Clinical question: Is the observed drop in COVID-19 mortality caused by changing demographics or improvements in patient care?

Dr. Halpern is a med-peds hospitalist at Brigham and Women’s Hospital in Boston.

Clinical question: Is the observed drop in COVID-19 mortality caused by changing demographics or improvements in patient care?

Dr. Halpern is a med-peds hospitalist at Brigham and Women’s Hospital in Boston.

Clinical question: Is the observed drop in COVID-19 mortality caused by changing demographics or improvements in patient care?

Dr. Halpern is a med-peds hospitalist at Brigham and Women’s Hospital in Boston.

A gene expression signature may help physicians diagnose endometriosis by analyzing samples from endometrial biopsies instead of relying on more invasive methods, research suggests.

Yana B. Aznaurova, MD, and colleagues identified and validated a genetic biomarker based on differences in the endometrium of women with and without endometriosis. The biomarker is based on five genes that were down-regulated in patients with the disease.

Endometriosis is an enigmatic gynecologic disease that is associated with chronic pelvic pain, dyspareunia, and dysmenorrhea, said Dr. Aznaurova, of the department of reproductive medicine and surgery at A.I. Evdokimov Moscow State Medical and Dental University. Laparoscopy with histological confirmation is the standard method of diagnosis.

“Development of minimally invasive or even noninvasive diagnostic tests is a research priority in endometriosis,” she said at the meeting sponsored by the American Association of Gynecologic Laparoscopists, held virtually this year.

Attempts to identify biomarkers have tended to focus on single genes or proteins, but “endometriosis is a ... multifactorial disease,” said Dr. Aznaurova. Researchers have found that signaling pathway activation profiles are a more stable and reliable marker of some diseases.

To validate a complex gene expression biomarker for the diagnosis of endometriosis, the researchers conducted an observational cohort study that included 50 women with endometriosis and 35 controls. The patients with endometriosis were 18-49 years old, had not received hormone therapy in the past year, and did not have other gynecologic diseases. Patients in the control group had uterine scar incompetence after cesarean section, but did not have endometriosis or other gynecologic disease.

Investigators performed RNA sequencing of endometrial samples, including 50 eutopic and 50 ectopic samples from patients with endometriosis, and 35 samples from patients in the control group.

They analyzed gene expression and intracellular pathway activation profiles to identify an endometrial gene expression signature that differentiated samples from patients with and without the disease, with an area under the receiver operating characteristic curve of approximately 0.99.

The researchers further studied the biomarker using preexisting datasets with 120 other tissue samples, including from the cervix, ovarian surface epithelium, stomach, and lung. The biomarker had a sensitivity of 94% and specificity of 97% for endometriosis in these analyses.

The results suggest that the genetic biomarker “could be potentially used as a basis for early diagnosis of endometriosis via utilization of endometrial biopsy only,” Dr. Aznaurova said.

Further studies are needed to validate these findings, she noted.

“If we had a noninvasive way to look for endometriosis, this would be very powerful – very important as potentially a diagnostic test, or a triage test, or a monitoring test of treatment,” Patrick P. Yeung Jr., MD, said in a discussion following Dr. Aznaurova’s presentation.

The test might even suggest a target for treatment, said Dr. Yeung, professor of obstetrics, gynecology, and women’s health at Saint Louis University.

Dr. Aznaurova and Dr. Yeung had no relevant financial disclosures.
 

[email protected]

SOURCE: Aznaurova YB et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.040.

A gene expression signature may help physicians diagnose endometriosis by analyzing samples from endometrial biopsies instead of relying on more invasive methods, research suggests.

Yana B. Aznaurova, MD, and colleagues identified and validated a genetic biomarker based on differences in the endometrium of women with and without endometriosis. The biomarker is based on five genes that were down-regulated in patients with the disease.

Endometriosis is an enigmatic gynecologic disease that is associated with chronic pelvic pain, dyspareunia, and dysmenorrhea, said Dr. Aznaurova, of the department of reproductive medicine and surgery at A.I. Evdokimov Moscow State Medical and Dental University. Laparoscopy with histological confirmation is the standard method of diagnosis.

“Development of minimally invasive or even noninvasive diagnostic tests is a research priority in endometriosis,” she said at the meeting sponsored by the American Association of Gynecologic Laparoscopists, held virtually this year.

Attempts to identify biomarkers have tended to focus on single genes or proteins, but “endometriosis is a ... multifactorial disease,” said Dr. Aznaurova. Researchers have found that signaling pathway activation profiles are a more stable and reliable marker of some diseases.

To validate a complex gene expression biomarker for the diagnosis of endometriosis, the researchers conducted an observational cohort study that included 50 women with endometriosis and 35 controls. The patients with endometriosis were 18-49 years old, had not received hormone therapy in the past year, and did not have other gynecologic diseases. Patients in the control group had uterine scar incompetence after cesarean section, but did not have endometriosis or other gynecologic disease.

Investigators performed RNA sequencing of endometrial samples, including 50 eutopic and 50 ectopic samples from patients with endometriosis, and 35 samples from patients in the control group.

They analyzed gene expression and intracellular pathway activation profiles to identify an endometrial gene expression signature that differentiated samples from patients with and without the disease, with an area under the receiver operating characteristic curve of approximately 0.99.

The researchers further studied the biomarker using preexisting datasets with 120 other tissue samples, including from the cervix, ovarian surface epithelium, stomach, and lung. The biomarker had a sensitivity of 94% and specificity of 97% for endometriosis in these analyses.

The results suggest that the genetic biomarker “could be potentially used as a basis for early diagnosis of endometriosis via utilization of endometrial biopsy only,” Dr. Aznaurova said.

Further studies are needed to validate these findings, she noted.

“If we had a noninvasive way to look for endometriosis, this would be very powerful – very important as potentially a diagnostic test, or a triage test, or a monitoring test of treatment,” Patrick P. Yeung Jr., MD, said in a discussion following Dr. Aznaurova’s presentation.

The test might even suggest a target for treatment, said Dr. Yeung, professor of obstetrics, gynecology, and women’s health at Saint Louis University.

Dr. Aznaurova and Dr. Yeung had no relevant financial disclosures.
 

[email protected]

SOURCE: Aznaurova YB et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.040.

A gene expression signature may help physicians diagnose endometriosis by analyzing samples from endometrial biopsies instead of relying on more invasive methods, research suggests.

Yana B. Aznaurova, MD, and colleagues identified and validated a genetic biomarker based on differences in the endometrium of women with and without endometriosis. The biomarker is based on five genes that were down-regulated in patients with the disease.

Endometriosis is an enigmatic gynecologic disease that is associated with chronic pelvic pain, dyspareunia, and dysmenorrhea, said Dr. Aznaurova, of the department of reproductive medicine and surgery at A.I. Evdokimov Moscow State Medical and Dental University. Laparoscopy with histological confirmation is the standard method of diagnosis.

“Development of minimally invasive or even noninvasive diagnostic tests is a research priority in endometriosis,” she said at the meeting sponsored by the American Association of Gynecologic Laparoscopists, held virtually this year.

Attempts to identify biomarkers have tended to focus on single genes or proteins, but “endometriosis is a ... multifactorial disease,” said Dr. Aznaurova. Researchers have found that signaling pathway activation profiles are a more stable and reliable marker of some diseases.

To validate a complex gene expression biomarker for the diagnosis of endometriosis, the researchers conducted an observational cohort study that included 50 women with endometriosis and 35 controls. The patients with endometriosis were 18-49 years old, had not received hormone therapy in the past year, and did not have other gynecologic diseases. Patients in the control group had uterine scar incompetence after cesarean section, but did not have endometriosis or other gynecologic disease.

Investigators performed RNA sequencing of endometrial samples, including 50 eutopic and 50 ectopic samples from patients with endometriosis, and 35 samples from patients in the control group.

They analyzed gene expression and intracellular pathway activation profiles to identify an endometrial gene expression signature that differentiated samples from patients with and without the disease, with an area under the receiver operating characteristic curve of approximately 0.99.

The researchers further studied the biomarker using preexisting datasets with 120 other tissue samples, including from the cervix, ovarian surface epithelium, stomach, and lung. The biomarker had a sensitivity of 94% and specificity of 97% for endometriosis in these analyses.

The results suggest that the genetic biomarker “could be potentially used as a basis for early diagnosis of endometriosis via utilization of endometrial biopsy only,” Dr. Aznaurova said.

Further studies are needed to validate these findings, she noted.

“If we had a noninvasive way to look for endometriosis, this would be very powerful – very important as potentially a diagnostic test, or a triage test, or a monitoring test of treatment,” Patrick P. Yeung Jr., MD, said in a discussion following Dr. Aznaurova’s presentation.

The test might even suggest a target for treatment, said Dr. Yeung, professor of obstetrics, gynecology, and women’s health at Saint Louis University.

Dr. Aznaurova and Dr. Yeung had no relevant financial disclosures.
 

[email protected]

SOURCE: Aznaurova YB et al. J Minim Invasive Gynecol. 2020 Nov. doi: 10.1016/j.jmig.2020.08.040.

It should not be surprising that the RA drug baricitinib (Olumiant), a Janus kinase (JAK) 1/2 inhibitor, might be beneficial in controlling the cytokine storm of hyperinflammation that can follow severe SARS-CoV-2 infections and lead to lung damage and acute respiratory distress syndrome – the leading cause of death from the virus.

But to demonstrate within a matter of months, at least preliminarily, that baricitinib reduces mortality and morbidity in hospitalized patients with COVID-19 pneumonia required a widely cross-disciplinary international team of researchers from 10 countries working at breakneck speed, said Justin Stebbing, PhD, the principal investigator of a new baricitinib study published Nov. 13 in Science Advances. “We went from modeling and mechanistic investigations to clinical tests in a number of settings and laboratory analysis in record time.”

The international team of 50 researchers included medical specialists in rheumatology, virology, geriatrics, oncology, and general medicine, along with experts in molecular and cellular biology, bioinformatics, statistics and trial design, computer modeling, pathology, genetics, and super-resolution microscopy, Dr. Stebbing, professor of cancer medicine and medical oncology at Imperial College, London, said in an interview.

Artificial intelligence, provided by the London-based firm BenevolentAI, was used to sift through a huge repository of structured medical information to identify drugs that might block the SARS-CoV-2 infection process. It predicted that baricitinib would be a promising candidate to inhibit inflammation and reduce viral load in COVID-19. Previous reports by Dr. Stebbing and colleagues (here and here) describe this AI-mediated testing, which was validated by the new study.

The researchers also used three-dimensional miniature human liver organoids in vitro and super-resolution microscopy to perform further lab investigations, which showed that baricitinib reversed expression of the SARS-CoV-2 receptor ACE2 triggered by type I interferons. Baricitinib inhibited the significant increase in ACE2 expression caused by interferon alpha-2, and thus cytokine-mediated inflammation, and also reduced infectivity, Dr. Stebbing said. “Our study of baricitinib shows that it has both antiviral and anticytokine effects and appears to be safe.”
 

71% mortality reduction

The team found a 71% reduction in mortality for a group of 83 hospitalized patients with COVID-19 pneumonia in Italy and Spain – early epicenters of the pandemic – who received baricitinib along with standard care, compared with propensity-matched groups that received only standard care. At that time, between mid-March and mid-April, standard COVID-19 care included antibiotics, glucocorticoids, hydroxychloroquine, low-molecular-weight heparin, and the antiretroviral combination lopinavir/ritonavir.

In the Spanish and Italian cohorts, baricitinib was generally well tolerated, although not without side effects, including bacterial infections and increases in liver enzyme levels, which may not have been related to baricitinib. Patients showed reductions in inflammation within days of starting treatment. “We did not observe thrombotic or vascular events in our cohorts, but most of the patients were receiving low molecular weight heparin,” he said.

The fact that baricitinib is approved by the Food and Drug Administration, is already well studied for safety, can be taken conveniently as a once-daily oral tablet, and is less expensive than many other antiviral treatments all make it an good target for further study, including randomized, controlled trials that are already underway, Dr. Stebbing noted. His study cohort also included elderly patients (median age, 81 years) who are the most likely to experience severe disease or death from COVID-19.

The National Library of Medicine’s clinicaltrials.gov registry of federally funded clinical studies lists 15 current research initiatives involving baricitinib and COVID-19. Dr. Stebbing suggested that data generated so far are helping to guide ongoing studies on dose and duration of treatment – in other words, who it works for, when to give it, and at what dose it should be taken and for how long.

Manufacturer Eli Lilly, which markets baricitinib in 2-mg or 4-mg tablets, announced in October that initial data are starting to emerge from 1,000-plus patients enrolled in ACTT-2 (the Adaptive COVID-19 Treatment Trial 2). ACTT-2 compared patients on the broad-spectrum intravenous antiviral drug remdesivir (Veklury) with those receiving remdesivir in combination with baricitinib. Based on ACTT-2 results that suggested a reduced time to recovery and improved clinical outcomes for the combination group, the FDA issued an emergency-use authorization on Nov. 19 for the combination of baricitinib and remdesivir for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized adults and pediatric patients aged 2 years or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.

Interrupting the cytokine outbreak

Baricitinib has the potential to reduce or interrupt the passage of SARS-CoV-2 into cells, and thus to inhibit the JAK1- and JAK2-mediated cytokine outbreak, researcher Heinz-Josef Lenz, MD, professor of medicine and preventive medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, said in a comment. Baricitinib was also identified, using BenevolentAI’s proprietary, artificial intelligence-derived knowledge graph, as a numb-associated kinase inhibitor, with high affinity for AP2-associated protein kinase 1, an important endocytosis regulator.

Early clinical data suggest a potent biologic effect of baricitinib 2 mg or 4 mg daily on circulating interleukin-6 levels and other inflammatory markers, including C-reactive protein. Dr. Lenz said the evidence for advantageous action of baricitinib on viral endocytosis and excessive cytokine release constitutes the rationale for using it in combination with other antivirals such as remdesivir in patients with moderate to severe COVID-19 illness.

“Although baricitinib may display antiviral activity on its own, its anti-inflammatory effects could hypothetically delay viral clearance,” Dr. Lenz added. “The data from Stebbing et al. confirm the dual actions of baricitinib, demonstrating its ability to inhibit viral entry into primary human hepatocyte spheroids and the reduction in inflammatory markers in COVID-19 patients.”

Other JAK inhibitors were not advanced as promising candidates for the research team’s attention by its artificial intelligence search, Dr. Stebbing noted. “The history of the pandemic has taught us the importance of well-designed observational studies as well as randomized, controlled trials. When it comes to COVID, pyrite looks much like gold, as failed studies of four antivirals have shown.”

Although the current translational research study did not use a placebo group, it is an important next step toward future randomized, controlled trials. “What’s great about this study is its high degree of collaboration, done with real urgency,” he added. “It’s harder to produce a paper that crosses multiple boundaries, like this one does, than a single-focused piece of work. But we wanted to link all of these threads together.”

The study was supported by the Imperial Biomedical Research Centre and Experimental Cancer Medicine Centre, the National Institute for Health Research, and the U.K. National Health Service’s Accelerated Access Collaborative. Dr. Stebbing has served on scientific advisory boards for Eli Lilly and other companies. Dr. Lenz had no relevant disclosures to report.

SOURCE: Stebbing J et al. Sci Adv. 2020 Nov 13. doi: 10.1126/sciadv.abe4724.

It should not be surprising that the RA drug baricitinib (Olumiant), a Janus kinase (JAK) 1/2 inhibitor, might be beneficial in controlling the cytokine storm of hyperinflammation that can follow severe SARS-CoV-2 infections and lead to lung damage and acute respiratory distress syndrome – the leading cause of death from the virus.

But to demonstrate within a matter of months, at least preliminarily, that baricitinib reduces mortality and morbidity in hospitalized patients with COVID-19 pneumonia required a widely cross-disciplinary international team of researchers from 10 countries working at breakneck speed, said Justin Stebbing, PhD, the principal investigator of a new baricitinib study published Nov. 13 in Science Advances. “We went from modeling and mechanistic investigations to clinical tests in a number of settings and laboratory analysis in record time.”

The international team of 50 researchers included medical specialists in rheumatology, virology, geriatrics, oncology, and general medicine, along with experts in molecular and cellular biology, bioinformatics, statistics and trial design, computer modeling, pathology, genetics, and super-resolution microscopy, Dr. Stebbing, professor of cancer medicine and medical oncology at Imperial College, London, said in an interview.

Artificial intelligence, provided by the London-based firm BenevolentAI, was used to sift through a huge repository of structured medical information to identify drugs that might block the SARS-CoV-2 infection process. It predicted that baricitinib would be a promising candidate to inhibit inflammation and reduce viral load in COVID-19. Previous reports by Dr. Stebbing and colleagues (here and here) describe this AI-mediated testing, which was validated by the new study.

The researchers also used three-dimensional miniature human liver organoids in vitro and super-resolution microscopy to perform further lab investigations, which showed that baricitinib reversed expression of the SARS-CoV-2 receptor ACE2 triggered by type I interferons. Baricitinib inhibited the significant increase in ACE2 expression caused by interferon alpha-2, and thus cytokine-mediated inflammation, and also reduced infectivity, Dr. Stebbing said. “Our study of baricitinib shows that it has both antiviral and anticytokine effects and appears to be safe.”
 

71% mortality reduction

The team found a 71% reduction in mortality for a group of 83 hospitalized patients with COVID-19 pneumonia in Italy and Spain – early epicenters of the pandemic – who received baricitinib along with standard care, compared with propensity-matched groups that received only standard care. At that time, between mid-March and mid-April, standard COVID-19 care included antibiotics, glucocorticoids, hydroxychloroquine, low-molecular-weight heparin, and the antiretroviral combination lopinavir/ritonavir.

In the Spanish and Italian cohorts, baricitinib was generally well tolerated, although not without side effects, including bacterial infections and increases in liver enzyme levels, which may not have been related to baricitinib. Patients showed reductions in inflammation within days of starting treatment. “We did not observe thrombotic or vascular events in our cohorts, but most of the patients were receiving low molecular weight heparin,” he said.

The fact that baricitinib is approved by the Food and Drug Administration, is already well studied for safety, can be taken conveniently as a once-daily oral tablet, and is less expensive than many other antiviral treatments all make it an good target for further study, including randomized, controlled trials that are already underway, Dr. Stebbing noted. His study cohort also included elderly patients (median age, 81 years) who are the most likely to experience severe disease or death from COVID-19.

The National Library of Medicine’s clinicaltrials.gov registry of federally funded clinical studies lists 15 current research initiatives involving baricitinib and COVID-19. Dr. Stebbing suggested that data generated so far are helping to guide ongoing studies on dose and duration of treatment – in other words, who it works for, when to give it, and at what dose it should be taken and for how long.

Manufacturer Eli Lilly, which markets baricitinib in 2-mg or 4-mg tablets, announced in October that initial data are starting to emerge from 1,000-plus patients enrolled in ACTT-2 (the Adaptive COVID-19 Treatment Trial 2). ACTT-2 compared patients on the broad-spectrum intravenous antiviral drug remdesivir (Veklury) with those receiving remdesivir in combination with baricitinib. Based on ACTT-2 results that suggested a reduced time to recovery and improved clinical outcomes for the combination group, the FDA issued an emergency-use authorization on Nov. 19 for the combination of baricitinib and remdesivir for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized adults and pediatric patients aged 2 years or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.

Interrupting the cytokine outbreak

Baricitinib has the potential to reduce or interrupt the passage of SARS-CoV-2 into cells, and thus to inhibit the JAK1- and JAK2-mediated cytokine outbreak, researcher Heinz-Josef Lenz, MD, professor of medicine and preventive medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, said in a comment. Baricitinib was also identified, using BenevolentAI’s proprietary, artificial intelligence-derived knowledge graph, as a numb-associated kinase inhibitor, with high affinity for AP2-associated protein kinase 1, an important endocytosis regulator.

Early clinical data suggest a potent biologic effect of baricitinib 2 mg or 4 mg daily on circulating interleukin-6 levels and other inflammatory markers, including C-reactive protein. Dr. Lenz said the evidence for advantageous action of baricitinib on viral endocytosis and excessive cytokine release constitutes the rationale for using it in combination with other antivirals such as remdesivir in patients with moderate to severe COVID-19 illness.

“Although baricitinib may display antiviral activity on its own, its anti-inflammatory effects could hypothetically delay viral clearance,” Dr. Lenz added. “The data from Stebbing et al. confirm the dual actions of baricitinib, demonstrating its ability to inhibit viral entry into primary human hepatocyte spheroids and the reduction in inflammatory markers in COVID-19 patients.”

Other JAK inhibitors were not advanced as promising candidates for the research team’s attention by its artificial intelligence search, Dr. Stebbing noted. “The history of the pandemic has taught us the importance of well-designed observational studies as well as randomized, controlled trials. When it comes to COVID, pyrite looks much like gold, as failed studies of four antivirals have shown.”

Although the current translational research study did not use a placebo group, it is an important next step toward future randomized, controlled trials. “What’s great about this study is its high degree of collaboration, done with real urgency,” he added. “It’s harder to produce a paper that crosses multiple boundaries, like this one does, than a single-focused piece of work. But we wanted to link all of these threads together.”

The study was supported by the Imperial Biomedical Research Centre and Experimental Cancer Medicine Centre, the National Institute for Health Research, and the U.K. National Health Service’s Accelerated Access Collaborative. Dr. Stebbing has served on scientific advisory boards for Eli Lilly and other companies. Dr. Lenz had no relevant disclosures to report.

SOURCE: Stebbing J et al. Sci Adv. 2020 Nov 13. doi: 10.1126/sciadv.abe4724.

It should not be surprising that the RA drug baricitinib (Olumiant), a Janus kinase (JAK) 1/2 inhibitor, might be beneficial in controlling the cytokine storm of hyperinflammation that can follow severe SARS-CoV-2 infections and lead to lung damage and acute respiratory distress syndrome – the leading cause of death from the virus.

But to demonstrate within a matter of months, at least preliminarily, that baricitinib reduces mortality and morbidity in hospitalized patients with COVID-19 pneumonia required a widely cross-disciplinary international team of researchers from 10 countries working at breakneck speed, said Justin Stebbing, PhD, the principal investigator of a new baricitinib study published Nov. 13 in Science Advances. “We went from modeling and mechanistic investigations to clinical tests in a number of settings and laboratory analysis in record time.”

The international team of 50 researchers included medical specialists in rheumatology, virology, geriatrics, oncology, and general medicine, along with experts in molecular and cellular biology, bioinformatics, statistics and trial design, computer modeling, pathology, genetics, and super-resolution microscopy, Dr. Stebbing, professor of cancer medicine and medical oncology at Imperial College, London, said in an interview.

Artificial intelligence, provided by the London-based firm BenevolentAI, was used to sift through a huge repository of structured medical information to identify drugs that might block the SARS-CoV-2 infection process. It predicted that baricitinib would be a promising candidate to inhibit inflammation and reduce viral load in COVID-19. Previous reports by Dr. Stebbing and colleagues (here and here) describe this AI-mediated testing, which was validated by the new study.

The researchers also used three-dimensional miniature human liver organoids in vitro and super-resolution microscopy to perform further lab investigations, which showed that baricitinib reversed expression of the SARS-CoV-2 receptor ACE2 triggered by type I interferons. Baricitinib inhibited the significant increase in ACE2 expression caused by interferon alpha-2, and thus cytokine-mediated inflammation, and also reduced infectivity, Dr. Stebbing said. “Our study of baricitinib shows that it has both antiviral and anticytokine effects and appears to be safe.”
 

71% mortality reduction

The team found a 71% reduction in mortality for a group of 83 hospitalized patients with COVID-19 pneumonia in Italy and Spain – early epicenters of the pandemic – who received baricitinib along with standard care, compared with propensity-matched groups that received only standard care. At that time, between mid-March and mid-April, standard COVID-19 care included antibiotics, glucocorticoids, hydroxychloroquine, low-molecular-weight heparin, and the antiretroviral combination lopinavir/ritonavir.

In the Spanish and Italian cohorts, baricitinib was generally well tolerated, although not without side effects, including bacterial infections and increases in liver enzyme levels, which may not have been related to baricitinib. Patients showed reductions in inflammation within days of starting treatment. “We did not observe thrombotic or vascular events in our cohorts, but most of the patients were receiving low molecular weight heparin,” he said.

The fact that baricitinib is approved by the Food and Drug Administration, is already well studied for safety, can be taken conveniently as a once-daily oral tablet, and is less expensive than many other antiviral treatments all make it an good target for further study, including randomized, controlled trials that are already underway, Dr. Stebbing noted. His study cohort also included elderly patients (median age, 81 years) who are the most likely to experience severe disease or death from COVID-19.

The National Library of Medicine’s clinicaltrials.gov registry of federally funded clinical studies lists 15 current research initiatives involving baricitinib and COVID-19. Dr. Stebbing suggested that data generated so far are helping to guide ongoing studies on dose and duration of treatment – in other words, who it works for, when to give it, and at what dose it should be taken and for how long.

Manufacturer Eli Lilly, which markets baricitinib in 2-mg or 4-mg tablets, announced in October that initial data are starting to emerge from 1,000-plus patients enrolled in ACTT-2 (the Adaptive COVID-19 Treatment Trial 2). ACTT-2 compared patients on the broad-spectrum intravenous antiviral drug remdesivir (Veklury) with those receiving remdesivir in combination with baricitinib. Based on ACTT-2 results that suggested a reduced time to recovery and improved clinical outcomes for the combination group, the FDA issued an emergency-use authorization on Nov. 19 for the combination of baricitinib and remdesivir for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized adults and pediatric patients aged 2 years or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.

Interrupting the cytokine outbreak

Baricitinib has the potential to reduce or interrupt the passage of SARS-CoV-2 into cells, and thus to inhibit the JAK1- and JAK2-mediated cytokine outbreak, researcher Heinz-Josef Lenz, MD, professor of medicine and preventive medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, said in a comment. Baricitinib was also identified, using BenevolentAI’s proprietary, artificial intelligence-derived knowledge graph, as a numb-associated kinase inhibitor, with high affinity for AP2-associated protein kinase 1, an important endocytosis regulator.

Early clinical data suggest a potent biologic effect of baricitinib 2 mg or 4 mg daily on circulating interleukin-6 levels and other inflammatory markers, including C-reactive protein. Dr. Lenz said the evidence for advantageous action of baricitinib on viral endocytosis and excessive cytokine release constitutes the rationale for using it in combination with other antivirals such as remdesivir in patients with moderate to severe COVID-19 illness.

“Although baricitinib may display antiviral activity on its own, its anti-inflammatory effects could hypothetically delay viral clearance,” Dr. Lenz added. “The data from Stebbing et al. confirm the dual actions of baricitinib, demonstrating its ability to inhibit viral entry into primary human hepatocyte spheroids and the reduction in inflammatory markers in COVID-19 patients.”

Other JAK inhibitors were not advanced as promising candidates for the research team’s attention by its artificial intelligence search, Dr. Stebbing noted. “The history of the pandemic has taught us the importance of well-designed observational studies as well as randomized, controlled trials. When it comes to COVID, pyrite looks much like gold, as failed studies of four antivirals have shown.”

Although the current translational research study did not use a placebo group, it is an important next step toward future randomized, controlled trials. “What’s great about this study is its high degree of collaboration, done with real urgency,” he added. “It’s harder to produce a paper that crosses multiple boundaries, like this one does, than a single-focused piece of work. But we wanted to link all of these threads together.”

The study was supported by the Imperial Biomedical Research Centre and Experimental Cancer Medicine Centre, the National Institute for Health Research, and the U.K. National Health Service’s Accelerated Access Collaborative. Dr. Stebbing has served on scientific advisory boards for Eli Lilly and other companies. Dr. Lenz had no relevant disclosures to report.

SOURCE: Stebbing J et al. Sci Adv. 2020 Nov 13. doi: 10.1126/sciadv.abe4724.

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

The more time older women spent sitting or lying down, the more likely their risk of hospitalization for heart failure, based on data from more than 80,000 postmenopausal women.

Cecilie_Arcurs/E+

The 2018 Physical Activity Guidelines show evidence of the impact of physical activity on reducing heart failure risk, but the association between activity, sedentary behavior (SB) and heart failure (HF) in older women in particular has not been well studied, wrote Michael J. LaMonte, PhD, MPH, of the State University of New York at Buffalo, and colleagues in a study published in Circulation: Heart Failure. “Given the high prevalence of prolonged sedentary time among U.S. adults aged 65 and older, among whom HF burden is substantial, understanding the role SB has in HF development is relevant to future HF prevention strategies,” the researchers wrote.

The researchers identified 80,982 women aged 50-79 years who were enrolled in the Women’s Health Initiative Observational Study, had no known HF, and could walk at least one block unassisted. The average follow-up period was 9 years, and a total of 1,402 women were hospitalized for heart failure during the period of time they were observed.

The time spent sedentary (combined sitting or lying down) was divided into tertiles of 6.5 hours or less, 6.6-9.5 hours, and more than 9.5 hours. Time spent sitting was divided into tertiles of 4.5 hours or less; 4.6-8.5 hours; and more than 8.5 hours.
 

Heart failure risk goes up with more down time

After controlling for multiple variables including age, race, education, income, smoking status alcohol use, menopausal hormone therapy, and hysterectomy status, the researchers found that patients in the second tertile for sedentary behavior had a significantly increased heart failure risk than patients in the first tertile for sedentary behavior. This risk was even greater for patients falling in the third tertile for sedentary behavior. Odds ratios were 1.00 (referent), 1.15, and 1.42 for the lowest to highest tertiles for total sedentary behavior, respectively, and 1.00 (referent), 1.14, and 1.54 for sitting (P < .001 for both total sedentary behavior and sitting only).

The trends remained significant after controlling for comorbidities including MI and coronary revascularization, and the associations were similar among categories of women with additional HF risk factors, including body mass index, diabetes, hypertension, and coronary heart disease.

Notably, the association between hours spent sitting or lying down and HF risk persisted even in women who met recommended activity levels, the researchers wrote.

The study findings were limited by the use of self-reports and by the inability to evaluate SB patterns or SB and HF subtypes, the researchers noted. However, the results were strengthened by the large sample size, use of time-varying SB exposure, and extensive controlling, and the data support the risk of increased SB on adverse cardiovascular outcomes.

“Results of this study underscore the need for effective strategies to reduce daily SB time, in addition to increasing recreational physical activity, as part of population efforts for HF prevention,” they concluded.

Clinicians know the value of a physically active lifestyle for heart health, said lead author Dr. LaMonte in a statement accompanying the study’s release. “However, our study clearly shows that we also need to increase efforts to reduce daily sedentary time and encourage adults to frequently interrupt their sedentary time. This does not necessarily require an extended bout of physical activity; it might simply be standing up for 5 minutes or standing and moving one’s feet in place.

“We do not have sufficient evidence on the best approach to recommend for interrupting sedentary time. However, accumulating data suggest that habitual activities such as steps taken during household and other activities of daily living are an important aspect of cardiovascular disease prevention and healthy aging,” Dr. LaMonte added.
 

Promote more movement and less sitting

“This is the first study to assess sedentary time and the risk for incident heart failure hospitalization in postmenopausal women,” said Robert H. Hopkins Jr., MD, of the University of Arkansas for Medical Sciences, Little Rock, in an interview.

“Heart failure is the cause of approximately 35% of cardiovascular mortalities in women, and sedentary behaviors are common in older adults,” he noted.

Kashif J. Piracha, MD, of Houston Methodist Willowbrook Hospital, agreed that there is a lack of existing data looking at the relationship between sedentary behavior and the risk of the development of heart failure in postmenopausal women. In an interview, he cited this as a reason “it was important to conduct this study.”

Dr. Hopkins added that he was not surprised by the study results “There are a number of studies which have demonstrated reduction in risk for heart failure in men and in combined populations of men and women with increased physical activity.” There are fewer data (but similar outcomes) in studies of men with increased levels of sedentary behaviors, he said.

“This study adds one more reason that other clinicians in primary care and me need to encourage our older patients to get up and move,” said Dr. Hopkins, who also serves on the editorial advisory board of Internal Medicine News. “Many of us have focused our efforts in the past on achieving exercise goals and this study provides a foundation for a recommendation that ‘it is not just about exercise;’ we need to also encourage our patients to minimize their time in sedentary pursuits in addition to exercise if we are to optimize their health into older age.”

Dr. Hopkins noted that the large size of the study was a strength, but the observational design and use of patient surveys were limitations.

“We need further studies to better tease out whether there are risk differences in different sedentary behavior patterns, whether this applies across heart failure with reduced ejection fraction versus heart failure with preserved ejection fraction, and whether there are additional ways we can mitigate these risks as our society ages,” he said.
 

Findings differ from California Men’s Health Study’s

“The results corroborate the fact that there is less risk of heart failure in physically active patients,” Dr. Piracha noted.

The message for clinicians is to encourage postmenopausal female patients to engage in physical activity as much as possible, said Dr. Piracha. “Also, it appears that in this population, even with good physical activity, prolonged sedentary behavior of more than 8.5 hours a day was still associated with a higher risk of incident HF hospitalization. Therefore, a case can be made to focus on carrying out physical activity with an intensity that can be sustained for longer, rather than shorter periods of time.”

Notably, the finding of increased HF hospitalization in women who reported high amounts of physical activity but were still sedentary for more than 8.5 hours a day “is contrary to what was seen in the California Men’s Health Study.” In that study, “men with high physical activity levels who also had prolonged sitting time did not have increased risk of HF hospitalization,” Dr. Piracha noted. “Further research is needed to elucidate what hormonal or other factors contribute to this difference.”

The new study was supported by the National Heart, Lung, and Blood Institute. The researchers had no financial conflicts to disclose. Dr. Hopkins and Dr. Piracha had no financial conflicts to disclose.

SOURCE: LaMonte MJ et al. Circ Heart Fail. 2020 Nov 24. doi: 10.1161/CIRCHEARTFAILURE.120.007508.

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An infectious disease expert panel cautions against routine use of bamlanivimab (Eli Lilly) and notes that remdesivir (Veklury) can shorten the clinical course of COVID-19 – which could be critical “as hospitals fill up” across the United States.

The group also said the monoclonal antibodies approved for emergency use by the Food and Drug Administration and still in development hold promise, although more clinical trial data are needed.

These and other recommendations appear in updated guidelines from the Infectious Diseases Society of America, released Nov. 18 and Nov. 22.
 

A conditional ‘no’ on routine bamlanivimab

“The guideline panel gave a conditional recommendation against the routine use of bamlanivimab,” Adarsh Bhimraj, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel, said.

On Nov. 10, the FDA issued an emergency-use authorization (EUA) for bamlanivimab for use in ambulatory patients with mild to moderate COVID-19.

“We did have a remark that it may be used in patients who have increased risk of severe COVID-19, as it is outlined in the FDA emergency-use authorization issued last week,” he said. He added that use should follow an informed discussion between provider and patient, one in which “the patient puts a very high value on the uncertain benefits and a low value on uncertain adverse events.”

The panel’s rationale was based in part on interim analysis of the phase 2 BLAZE-1 trial, which found 1.6% of people randomly assigned to bamlanivimab had an emergency department visit or hospitalization compared with 6.3% of those receiving a placebo.

“We thought the estimate was too fragile because the number in each arm was very low. Even a small change in these numbers could make the difference nonsignificant,” said Bhimraj, head of the neurologic infectious diseases section in the department of infectious diseases at the Cleveland (Ohio) Clinic.
 

Awaiting more data on antibody combination

On November 21, the FDA granted an EUA to the casirivimab and imbdevimab monoclonal antibody combination (Regeneron), indicated to treated mild to moderate COVID-19.

“Surprisingly, the preliminary results released in the EUA look a lot like bamlanivimab,” Dr. Bhimraj said.

Unlike bamlanivimab, for which trial details were published, the panel does not yet have the totality of data on casirivimab and imbdevimab, and therefore is not yet making a recommendation. “We want to be cautious as a guideline panel. We are anxiously awaiting the full publication,” he added.

“I do think these monoclonal antibodies show potential for benefit, but as Dr. Bhimraj said, it’s very difficult with the relatively small numbers we’re talking about,” said Rajesh T. Gandhi, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel.

Remaining questions include the degree of efficacy these antibody therapies will have, as well as which patients are most likely to benefit, added Dr. Gandhi, who is also a professor of medicine at Harvard Medical School and director of HIV Clinical Services and Education at Massachusetts General Hospital, both in Boston.

Furthermore, although there appear to be adequate supplies of remdesivir and dexamethasone, for example, availability and distribution of monoclonal antibodies could present logistic challenges. Prioritizing which high-risk patients receive this therapy and ensuring equity and access to communities most affected by COVID-19, including minority and low socioeconomic populations, need to be addressed, Dr. Gandhi said.  
 

Remdesivir recommended to shorten hospital stays

The panel’s recommendations regarding the use of remdesivir “has largely remained the same,” Dr. Gandhi said. Evidence indicates recovery is faster with remdesivir at 10 days vs 15 days in people taking a placebo.

In the ACTT-1 trial, for example, participants in the treatment group recovered in a median 10 days versus 15 days in the placebo group.

Therefore, the IDSA panel continues to recommend remdesivir treatment for hospitalized patients with COVID-19.

“As hospitals around the United States fill up, the IDSA panel believes the effect of remdesivir on speeding up recovery could be an important benefit, and that is why we continue to suggest its use,” Dr. Gandhi said.

When asked about the World Health Organization–sponsored trial that showed no benefit in terms of mortality, he replied, “Remdesivir is not a home run – we need better drugs.”
 

A recommendation against lopinavir and ritonavir

In contrast, the panel recommends against use of the lopinavir/ritonavir protease inhibitor combination therapy, based in part on data from a preprint of the Solidarity study.

The open-label Solidarity trial in 30 countries, sponsored by WHO, assessed hydroxychloroquine, interferon, lopinavir/ritonavir, and remdesivir in people hospitalized with COVID-19.

None of these drugs showed an effect on mortality, Dr. Gandhi said. “Better medicines that improve survival are clearly needed.”

Dexamethasone remains the only agent demonstrated to reduce mortality in people hospitalized with COVID-19, he added.
 

Tocilizumab not for routine use

After critical review of the studies that have emerged since the last IDSA recommendation regarding tocilizumab (Actemra) in September, “the panel still stood with the recommendation against routine use of tocilizumab in hospitalized patients with COVID-19,” Dr. Bhimraj said.

The guidance is based on trials including COVACTA and EMPACTA. Treatment with tocilizumab was not associated with significant differences in mortality. In these and other studies, “we did not really find a significant difference, and that was the reason for the conditional recommendation against routine use of tocilizumab in hospitalized patients,” Dr. Bhimraj said.

Also, although the trials were blinded, “we know treatment with tocilizumab can cause a reduction in C-reactive protein levels,” which could indicate to researchers which participants were receiving active treatment versus placebo, he said.
 

Jury still out on baricitinib, remdesivir combination

The FDA granted an EUA to the combination of remdesivir and baricitinib (Olumiant) on Nov. 19. However, the IDSA panel is reserving its recommendation on this therapeutic combination until more data emerge.

“We still don’t have complete results of the ACTT-2 study, and the information we do have is what is available in the EUA,” Dr. Bhimraj said. The panel expects to issue guidance once the totality of data become available.

Unanswered questions include why investigators chose a 4-mg dose of baricitinib – twice the 2-mg dose commonly used for treating rheumatoid arthritis – and how many patients in the trial also were treated with steroids.

Dr. Gandhi agreed that the proportion of patients taking a steroid is “really an important consideration.” He added that dexamethasone has become standard of care because it reduces mortality, as well as the number of people requiring oxygen. He said it will be important to know how the baricitinib/remdesivir combination compares with dexamethasone.

“You don’t want to give a drug with less certain benefit over a drug for which there is more certain benefit,” Dr. Gandhi said.
 

Future possibilities

“The monoclonal antibodies are important to continue studying, particularly in combinations,” Dr. Gandhi said. Researchers are investigating formulations other than IV infusion to make therapy more convenient. For example, a subcutaneous injection like insulin would make administration at home more of a possibility.

Investigators are also looking at oral antiviral therapy, inhaled antivirals, and the promise of using interferon therapy. Dr. Gandhi added there is also “a lot of work around medications to reduce the excess inflammation that drives very severe COVID-19.”
 

‘Exciting news’ on AstraZeneca vaccine

Although not part of the IDSA guidelines, “we saw the news from AstraZeneca this morning, which is exciting,” Dr. Gandhi said during a media briefing.

Unlike the Pfizer and Moderna messenger RNA vaccines, which use the genetic material of the virus to make the virus proteins that elicit an immune response, the AstraZeneca/Oxford University vaccine uses a viral vector to carry the SARS-CoV-2 protein, to which the body produces an immune response.

“I’m thrilled that several different vaccines are showing important effects at rates higher than the FDA benchmark of 50%, and these are well exceeding that,” Dr. Gandhi said.

“One interesting thing from the [AstraZeneca] press release is they show asymptomatic infection being reduced,” he added. “That is critical because we know a lot of transmission of SARS-CoV-2 comes from asymptomatic people.”
 

Reasons for optimism

In response to a question about whether the experts feel more optimistic about COVID-19, Dr. Bhimraj said he is cautiously optimistic. “We have made tremendous progress in therapeutic agents, and in how the world has come together in the middle of a catastrophe to collaborate, setting our differences apart, to do trials. That is commendable.”

Dr. Gandhi said he felt more optimistic than he did in the spring. He pointed out that physicians and researchers know a lot more about potential blood clotting complications, how to support patients through severe COVID-19 and keep them off a ventilator whenever possible, and how to provide dexamethasone to reduce the risk of death.

Those benefits are in hospitalized patients, however, and “we need ways to prevent people from getting into the hospital, and that is why we are looking at the monoclonal antibodies,” Dr. Gandhi said. “If borne out in larger trials, that will be a major advance.”

“We need to keep our focus on prevention and go back to our idea of flattening the curve. That is critical so our health care systems do not get overwhelmed during this massive surge we are in,” Dr. Gandhi said. “So masking and social distancing are just as important as they always have been.”

Dr. Bhimraj disclosed no relevant financial relationships. Dr. Gandhi has no disclosures for the past 12 months; in the past 3 years, he has served on scientific advisory boards for Gilead and Merck.

This article first appeared on Medscape.com.

An infectious disease expert panel cautions against routine use of bamlanivimab (Eli Lilly) and notes that remdesivir (Veklury) can shorten the clinical course of COVID-19 – which could be critical “as hospitals fill up” across the United States.

The group also said the monoclonal antibodies approved for emergency use by the Food and Drug Administration and still in development hold promise, although more clinical trial data are needed.

These and other recommendations appear in updated guidelines from the Infectious Diseases Society of America, released Nov. 18 and Nov. 22.
 

A conditional ‘no’ on routine bamlanivimab

“The guideline panel gave a conditional recommendation against the routine use of bamlanivimab,” Adarsh Bhimraj, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel, said.

On Nov. 10, the FDA issued an emergency-use authorization (EUA) for bamlanivimab for use in ambulatory patients with mild to moderate COVID-19.

“We did have a remark that it may be used in patients who have increased risk of severe COVID-19, as it is outlined in the FDA emergency-use authorization issued last week,” he said. He added that use should follow an informed discussion between provider and patient, one in which “the patient puts a very high value on the uncertain benefits and a low value on uncertain adverse events.”

The panel’s rationale was based in part on interim analysis of the phase 2 BLAZE-1 trial, which found 1.6% of people randomly assigned to bamlanivimab had an emergency department visit or hospitalization compared with 6.3% of those receiving a placebo.

“We thought the estimate was too fragile because the number in each arm was very low. Even a small change in these numbers could make the difference nonsignificant,” said Bhimraj, head of the neurologic infectious diseases section in the department of infectious diseases at the Cleveland (Ohio) Clinic.
 

Awaiting more data on antibody combination

On November 21, the FDA granted an EUA to the casirivimab and imbdevimab monoclonal antibody combination (Regeneron), indicated to treated mild to moderate COVID-19.

“Surprisingly, the preliminary results released in the EUA look a lot like bamlanivimab,” Dr. Bhimraj said.

Unlike bamlanivimab, for which trial details were published, the panel does not yet have the totality of data on casirivimab and imbdevimab, and therefore is not yet making a recommendation. “We want to be cautious as a guideline panel. We are anxiously awaiting the full publication,” he added.

“I do think these monoclonal antibodies show potential for benefit, but as Dr. Bhimraj said, it’s very difficult with the relatively small numbers we’re talking about,” said Rajesh T. Gandhi, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel.

Remaining questions include the degree of efficacy these antibody therapies will have, as well as which patients are most likely to benefit, added Dr. Gandhi, who is also a professor of medicine at Harvard Medical School and director of HIV Clinical Services and Education at Massachusetts General Hospital, both in Boston.

Furthermore, although there appear to be adequate supplies of remdesivir and dexamethasone, for example, availability and distribution of monoclonal antibodies could present logistic challenges. Prioritizing which high-risk patients receive this therapy and ensuring equity and access to communities most affected by COVID-19, including minority and low socioeconomic populations, need to be addressed, Dr. Gandhi said.  
 

Remdesivir recommended to shorten hospital stays

The panel’s recommendations regarding the use of remdesivir “has largely remained the same,” Dr. Gandhi said. Evidence indicates recovery is faster with remdesivir at 10 days vs 15 days in people taking a placebo.

In the ACTT-1 trial, for example, participants in the treatment group recovered in a median 10 days versus 15 days in the placebo group.

Therefore, the IDSA panel continues to recommend remdesivir treatment for hospitalized patients with COVID-19.

“As hospitals around the United States fill up, the IDSA panel believes the effect of remdesivir on speeding up recovery could be an important benefit, and that is why we continue to suggest its use,” Dr. Gandhi said.

When asked about the World Health Organization–sponsored trial that showed no benefit in terms of mortality, he replied, “Remdesivir is not a home run – we need better drugs.”
 

A recommendation against lopinavir and ritonavir

In contrast, the panel recommends against use of the lopinavir/ritonavir protease inhibitor combination therapy, based in part on data from a preprint of the Solidarity study.

The open-label Solidarity trial in 30 countries, sponsored by WHO, assessed hydroxychloroquine, interferon, lopinavir/ritonavir, and remdesivir in people hospitalized with COVID-19.

None of these drugs showed an effect on mortality, Dr. Gandhi said. “Better medicines that improve survival are clearly needed.”

Dexamethasone remains the only agent demonstrated to reduce mortality in people hospitalized with COVID-19, he added.
 

Tocilizumab not for routine use

After critical review of the studies that have emerged since the last IDSA recommendation regarding tocilizumab (Actemra) in September, “the panel still stood with the recommendation against routine use of tocilizumab in hospitalized patients with COVID-19,” Dr. Bhimraj said.

The guidance is based on trials including COVACTA and EMPACTA. Treatment with tocilizumab was not associated with significant differences in mortality. In these and other studies, “we did not really find a significant difference, and that was the reason for the conditional recommendation against routine use of tocilizumab in hospitalized patients,” Dr. Bhimraj said.

Also, although the trials were blinded, “we know treatment with tocilizumab can cause a reduction in C-reactive protein levels,” which could indicate to researchers which participants were receiving active treatment versus placebo, he said.
 

Jury still out on baricitinib, remdesivir combination

The FDA granted an EUA to the combination of remdesivir and baricitinib (Olumiant) on Nov. 19. However, the IDSA panel is reserving its recommendation on this therapeutic combination until more data emerge.

“We still don’t have complete results of the ACTT-2 study, and the information we do have is what is available in the EUA,” Dr. Bhimraj said. The panel expects to issue guidance once the totality of data become available.

Unanswered questions include why investigators chose a 4-mg dose of baricitinib – twice the 2-mg dose commonly used for treating rheumatoid arthritis – and how many patients in the trial also were treated with steroids.

Dr. Gandhi agreed that the proportion of patients taking a steroid is “really an important consideration.” He added that dexamethasone has become standard of care because it reduces mortality, as well as the number of people requiring oxygen. He said it will be important to know how the baricitinib/remdesivir combination compares with dexamethasone.

“You don’t want to give a drug with less certain benefit over a drug for which there is more certain benefit,” Dr. Gandhi said.
 

Future possibilities

“The monoclonal antibodies are important to continue studying, particularly in combinations,” Dr. Gandhi said. Researchers are investigating formulations other than IV infusion to make therapy more convenient. For example, a subcutaneous injection like insulin would make administration at home more of a possibility.

Investigators are also looking at oral antiviral therapy, inhaled antivirals, and the promise of using interferon therapy. Dr. Gandhi added there is also “a lot of work around medications to reduce the excess inflammation that drives very severe COVID-19.”
 

‘Exciting news’ on AstraZeneca vaccine

Although not part of the IDSA guidelines, “we saw the news from AstraZeneca this morning, which is exciting,” Dr. Gandhi said during a media briefing.

Unlike the Pfizer and Moderna messenger RNA vaccines, which use the genetic material of the virus to make the virus proteins that elicit an immune response, the AstraZeneca/Oxford University vaccine uses a viral vector to carry the SARS-CoV-2 protein, to which the body produces an immune response.

“I’m thrilled that several different vaccines are showing important effects at rates higher than the FDA benchmark of 50%, and these are well exceeding that,” Dr. Gandhi said.

“One interesting thing from the [AstraZeneca] press release is they show asymptomatic infection being reduced,” he added. “That is critical because we know a lot of transmission of SARS-CoV-2 comes from asymptomatic people.”
 

Reasons for optimism

In response to a question about whether the experts feel more optimistic about COVID-19, Dr. Bhimraj said he is cautiously optimistic. “We have made tremendous progress in therapeutic agents, and in how the world has come together in the middle of a catastrophe to collaborate, setting our differences apart, to do trials. That is commendable.”

Dr. Gandhi said he felt more optimistic than he did in the spring. He pointed out that physicians and researchers know a lot more about potential blood clotting complications, how to support patients through severe COVID-19 and keep them off a ventilator whenever possible, and how to provide dexamethasone to reduce the risk of death.

Those benefits are in hospitalized patients, however, and “we need ways to prevent people from getting into the hospital, and that is why we are looking at the monoclonal antibodies,” Dr. Gandhi said. “If borne out in larger trials, that will be a major advance.”

“We need to keep our focus on prevention and go back to our idea of flattening the curve. That is critical so our health care systems do not get overwhelmed during this massive surge we are in,” Dr. Gandhi said. “So masking and social distancing are just as important as they always have been.”

Dr. Bhimraj disclosed no relevant financial relationships. Dr. Gandhi has no disclosures for the past 12 months; in the past 3 years, he has served on scientific advisory boards for Gilead and Merck.

This article first appeared on Medscape.com.

An infectious disease expert panel cautions against routine use of bamlanivimab (Eli Lilly) and notes that remdesivir (Veklury) can shorten the clinical course of COVID-19 – which could be critical “as hospitals fill up” across the United States.

The group also said the monoclonal antibodies approved for emergency use by the Food and Drug Administration and still in development hold promise, although more clinical trial data are needed.

These and other recommendations appear in updated guidelines from the Infectious Diseases Society of America, released Nov. 18 and Nov. 22.
 

A conditional ‘no’ on routine bamlanivimab

“The guideline panel gave a conditional recommendation against the routine use of bamlanivimab,” Adarsh Bhimraj, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel, said.

On Nov. 10, the FDA issued an emergency-use authorization (EUA) for bamlanivimab for use in ambulatory patients with mild to moderate COVID-19.

“We did have a remark that it may be used in patients who have increased risk of severe COVID-19, as it is outlined in the FDA emergency-use authorization issued last week,” he said. He added that use should follow an informed discussion between provider and patient, one in which “the patient puts a very high value on the uncertain benefits and a low value on uncertain adverse events.”

The panel’s rationale was based in part on interim analysis of the phase 2 BLAZE-1 trial, which found 1.6% of people randomly assigned to bamlanivimab had an emergency department visit or hospitalization compared with 6.3% of those receiving a placebo.

“We thought the estimate was too fragile because the number in each arm was very low. Even a small change in these numbers could make the difference nonsignificant,” said Bhimraj, head of the neurologic infectious diseases section in the department of infectious diseases at the Cleveland (Ohio) Clinic.
 

Awaiting more data on antibody combination

On November 21, the FDA granted an EUA to the casirivimab and imbdevimab monoclonal antibody combination (Regeneron), indicated to treated mild to moderate COVID-19.

“Surprisingly, the preliminary results released in the EUA look a lot like bamlanivimab,” Dr. Bhimraj said.

Unlike bamlanivimab, for which trial details were published, the panel does not yet have the totality of data on casirivimab and imbdevimab, and therefore is not yet making a recommendation. “We want to be cautious as a guideline panel. We are anxiously awaiting the full publication,” he added.

“I do think these monoclonal antibodies show potential for benefit, but as Dr. Bhimraj said, it’s very difficult with the relatively small numbers we’re talking about,” said Rajesh T. Gandhi, MD, cochair of the IDSA COVID-19 Treatment and Management Guidelines Expert Panel.

Remaining questions include the degree of efficacy these antibody therapies will have, as well as which patients are most likely to benefit, added Dr. Gandhi, who is also a professor of medicine at Harvard Medical School and director of HIV Clinical Services and Education at Massachusetts General Hospital, both in Boston.

Furthermore, although there appear to be adequate supplies of remdesivir and dexamethasone, for example, availability and distribution of monoclonal antibodies could present logistic challenges. Prioritizing which high-risk patients receive this therapy and ensuring equity and access to communities most affected by COVID-19, including minority and low socioeconomic populations, need to be addressed, Dr. Gandhi said.  
 

Remdesivir recommended to shorten hospital stays

The panel’s recommendations regarding the use of remdesivir “has largely remained the same,” Dr. Gandhi said. Evidence indicates recovery is faster with remdesivir at 10 days vs 15 days in people taking a placebo.

In the ACTT-1 trial, for example, participants in the treatment group recovered in a median 10 days versus 15 days in the placebo group.

Therefore, the IDSA panel continues to recommend remdesivir treatment for hospitalized patients with COVID-19.

“As hospitals around the United States fill up, the IDSA panel believes the effect of remdesivir on speeding up recovery could be an important benefit, and that is why we continue to suggest its use,” Dr. Gandhi said.

When asked about the World Health Organization–sponsored trial that showed no benefit in terms of mortality, he replied, “Remdesivir is not a home run – we need better drugs.”
 

A recommendation against lopinavir and ritonavir

In contrast, the panel recommends against use of the lopinavir/ritonavir protease inhibitor combination therapy, based in part on data from a preprint of the Solidarity study.

The open-label Solidarity trial in 30 countries, sponsored by WHO, assessed hydroxychloroquine, interferon, lopinavir/ritonavir, and remdesivir in people hospitalized with COVID-19.

None of these drugs showed an effect on mortality, Dr. Gandhi said. “Better medicines that improve survival are clearly needed.”

Dexamethasone remains the only agent demonstrated to reduce mortality in people hospitalized with COVID-19, he added.
 

Tocilizumab not for routine use

After critical review of the studies that have emerged since the last IDSA recommendation regarding tocilizumab (Actemra) in September, “the panel still stood with the recommendation against routine use of tocilizumab in hospitalized patients with COVID-19,” Dr. Bhimraj said.

The guidance is based on trials including COVACTA and EMPACTA. Treatment with tocilizumab was not associated with significant differences in mortality. In these and other studies, “we did not really find a significant difference, and that was the reason for the conditional recommendation against routine use of tocilizumab in hospitalized patients,” Dr. Bhimraj said.

Also, although the trials were blinded, “we know treatment with tocilizumab can cause a reduction in C-reactive protein levels,” which could indicate to researchers which participants were receiving active treatment versus placebo, he said.
 

Jury still out on baricitinib, remdesivir combination

The FDA granted an EUA to the combination of remdesivir and baricitinib (Olumiant) on Nov. 19. However, the IDSA panel is reserving its recommendation on this therapeutic combination until more data emerge.

“We still don’t have complete results of the ACTT-2 study, and the information we do have is what is available in the EUA,” Dr. Bhimraj said. The panel expects to issue guidance once the totality of data become available.

Unanswered questions include why investigators chose a 4-mg dose of baricitinib – twice the 2-mg dose commonly used for treating rheumatoid arthritis – and how many patients in the trial also were treated with steroids.

Dr. Gandhi agreed that the proportion of patients taking a steroid is “really an important consideration.” He added that dexamethasone has become standard of care because it reduces mortality, as well as the number of people requiring oxygen. He said it will be important to know how the baricitinib/remdesivir combination compares with dexamethasone.

“You don’t want to give a drug with less certain benefit over a drug for which there is more certain benefit,” Dr. Gandhi said.
 

Future possibilities

“The monoclonal antibodies are important to continue studying, particularly in combinations,” Dr. Gandhi said. Researchers are investigating formulations other than IV infusion to make therapy more convenient. For example, a subcutaneous injection like insulin would make administration at home more of a possibility.

Investigators are also looking at oral antiviral therapy, inhaled antivirals, and the promise of using interferon therapy. Dr. Gandhi added there is also “a lot of work around medications to reduce the excess inflammation that drives very severe COVID-19.”
 

‘Exciting news’ on AstraZeneca vaccine

Although not part of the IDSA guidelines, “we saw the news from AstraZeneca this morning, which is exciting,” Dr. Gandhi said during a media briefing.

Unlike the Pfizer and Moderna messenger RNA vaccines, which use the genetic material of the virus to make the virus proteins that elicit an immune response, the AstraZeneca/Oxford University vaccine uses a viral vector to carry the SARS-CoV-2 protein, to which the body produces an immune response.

“I’m thrilled that several different vaccines are showing important effects at rates higher than the FDA benchmark of 50%, and these are well exceeding that,” Dr. Gandhi said.

“One interesting thing from the [AstraZeneca] press release is they show asymptomatic infection being reduced,” he added. “That is critical because we know a lot of transmission of SARS-CoV-2 comes from asymptomatic people.”
 

Reasons for optimism

In response to a question about whether the experts feel more optimistic about COVID-19, Dr. Bhimraj said he is cautiously optimistic. “We have made tremendous progress in therapeutic agents, and in how the world has come together in the middle of a catastrophe to collaborate, setting our differences apart, to do trials. That is commendable.”

Dr. Gandhi said he felt more optimistic than he did in the spring. He pointed out that physicians and researchers know a lot more about potential blood clotting complications, how to support patients through severe COVID-19 and keep them off a ventilator whenever possible, and how to provide dexamethasone to reduce the risk of death.

Those benefits are in hospitalized patients, however, and “we need ways to prevent people from getting into the hospital, and that is why we are looking at the monoclonal antibodies,” Dr. Gandhi said. “If borne out in larger trials, that will be a major advance.”

“We need to keep our focus on prevention and go back to our idea of flattening the curve. That is critical so our health care systems do not get overwhelmed during this massive surge we are in,” Dr. Gandhi said. “So masking and social distancing are just as important as they always have been.”

Dr. Bhimraj disclosed no relevant financial relationships. Dr. Gandhi has no disclosures for the past 12 months; in the past 3 years, he has served on scientific advisory boards for Gilead and Merck.

This article first appeared on Medscape.com.

In patients with RA whose disease is well controlled by methotrexate combined with etanercept, withdrawal of methotrexate led to long-term outcomes that were nearly as good as continuation of combination therapy. The finding comes from the randomized, controlled SEAM-RA trial that sought to address weaknesses of previous studies. It included a long lead-in time with stringent criteria to ensure that participants had very good disease control.

Courtesy University of Alabama at Birmingham

Both the American College of Rheumatology and the European League Against Rheumatism recommend tapering medication in RA patients who are in long-term remission, but there is no established optimal strategy.

“There have been some prior RA trials that have looked at therapy reduction or withdrawal, but most did not use a very stringent definition of how well people were when they began. Were they in remission, or only in low disease activity?” said Jeffrey R. Curtis, MD, during a presentation of the results at the virtual annual meeting of the ACR. The study was also published online Nov. 18 in Arthritis & Rheumatology.
 

Stringent remission criteria

The key feature of the trial was the 6-month run-in period, when subjects were taking 50 mg etanercept once per week and 10-25 mg of oral methotrexate once per week, and had to complete at least three visits. They were excluded from the ensuing randomization if they had a Simplified Disease Activity Index (SDAI) score >3.3 and ≤11 at two or more visits, had an SDAI >11 at any time during the run-in period, or had an SDAI >3.3 at the third run-in visit.

“We [wanted them] to be doing quite well for a long period of time. That was empirically confirmed under observation as part of the lead-in period, and even before that, the clinical investigator had to affirm that they believed the patient was doing well for 6 or more months even before they were screened to enter the trial,” said Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Once enrolled in the trial, patients were randomized 2:2:1 to continuing etanercept only (n = 101), continuing methotrexate only (n = 101), or continuing both medications (n = 51). Patients were eligible for rescue after randomization if they had an SDAI score >11 at any time, SDAI between 3.3 and 11 on three separate visits, or between 3.3 and 11 at two consecutive visits at least 2 weeks apart. About three-quarters of patients in each treatment arm were female, with a mean age of about 55 years, and 82%-91% were White.

Good remission recovery with rescue therapy

At week 48, 28.7% of the methotrexate-only group were in remission (SDAI ≤3.3), compared with 49.5% of the etanercept-only group (P = .004) and 52.9% of the combination group (P = .006). Time to disease worsening was shorter in the methotrexate-only group (median, 198 days) than in the etanercept-only group (median, not estimable; P < .001) and the combined therapy group (median, not estimable; P < .001).

The researchers also found that most patients who underwent rescue therapy once again achieved remission, including 71% of the methotrexate-only group, 75% of the etanercept-only group, and 80% of the combination therapy group. There was no between-group differences in the time required to reattain remission.

The high rate of remission recovery was a good sign, Dr. Curtis said. “To me as a clinician, the risk to try [withdrawing a medication] is quite low because the likelihood you can regain where you were before is quite good. It’s obviously more successful if you stop methotrexate and continue etanercept than if you do the reverse, but to me, this is quite a practical trial, and in fact the rigor of the inclusion criteria are much more like the patients I’m talking to about stopping therapy than some of the past studies in this regard. I think it’s quite useful in terms of generalizability. We want people that are doing this well or close to it before we take away medication.”
 

Positive reactions from rheumatologists

The reaction from the viewing audience was also positive. “I think this study fills a big data gap for what we do in clinical practice,” wrote Janet Pope, MD, in comments during the session.

Dr. Pope, who is a professor of medicine at the University of Western Ontario and head of rheumatology at St. Joseph’s Health Centre, both in London, said that the results build on previous work, including the CAMEO study, which showed that discontinuation of methotrexate in patients taking methotrexate and etanercept failed to achieve noninferiority to continuation of both medications, and the PRIZE study, which showed that continuing combination therapy at a reduced dose led to better outcomes than did switching to methotrexate alone or placebo. “This may be for some patients what they prefer if they don’t tolerate methotrexate,” she added.

“It’s wonderful to have these data to counsel patients. This is something we face every day,” wrote Elizabeth Wahl, MD, who is an acting assistant professor at the University of Washington, Seattle, and acting chief of rheumatology at the VA Puget Sound Healthcare System.

The study was funded by Amgen. Dr. Curtis has received grants or research support from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB. Dr. Pope consults for a variety of pharmaceutical companies. Dr. Wahl has no relevant financial disclosures.

SOURCE: Curtis JR et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0939.

In patients with RA whose disease is well controlled by methotrexate combined with etanercept, withdrawal of methotrexate led to long-term outcomes that were nearly as good as continuation of combination therapy. The finding comes from the randomized, controlled SEAM-RA trial that sought to address weaknesses of previous studies. It included a long lead-in time with stringent criteria to ensure that participants had very good disease control.

Courtesy University of Alabama at Birmingham

Both the American College of Rheumatology and the European League Against Rheumatism recommend tapering medication in RA patients who are in long-term remission, but there is no established optimal strategy.

“There have been some prior RA trials that have looked at therapy reduction or withdrawal, but most did not use a very stringent definition of how well people were when they began. Were they in remission, or only in low disease activity?” said Jeffrey R. Curtis, MD, during a presentation of the results at the virtual annual meeting of the ACR. The study was also published online Nov. 18 in Arthritis & Rheumatology.
 

Stringent remission criteria

The key feature of the trial was the 6-month run-in period, when subjects were taking 50 mg etanercept once per week and 10-25 mg of oral methotrexate once per week, and had to complete at least three visits. They were excluded from the ensuing randomization if they had a Simplified Disease Activity Index (SDAI) score >3.3 and ≤11 at two or more visits, had an SDAI >11 at any time during the run-in period, or had an SDAI >3.3 at the third run-in visit.

“We [wanted them] to be doing quite well for a long period of time. That was empirically confirmed under observation as part of the lead-in period, and even before that, the clinical investigator had to affirm that they believed the patient was doing well for 6 or more months even before they were screened to enter the trial,” said Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Once enrolled in the trial, patients were randomized 2:2:1 to continuing etanercept only (n = 101), continuing methotrexate only (n = 101), or continuing both medications (n = 51). Patients were eligible for rescue after randomization if they had an SDAI score >11 at any time, SDAI between 3.3 and 11 on three separate visits, or between 3.3 and 11 at two consecutive visits at least 2 weeks apart. About three-quarters of patients in each treatment arm were female, with a mean age of about 55 years, and 82%-91% were White.

Good remission recovery with rescue therapy

At week 48, 28.7% of the methotrexate-only group were in remission (SDAI ≤3.3), compared with 49.5% of the etanercept-only group (P = .004) and 52.9% of the combination group (P = .006). Time to disease worsening was shorter in the methotrexate-only group (median, 198 days) than in the etanercept-only group (median, not estimable; P < .001) and the combined therapy group (median, not estimable; P < .001).

The researchers also found that most patients who underwent rescue therapy once again achieved remission, including 71% of the methotrexate-only group, 75% of the etanercept-only group, and 80% of the combination therapy group. There was no between-group differences in the time required to reattain remission.

The high rate of remission recovery was a good sign, Dr. Curtis said. “To me as a clinician, the risk to try [withdrawing a medication] is quite low because the likelihood you can regain where you were before is quite good. It’s obviously more successful if you stop methotrexate and continue etanercept than if you do the reverse, but to me, this is quite a practical trial, and in fact the rigor of the inclusion criteria are much more like the patients I’m talking to about stopping therapy than some of the past studies in this regard. I think it’s quite useful in terms of generalizability. We want people that are doing this well or close to it before we take away medication.”
 

Positive reactions from rheumatologists

The reaction from the viewing audience was also positive. “I think this study fills a big data gap for what we do in clinical practice,” wrote Janet Pope, MD, in comments during the session.

Dr. Pope, who is a professor of medicine at the University of Western Ontario and head of rheumatology at St. Joseph’s Health Centre, both in London, said that the results build on previous work, including the CAMEO study, which showed that discontinuation of methotrexate in patients taking methotrexate and etanercept failed to achieve noninferiority to continuation of both medications, and the PRIZE study, which showed that continuing combination therapy at a reduced dose led to better outcomes than did switching to methotrexate alone or placebo. “This may be for some patients what they prefer if they don’t tolerate methotrexate,” she added.

“It’s wonderful to have these data to counsel patients. This is something we face every day,” wrote Elizabeth Wahl, MD, who is an acting assistant professor at the University of Washington, Seattle, and acting chief of rheumatology at the VA Puget Sound Healthcare System.

The study was funded by Amgen. Dr. Curtis has received grants or research support from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB. Dr. Pope consults for a variety of pharmaceutical companies. Dr. Wahl has no relevant financial disclosures.

SOURCE: Curtis JR et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0939.

In patients with RA whose disease is well controlled by methotrexate combined with etanercept, withdrawal of methotrexate led to long-term outcomes that were nearly as good as continuation of combination therapy. The finding comes from the randomized, controlled SEAM-RA trial that sought to address weaknesses of previous studies. It included a long lead-in time with stringent criteria to ensure that participants had very good disease control.

Courtesy University of Alabama at Birmingham

Both the American College of Rheumatology and the European League Against Rheumatism recommend tapering medication in RA patients who are in long-term remission, but there is no established optimal strategy.

“There have been some prior RA trials that have looked at therapy reduction or withdrawal, but most did not use a very stringent definition of how well people were when they began. Were they in remission, or only in low disease activity?” said Jeffrey R. Curtis, MD, during a presentation of the results at the virtual annual meeting of the ACR. The study was also published online Nov. 18 in Arthritis & Rheumatology.
 

Stringent remission criteria

The key feature of the trial was the 6-month run-in period, when subjects were taking 50 mg etanercept once per week and 10-25 mg of oral methotrexate once per week, and had to complete at least three visits. They were excluded from the ensuing randomization if they had a Simplified Disease Activity Index (SDAI) score >3.3 and ≤11 at two or more visits, had an SDAI >11 at any time during the run-in period, or had an SDAI >3.3 at the third run-in visit.

“We [wanted them] to be doing quite well for a long period of time. That was empirically confirmed under observation as part of the lead-in period, and even before that, the clinical investigator had to affirm that they believed the patient was doing well for 6 or more months even before they were screened to enter the trial,” said Dr. Curtis, professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.

Once enrolled in the trial, patients were randomized 2:2:1 to continuing etanercept only (n = 101), continuing methotrexate only (n = 101), or continuing both medications (n = 51). Patients were eligible for rescue after randomization if they had an SDAI score >11 at any time, SDAI between 3.3 and 11 on three separate visits, or between 3.3 and 11 at two consecutive visits at least 2 weeks apart. About three-quarters of patients in each treatment arm were female, with a mean age of about 55 years, and 82%-91% were White.

Good remission recovery with rescue therapy

At week 48, 28.7% of the methotrexate-only group were in remission (SDAI ≤3.3), compared with 49.5% of the etanercept-only group (P = .004) and 52.9% of the combination group (P = .006). Time to disease worsening was shorter in the methotrexate-only group (median, 198 days) than in the etanercept-only group (median, not estimable; P < .001) and the combined therapy group (median, not estimable; P < .001).

The researchers also found that most patients who underwent rescue therapy once again achieved remission, including 71% of the methotrexate-only group, 75% of the etanercept-only group, and 80% of the combination therapy group. There was no between-group differences in the time required to reattain remission.

The high rate of remission recovery was a good sign, Dr. Curtis said. “To me as a clinician, the risk to try [withdrawing a medication] is quite low because the likelihood you can regain where you were before is quite good. It’s obviously more successful if you stop methotrexate and continue etanercept than if you do the reverse, but to me, this is quite a practical trial, and in fact the rigor of the inclusion criteria are much more like the patients I’m talking to about stopping therapy than some of the past studies in this regard. I think it’s quite useful in terms of generalizability. We want people that are doing this well or close to it before we take away medication.”
 

Positive reactions from rheumatologists

The reaction from the viewing audience was also positive. “I think this study fills a big data gap for what we do in clinical practice,” wrote Janet Pope, MD, in comments during the session.

Dr. Pope, who is a professor of medicine at the University of Western Ontario and head of rheumatology at St. Joseph’s Health Centre, both in London, said that the results build on previous work, including the CAMEO study, which showed that discontinuation of methotrexate in patients taking methotrexate and etanercept failed to achieve noninferiority to continuation of both medications, and the PRIZE study, which showed that continuing combination therapy at a reduced dose led to better outcomes than did switching to methotrexate alone or placebo. “This may be for some patients what they prefer if they don’t tolerate methotrexate,” she added.

“It’s wonderful to have these data to counsel patients. This is something we face every day,” wrote Elizabeth Wahl, MD, who is an acting assistant professor at the University of Washington, Seattle, and acting chief of rheumatology at the VA Puget Sound Healthcare System.

The study was funded by Amgen. Dr. Curtis has received grants or research support from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB. Dr. Pope consults for a variety of pharmaceutical companies. Dr. Wahl has no relevant financial disclosures.

SOURCE: Curtis JR et al. Arthritis Rheumatol. 2020;72(suppl 10), Abstract 0939.

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

Circulating microRNAs (miRNAs) could be a potential noninvasive biomarker for early diagnosis of multiple myeloma (MM), according to the results of a meta-analysis published online in the Journal of Bone Oncology.

In recent years, because of the rise of the miRNA technique, many scholars have studied its value in the diagnosis of MM, and have obtained good but inconsistent results, according to Shuai-Shuai Gao, of the Xi’an (China) Daxing Hospital, and colleagues. For this reason, they conducted the meta-analysis in order to more clearly determine the role of miRNA in the early diagnosis of MM. The meta-analysis ultimately assessed 32 studies from 15 articles comprising 2,053 MM patients and 1,118 healthy controls.

All the included studies involved newly diagnosed MM patients and healthy controls; the obtained miRNA was derived from serum or plasma specimens; and the report contained relevant statistics such as sensitivity, specificity, and area-under-the-curve values.
 

High sensitivity and specificity

The researchers found that the overall sensitivity and specificity of using miRNAs for the diagnosis of MM were 0.81 and 0.85, respectively. In addition, the overall positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve were 5.5, 0.22, 25 and 0.90, respectively.

A subgroup analysis showed that the down-regulation of miRNA clusters with larger samples size of plasma type could carry out a better diagnostic accuracy of MM patients, according to the authors.

“[Circulating miRNAs] not only had high sensitivity and strong specificity, but also had noninvasive and no radiation risks. It is worth continuing to optimize its practicality. In the future, multicenter, more rigorous, and high-quality case-control studies are still needed in clinical practice to improve the efficacy of circulating miRNA in the early diagnosis of MM,” the researchers concluded.

The study did not receive any outside funding and the researchers reported that they had no conflicts.

[email protected]

SOURCE: Gao S-S et al. J Bone Oncol. 2020 Oct 21. doi: 10.1016/j.jbo.2020.100327.

As a result of technology, data to which individuals have long had a legal right of access are now easily accessible. The advent of secure online portals has converted what was once largely a hypothetical proposition – i.e., ready patient access to clinical records – into the increasing reality of open notes. Unsurprisingly, this movement toward greater transparency carries special implications and complexities for mental health professionals concerned with balancing patient autonomy and safety.¹

In setting clinician expectations for incorporating clinical note-sharing into patient care, it is important to clarify the already robust legal rights of patients to obtain copies of their treatment records, including in the mental health context. For example, the provision of access to one’s own health information is one of the rare circumstances in which the HIPAA Privacy Rule compels, rather than merely permits, health care organizations to disclose records to external parties.² This requirement accords with a prevailing principle of medical ethics that records should be furnished to patients or their designees upon request.³

While HIPAA provides mechanisms for denying individuals access to their health records when a licensed health care professional determines that such access is “reasonably likely” to jeopardize someone’s life or physical safety, this standard sets a high bar of physical endangerment. A psychiatrist or other physician’s concern that sharing clinical notes would be therapeutically suboptimal, discomforting, emotionally harmful, confusing, or deleterious to the doctor-patient relationship would not constitute sufficient legal grounds for denial of access.⁴

Moreover, because access is framed as a patient right, denial on the aforementioned safety grounds implicates due process requirements to include a written explanation and appellate review by a designated disinterested official. Importantly, this federally mandated right of access would preempt or override any contrary state law classified as less protective of patient prerogatives.

Contrary to popular misconception, mental health notes are not necessarily entitled to a greater degree of secrecy vis-à-vis patients than records pertaining to physical health. The HIPAA Privacy Rule, for example, generally does not distinguish between medical and mental health information, nor does it provide special rules for the latter.5 Specifically, patients’ access rights remain unchanged regardless of whether the requested record is classified as medical or psychiatric.

One narrow exception involves “psychotherapy notes,” but the legal definition of this term is considerably more restrictive than in common psychiatric usage. Psychotherapy notes under health privacy law include therapists’ private, desk-drawer notes on counseling sessions intended for personal use as memory joggers.They explicitly exclude any discussion of treatment modalities, diagnosis, or clinical progress. To retain their protected status, psychotherapy notes must be kept separate and apart from the patient chart. Indeed, a primary reason why such notes are exempted from patient access is because they have so little legitimate use other than to their creator.

Integrating the proliferation of open notes into practice regimens will likely pose a continuing and growing challenge for mental health professionals. From a medicolegal perspective, however, even psychiatrists who are understandably hesitant about widespread note-sharing would do well to remember that patients’ underlying right of access is generally well established, and is merely being operationalized and automated via web portals. Ultimately, adapting clinical record-keeping to both anticipate patient access – and, where possible, leverage it to improve care – may prove the most effective path forward for practicing psychiatry in the digital age.

Lt. Col. Kels teaches at the U.S. Army Medical Center of Excellence, and Dr. Kels teaches and practices psychiatry at the University of the Incarnate Word School of Osteopathic Medicine, both in San Antonio, Tex. Neither Lt. Col. Kels nor Dr. Kels have any conflicts of interest to disclose. Opinions expressed in this article are those of the authors alone and do not necessarily reflect those of any government agency.

References

1. Lancet Psychiatry. 2020;7(11):924-5.

2. 45 CFR Parts 160 and 164, subparts A and E.

3. American Medical Association. Code of medical ethics, opinion 3.3.1: management of medical records.

4. Department of Health & Human Services. Individuals’ right under HIPAA to access their health information.

5. Department of Health & Human Services. HIPAA privacy rule and sharing information related to mental health.

As a result of technology, data to which individuals have long had a legal right of access are now easily accessible. The advent of secure online portals has converted what was once largely a hypothetical proposition – i.e., ready patient access to clinical records – into the increasing reality of open notes. Unsurprisingly, this movement toward greater transparency carries special implications and complexities for mental health professionals concerned with balancing patient autonomy and safety.¹

In setting clinician expectations for incorporating clinical note-sharing into patient care, it is important to clarify the already robust legal rights of patients to obtain copies of their treatment records, including in the mental health context. For example, the provision of access to one’s own health information is one of the rare circumstances in which the HIPAA Privacy Rule compels, rather than merely permits, health care organizations to disclose records to external parties.² This requirement accords with a prevailing principle of medical ethics that records should be furnished to patients or their designees upon request.³

While HIPAA provides mechanisms for denying individuals access to their health records when a licensed health care professional determines that such access is “reasonably likely” to jeopardize someone’s life or physical safety, this standard sets a high bar of physical endangerment. A psychiatrist or other physician’s concern that sharing clinical notes would be therapeutically suboptimal, discomforting, emotionally harmful, confusing, or deleterious to the doctor-patient relationship would not constitute sufficient legal grounds for denial of access.⁴

Moreover, because access is framed as a patient right, denial on the aforementioned safety grounds implicates due process requirements to include a written explanation and appellate review by a designated disinterested official. Importantly, this federally mandated right of access would preempt or override any contrary state law classified as less protective of patient prerogatives.

Contrary to popular misconception, mental health notes are not necessarily entitled to a greater degree of secrecy vis-à-vis patients than records pertaining to physical health. The HIPAA Privacy Rule, for example, generally does not distinguish between medical and mental health information, nor does it provide special rules for the latter.5 Specifically, patients’ access rights remain unchanged regardless of whether the requested record is classified as medical or psychiatric.

One narrow exception involves “psychotherapy notes,” but the legal definition of this term is considerably more restrictive than in common psychiatric usage. Psychotherapy notes under health privacy law include therapists’ private, desk-drawer notes on counseling sessions intended for personal use as memory joggers.They explicitly exclude any discussion of treatment modalities, diagnosis, or clinical progress. To retain their protected status, psychotherapy notes must be kept separate and apart from the patient chart. Indeed, a primary reason why such notes are exempted from patient access is because they have so little legitimate use other than to their creator.

Integrating the proliferation of open notes into practice regimens will likely pose a continuing and growing challenge for mental health professionals. From a medicolegal perspective, however, even psychiatrists who are understandably hesitant about widespread note-sharing would do well to remember that patients’ underlying right of access is generally well established, and is merely being operationalized and automated via web portals. Ultimately, adapting clinical record-keeping to both anticipate patient access – and, where possible, leverage it to improve care – may prove the most effective path forward for practicing psychiatry in the digital age.

Lt. Col. Kels teaches at the U.S. Army Medical Center of Excellence, and Dr. Kels teaches and practices psychiatry at the University of the Incarnate Word School of Osteopathic Medicine, both in San Antonio, Tex. Neither Lt. Col. Kels nor Dr. Kels have any conflicts of interest to disclose. Opinions expressed in this article are those of the authors alone and do not necessarily reflect those of any government agency.

References

1. Lancet Psychiatry. 2020;7(11):924-5.

2. 45 CFR Parts 160 and 164, subparts A and E.

3. American Medical Association. Code of medical ethics, opinion 3.3.1: management of medical records.

4. Department of Health & Human Services. Individuals’ right under HIPAA to access their health information.

5. Department of Health & Human Services. HIPAA privacy rule and sharing information related to mental health.

As a result of technology, data to which individuals have long had a legal right of access are now easily accessible. The advent of secure online portals has converted what was once largely a hypothetical proposition – i.e., ready patient access to clinical records – into the increasing reality of open notes. Unsurprisingly, this movement toward greater transparency carries special implications and complexities for mental health professionals concerned with balancing patient autonomy and safety.¹

In setting clinician expectations for incorporating clinical note-sharing into patient care, it is important to clarify the already robust legal rights of patients to obtain copies of their treatment records, including in the mental health context. For example, the provision of access to one’s own health information is one of the rare circumstances in which the HIPAA Privacy Rule compels, rather than merely permits, health care organizations to disclose records to external parties.² This requirement accords with a prevailing principle of medical ethics that records should be furnished to patients or their designees upon request.³

While HIPAA provides mechanisms for denying individuals access to their health records when a licensed health care professional determines that such access is “reasonably likely” to jeopardize someone’s life or physical safety, this standard sets a high bar of physical endangerment. A psychiatrist or other physician’s concern that sharing clinical notes would be therapeutically suboptimal, discomforting, emotionally harmful, confusing, or deleterious to the doctor-patient relationship would not constitute sufficient legal grounds for denial of access.⁴

Moreover, because access is framed as a patient right, denial on the aforementioned safety grounds implicates due process requirements to include a written explanation and appellate review by a designated disinterested official. Importantly, this federally mandated right of access would preempt or override any contrary state law classified as less protective of patient prerogatives.

Contrary to popular misconception, mental health notes are not necessarily entitled to a greater degree of secrecy vis-à-vis patients than records pertaining to physical health. The HIPAA Privacy Rule, for example, generally does not distinguish between medical and mental health information, nor does it provide special rules for the latter.5 Specifically, patients’ access rights remain unchanged regardless of whether the requested record is classified as medical or psychiatric.

One narrow exception involves “psychotherapy notes,” but the legal definition of this term is considerably more restrictive than in common psychiatric usage. Psychotherapy notes under health privacy law include therapists’ private, desk-drawer notes on counseling sessions intended for personal use as memory joggers.They explicitly exclude any discussion of treatment modalities, diagnosis, or clinical progress. To retain their protected status, psychotherapy notes must be kept separate and apart from the patient chart. Indeed, a primary reason why such notes are exempted from patient access is because they have so little legitimate use other than to their creator.

Integrating the proliferation of open notes into practice regimens will likely pose a continuing and growing challenge for mental health professionals. From a medicolegal perspective, however, even psychiatrists who are understandably hesitant about widespread note-sharing would do well to remember that patients’ underlying right of access is generally well established, and is merely being operationalized and automated via web portals. Ultimately, adapting clinical record-keeping to both anticipate patient access – and, where possible, leverage it to improve care – may prove the most effective path forward for practicing psychiatry in the digital age.

Lt. Col. Kels teaches at the U.S. Army Medical Center of Excellence, and Dr. Kels teaches and practices psychiatry at the University of the Incarnate Word School of Osteopathic Medicine, both in San Antonio, Tex. Neither Lt. Col. Kels nor Dr. Kels have any conflicts of interest to disclose. Opinions expressed in this article are those of the authors alone and do not necessarily reflect those of any government agency.

References

1. Lancet Psychiatry. 2020;7(11):924-5.

2. 45 CFR Parts 160 and 164, subparts A and E.

3. American Medical Association. Code of medical ethics, opinion 3.3.1: management of medical records.

4. Department of Health & Human Services. Individuals’ right under HIPAA to access their health information.

5. Department of Health & Human Services. HIPAA privacy rule and sharing information related to mental health.