “He wrote himself a $25,000 check from the organization’s funds without telling his partners, left a patient he should have been watching and she fell over and sued the practice, and the staff started noticing that he was forgetting or not doing things,” says Ms. Phairas.
She sought guidance from a good HR attorney and involved a malpractice attorney. She then met with the senior partner. “I reminded him of his Hippocratic Oath that he took when he became a doctor and told him that his actions were harming patients. I pleaded with him that it was time to retire. He didn’t.”
Because this physician wouldn’t retire, the practice referred to their updated shareholder agreement, which stated that they could insist that the physician undergo a neuropsychiatric assessment from a certified specialist. He didn’t pass the evaluation, which then provided evidence of his declining cognitive skills.
“All the doctors, myself, and the HR attorney talked to him about this and laid out all the facts. It was hard to say these things, but he listened and left. We went through the termination process to protect the practice and avoid litigation. The malpractice insurer also refused to renew his policy,” says Ms. Phairas.
A version of this article first appeared on Medscape.com.
Knowing what to say and do can lead to a positive outcome for the physician involved and the organization.
Misbehaving and impaired physicians put their organizations at risk, which can lead to malpractice/patient injury lawsuits, labor law and harassment claims, and a damaged reputation through negative social media reviews, said Debra Phairas, MBA, president of Practice and Liability Consultants LLC, at the annual meeting of the Medical Group Management Association (MGMA) .
“Verbal harassment or bullying claims can result in large dollar awards against the organizations that knew about the behavior and did nothing to stop it. Organizations can be sued for that,” says Ms. Phairas.
She recalls a doctor who called a female doctor “an entitled bitch” and the administrator “incompetent” in front of other staff. “He would pick on one department manager at every meeting and humiliate them in front of the others,” says Ms. Phairas.
After working with a human resources (HR) attorney and conducting independent reviews, they used a strategy Ms. Phairas calls her “3 C’s” for dealing with disruptive doctors.
Confront, correct, and/or counsel
The three C’s can work individually or together, depending on the doctor’s situation. Confronting a physician can start with an informal discussion; correcting can involve seeking a written apology that directly addresses the problem or sending a letter of admonition; and coaching or counseling can be offered. If the doctor resists those efforts, practice administrators can issue a final letter of warning and then suspend or terminate the physician, says Ms. Phairas.
Sometimes having a conversation with a disruptive doctor about the risks and consequences is enough to change the offending behavior, says Ms. Phairas.
She recalled being asked by a medical group to meet with a physician who she says was “snapping the bra straps of medical assistants in the hall — everyone there was horrified. I told him that’s not appropriate, that he was placing everyone at risk and they will terminate him if he didn’t stop. I asked for his commitment to stop, and he agreed,” says Ms. Phairas.
She also recommends implementing these strategies to prevent and deal with disruptive physicians:
- Implement a code of conduct and share it during interviews;
- Have zero tolerance policies and procedures for documenting behavior;
- Get advice from a good employment attorney;
- Implement written performance improvement plans;
- Provide resources to change the behavior;
- Follow through with suspension and termination; and
- Add to shareholder agreements a clause stating that partners/shareholders can gently ask or insist that the physician obtain counseling or help.
Getting impaired doctors help
Doctors can be impaired through substance abuse, a serious medical illness, mental illness, or age-related deterioration.
Life events such as divorce or the death of a spouse, child, or a physician partner can affect a doctor’s mental health. “In those cases, you need to have the courage to say you’re really depressed and we all agree you need to get help,” says Ms. Phairas.
She recalls one occasion in which a practice administration staff member could not locate a doctor whose patients were waiting to be seen. “He was so devastated from his divorce that he had crawled into a ball beneath his desk. She had to coax him out and tell him that they were worried about him and he needed to get help.”
Another reason doctors may not be performing well may be because of an undiagnosed medical illness. Doctors in an orthopedic group were mad at another partner who had slowed down and couldn’t help pay the expenses. “They were ready to terminate him when he went to the doctor and learned he had colon cancer,” says Ms. Phairas.
Ms. Phairas recommends that practices update their partner shareholder agreements regularly with the following:
- Include “fit for duty” examinations, especially after age 65.
- Insist that a physician be evaluated by a doctor outside the practice. The doctor may be one that they agree upon or one chosen by the local medical society president.
- Include in the agreement the clause, “Partners and employees will be subject to review for impairment due to matters including but not limited to age-related, physical, or mental conditions.”
- Establish a voting mechanism for terminating a physician.
Aging doctors who won’t retire
Some doctors have retired early because of COVID, whereas others are staying on because they are feeling financial pressures — they lost a lot of money last year and need to make up for it, says Ms. Phairas.
She warned that administrators have to be careful in dealing with older doctors because of age discrimination laws.
Doctors may not notice they are declining mentally until it becomes a problem. Ms. Phairas recalls an internist senior partner who started behaving erratically when he was 78 years old. “He wrote himself a $25,000 check from the organization’s funds without telling his partners, left a patient he should have been watching and she fell over and sued the practice, and the staff started noticing that he was forgetting or not doing things,” says Ms. Phairas.
She sought guidance from a good HR attorney and involved a malpractice attorney. She then met with the senior partner. “I reminded him of his Hippocratic Oath that he took when he became a doctor and told him that his actions were harming patients. I pleaded with him that it was time to retire. He didn’t.”
Because this physician wouldn’t retire, the practice referred to their updated shareholder agreement, which stated that they could insist that the physician undergo a neuropsychiatric assessment from a certified specialist. He didn’t pass the evaluation, which then provided evidence of his declining cognitive skills.
“All the doctors, myself, and the HR attorney talked to him about this and laid out all the facts. It was hard to say these things, but he listened and left. We went through the termination process to protect the practice and avoid litigation. The malpractice insurer also refused to renew his policy,” says Ms. Phairas.
A version of this article first appeared on Medscape.com.
Ulcerative colitis study: Ozanimod tops adalimumab, equals vedolizumab
LAS VEGAS – In a comparison of data from clinical trials for ulcerative colitis, ozanimod (Zeposia) appeared to be more useful than adalimumab (Humira) and as useful as vedolizumab (Entyvio).
The U.S. Food and Drug Administration approved ozanimod for ulcerative colitis in May of this year, and clinicians are trying to figure out where it fits into the armamentarium, said Marla Dubinsky, MD, professor of pediatrics and medicine in the Division of Pediatric Gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
“It’s an extremely heterogeneous disease,” Dr. Dubinsky told this news organization. “A lot of these indirect comparisons are being done, because these therapies are coming out so quickly.”
No clinical trials have compared either ozanimod to adalimumab or ozanimod to vedolizumab head to head, so Dr. Dubinsky and colleagues pitted the drugs against each other by matching data from individual patients from the True North trial of ozanimod to published data from the ULTRA 1 and 2 trials of adalimumab and the GEMINI 1 trial of vedolizumab.
She presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.
From the 1990s until 2014, physicians relied heavily on tumor necrosis factor (TNF) inhibitors, such as adalimumab, to treat ulcerative colitis, Dr. Dubinsky said. Although often effective, these drugs can increase patients’ vulnerability to infections and malignancies.
Approved by the FDA in 2014, vedolizumab works differently: it blocks α4β7 integrin. “The safety profile was extremely favorable,” Dr. Dubinsky said. “That was a revolution, in my opinion.” Still, vedolizumab isn’t always effective, especially for patients who have already received TNF inhibitors without success.
As reported by this news organization, ozanimod works by yet another mechanism: sphingosine l-phosphate receptor modulation.
How does ozanimod measure up?
To see how ozanimod stacks up to the two older drugs, Dr. Dubinsky and colleagues weighted the data from True North to match the patient populations in the other trials by age, sex, baseline total Mayo score, disease extent, and prior anti-TNF treatment.
They calculated the odds that ozanimod would produce better clinical and endoscopic responses or be associated with more serious or infectious adverse events in comparison with each of the other drugs. The comparisons included both the induction and maintenance phases of the trials.
The researchers compared ozanimod to adalimumab for patients who were anti-TNF naive. They found that the patients who took ozanimod were more likely to experience a clinical response than those who took adalimumab (odds ratio, 1.68; 95% CI, 1.03-2.74). The patients who took ozanimod were also more likely to have endoscopic improvement (OR, 2.73; 95% CI, 1.44-5.17).
They found that the patients who had received a TNF inhibitor were also more likely to experience a clinical response with ozanimod than with adalimumab (OR, 2.53; 95% CI, 1.13-5.67).
In both the induction and the maintenance phases, the other differences in efficacy between ozanimod and adalimumab did not reach statistical significance.
As for safety, in the induction phases of the trials, the researchers found that 11.3% of patients who received ozanimod had infections, compared to 20.2% of those taking adalimumab, which was statistically significant (P < .01). Other differences in safety were not statistically significant.
With regard to vedolizumab, Dr. Dubinsky and colleagues found no statistically significant differences between it and ozanimod in the induction phases.
In the maintenance phases, among patients who were anti-TNF naive, the odds of clinical response were lower with ozanimod than with vedolizumab (OR, 0.40; 95% CI, 0.21-0.76). The odds of endoscopic improvement were very nearly lower (OR, 0.52; 95% CI, 0.27-1.01). The researchers attributed these findings to a higher placebo response in the True North trial (the ozanimod trial) than in GEMINI 1 (the vedolizumab trial).
There were no other significant differences in efficacy between ozanimod and vedolizumab, either in the cohort that had received a TNF inhibitor or in the cohort that had not.
As for safety, there were also no statistically significant differences between vedolizumab and ozanimod in the induction phases. During the maintenance phases, 71.3% of patients who received vedolizumab had infections, compared to 25.0% in the matched cohort of patients who received ozanimod, which was a statistically significant difference (P < .001). The other differences in this phase were not significant.
Dr. Dubinsky acknowledged that the results were not as reliable as would have been the case in a prospective, head-to-head comparison, because the researchers could not be sure that they had fully adjusted for the differences in the populations and the designs of the studies.
“In TNF-inhibitor–naive patients, I could use vedolizumab or ozanimod,” Dr. Dubinsky said. But these are not the only options, she said. She said that “in TNF failure, I would use ustekinumab or even tofacitinib.” Ustekinumab (Stelara) is a human interleukin-12 and -23 antagonist; tofacitinib (Xeljanz) is a Janus kinase inhibitor.
The study’s limitations are significant, said session moderator Jonathan Leighton, MD, a professor of medicine at the Mayo Clinic in Phoenix, Arizona, “but it certainly shows that ozanimod had a positive profile compared to adalimumab and has overall comparable benefits with vedolizumab,” he said in an interview.
Dr. Leighton added that someday researchers may find biomarkers that will identify the best drug for each patient. In the meantime, clinicians are often left choosing therapies on the basis of such factors as which route of administration the patients prefer, he said. Vedolizumab is given by intravenous infusion, ozanimod is taken orally, and adalimumab is given by subcutaneous injection.
The study was funded by Bristol-Myers Squibb. Dr. Leighton has financial relationships with Olympus and Pfizer. Dr. Dubinsky has relationships with all or most of the companies that make drugs for inflammatory bowel disease.
A version of this article first appeared on Medscape.com.
LAS VEGAS – In a comparison of data from clinical trials for ulcerative colitis, ozanimod (Zeposia) appeared to be more useful than adalimumab (Humira) and as useful as vedolizumab (Entyvio).
The U.S. Food and Drug Administration approved ozanimod for ulcerative colitis in May of this year, and clinicians are trying to figure out where it fits into the armamentarium, said Marla Dubinsky, MD, professor of pediatrics and medicine in the Division of Pediatric Gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
“It’s an extremely heterogeneous disease,” Dr. Dubinsky told this news organization. “A lot of these indirect comparisons are being done, because these therapies are coming out so quickly.”
No clinical trials have compared either ozanimod to adalimumab or ozanimod to vedolizumab head to head, so Dr. Dubinsky and colleagues pitted the drugs against each other by matching data from individual patients from the True North trial of ozanimod to published data from the ULTRA 1 and 2 trials of adalimumab and the GEMINI 1 trial of vedolizumab.
She presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.
From the 1990s until 2014, physicians relied heavily on tumor necrosis factor (TNF) inhibitors, such as adalimumab, to treat ulcerative colitis, Dr. Dubinsky said. Although often effective, these drugs can increase patients’ vulnerability to infections and malignancies.
Approved by the FDA in 2014, vedolizumab works differently: it blocks α4β7 integrin. “The safety profile was extremely favorable,” Dr. Dubinsky said. “That was a revolution, in my opinion.” Still, vedolizumab isn’t always effective, especially for patients who have already received TNF inhibitors without success.
As reported by this news organization, ozanimod works by yet another mechanism: sphingosine l-phosphate receptor modulation.
How does ozanimod measure up?
To see how ozanimod stacks up to the two older drugs, Dr. Dubinsky and colleagues weighted the data from True North to match the patient populations in the other trials by age, sex, baseline total Mayo score, disease extent, and prior anti-TNF treatment.
They calculated the odds that ozanimod would produce better clinical and endoscopic responses or be associated with more serious or infectious adverse events in comparison with each of the other drugs. The comparisons included both the induction and maintenance phases of the trials.
The researchers compared ozanimod to adalimumab for patients who were anti-TNF naive. They found that the patients who took ozanimod were more likely to experience a clinical response than those who took adalimumab (odds ratio, 1.68; 95% CI, 1.03-2.74). The patients who took ozanimod were also more likely to have endoscopic improvement (OR, 2.73; 95% CI, 1.44-5.17).
They found that the patients who had received a TNF inhibitor were also more likely to experience a clinical response with ozanimod than with adalimumab (OR, 2.53; 95% CI, 1.13-5.67).
In both the induction and the maintenance phases, the other differences in efficacy between ozanimod and adalimumab did not reach statistical significance.
As for safety, in the induction phases of the trials, the researchers found that 11.3% of patients who received ozanimod had infections, compared to 20.2% of those taking adalimumab, which was statistically significant (P < .01). Other differences in safety were not statistically significant.
With regard to vedolizumab, Dr. Dubinsky and colleagues found no statistically significant differences between it and ozanimod in the induction phases.
In the maintenance phases, among patients who were anti-TNF naive, the odds of clinical response were lower with ozanimod than with vedolizumab (OR, 0.40; 95% CI, 0.21-0.76). The odds of endoscopic improvement were very nearly lower (OR, 0.52; 95% CI, 0.27-1.01). The researchers attributed these findings to a higher placebo response in the True North trial (the ozanimod trial) than in GEMINI 1 (the vedolizumab trial).
There were no other significant differences in efficacy between ozanimod and vedolizumab, either in the cohort that had received a TNF inhibitor or in the cohort that had not.
As for safety, there were also no statistically significant differences between vedolizumab and ozanimod in the induction phases. During the maintenance phases, 71.3% of patients who received vedolizumab had infections, compared to 25.0% in the matched cohort of patients who received ozanimod, which was a statistically significant difference (P < .001). The other differences in this phase were not significant.
Dr. Dubinsky acknowledged that the results were not as reliable as would have been the case in a prospective, head-to-head comparison, because the researchers could not be sure that they had fully adjusted for the differences in the populations and the designs of the studies.
“In TNF-inhibitor–naive patients, I could use vedolizumab or ozanimod,” Dr. Dubinsky said. But these are not the only options, she said. She said that “in TNF failure, I would use ustekinumab or even tofacitinib.” Ustekinumab (Stelara) is a human interleukin-12 and -23 antagonist; tofacitinib (Xeljanz) is a Janus kinase inhibitor.
The study’s limitations are significant, said session moderator Jonathan Leighton, MD, a professor of medicine at the Mayo Clinic in Phoenix, Arizona, “but it certainly shows that ozanimod had a positive profile compared to adalimumab and has overall comparable benefits with vedolizumab,” he said in an interview.
Dr. Leighton added that someday researchers may find biomarkers that will identify the best drug for each patient. In the meantime, clinicians are often left choosing therapies on the basis of such factors as which route of administration the patients prefer, he said. Vedolizumab is given by intravenous infusion, ozanimod is taken orally, and adalimumab is given by subcutaneous injection.
The study was funded by Bristol-Myers Squibb. Dr. Leighton has financial relationships with Olympus and Pfizer. Dr. Dubinsky has relationships with all or most of the companies that make drugs for inflammatory bowel disease.
A version of this article first appeared on Medscape.com.
LAS VEGAS – In a comparison of data from clinical trials for ulcerative colitis, ozanimod (Zeposia) appeared to be more useful than adalimumab (Humira) and as useful as vedolizumab (Entyvio).
The U.S. Food and Drug Administration approved ozanimod for ulcerative colitis in May of this year, and clinicians are trying to figure out where it fits into the armamentarium, said Marla Dubinsky, MD, professor of pediatrics and medicine in the Division of Pediatric Gastroenterology at Icahn School of Medicine at Mount Sinai, New York.
“It’s an extremely heterogeneous disease,” Dr. Dubinsky told this news organization. “A lot of these indirect comparisons are being done, because these therapies are coming out so quickly.”
No clinical trials have compared either ozanimod to adalimumab or ozanimod to vedolizumab head to head, so Dr. Dubinsky and colleagues pitted the drugs against each other by matching data from individual patients from the True North trial of ozanimod to published data from the ULTRA 1 and 2 trials of adalimumab and the GEMINI 1 trial of vedolizumab.
She presented the findings here at the American College of Gastroenterology (ACG) 2021 Annual Scientific Meeting.
From the 1990s until 2014, physicians relied heavily on tumor necrosis factor (TNF) inhibitors, such as adalimumab, to treat ulcerative colitis, Dr. Dubinsky said. Although often effective, these drugs can increase patients’ vulnerability to infections and malignancies.
Approved by the FDA in 2014, vedolizumab works differently: it blocks α4β7 integrin. “The safety profile was extremely favorable,” Dr. Dubinsky said. “That was a revolution, in my opinion.” Still, vedolizumab isn’t always effective, especially for patients who have already received TNF inhibitors without success.
As reported by this news organization, ozanimod works by yet another mechanism: sphingosine l-phosphate receptor modulation.
How does ozanimod measure up?
To see how ozanimod stacks up to the two older drugs, Dr. Dubinsky and colleagues weighted the data from True North to match the patient populations in the other trials by age, sex, baseline total Mayo score, disease extent, and prior anti-TNF treatment.
They calculated the odds that ozanimod would produce better clinical and endoscopic responses or be associated with more serious or infectious adverse events in comparison with each of the other drugs. The comparisons included both the induction and maintenance phases of the trials.
The researchers compared ozanimod to adalimumab for patients who were anti-TNF naive. They found that the patients who took ozanimod were more likely to experience a clinical response than those who took adalimumab (odds ratio, 1.68; 95% CI, 1.03-2.74). The patients who took ozanimod were also more likely to have endoscopic improvement (OR, 2.73; 95% CI, 1.44-5.17).
They found that the patients who had received a TNF inhibitor were also more likely to experience a clinical response with ozanimod than with adalimumab (OR, 2.53; 95% CI, 1.13-5.67).
In both the induction and the maintenance phases, the other differences in efficacy between ozanimod and adalimumab did not reach statistical significance.
As for safety, in the induction phases of the trials, the researchers found that 11.3% of patients who received ozanimod had infections, compared to 20.2% of those taking adalimumab, which was statistically significant (P < .01). Other differences in safety were not statistically significant.
With regard to vedolizumab, Dr. Dubinsky and colleagues found no statistically significant differences between it and ozanimod in the induction phases.
In the maintenance phases, among patients who were anti-TNF naive, the odds of clinical response were lower with ozanimod than with vedolizumab (OR, 0.40; 95% CI, 0.21-0.76). The odds of endoscopic improvement were very nearly lower (OR, 0.52; 95% CI, 0.27-1.01). The researchers attributed these findings to a higher placebo response in the True North trial (the ozanimod trial) than in GEMINI 1 (the vedolizumab trial).
There were no other significant differences in efficacy between ozanimod and vedolizumab, either in the cohort that had received a TNF inhibitor or in the cohort that had not.
As for safety, there were also no statistically significant differences between vedolizumab and ozanimod in the induction phases. During the maintenance phases, 71.3% of patients who received vedolizumab had infections, compared to 25.0% in the matched cohort of patients who received ozanimod, which was a statistically significant difference (P < .001). The other differences in this phase were not significant.
Dr. Dubinsky acknowledged that the results were not as reliable as would have been the case in a prospective, head-to-head comparison, because the researchers could not be sure that they had fully adjusted for the differences in the populations and the designs of the studies.
“In TNF-inhibitor–naive patients, I could use vedolizumab or ozanimod,” Dr. Dubinsky said. But these are not the only options, she said. She said that “in TNF failure, I would use ustekinumab or even tofacitinib.” Ustekinumab (Stelara) is a human interleukin-12 and -23 antagonist; tofacitinib (Xeljanz) is a Janus kinase inhibitor.
The study’s limitations are significant, said session moderator Jonathan Leighton, MD, a professor of medicine at the Mayo Clinic in Phoenix, Arizona, “but it certainly shows that ozanimod had a positive profile compared to adalimumab and has overall comparable benefits with vedolizumab,” he said in an interview.
Dr. Leighton added that someday researchers may find biomarkers that will identify the best drug for each patient. In the meantime, clinicians are often left choosing therapies on the basis of such factors as which route of administration the patients prefer, he said. Vedolizumab is given by intravenous infusion, ozanimod is taken orally, and adalimumab is given by subcutaneous injection.
The study was funded by Bristol-Myers Squibb. Dr. Leighton has financial relationships with Olympus and Pfizer. Dr. Dubinsky has relationships with all or most of the companies that make drugs for inflammatory bowel disease.
A version of this article first appeared on Medscape.com.
Advanced CKD doesn’t derail empagliflozin in EMPEROR-preserved
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
More than half of the nearly 6,000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73 m2, which categorized them as having stage 4 CKD.
The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure “across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m2,” said Faiez Zannad, MD, PhD, who presented the findings at the annual meeting of the American Society of Nephrology.
Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR <60 mL/min/1/73 m2 or a urinary albumin to creatinine ratio >300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.
Empagliflozin was also “well tolerated” by patients with HFpEF, whether or not they also had CKD, “including patients with severely impaired kidney function,” said Dr. Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France, at the virtual meeting.
An end to ‘renalism’
“This is a nail in the coffin for the concept of ‘renalism,’” the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University, Washington, D.C.
In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the “groundbreaking step” of enrolling patients with moderate-severe CKD, noted Dr. Rangaswami in an interview. In particular, two trials took this approach when enrolling patients with heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).
“It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m2,” Dr. Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m2.
EMPEROR-Reduced and DAPA-HF – published earlier this year – both had similar findings as EMPEROR-Preserved as reported by Dr. Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.
In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure; hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.
These observations “make it easier to focus on the group with moderate-to-severe CKD,” both in the routine care setting as well as in future trials, said Dr. Rangaswami.
“This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients ... excluded from trials in the past,” she said.
In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD “means there is simply no room for renalism. There is no room for clinicians to say that because a patient’s eGFR is 30 mL/min/1.73m2 they are worried about starting an SGLT2 inhibitor,” she stressed.
More CKD-independent effects of empagliflozin
Results of other new analyses from EMPEROR-Preserved, also reported by Dr. Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.
In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73 m2/year, and in those without CKD, by 1.3 mL/min/1.73 m2/year, relative to placebo.
“Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin,” Dr. Zannad said.
At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73 m2 relative to placebo.
Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.
EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction >40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial’s primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.
EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.
EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Dr. Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Dr. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM KIDNEY WEEK 2021
Low-dose rituximab may keep RA disease activity low in responders
Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.
“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.
The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.
The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.
“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.”
After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.
“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”
The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.
“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”
Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.
Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.
Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.
Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.
Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.
“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.
The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.
The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.
“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.”
After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.
“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”
The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.
“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”
Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.
Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.
Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.
Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.
Rituximab doses as low as 200 mg reduced disease activity in patients with rheumatoid arthritis to an extent that’s similar to the standard 1,000-mg dose during more than 3 years of follow-up, according to results from an extension study of a clinical trial in the Netherlands.
“We could not formally statistically show that the lower doses were less effective than the higher dose,” study leader Nathan den Broeder, MSc, a PhD candidate at St. Maarten Clinic and the Radboud Institute for Health Sciences in Nijmegen, the Netherlands, said in a presentation at the virtual annual meeting of the American College of Rheumatology. “We concluded at this time that only 6% of patients needed to switch to another biologic or targeted disease-modifying antirheumatic drug and that mean disease activity remained very low,” he said of the patients treated with 200- and 500-mg doses of rituximab.
The extension study included 118 of 142 patients in the REDO trial, following them from the start of the trial in 2017-2018 through April 2021. They were randomized to three treatment arms: the standard 1,000-mg dose (24 patients), a 500-mg dose (n = 48), and the 200-mg dose (n = 46). The mean follow-up was 3.2 years.
The study evaluated disease activity by mean Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP), which during follow-up were 2.2-2.3 in the groups. Seven patients in the study cohort switched to a different DMARD, he said.
“On average, we saw a DAS28-CRP 0.15 points lower per 1,000 mg rituximab used in the past year,” Mr. den Broeder said in an interview. “For context, this is compared to a measurement error of about 0.6. A good response to a drug would be a reduction in DAS28-CRP of 1.2. This means we can just about get an effect that is bigger than the measurement error if we compare the highest dose in our study to the lowest one.”
After a year, the median yearly rituximab dose was 978 mg, with an interquartile range of 704-1,425 mg. At the end of the study, 31% of patients took 200 mg every 6 months, 40% took 500 mg every 6.2 months, and 29% took 1,000 mg every 6.4 months.
“It’s important to note, though, this is in a situation where patients are given a dose based on disease activity,” Mr. den Broeder said. “That is, we try one dose; if the patient does well, we try a lower one; if not, we might go back up to a higher dose. We could expect somewhat larger differences if all patients were to be switched to a lower dose, regardless of whether that works well for them.”
The results were achieved without a high reliance on glucocorticoids (GCs), he said. Use of comedication in the extension study population was 0.38 GC injections per patient-year and starting or increasing an oral GC occurred at a rate of only 0.05 per patient-year.
“As a result of this study, we are now implementing a strategy of rituximab dose reduction in clinical practice at our center,” Mr. den Broeder said. Patients with RA start on a 1,000-mg dose for 6 months, and if they respond well they’re put on a 500-mg dose. If they respond well after 6 months on the 500-mg dose, they’re then moved to the 200-mg dose. “With this, we hope to gain that patients have fewer side effects,” he said. “We hope to reduce the cost of treatment, and also, what we instantly gain is that the infusion time for patients is also reduced.”
Future research considerations include evaluating the 200-mg dose as a subcutaneous injection. “Another thing you might think of as well: Are even lower doses possible?” he said.
Session moderator Maya Buch, MD, professor of rheumatology and director of Experimental Medicine at the Centre for Musculoskeletal Research at the University of Manchester (England), asked if the investigators used CD19 testing to measure B-cell levels or immunoglobulin G levels to determine dose escalation.
Mr. den Broeder said that CD19 wasn’t used in clinical practice but was used in the original trial. However, it wasn’t found to have any predictive ability, while immunoglobulin G levels were measured in patients who had multiple infections. “Sporadically, a lower dose might have been initiated because of that, but not systematically,” he said.
Mr. den Broeder had no relevant relationships to disclose. Dr. Buch reported financial relationships with AbbVie, Eli Lilly, Gilead Sciences, Merck-Serono, Pfizer, Roche, Sanofi, and UCB.
FROM ACR 2021
Distance learning may cause convergence insufficiency
NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.
Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.
“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.
Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.
Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.
“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.
Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.
They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.
The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.
The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.
Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.
The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.
This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.
Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.
The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.
Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.
Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.
“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”
Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.
“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”
Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.
Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.
“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.
Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.
Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.
“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.
Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.
They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.
The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.
The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.
Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.
The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.
This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.
Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.
The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.
Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.
Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.
“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”
Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.
“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”
Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – The increased use of digital screens for school during the COVID-19 pandemic may be causing convergence insufficiency in children, researchers say.
Although the long-term implications for current schoolchildren are not clear, convergence insufficiency sometimes persists for a lifetime, said Kammi Gunton, MD, interim chief of pediatric ophthalmology and strabismus at Wills Eye Hospital, Philadelphia.
“It’s important, if we use digital technology for education, that we are aware that it might contribute to increased eye symptoms in children,” Dr. Gunton told this news organization.
Dr. Gunton’s colleague, Jordan Hamburger, an MD candidate at Sidney Kimmel Medical College, Philadelphia, presented the finding at the American Academy of Ophthalmology 2021 Annual Meeting.
Convergence insufficiency is an impairment of binocularity. Symptoms include headaches while reading, words that seem to move around the page, blurriness, diplopia, and eye fatigue. It can be treated with exercise, prism glasses, or, rarely, surgery.
“We have some kids who improve with either time or maturity, then we have other patients who suffer from it for their entire lives,” Dr. Gunton said.
Previous research has linked the use of digital screens to convergence insufficiency, so when many schools shifted to distance learning for the pandemic, Dr. Gunton and her colleagues wanted to see whether it would have this effect on the students’ eyes.
They surveyed 110 healthy schoolchildren and adolescent students regarding eye symptoms before and after a day of virtual school. The mean age of the participants was 14 years (range, 10-17 years). The participants spent an average of 6.96 hours per day in virtual school. Forty-one percent also attended school in person part time. These students filled out the survey on days when they were in virtual school.
The participants answered questions on the Convergence Insufficiency Symptom Survey (CISS). The survey consists of 15 questions about eye complaints. On each question, the students rated symptoms from 0 to 4, with 4 indicating a severe symptom.
The average sum of the CISS scores rose from 5.17 before school to 9.82 after school, a statistically significant change (P < .001). Sixty-one percent of the participants reported an increase in convergence insufficiency symptoms.
Seventeen percent scored a total of at least 16, which is the threshold score considered suggestive of convergence insufficiency.
The researchers also found that, on average, the more hours each student spent in virtual school, the higher their CISS scores.
This makes sense, because reading requires convergence, Dr. Gunton said. The same problem might occur in traditional school if the students were looking at books all day instead of focusing on objects at various distances in their classrooms, such as the teacher or the whiteboard. “So, in the past, if you read a book, maybe you wouldn’t read for several hours, but now we’re asking children during virtual learning to stay on a device with the camera on,” she said.
Previous research has shown that people blink less when reading or using electronic devices, probably because of their increased concentration. This might explain symptoms such as burning and itching. Fifty-three percent of the students reported an increase in asthenopia symptoms.
The researchers would have liked to have compared the students in virtual school to a matched group of students in traditional school. However, almost all students were enrolled in virtual school when the study was conducted, making such a control difficult.
Although previous research has related virtual learning to myopia, as reported by this news organization, this study did not investigate myopia, and the researchers do not believe that convergence insufficiency causes myopia or vice versa.
Parents can help prevent convergence insufficiency during school by reminding their children to take breaks, Dr. Gunton said. She recommends the 20/20/20 rule: After 20 minutes of work that involves looking at objects nearby, students should take a 20-second break and look at something 20 feet away.
“I also think the take-home message is for parents to ask students if they’re having symptoms,” she said, “and if they hear complaints while kids are on the computers, to have them see an eye doctor and have an evaluation.”
Stephen Lipsky, MD, who wasn’t involved in the study, said he is seeing more cases of eye strain at Children’s Healthcare of Atlanta, where he is a consulting ophthalmologist.
“The study is very valuable in that it shines a light on the fact that these children do have symptoms, such as asthenopia or convergence insufficiency,” he told this news organization. “But I’m optimistic that with a return to more traditional learning, we will return the more traditional incidence of these problems.”
Dr. Gunton and Dr. Lipsky have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM AAO 2021
Empagliflozin a winner in challenging arena of stabilized acute HF
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
The sodium-glucose transporter 2 inhibitors, relative newcomers among first-line agents for chronic heart failure (HF), could well attain the same go-to status in patients hospitalized with acute HF if the EMPULSE trial has anything to say about it.
Of the study’s 530 such patients, those started on daily empagliflozin (Jardiance) soon after they were stabilized, compared with a control group, were less likely to die or be rehospitalized for HF over the next 3 months.
Also, “we saw an improvement in quality of life, we saw a greater reduction in body weight, and we didn’t see any safety concerns in this very vulnerable and sick patient population,” Adriaan A. Voors, MD, University Medical Center Groningen (the Netherlands), said when presenting the trial at the American Heart Association scientific sessions.
Patients assigned to empagliflozin had a 36% greater likelihood of showing a benefit as reflected in the treatment’s win ratio when opposed by placebo, an emerging way to express outcomes in cardiovascular clinical trials. The SGLT2 inhibitor’s win ratio for the primary endpoint was 1.36 (95% confidence interval, 1.09-1.68, P = .0054), Dr. Voors reported. The outcome consisted of death, number of HF events, time to first HF event, and 90-day change in quality of life scores.
There is reluctance in practice to start patients that early after decompensation on drugs used in chronic HF, Dr. Voors said in an interview. Empagliflozin in the trial was initiated in the stabilized setting an average of 3 days after hospital admission, he said. The trial should reassure physicians that the drug “is not only safe to start early in hospital, but it’s also beneficial to start early in hospital.”
EMPULSE, combined with support from other recent trials, “should be clinical practice changing, with early in-hospital initiation of SGLT2 inhibitors in patients hospitalized with HF being the expectation, along with clear recognition that delaying SGLT2 inhibitor initiation may expose patients to unnecessary harms and delays in improved health status,” Gregg C. Fonarow, MD, University of California Los Angeles Medical Center, told this news organization.
“For patients with HF, irrespective of ejection fraction, early in-hospital initiation of SGLT2 inhibitors – once stabilized and in the absence of contraindications – should be considered a new standard of care,” said Fonarow, who was not part of EMPULSE.
The trial also lends new weight to the strategy of “simultaneous or rapid-sequence initiation” of the so-called four pillars of guideline-directed medical therapy of HF with reduced ejection fraction in patients hospitalized with HFrEF, once they are stabilized, Dr. Fonarow said. The four-pronged approach, he noted, consists of sacubitril/valsartan (Entresto), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor.
Indeed, the new findings “fill an important gap and are clearly practice changing,” agreed Nancy K. Sweitzer, MD, PhD, University of Arizona Sarver Heart Center, Tucson, as an invited discussant following Dr. Voors’ presentation. “Few therapies have been shown to impact the course of those hospitalized with acute decompensated heart failure.”
Of note in the trial, Dr. Sweitzer continued, patients were started on empagliflozin regardless of any drug therapy they might already be on for chronic HF. “Because patients in the EMPULSE trial could be enrolled with a new diagnosis of heart failure, they were, by definition, not all on chronic guideline-directed heart failure therapy. Nevertheless, such patients benefited equally from the study intervention,” she said.
“This is crucial, as it tells us these drugs have immediate and important effects and should not be withheld while other drug classes are initiated and optimized.”
EMPULSE entered patients hospitalized for acute HF, which could be de novo or a decompensation of chronic HF, without regard to ejection fraction or whether they had diabetes, and who were clinically stable after at least one dose of loop diuretics. Their ejection fractions averaged 35% and exceeded 40% in about one-third of the total cohort.
At 90 days in the win ratio analysis, the 265 patients assigned to empagliflozin 10 mg once daily were the “winners”; that is, they were more likely to show a clinical benefit about 54% of the time in paired match-ups of patient outcomes, compared with about 40% for the 265 in the control group. The match-ups were a tie 6.4% of the time.
The empagliflozin group also benefited significantly for the endpoint of death from any cause or first HF event, with a hazard ratio of 0.65 (95% CI, 0.43-0.99; P = .042). They also were less likely to experience acute renal failure (7.7% vs. 12.1% for the control group) or serious adverse events (32.3% vs. 43.6%), Dr. Voors reported.
Tempting as it might be, the findings can’t necessarily be generalized to other SGLT2 inhibitors without an evidence base. But as Dr. Voors observed, several ongoing trials are exploring dapagliflozin (Farxiga) in a similar clinical setting.
They include DICTATE-AHF in patients with diabetes admitted with acute HF, and DAPA ACT HF-TIMI 68, which is entering patients stabilized during hospitalization with acute decompensated HFrEF. The trials are scheduled for completion in 2022 and 2023, respectively.
EMPULSE was supported by the Boehringer Ingelheim–Eli Lilly Diabetes Alliance. Dr. Voors disclosed research support and consulting for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr. Sweitzer disclosed honoraria from Acorda and Myokardia, and reported receiving research support from Novartis and Merck. Dr. Fonarow cited honoraria from Abbott, Amgen, Janssen, Medtronic, Bayer, Merck, AstraZeneca, Cytokinetics, and Novartis.
A version of this article first appeared on Medscape.com.
FROM AHA 2021
Endoscopic resection of esophageal cancer requires long-term post-op surveillance
LAS VEGAS – Although endoscopic resection of T1 esophageal adenocarcinoma (EAC) is associated with excellent overall survival, recurrence can occur years later, emphasizing the need for long-term surveillance, according to investigators.
Recurrence was about twice as common among patients lacking complete remission of intestinal metaplasia (CRIM) upon follow-up, reported lead author Kevin Song, MD, of the Mayo Clinic, Scottsdale, Ariz., and colleagues.
“Endoscopic resection of early-stage EAC has gained acceptance in recent years,” Dr. Song said during his presentation at the annual meeting of the American College of Gastroenterology. “While studies have demonstrated promising outcomes for short-term remission and recurrence, little is known about long-term recurrence and EAC-related mortality beyond 5 years.”
To address this knowledge gap, Dr. Song and colleagues reviewed data from 98 patients who had undergone endoscopic resection of T1 EAC at four tertiary academic centers with follow-up of at least 5 years. CRIM was defined by negative biopsies from the tubular esophagus and the gastroesophageal junction at one posttreatment surveillance endoscopy. Early recurrence was defined by a 2-year limit.
After a median follow-up of 8.76 years, 93 out of 98 patients (95%) experienced remission, while 82 patients (84%) demonstrated CRIM. Fourteen patients (14%) had recurrence of EAC, among whom eight (57%) had early recurrence at a median of 0.75 years (interquartile range, 0.43-0.80 years), while the other six (43%) had late recurrence at a median of 7.7 years (IQR, 5.20-8.77 years). Among the 93 patients entering remission, five (5.38%) had recurrence after 5 years.
CRIM was associated with a significantly lower rate of recurrence (11% vs. 46%; P = .01), generating an odds ratio of 6.55 (95% confidence interval, 1.71-26.71). Patients with CRIM also had later recurrence, at a median of 5.20 years, compared with 0.81 years for patients without CRIM. Moreover, the overall EAC-related mortality rate was 6.45%.
Dr. Song noted excellent overall survival and concluded his presentation by emphasizing the predictive value of CRIM and the need for long-term surveillance.
“CRIM should be considered the most significant endpoint for endotherapy of T1 EAC,” he said. “Surveillance is important even when early recurrence is not observed.”
Rishindra M. Reddy, MD, professor of thoracic surgery at the University of Michigan Health, Ann Arbor, agreed “100%” with Dr. Song and colleagues’ conclusion about the need for long-term surveillance.
“We struggle, in our patient population, to get people to do regular surveillance,” he said. “I think you have to have patients who have regular access to their gastroenterologist or surgeons and are willing to come in every 3 months to 6 months for surveillance endoscopies as well as CT scans.”
Dr. Reddy recommended that endoscopic resection of EAC be handled at high-volume centers.
“This really needs to be done in a multidisciplinary setting where you have both experienced endoscopists and thoracic surgeons and/or surgical oncologists who do esophagectomies to make these decisions about optimal treatment,” he said, “as well as pathologists who are more experienced in what to look for in terms of depth or lateral margins.”
The present work is a “great first study,” Dr. Reddy said. He suggested that larger real-world trials are needed to confirm findings and compare outcomes between tumor subtypes.
“I think for T1a tumors, there’s a good consensus on endoscopic mucosal resection,” he said. “I think T1b is an area where we would suggest more often doing surgery… and there’s even some nuance at a T1a level about the depth. It would be helpful to understand the risks of recurrence after [resecting] different levels of T1 tumors.”
The investigators disclosed relationships with CDX, Interpace, Lucid, and others. Dr. Reddy disclosed no relevant conflicts of interest.
LAS VEGAS – Although endoscopic resection of T1 esophageal adenocarcinoma (EAC) is associated with excellent overall survival, recurrence can occur years later, emphasizing the need for long-term surveillance, according to investigators.
Recurrence was about twice as common among patients lacking complete remission of intestinal metaplasia (CRIM) upon follow-up, reported lead author Kevin Song, MD, of the Mayo Clinic, Scottsdale, Ariz., and colleagues.
“Endoscopic resection of early-stage EAC has gained acceptance in recent years,” Dr. Song said during his presentation at the annual meeting of the American College of Gastroenterology. “While studies have demonstrated promising outcomes for short-term remission and recurrence, little is known about long-term recurrence and EAC-related mortality beyond 5 years.”
To address this knowledge gap, Dr. Song and colleagues reviewed data from 98 patients who had undergone endoscopic resection of T1 EAC at four tertiary academic centers with follow-up of at least 5 years. CRIM was defined by negative biopsies from the tubular esophagus and the gastroesophageal junction at one posttreatment surveillance endoscopy. Early recurrence was defined by a 2-year limit.
After a median follow-up of 8.76 years, 93 out of 98 patients (95%) experienced remission, while 82 patients (84%) demonstrated CRIM. Fourteen patients (14%) had recurrence of EAC, among whom eight (57%) had early recurrence at a median of 0.75 years (interquartile range, 0.43-0.80 years), while the other six (43%) had late recurrence at a median of 7.7 years (IQR, 5.20-8.77 years). Among the 93 patients entering remission, five (5.38%) had recurrence after 5 years.
CRIM was associated with a significantly lower rate of recurrence (11% vs. 46%; P = .01), generating an odds ratio of 6.55 (95% confidence interval, 1.71-26.71). Patients with CRIM also had later recurrence, at a median of 5.20 years, compared with 0.81 years for patients without CRIM. Moreover, the overall EAC-related mortality rate was 6.45%.
Dr. Song noted excellent overall survival and concluded his presentation by emphasizing the predictive value of CRIM and the need for long-term surveillance.
“CRIM should be considered the most significant endpoint for endotherapy of T1 EAC,” he said. “Surveillance is important even when early recurrence is not observed.”
Rishindra M. Reddy, MD, professor of thoracic surgery at the University of Michigan Health, Ann Arbor, agreed “100%” with Dr. Song and colleagues’ conclusion about the need for long-term surveillance.
“We struggle, in our patient population, to get people to do regular surveillance,” he said. “I think you have to have patients who have regular access to their gastroenterologist or surgeons and are willing to come in every 3 months to 6 months for surveillance endoscopies as well as CT scans.”
Dr. Reddy recommended that endoscopic resection of EAC be handled at high-volume centers.
“This really needs to be done in a multidisciplinary setting where you have both experienced endoscopists and thoracic surgeons and/or surgical oncologists who do esophagectomies to make these decisions about optimal treatment,” he said, “as well as pathologists who are more experienced in what to look for in terms of depth or lateral margins.”
The present work is a “great first study,” Dr. Reddy said. He suggested that larger real-world trials are needed to confirm findings and compare outcomes between tumor subtypes.
“I think for T1a tumors, there’s a good consensus on endoscopic mucosal resection,” he said. “I think T1b is an area where we would suggest more often doing surgery… and there’s even some nuance at a T1a level about the depth. It would be helpful to understand the risks of recurrence after [resecting] different levels of T1 tumors.”
The investigators disclosed relationships with CDX, Interpace, Lucid, and others. Dr. Reddy disclosed no relevant conflicts of interest.
LAS VEGAS – Although endoscopic resection of T1 esophageal adenocarcinoma (EAC) is associated with excellent overall survival, recurrence can occur years later, emphasizing the need for long-term surveillance, according to investigators.
Recurrence was about twice as common among patients lacking complete remission of intestinal metaplasia (CRIM) upon follow-up, reported lead author Kevin Song, MD, of the Mayo Clinic, Scottsdale, Ariz., and colleagues.
“Endoscopic resection of early-stage EAC has gained acceptance in recent years,” Dr. Song said during his presentation at the annual meeting of the American College of Gastroenterology. “While studies have demonstrated promising outcomes for short-term remission and recurrence, little is known about long-term recurrence and EAC-related mortality beyond 5 years.”
To address this knowledge gap, Dr. Song and colleagues reviewed data from 98 patients who had undergone endoscopic resection of T1 EAC at four tertiary academic centers with follow-up of at least 5 years. CRIM was defined by negative biopsies from the tubular esophagus and the gastroesophageal junction at one posttreatment surveillance endoscopy. Early recurrence was defined by a 2-year limit.
After a median follow-up of 8.76 years, 93 out of 98 patients (95%) experienced remission, while 82 patients (84%) demonstrated CRIM. Fourteen patients (14%) had recurrence of EAC, among whom eight (57%) had early recurrence at a median of 0.75 years (interquartile range, 0.43-0.80 years), while the other six (43%) had late recurrence at a median of 7.7 years (IQR, 5.20-8.77 years). Among the 93 patients entering remission, five (5.38%) had recurrence after 5 years.
CRIM was associated with a significantly lower rate of recurrence (11% vs. 46%; P = .01), generating an odds ratio of 6.55 (95% confidence interval, 1.71-26.71). Patients with CRIM also had later recurrence, at a median of 5.20 years, compared with 0.81 years for patients without CRIM. Moreover, the overall EAC-related mortality rate was 6.45%.
Dr. Song noted excellent overall survival and concluded his presentation by emphasizing the predictive value of CRIM and the need for long-term surveillance.
“CRIM should be considered the most significant endpoint for endotherapy of T1 EAC,” he said. “Surveillance is important even when early recurrence is not observed.”
Rishindra M. Reddy, MD, professor of thoracic surgery at the University of Michigan Health, Ann Arbor, agreed “100%” with Dr. Song and colleagues’ conclusion about the need for long-term surveillance.
“We struggle, in our patient population, to get people to do regular surveillance,” he said. “I think you have to have patients who have regular access to their gastroenterologist or surgeons and are willing to come in every 3 months to 6 months for surveillance endoscopies as well as CT scans.”
Dr. Reddy recommended that endoscopic resection of EAC be handled at high-volume centers.
“This really needs to be done in a multidisciplinary setting where you have both experienced endoscopists and thoracic surgeons and/or surgical oncologists who do esophagectomies to make these decisions about optimal treatment,” he said, “as well as pathologists who are more experienced in what to look for in terms of depth or lateral margins.”
The present work is a “great first study,” Dr. Reddy said. He suggested that larger real-world trials are needed to confirm findings and compare outcomes between tumor subtypes.
“I think for T1a tumors, there’s a good consensus on endoscopic mucosal resection,” he said. “I think T1b is an area where we would suggest more often doing surgery… and there’s even some nuance at a T1a level about the depth. It would be helpful to understand the risks of recurrence after [resecting] different levels of T1 tumors.”
The investigators disclosed relationships with CDX, Interpace, Lucid, and others. Dr. Reddy disclosed no relevant conflicts of interest.
FROM ACG 2021