Conference Coverage

Children whose parents are coping with illness and injuries were more likely to need medical treatment and prescriptions for gastrointestinal conditions, for which previous research already has indicated a brain-gut connection, an investigator said.

In a self-controlled case series using records from the Military Health System Data Repository, pediatric visits for disorders linked to gut-brain interactions were found to have increased 9% (incidence rate ratio, 1.09; 95% CI, 1.07-1.10) following a parent’s illness or injury, reported lead author Patrick Short, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., said in an interview. The Military Health System Data Repository receives records from the Department of Defense’s global network of more than 260 medical facilities as well as outside health care organizations where military families are seen.

A secondary analysis done for this study found children of brain injured parents had 4% more postinjury visits for abdominal pain and 23% increased odds of antispasmodic prescription, compared with children whose parents had other physical injuries, Dr. Short said. He presented his research in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19. The study focused on children aged 3-16 years with a parent who served in the military and was ill or injured between 2004 and 2014. Excluded from this research were records for children with diagnosed systemic or organic gastrointestinal disease, such as celiac disease.

The study used ICD-9 codes to identify outpatient visits for irritable bowel syndrome, abdominal pain, constipation, and fecal incontinence in the 2 years before and after parental injury or diagnosis of illness. Outpatient pharmacy records showed which of the children studied took laxatives and antispasmodics.

Parental injury or illness was defined by the placement of the children’s mothers and fathers on the injured, ill, or wounded file in the data repository. The data file generally covers people with conditions that severely limit their ability to do their usual jobs. These include traumatic brain injury, PTSD, amputation, shrapnel injury, and illnesses such as cancer.

There was a 7% increase in visits for constipation but fecal incontinence did not significantly change following parental illness or injury, Dr. Short said. But the odds of being prescribed an antispasmodic increased 23% following parents’ injuries and serious illnesses, while the odds for laxative prescription decreased by 5%.

The study highlights the potential physical impact of stress on children when families experience a crisis, Dr. Short said in an interview. Children may feel anxious about their parent’s health, while at the same time experiencing unavoidable disruption in family life because of an injury or illness.

“It impacts the day-to-day regimens and routines and decreases the family support,” Dr. Short said. “As humans we are limited in what we have to offer. When we are trying to take care of things on our own, it limits what we can give to people around us.”

The findings of this study should serve to remind physicians to alert parents that their children could experience worsening of GI conditions because of the stress of an ill or injured parent. They then can focus on securing help ahead of the time for the child, such as therapy, he said.

The next step in advancing on the research he prepared for DDW could be testing through prospective studies how well preventive measures such as family counseling work, Dr. Short said.

Dr. Short’s research adds to the growing body of evidence about the brain-gut connection, said Kara Gross Margolis, MD, a spokesperson for the American Gastroenterological Association. An associate professor of pediatrics at Columbia University Medical Center, New York, Dr. Margolis has published research on the brain-gut axis. Her lab focuses on the effects of neurotransmitters and inflammation on enteric nervous system development and function.

Physicians should take a broad view when treating children for functional GI illnesses. Behavioral therapy and antidepressants, for example, have been shown to help children with conditions such as irritable bowel syndrome and other functional gastrointestinal diseases, said Dr. Margolis.

“In a number of these cases, we not only have to treat the gut. We have to treat the brain as well,” Dr. Margolis said.

“When mental health issues are involved that impact the parents of these kids, You have to look at a family as an entire unit,” she added. “You not only treat the child for those symptoms, but you really have to look at how their parents can also be cared for so that their impact on their children will be positive as well.”

Research in the vein explored by Dr. Short will be important to remember as society works through the legacy of the COVID-19 pandemic, Dr. Margolis said. “We have huge numbers of families undergoing tremendous stress due to loss of jobs, health care, medical issues, and parental injury potentially from coronavirus.”

No outside funding was reported, and the study was covered through Uniformed Services University budget.

SOURCE: Short P et al. DDW 2020, Abstract 815.

Children whose parents are coping with illness and injuries were more likely to need medical treatment and prescriptions for gastrointestinal conditions, for which previous research already has indicated a brain-gut connection, an investigator said.

In a self-controlled case series using records from the Military Health System Data Repository, pediatric visits for disorders linked to gut-brain interactions were found to have increased 9% (incidence rate ratio, 1.09; 95% CI, 1.07-1.10) following a parent’s illness or injury, reported lead author Patrick Short, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., said in an interview. The Military Health System Data Repository receives records from the Department of Defense’s global network of more than 260 medical facilities as well as outside health care organizations where military families are seen.

A secondary analysis done for this study found children of brain injured parents had 4% more postinjury visits for abdominal pain and 23% increased odds of antispasmodic prescription, compared with children whose parents had other physical injuries, Dr. Short said. He presented his research in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19. The study focused on children aged 3-16 years with a parent who served in the military and was ill or injured between 2004 and 2014. Excluded from this research were records for children with diagnosed systemic or organic gastrointestinal disease, such as celiac disease.

The study used ICD-9 codes to identify outpatient visits for irritable bowel syndrome, abdominal pain, constipation, and fecal incontinence in the 2 years before and after parental injury or diagnosis of illness. Outpatient pharmacy records showed which of the children studied took laxatives and antispasmodics.

Parental injury or illness was defined by the placement of the children’s mothers and fathers on the injured, ill, or wounded file in the data repository. The data file generally covers people with conditions that severely limit their ability to do their usual jobs. These include traumatic brain injury, PTSD, amputation, shrapnel injury, and illnesses such as cancer.

There was a 7% increase in visits for constipation but fecal incontinence did not significantly change following parental illness or injury, Dr. Short said. But the odds of being prescribed an antispasmodic increased 23% following parents’ injuries and serious illnesses, while the odds for laxative prescription decreased by 5%.

The study highlights the potential physical impact of stress on children when families experience a crisis, Dr. Short said in an interview. Children may feel anxious about their parent’s health, while at the same time experiencing unavoidable disruption in family life because of an injury or illness.

“It impacts the day-to-day regimens and routines and decreases the family support,” Dr. Short said. “As humans we are limited in what we have to offer. When we are trying to take care of things on our own, it limits what we can give to people around us.”

The findings of this study should serve to remind physicians to alert parents that their children could experience worsening of GI conditions because of the stress of an ill or injured parent. They then can focus on securing help ahead of the time for the child, such as therapy, he said.

The next step in advancing on the research he prepared for DDW could be testing through prospective studies how well preventive measures such as family counseling work, Dr. Short said.

Dr. Short’s research adds to the growing body of evidence about the brain-gut connection, said Kara Gross Margolis, MD, a spokesperson for the American Gastroenterological Association. An associate professor of pediatrics at Columbia University Medical Center, New York, Dr. Margolis has published research on the brain-gut axis. Her lab focuses on the effects of neurotransmitters and inflammation on enteric nervous system development and function.

Physicians should take a broad view when treating children for functional GI illnesses. Behavioral therapy and antidepressants, for example, have been shown to help children with conditions such as irritable bowel syndrome and other functional gastrointestinal diseases, said Dr. Margolis.

“In a number of these cases, we not only have to treat the gut. We have to treat the brain as well,” Dr. Margolis said.

“When mental health issues are involved that impact the parents of these kids, You have to look at a family as an entire unit,” she added. “You not only treat the child for those symptoms, but you really have to look at how their parents can also be cared for so that their impact on their children will be positive as well.”

Research in the vein explored by Dr. Short will be important to remember as society works through the legacy of the COVID-19 pandemic, Dr. Margolis said. “We have huge numbers of families undergoing tremendous stress due to loss of jobs, health care, medical issues, and parental injury potentially from coronavirus.”

No outside funding was reported, and the study was covered through Uniformed Services University budget.

SOURCE: Short P et al. DDW 2020, Abstract 815.

Children whose parents are coping with illness and injuries were more likely to need medical treatment and prescriptions for gastrointestinal conditions, for which previous research already has indicated a brain-gut connection, an investigator said.

In a self-controlled case series using records from the Military Health System Data Repository, pediatric visits for disorders linked to gut-brain interactions were found to have increased 9% (incidence rate ratio, 1.09; 95% CI, 1.07-1.10) following a parent’s illness or injury, reported lead author Patrick Short, MD, of the Uniformed Services University of the Health Sciences, Bethesda, Md., said in an interview. The Military Health System Data Repository receives records from the Department of Defense’s global network of more than 260 medical facilities as well as outside health care organizations where military families are seen.

A secondary analysis done for this study found children of brain injured parents had 4% more postinjury visits for abdominal pain and 23% increased odds of antispasmodic prescription, compared with children whose parents had other physical injuries, Dr. Short said. He presented his research in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19. The study focused on children aged 3-16 years with a parent who served in the military and was ill or injured between 2004 and 2014. Excluded from this research were records for children with diagnosed systemic or organic gastrointestinal disease, such as celiac disease.

The study used ICD-9 codes to identify outpatient visits for irritable bowel syndrome, abdominal pain, constipation, and fecal incontinence in the 2 years before and after parental injury or diagnosis of illness. Outpatient pharmacy records showed which of the children studied took laxatives and antispasmodics.

Parental injury or illness was defined by the placement of the children’s mothers and fathers on the injured, ill, or wounded file in the data repository. The data file generally covers people with conditions that severely limit their ability to do their usual jobs. These include traumatic brain injury, PTSD, amputation, shrapnel injury, and illnesses such as cancer.

There was a 7% increase in visits for constipation but fecal incontinence did not significantly change following parental illness or injury, Dr. Short said. But the odds of being prescribed an antispasmodic increased 23% following parents’ injuries and serious illnesses, while the odds for laxative prescription decreased by 5%.

The study highlights the potential physical impact of stress on children when families experience a crisis, Dr. Short said in an interview. Children may feel anxious about their parent’s health, while at the same time experiencing unavoidable disruption in family life because of an injury or illness.

“It impacts the day-to-day regimens and routines and decreases the family support,” Dr. Short said. “As humans we are limited in what we have to offer. When we are trying to take care of things on our own, it limits what we can give to people around us.”

The findings of this study should serve to remind physicians to alert parents that their children could experience worsening of GI conditions because of the stress of an ill or injured parent. They then can focus on securing help ahead of the time for the child, such as therapy, he said.

The next step in advancing on the research he prepared for DDW could be testing through prospective studies how well preventive measures such as family counseling work, Dr. Short said.

Dr. Short’s research adds to the growing body of evidence about the brain-gut connection, said Kara Gross Margolis, MD, a spokesperson for the American Gastroenterological Association. An associate professor of pediatrics at Columbia University Medical Center, New York, Dr. Margolis has published research on the brain-gut axis. Her lab focuses on the effects of neurotransmitters and inflammation on enteric nervous system development and function.

Physicians should take a broad view when treating children for functional GI illnesses. Behavioral therapy and antidepressants, for example, have been shown to help children with conditions such as irritable bowel syndrome and other functional gastrointestinal diseases, said Dr. Margolis.

“In a number of these cases, we not only have to treat the gut. We have to treat the brain as well,” Dr. Margolis said.

“When mental health issues are involved that impact the parents of these kids, You have to look at a family as an entire unit,” she added. “You not only treat the child for those symptoms, but you really have to look at how their parents can also be cared for so that their impact on their children will be positive as well.”

Research in the vein explored by Dr. Short will be important to remember as society works through the legacy of the COVID-19 pandemic, Dr. Margolis said. “We have huge numbers of families undergoing tremendous stress due to loss of jobs, health care, medical issues, and parental injury potentially from coronavirus.”

No outside funding was reported, and the study was covered through Uniformed Services University budget.

SOURCE: Short P et al. DDW 2020, Abstract 815.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

Two MEK inhibitors were tested against recurrent low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum, but only one inhibitor offered clinical benefit over standard care, investigators from two randomized trials reported.

Trametinib improved progression-free survival (PFS) when compared with standard care, while binimetinib conferred no PFS benefit.

In a phase 2/3 trial, the median PFS was 13 months for patients treated with trametinib and 7.2 months for patients who received an aromatase inhibitor or chemotherapy (P < .0001).

“Our findings suggest that trametinib represents a new standard-of-care treatment option for women with recurrent low-grade serous carcinoma,” said investigator David M. Gershenson, MD, of the University of Texas MD Anderson Cancer Center in Houston.

In contrast, in the phase 3 MILO/ENGOT-ov11 trial, there was no significant difference in PFS between patients treated with binimetinib and those who received physician’s choice of chemotherapy. The median PFS was 11.2 months with binimetinib and 14.1 months with chemotherapy (P = .752).

“Although this study did not meet its primary endpoint, binimetinib showed activity in low-grade serous ovarian cancer across the efficacy endpoints evaluated, with a response rate of 24% and a median PFS of 11.2 months on updated analysis. Chemotherapy responses were better than predicted, based on historical retrospective data,” said investigator Rachel N. Grisham, MD, of Memorial Sloan Kettering Cancer Center in New York.

The binimetinib trial and the trametinib trial were both discussed during a webinar on rare tumors covering research slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic.
 

Chemoresistant cancers

Low-grade serous ovarian or peritoneal cancers are rare, accounting for only 5% to 10% of all serous cancers, Dr. Gershenson noted.

“[Low-grade serous cancers are] characterized by alterations in the MAP kinase pathway, as well as relative chemoresistance, and prolonged overall survival compared to high-grade serous cancers. Because of this subtype’s relative chemoresistance, the search for novel therapeutics has predominated over the last decade or so,” he said.

MEK inhibitors interfere with the MEK1 and MEK2 enzymes in the MAPK pathway. Alterations in MAPK, especially in KRAS and BRAF proteins, are found in 30%-60% of low-grade serous carcinomas, providing the rationale for MEK inhibitors in these rare malignancies.
 

Trametinib study

In a phase 2/3 study, Dr. Gershenson and colleagues enrolled 260 patients with recurrent, low-grade serous carcinoma of the ovary or peritoneum. Patients were randomized to receive either trametinib at 2 mg daily continuously until progression (n = 130) or standard care (n = 130).

Standard care consisted of one of the following: letrozole at 2.5 mg daily; pegylated liposomal doxorubicin at 40-50 mg IV every 28 days; weekly paclitaxel at 80 mg/m² for 3 out of 4 weeks; tamoxifen at 20 mg twice daily; or topotecan at 4 mg/m² on days 1, 8, and 15 every 28 days. Patients randomized to standard care could be crossed over to trametinib at progression.

All patients had at least one prior line of platinum-based chemotherapy, and nearly half had three or more prior lines of therapy. The median age was 56.6 years in the trametinib arm and 55.3 years in the control arm.

At a median follow-up of 31.4 months, median PFS, the primary endpoint, was 13 months with trametinib vs. 7.2 months with standard care. The hazard ratio (HR) for progression on trametinib was 0.48 (P < .0001).

The overall response rates were 26.2% in the trametinib arm and 6.2% in the standard care arm. The odds ratio for response on trametinib was 5.4 (P < .0001).

For 88 patients who crossed over to trametinib, the median PFS was 10.8 months, and the overall response rate was 15%.

Trametinib was also associated with a significantly longer response duration, at a median of 13.6 months, compared with 5.9 months for standard care (P value not shown).

The median overall survival was 37 months with trametinib and 29.2 months with standard care, with an HR favoring trametinib of 0.75, although this just missed statistical significance (P = .054). Dr. Gershenson pointed out that the overall survival in the standard care arm included patients who had been crossed over to trametinib.

Grade 3 or greater adverse events included hematologic toxicities in 13.4% of patients on trametinib and 9.4% on standard care; gastrointestinal toxicity in 27.6% and 29%, respectively; skin toxicities in 15% and 3.9%, respectively; and vascular toxicities in 18.9% and 8.6%, respectively.
 

Binimetinib study

The phase 3 MILO/ENGOT-ov11 study enrolled 341 patients with low-grade serous carcinomas of the ovaries, fallopian tubes, or peritoneum. Patients were randomized on a 2:1 basis to receive either binimetinib at 45 mg twice daily (n = 228) or physician’s choice of chemotherapy (n = 113). Chemotherapy consisted of pegylated liposomal doxorubicin at 40 mg/m² on day 1 of each 28-day cycle; paclitaxel at 80 mg/m² on days 1, 8, and 15 of each 28-day cycle; or topotecan at 1.25 mg/m² IV on days 1-5 of each 21-day cycle.

The efficacy analysis included 227 patients assigned to binimetinib and 106 assigned to chemotherapy.

A planned interim analysis was performed in 2016 after the first 303 patients were enrolled. At that time, the median PFS by blinded central review was 9.1 months in the binimetinib arm and 10.6 months in the physician’s choice arm (HR, 1.21; P = .807), so the trial was halted early for futility. Patients on active treatment at the time could continue until progression and were followed by local radiology.

At the interim analysis, secondary endpoints were also similar between the arms. The overall response rate was 16% in the binimetinib arm and 13% in the chemotherapy arm.

The most common grade 3 or greater adverse events with binimetinib were blood creatinine phosphokinase increase (26%) and vomiting (10%).

Dr. Grisham also reported updated follow-up results through January 2019.

The median PFS in the updated analysis was 11.2 months with the MEK inhibitor and 14.1 months with chemotherapy, a difference that was not statistically significant (HR, 1.12; P = .752). Updated overall response rates were the same in both arms, at 24%.

A post hoc molecular analysis of 215 patients suggested a possible association between KRAS mutation and response to binimetinib.
 

Two MEKs, one ‘meh’

Discussant Jubilee Brown, MD, of the Levine Cancer Institute at Atrium Health in Charlotte, N.C., said that “with a 2% to 5% chance of response in patients with low-grade serous ovarian cancer, there is a low bar for any compound to demonstrate success.”

Regarding the MILO/ENGOT-ov11 trial, she noted that “this study did not meet its primary endpoint, but perhaps the endpoint is not reflective of the importance of the study.”

A different outcome might have occurred had investigators stratified patients by KRAS status upfront, comparing patients with KRAS mutations treated with binimetinib to KRAS wild-type patients treated with either a MEK inhibitor or physician’s choice of care, Dr. Brown said.

She agreed with the assertion by Dr. Gershenson and colleagues that improved PFS qualifies trametinib to be considered a new option for standard care, ”especially in a rare tumor setting with limited options. This is a huge win for patients.”

The trametinib study was sponsored by NRG Oncology and the UK National Cancer Research Institute. Dr. Gershenson disclosed relationships with NRG Oncology, Genentech, Novartis, Elsevier, and UpToDate, as well as stock in several companies.

The binimetinib study was sponsored by Pfizer. Dr. Grisham disclosed relationships with Clovis, Regeneron, Mateon, Amgen, Abbvie, OncLive, PRIME, MCM, and Medscape. MDedge News and Medscape are owned by the same parent organization.

Dr. Brown disclosed consulting for Biodesix, Caris, Clovis, Genentech, Invitae, Janssen, Olympus, OncLive, and Tempus.

SOURCE: Gershenson DM et al. SGO 2020, Abstract 42; Grisham RN et al. SGO 2020, Abstract 41.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

Traditionally at this time of year, everyone working in cancer turns their attention toward Chicago, and 40,000 or so travel to the city for the annual meeting of the American Society of Clinical Oncology (ASCO).

Not this year.

The McCormick Place convention center has been converted to a field hospital to cope with the ongoing COVID-19 pandemic. The cavernous meeting halls have been filled with makeshift wards with 750 acute care beds, as shown in a tweet from Toni Choueiri, MD, chief of genitourinary oncology at the Dana Farber Cancer Center in Boston.

But the annual meeting is still going ahead, having been transferred online.

“We have to remember that even though there’s a pandemic going on and people are dying every day from coronavirus, people are still dying every day from cancer,” Richard Schilsky, MD, PhD, chief medical officer at ASCO, told Medscape Medical News.

“This pandemic will end, but cancer will continue, and we need to be able to continue to get the most cutting edge scientific results out there to our members and our constituents so they can act on those results on behalf of their patients,” he said.

The ASCO Virtual Scientific Program will take place over the weekend of May 30-31.

“We’re certainly hoping that we’re going to deliver a program that features all of the most important science that would have been presented in person in Chicago,” Schilsky commented in an interview.

Most of the presentations will be prerecorded and then streamed, which “we hope will mitigate any of the technical glitches that could come from trying to do a live broadcast of the meeting,” he said.

There will be 250 oral and 2500 poster presentations in 24 disease-based and specialty tracks.

The majority of the abstracts will be released online on May 13. The majority of the on-demand content will be released on May 29. Some of the abstracts will be highlighted at ASCO press briefings and released on those two dates.

But some of the material will be made available only on the weekend of the meeting. The opening session, plenaries featuring late-breaking abstracts, special highlights sessions, and other clinical science symposia will be broadcast on Saturday, May 30, and Sunday, May 31 (the schedule for the weekend program is available on the ASCO meeting website).

Among the plenary presentations are some clinical results that are likely to change practice immediately, Schilsky predicted. These include data to be presented in the following abstracts:

• Abstract LBA4 on the KEYNOTE-177 study comparing immunotherapy using pembrolizumab (Keytruda, Merck & Co) with chemotherapy in patients with metastatic colorectal cancer whose tumors show microsatellite instability or mismatch repair deficiency;
• Abstract LBA5 on the ADAURA study exploring osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy after complete tumor reseaction in patients with early-stage non–small cell lung cancer whose tumors are EGFR mutation positive;
• Abstract LBA1 on the JAVELIN Bladder 100 study exploring maintenance avelumab (Bavencio, Merck and Pfizer) with best supportive care after platinum-based first-line chemotherapy in patients with advanced urothelial carcinoma.

However, some of the material that would have been part of the annual meeting, which includes mostly educational sessions and invited talks, has been moved to another event, the ASCO Educational Program, to be held in August 2020.

“So I suppose, in the grand scheme of things, the meeting is going to be compressed a little bit,” Schilsky commented. “Obviously, we can’t deliver all the interactions that happen in the hallways and everywhere else at the meeting that really gives so much energy to the meeting, but, at this moment in our history, probably getting the science out there is what’s most important.”
 

Virtual exhibition hall

There will also be a virtual exhibition hall, which will open on May 29.

“Just as there is a typical exhibit hall in the convention center,” Schilsky commented, most of the companies that were planning to be in Chicago have “now transitioned to creating a virtual booth that people who are participating in the virtual meeting can visit.

“I don’t know exactly how each company is going to use their time and their virtual space, and that’s part of the whole learning process here to see how this whole experiment is going to work out,” he added.

Unlike some of the other conferences that have gone virtual, in which access has been made available to everyone for free, registration is still required for the ASCO meeting. But the society notes that the registration fee has been discounted for nonmembers and has been waived for ASCO members. Also, the fee covers both the Virtual Scientific Program in May and the ASCO Educational Program in August.

Registrants will have access to video and slide presentations, as well as discussant commentaries, for 180 days.

The article first appeared on Medscape.com.

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com

Evolocumab proved effective, well tolerated, and safe for the treatment of refractory dyslipidemia in persons living with HIV in the phase 3, randomized, double-blind BEIJERINCK study.

At 24 weeks, nearly three-quarters of patients randomized to evolocumab (Repatha) achieved at least a 50% reduction in LDL cholesterol while on maximally tolerated background lipid lowering with a statin and/or other drugs. This was accompanied by significant reductions in other atherogenic lipids, Franck Boccara, MD, PhD, reported at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic.

Evolocumab thus shows the potential to help fill a major unmet need for more effective treatment of dyslipidemia in HIV-positive patients, who number an estimated 38 million worldwide, including 1.1 million in the United States. Access to highly active antiretroviral therapies has transformed HIV infection into a chronic manageable disease, but this major advance has been accompanied by a rate of premature atherosclerotic cardiovascular disease that’s nearly twice that of the general population, observed Dr. Boccara, a cardiologist at Sorbonne University, Paris.

The BEIJERINCK study included 464 HIV-infected patients in the United States and 14 other countries on five continents. Participants had a mean baseline LDL cholesterol of 133 mg/dL and triglycerides of about 190 mg/dL while on maximally tolerated lipid-lowering therapy. They had been diagnosed with HIV an average of 18 years earlier. One-third of them had known atherosclerotic cardiovascular disease. More than one-quarter of participants were cigarette smokers. Patients were randomized 2:1 to 24 weeks of double-blind subcutaneous evolocumab at 420 mg once monthly or placebo, then an additional 24 weeks of open-label evolocumab for all.

The primary endpoint was change in LDL from baseline to week 24: a 56.2% reduction in the evolocumab group and a 0.7% increase with placebo. About 73% of patients on evolocumab achieved at least a 50% reduction in LDL cholesterol, as did less than 1% of controls. Likewise, 73% of the evolocumab group got their LDL cholesterol below 70 mg/dL, compared with 7.9% with placebo.

The evolocumab group also experienced favorable placebo-subtracted differences from baseline of 23% in triglycerides, 27% in lipoprotein(a), and 22% in very-low-density lipoprotein cholesterol.

As was the case in the earlier, much larger landmark clinical trials, evolocumab was well tolerated in BEIJERINCK, with a side effect profile similar to placebo. Notably, there was no increase in liver abnormalities in evolocumab-treated patients on highly active antiretroviral therapy, and no one developed evolocumab neutralizing antibodies.

Dr. Boccara reported receiving a research grant from Amgen, the study sponsor, as well as lecture fees from several other pharmaceutical companies.

Simultaneous with the presentation at ACC 2020, the primary results of the BEIJERINCK study were published online (J Am Coll Cardiol. 2020 Mar 19. doi: 10.1016/j.jacc.2020.03.025).

bjancin@mdedge.com

Results from a prospective, multicenter, uncontrolled series of just over 1,500 patients with high bleeding risk who underwent coronary revascularization with a polymer-based, zotarolimus-eluting stent showed that these patients could safely receive dual-antiplatelet therapy (DAPT)for just 1 month.

This finding sets the stage for a new labeled indication for this device and management strategy in this patient population.

Results from the Onyx ONE Clear study “met its primary endpoint, with favorable rates of ischemic outcomes from 1-12 months after DAPT discontinuation within a high risk population of HBR [high-bleeding-risk] patients,” Ajay J. Kirtane, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. The rate of cardiac death or MI during months 1-12 of follow-up while patients were on single-antiplatelet therapy (SAPT) with either aspirin or a P2Y12 inhibitor, usually clopidogrel, was 7.0%, compared with a prespecified performance goal of 9.7% or less, a goal set in consultation with and approval from the Food and Drug Administration based on the results from earlier, short DAPT studies in HBR patients.

“We hope these data will support our submission to the FDA for a 1-month DAPT indication for high-bleeding-risk patients treated with Resolute Onyx,” the polymer-based, zotarolimus-eluting stent tested in the study, said an officer with Medtronic, the company that sponsored this study and markets this stent, in a written statement. Currently, no stent has received a U.S. indication for just 1 month of DAPT treatment.

Mitchel L. Zoler/MDedge News

“The Onyx ONE Clear study represents the largest analysis of 1-month DAPT among commercially available DES [drug-eluting stents], and extends findings from the Onyx ONE [randomized, controlled trial] assuring the safety of a 1-month DAPT strategy among selected patients with high bleeding risk,” said David E. Kandzari, MD, director of interventional cardiology at Piedmont Healthcare in Atlanta and coprincipal investigator for the study along with Dr. Kirtane.

“Despite the patient complexity included in the study, the observation of a favorably low rate of ischemic events despite abbreviated DAPT is consistent with a theme from other contemporary studies that, among HBR patients, bleeding risk rather than ischemic risk should guide clinical decision making regarding DAPT duration,” Dr. Kandzari said in an interview.
 

Two similar trials

The Onyx ONE Clear results were consistent with findings from a study with a somewhat similar design, LEADERS FREE II, a single-arm study that assessed the safety and efficacy of BioFreedom, a polymer-free umirolimus-coated coronary stent, in HBR patients treated with DAPT for 1 month followed by SAPT.

LEADERS FREE II showed a 12-month cardiac death or MI rate of 8.6% that compared favorably with the 12.3% 1-year rate among similar patients who received bare-metal stents and a similar timing of DAPT and SAPT in a historical control group (Circ Cardiovasc Interv. 2020 Apr 13. doi: 10.1161/CIRCINTERVENTIONS.119.008603). The primary goal of LEADERS FREE II was to serve as the pivotal trial for FDA approval of the BioFreedom stent, but as of May 2020 the FDA had not approved this stent for U.S. use.

Results of another recent study, Onyx ONE, that supplied more than half the patients included in the Onyx ONE Clear analysis, showed that, in a head-to-head comparison of the Onxy and BioFreedom stents in 1,996 HBR patients treated with DAPT for 1 month followed by 11 months of SAPT, the Onyx stent was noninferior for both a primary safety outcome and a secondary efficacy outcome (N Engl J Med. 2020 Mar 26;382[13]:1208-18).

“The major differences” between the Onyx and BioFreedom stents in the patients studied in Onxy ONE Clear and in LEADERS FREE II “lie in the fact that BioFreedom is not approved in the U.S., and that Onyx is a current generation, preferred DES platform for both conventional and HBR patients,” Dr. Kirtane said in an interview.

“Because of the performance characteristics of Onyx, as well as the fact that ONYX ONE studied a far more complex group of patients than other shorter DAPT studies with conventional DES, I personally feel that there will be a preference to use this stent as a result of these data,” added Dr. Kirtane, professor of medicine at Columbia University and director of the coronary catheterization laboratory at New York–Presbyterian Hospital in New York.

The results from Onyx ONE “are critical for changing practice” among U.S. interventionalists, commented Sunil V. Rao, MD, an interventional cardiologist and professor of medicine at Duke University, Durham, N.C. Based on the new findings, U.S. operators performing percutaneous coronary interventions “will feel comfortable stopping DAPT in patients who are at high bleeding risk,” he said in an interview.

Although the results from LEADERS FREE II showed that the BioFreedom stent was superior to a bare-metal stent with 1 month of DAPT in HBR patients, and the results from Onyx ONE showed that the Onyx stent was noninferior to BioFreedom in this setting, “it’s important not to assume that there is a class effect across DES platforms. Each platform has a different drug and different stent design, so the interventional community needs to see these data for each DES,” Dr. Rao maintained.
 

Onyx ONE Clear design

Onyx ONE Clear enrolled a total of 1,506 patients, including more than 1,000 patients who received the Onyx stent in the Onyx ONE trial and an additional 752 patients enrolled in the United States and Japan, but 263 of these patients had an adverse event during their first 30 days or follow-up leaving 1,506 patients eligible to continue into the Onyx ONE Clear analysis, and with 1,491 patients followed through 12 months. Patients were an average age of 74 years, a little over two-thirds were men, 49% had a recent acute coronary syndrome event and 41% had chronic coronary syndrome. The choice of which antiplatelet agent to continue when patients transitioned to SAPT after 30 days on DAPT was left to the discretion of the physicians for each enrolled patient.

One issue these studies did not address was whether 1 month is the ideal duration for DAPT before switching to SAPT in HBR patients following coronary stenting, or whether longer DAPT durations produce even better outcomes. “It was important to establish what happens if we need to stop DAPT early.” The Onyx ONE and Onyx ONE Clear studies “provide much-needed data informing clinicians of the risks and safety of SAPT after 1 month in appropriately selected patients,” Dr. Kirtane said.

“The results do not indicate that all HBR patients should be treated with 1 month [of] DAPT, but instead demonstrate the safety and effectiveness of this strategy when clinically appropriate.” This scenario “is quite common, given that HBR patients represent up to a third” of patients undergoing percutaneous coronary intervention, Dr. Kandzari said.

Onyx ONE and Onyx ONE Clear were sponsored by Medtronic, the company that markets the Onyx coronary stent. Dr. Kirtane’s institution has received research support from Medtronic, and from Abbott Vascular, Abiomed, Boston Scientific, Cathworks, CSI, Philips, ReCor Medical, and Siemens. Dr. Kandzari has received personal fees and research grants from medtronic, personal fees from Biotronik and Cardiovascular Systems, and research grants from Biotronik, Boston Scientific, and Cardiovascular Systems. Dr. Rao has received personal fees from Medtronic, as well as from CSI and Philips.

mzoler@mdedge.com

SOURCE: Kirtane AJ et al. ACC 2020, Abstract 903-06.

Results from a prospective, multicenter, uncontrolled series of just over 1,500 patients with high bleeding risk who underwent coronary revascularization with a polymer-based, zotarolimus-eluting stent showed that these patients could safely receive dual-antiplatelet therapy (DAPT)for just 1 month.

This finding sets the stage for a new labeled indication for this device and management strategy in this patient population.

Results from the Onyx ONE Clear study “met its primary endpoint, with favorable rates of ischemic outcomes from 1-12 months after DAPT discontinuation within a high risk population of HBR [high-bleeding-risk] patients,” Ajay J. Kirtane, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. The rate of cardiac death or MI during months 1-12 of follow-up while patients were on single-antiplatelet therapy (SAPT) with either aspirin or a P2Y12 inhibitor, usually clopidogrel, was 7.0%, compared with a prespecified performance goal of 9.7% or less, a goal set in consultation with and approval from the Food and Drug Administration based on the results from earlier, short DAPT studies in HBR patients.

“We hope these data will support our submission to the FDA for a 1-month DAPT indication for high-bleeding-risk patients treated with Resolute Onyx,” the polymer-based, zotarolimus-eluting stent tested in the study, said an officer with Medtronic, the company that sponsored this study and markets this stent, in a written statement. Currently, no stent has received a U.S. indication for just 1 month of DAPT treatment.

Mitchel L. Zoler/MDedge News

“The Onyx ONE Clear study represents the largest analysis of 1-month DAPT among commercially available DES [drug-eluting stents], and extends findings from the Onyx ONE [randomized, controlled trial] assuring the safety of a 1-month DAPT strategy among selected patients with high bleeding risk,” said David E. Kandzari, MD, director of interventional cardiology at Piedmont Healthcare in Atlanta and coprincipal investigator for the study along with Dr. Kirtane.

“Despite the patient complexity included in the study, the observation of a favorably low rate of ischemic events despite abbreviated DAPT is consistent with a theme from other contemporary studies that, among HBR patients, bleeding risk rather than ischemic risk should guide clinical decision making regarding DAPT duration,” Dr. Kandzari said in an interview.
 

Two similar trials

The Onyx ONE Clear results were consistent with findings from a study with a somewhat similar design, LEADERS FREE II, a single-arm study that assessed the safety and efficacy of BioFreedom, a polymer-free umirolimus-coated coronary stent, in HBR patients treated with DAPT for 1 month followed by SAPT.

LEADERS FREE II showed a 12-month cardiac death or MI rate of 8.6% that compared favorably with the 12.3% 1-year rate among similar patients who received bare-metal stents and a similar timing of DAPT and SAPT in a historical control group (Circ Cardiovasc Interv. 2020 Apr 13. doi: 10.1161/CIRCINTERVENTIONS.119.008603). The primary goal of LEADERS FREE II was to serve as the pivotal trial for FDA approval of the BioFreedom stent, but as of May 2020 the FDA had not approved this stent for U.S. use.

Results of another recent study, Onyx ONE, that supplied more than half the patients included in the Onyx ONE Clear analysis, showed that, in a head-to-head comparison of the Onxy and BioFreedom stents in 1,996 HBR patients treated with DAPT for 1 month followed by 11 months of SAPT, the Onyx stent was noninferior for both a primary safety outcome and a secondary efficacy outcome (N Engl J Med. 2020 Mar 26;382[13]:1208-18).

“The major differences” between the Onyx and BioFreedom stents in the patients studied in Onxy ONE Clear and in LEADERS FREE II “lie in the fact that BioFreedom is not approved in the U.S., and that Onyx is a current generation, preferred DES platform for both conventional and HBR patients,” Dr. Kirtane said in an interview.

“Because of the performance characteristics of Onyx, as well as the fact that ONYX ONE studied a far more complex group of patients than other shorter DAPT studies with conventional DES, I personally feel that there will be a preference to use this stent as a result of these data,” added Dr. Kirtane, professor of medicine at Columbia University and director of the coronary catheterization laboratory at New York–Presbyterian Hospital in New York.

The results from Onyx ONE “are critical for changing practice” among U.S. interventionalists, commented Sunil V. Rao, MD, an interventional cardiologist and professor of medicine at Duke University, Durham, N.C. Based on the new findings, U.S. operators performing percutaneous coronary interventions “will feel comfortable stopping DAPT in patients who are at high bleeding risk,” he said in an interview.

Although the results from LEADERS FREE II showed that the BioFreedom stent was superior to a bare-metal stent with 1 month of DAPT in HBR patients, and the results from Onyx ONE showed that the Onyx stent was noninferior to BioFreedom in this setting, “it’s important not to assume that there is a class effect across DES platforms. Each platform has a different drug and different stent design, so the interventional community needs to see these data for each DES,” Dr. Rao maintained.
 

Onyx ONE Clear design

Onyx ONE Clear enrolled a total of 1,506 patients, including more than 1,000 patients who received the Onyx stent in the Onyx ONE trial and an additional 752 patients enrolled in the United States and Japan, but 263 of these patients had an adverse event during their first 30 days or follow-up leaving 1,506 patients eligible to continue into the Onyx ONE Clear analysis, and with 1,491 patients followed through 12 months. Patients were an average age of 74 years, a little over two-thirds were men, 49% had a recent acute coronary syndrome event and 41% had chronic coronary syndrome. The choice of which antiplatelet agent to continue when patients transitioned to SAPT after 30 days on DAPT was left to the discretion of the physicians for each enrolled patient.

One issue these studies did not address was whether 1 month is the ideal duration for DAPT before switching to SAPT in HBR patients following coronary stenting, or whether longer DAPT durations produce even better outcomes. “It was important to establish what happens if we need to stop DAPT early.” The Onyx ONE and Onyx ONE Clear studies “provide much-needed data informing clinicians of the risks and safety of SAPT after 1 month in appropriately selected patients,” Dr. Kirtane said.

“The results do not indicate that all HBR patients should be treated with 1 month [of] DAPT, but instead demonstrate the safety and effectiveness of this strategy when clinically appropriate.” This scenario “is quite common, given that HBR patients represent up to a third” of patients undergoing percutaneous coronary intervention, Dr. Kandzari said.

Onyx ONE and Onyx ONE Clear were sponsored by Medtronic, the company that markets the Onyx coronary stent. Dr. Kirtane’s institution has received research support from Medtronic, and from Abbott Vascular, Abiomed, Boston Scientific, Cathworks, CSI, Philips, ReCor Medical, and Siemens. Dr. Kandzari has received personal fees and research grants from medtronic, personal fees from Biotronik and Cardiovascular Systems, and research grants from Biotronik, Boston Scientific, and Cardiovascular Systems. Dr. Rao has received personal fees from Medtronic, as well as from CSI and Philips.

mzoler@mdedge.com

SOURCE: Kirtane AJ et al. ACC 2020, Abstract 903-06.

Results from a prospective, multicenter, uncontrolled series of just over 1,500 patients with high bleeding risk who underwent coronary revascularization with a polymer-based, zotarolimus-eluting stent showed that these patients could safely receive dual-antiplatelet therapy (DAPT)for just 1 month.

This finding sets the stage for a new labeled indication for this device and management strategy in this patient population.

Results from the Onyx ONE Clear study “met its primary endpoint, with favorable rates of ischemic outcomes from 1-12 months after DAPT discontinuation within a high risk population of HBR [high-bleeding-risk] patients,” Ajay J. Kirtane, MD, said at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. The meeting was conducted online after its cancellation because of the COVID-19 pandemic. The rate of cardiac death or MI during months 1-12 of follow-up while patients were on single-antiplatelet therapy (SAPT) with either aspirin or a P2Y12 inhibitor, usually clopidogrel, was 7.0%, compared with a prespecified performance goal of 9.7% or less, a goal set in consultation with and approval from the Food and Drug Administration based on the results from earlier, short DAPT studies in HBR patients.

“We hope these data will support our submission to the FDA for a 1-month DAPT indication for high-bleeding-risk patients treated with Resolute Onyx,” the polymer-based, zotarolimus-eluting stent tested in the study, said an officer with Medtronic, the company that sponsored this study and markets this stent, in a written statement. Currently, no stent has received a U.S. indication for just 1 month of DAPT treatment.

Mitchel L. Zoler/MDedge News

“The Onyx ONE Clear study represents the largest analysis of 1-month DAPT among commercially available DES [drug-eluting stents], and extends findings from the Onyx ONE [randomized, controlled trial] assuring the safety of a 1-month DAPT strategy among selected patients with high bleeding risk,” said David E. Kandzari, MD, director of interventional cardiology at Piedmont Healthcare in Atlanta and coprincipal investigator for the study along with Dr. Kirtane.

“Despite the patient complexity included in the study, the observation of a favorably low rate of ischemic events despite abbreviated DAPT is consistent with a theme from other contemporary studies that, among HBR patients, bleeding risk rather than ischemic risk should guide clinical decision making regarding DAPT duration,” Dr. Kandzari said in an interview.
 

Two similar trials

The Onyx ONE Clear results were consistent with findings from a study with a somewhat similar design, LEADERS FREE II, a single-arm study that assessed the safety and efficacy of BioFreedom, a polymer-free umirolimus-coated coronary stent, in HBR patients treated with DAPT for 1 month followed by SAPT.

LEADERS FREE II showed a 12-month cardiac death or MI rate of 8.6% that compared favorably with the 12.3% 1-year rate among similar patients who received bare-metal stents and a similar timing of DAPT and SAPT in a historical control group (Circ Cardiovasc Interv. 2020 Apr 13. doi: 10.1161/CIRCINTERVENTIONS.119.008603). The primary goal of LEADERS FREE II was to serve as the pivotal trial for FDA approval of the BioFreedom stent, but as of May 2020 the FDA had not approved this stent for U.S. use.

Results of another recent study, Onyx ONE, that supplied more than half the patients included in the Onyx ONE Clear analysis, showed that, in a head-to-head comparison of the Onxy and BioFreedom stents in 1,996 HBR patients treated with DAPT for 1 month followed by 11 months of SAPT, the Onyx stent was noninferior for both a primary safety outcome and a secondary efficacy outcome (N Engl J Med. 2020 Mar 26;382[13]:1208-18).

“The major differences” between the Onyx and BioFreedom stents in the patients studied in Onxy ONE Clear and in LEADERS FREE II “lie in the fact that BioFreedom is not approved in the U.S., and that Onyx is a current generation, preferred DES platform for both conventional and HBR patients,” Dr. Kirtane said in an interview.

“Because of the performance characteristics of Onyx, as well as the fact that ONYX ONE studied a far more complex group of patients than other shorter DAPT studies with conventional DES, I personally feel that there will be a preference to use this stent as a result of these data,” added Dr. Kirtane, professor of medicine at Columbia University and director of the coronary catheterization laboratory at New York–Presbyterian Hospital in New York.

The results from Onyx ONE “are critical for changing practice” among U.S. interventionalists, commented Sunil V. Rao, MD, an interventional cardiologist and professor of medicine at Duke University, Durham, N.C. Based on the new findings, U.S. operators performing percutaneous coronary interventions “will feel comfortable stopping DAPT in patients who are at high bleeding risk,” he said in an interview.

Although the results from LEADERS FREE II showed that the BioFreedom stent was superior to a bare-metal stent with 1 month of DAPT in HBR patients, and the results from Onyx ONE showed that the Onyx stent was noninferior to BioFreedom in this setting, “it’s important not to assume that there is a class effect across DES platforms. Each platform has a different drug and different stent design, so the interventional community needs to see these data for each DES,” Dr. Rao maintained.
 

Onyx ONE Clear design

Onyx ONE Clear enrolled a total of 1,506 patients, including more than 1,000 patients who received the Onyx stent in the Onyx ONE trial and an additional 752 patients enrolled in the United States and Japan, but 263 of these patients had an adverse event during their first 30 days or follow-up leaving 1,506 patients eligible to continue into the Onyx ONE Clear analysis, and with 1,491 patients followed through 12 months. Patients were an average age of 74 years, a little over two-thirds were men, 49% had a recent acute coronary syndrome event and 41% had chronic coronary syndrome. The choice of which antiplatelet agent to continue when patients transitioned to SAPT after 30 days on DAPT was left to the discretion of the physicians for each enrolled patient.

One issue these studies did not address was whether 1 month is the ideal duration for DAPT before switching to SAPT in HBR patients following coronary stenting, or whether longer DAPT durations produce even better outcomes. “It was important to establish what happens if we need to stop DAPT early.” The Onyx ONE and Onyx ONE Clear studies “provide much-needed data informing clinicians of the risks and safety of SAPT after 1 month in appropriately selected patients,” Dr. Kirtane said.

“The results do not indicate that all HBR patients should be treated with 1 month [of] DAPT, but instead demonstrate the safety and effectiveness of this strategy when clinically appropriate.” This scenario “is quite common, given that HBR patients represent up to a third” of patients undergoing percutaneous coronary intervention, Dr. Kandzari said.

Onyx ONE and Onyx ONE Clear were sponsored by Medtronic, the company that markets the Onyx coronary stent. Dr. Kirtane’s institution has received research support from Medtronic, and from Abbott Vascular, Abiomed, Boston Scientific, Cathworks, CSI, Philips, ReCor Medical, and Siemens. Dr. Kandzari has received personal fees and research grants from medtronic, personal fees from Biotronik and Cardiovascular Systems, and research grants from Biotronik, Boston Scientific, and Cardiovascular Systems. Dr. Rao has received personal fees from Medtronic, as well as from CSI and Philips.

mzoler@mdedge.com

SOURCE: Kirtane AJ et al. ACC 2020, Abstract 903-06.

Antibiotic exposure within 14 days after screening colonoscopy may increase risk of irritable bowel syndrome (IBS), based on a retrospective analysis of more than 400,000 individuals.

Antibiotic use in the 2 weeks leading up to colonoscopy also trended toward an association with IBS, reported lead author Ravy Vajravelu, MD, of University of Pennsylvania, Philadelphia, and colleagues.

“Laboratory studies in mice have demonstrated that colon cleansing in conjunction with systemic antibiotic use can cause persistent intestinal dysbiosis,” the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19. “Because perturbation of the gut microbiome is thought to be a trigger for the development of IBS, we sought to assess whether humans who undergo bowel cleanse for colonoscopy in conjunction with antibiotic exposure develop new-onset IBS or IBS-related symptoms.”

According to Dr. Vajravelu, previous human studies have shown that bowel cleansing or antibiotics can alter the baseline gut microbiome, but no previous human research explored the impact of both triggers at once.

The present study involved individuals 50 years or older from the OptumInsight Clinformatics database who underwent screening colonoscopy between 2000 and 2016. Those with preexisting gastrointestinal conditions or symptoms within 180 days leading up to colonoscopy were excluded, leaving 402,259 individuals in the final cohort. From this group, individuals were identified who had exposure to antibiotics within 14 days before and/or after colonoscopy.

The primary outcome was a diagnosis of IBS in the 180 days following the antibiotic exposure window. Secondary outcomes included newly diagnosed diarrhea, change in bowel habits, and abdominal pain. A variety of covariates were tested through multivariable logistical regression, including gastrointestinal infections, medical comorbidities, and demographic factors, with only sex and age remaining in the final model.

Across the cohort, 2% of patients received antibiotics either before or after colonoscopy, while 1% had exposure both before and after. A total of 1,002 individuals (0.2%) were diagnosed with IBS within a median time frame of 112 days.

Multivariate analysis revealed that individuals exposed to antibiotics in the 14 days following colonoscopy had a 77% increased risk of developing IBS (adjusted odds ratio, 1.77; 95% confidence interval, 1.31-2.39). To a lesser degree, and not quite achieving statistical significance, trends toward an association were found for antibiotic exposure before colonoscopy (aOR, 1.38; 95% CI, 0.99-1.92), and for antibiotic exposure both before and after colonoscopy (aOR, 1.41; 95% CI, 0.97-2.04).

Dr. Vajravelu said that these preliminary findings are currently undergoing further analysis.

“In particular, we are interested in determining whether antibiotics that target gram-negative bacteria, which are abundant in the gut, have a greater association with subsequent IBS,” Dr. Vajravelu said.

In addition, they are taking steps to eliminate other confounding factors.

“The main objective of these new analyses is to ensure that the association between bowel cleanse and antibiotics with subsequent IBS is not related to the reasons antibiotics were prescribed initially,” Dr. Vajravelu said. “For example, someone experiencing diarrhea could receive a trial of empiric antibiotics and then receive a colonoscopy when the diarrhea does not resolve. In [the present analysis], we avoided including individuals like this by including only those who underwent screening colonoscopy, and therefore did not have any prior documented GI symptoms. In our [ongoing] analyses, we are including additional restrictions to strengthen the findings.”

If the findings do hold, Dr. Vajravelu suggested that they may have clinical implications.

“[I]t may be important to review whether patients scheduled for colonoscopy have received recent antibiotics and warn them to avoid antibiotics after colonoscopy, if possible,” Dr. Vajravelu said. “Additionally, for gastroenterologists, these data may underscore the importance of adhering to preprocedural antibiotic prophylaxis guidelines put forth by GI societies.”The investigators disclosed relationships with Merck, Pfizer, Gilead, and others.

SOURCE: Vajravelu R et al. DDW 2020. Abstract 404.

Antibiotic exposure within 14 days after screening colonoscopy may increase risk of irritable bowel syndrome (IBS), based on a retrospective analysis of more than 400,000 individuals.

Antibiotic use in the 2 weeks leading up to colonoscopy also trended toward an association with IBS, reported lead author Ravy Vajravelu, MD, of University of Pennsylvania, Philadelphia, and colleagues.

“Laboratory studies in mice have demonstrated that colon cleansing in conjunction with systemic antibiotic use can cause persistent intestinal dysbiosis,” the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19. “Because perturbation of the gut microbiome is thought to be a trigger for the development of IBS, we sought to assess whether humans who undergo bowel cleanse for colonoscopy in conjunction with antibiotic exposure develop new-onset IBS or IBS-related symptoms.”

According to Dr. Vajravelu, previous human studies have shown that bowel cleansing or antibiotics can alter the baseline gut microbiome, but no previous human research explored the impact of both triggers at once.

The present study involved individuals 50 years or older from the OptumInsight Clinformatics database who underwent screening colonoscopy between 2000 and 2016. Those with preexisting gastrointestinal conditions or symptoms within 180 days leading up to colonoscopy were excluded, leaving 402,259 individuals in the final cohort. From this group, individuals were identified who had exposure to antibiotics within 14 days before and/or after colonoscopy.

The primary outcome was a diagnosis of IBS in the 180 days following the antibiotic exposure window. Secondary outcomes included newly diagnosed diarrhea, change in bowel habits, and abdominal pain. A variety of covariates were tested through multivariable logistical regression, including gastrointestinal infections, medical comorbidities, and demographic factors, with only sex and age remaining in the final model.

Across the cohort, 2% of patients received antibiotics either before or after colonoscopy, while 1% had exposure both before and after. A total of 1,002 individuals (0.2%) were diagnosed with IBS within a median time frame of 112 days.

Multivariate analysis revealed that individuals exposed to antibiotics in the 14 days following colonoscopy had a 77% increased risk of developing IBS (adjusted odds ratio, 1.77; 95% confidence interval, 1.31-2.39). To a lesser degree, and not quite achieving statistical significance, trends toward an association were found for antibiotic exposure before colonoscopy (aOR, 1.38; 95% CI, 0.99-1.92), and for antibiotic exposure both before and after colonoscopy (aOR, 1.41; 95% CI, 0.97-2.04).

Dr. Vajravelu said that these preliminary findings are currently undergoing further analysis.

“In particular, we are interested in determining whether antibiotics that target gram-negative bacteria, which are abundant in the gut, have a greater association with subsequent IBS,” Dr. Vajravelu said.

In addition, they are taking steps to eliminate other confounding factors.

“The main objective of these new analyses is to ensure that the association between bowel cleanse and antibiotics with subsequent IBS is not related to the reasons antibiotics were prescribed initially,” Dr. Vajravelu said. “For example, someone experiencing diarrhea could receive a trial of empiric antibiotics and then receive a colonoscopy when the diarrhea does not resolve. In [the present analysis], we avoided including individuals like this by including only those who underwent screening colonoscopy, and therefore did not have any prior documented GI symptoms. In our [ongoing] analyses, we are including additional restrictions to strengthen the findings.”

If the findings do hold, Dr. Vajravelu suggested that they may have clinical implications.

“[I]t may be important to review whether patients scheduled for colonoscopy have received recent antibiotics and warn them to avoid antibiotics after colonoscopy, if possible,” Dr. Vajravelu said. “Additionally, for gastroenterologists, these data may underscore the importance of adhering to preprocedural antibiotic prophylaxis guidelines put forth by GI societies.”The investigators disclosed relationships with Merck, Pfizer, Gilead, and others.

SOURCE: Vajravelu R et al. DDW 2020. Abstract 404.

Antibiotic exposure within 14 days after screening colonoscopy may increase risk of irritable bowel syndrome (IBS), based on a retrospective analysis of more than 400,000 individuals.

Antibiotic use in the 2 weeks leading up to colonoscopy also trended toward an association with IBS, reported lead author Ravy Vajravelu, MD, of University of Pennsylvania, Philadelphia, and colleagues.

“Laboratory studies in mice have demonstrated that colon cleansing in conjunction with systemic antibiotic use can cause persistent intestinal dysbiosis,” the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19. “Because perturbation of the gut microbiome is thought to be a trigger for the development of IBS, we sought to assess whether humans who undergo bowel cleanse for colonoscopy in conjunction with antibiotic exposure develop new-onset IBS or IBS-related symptoms.”

According to Dr. Vajravelu, previous human studies have shown that bowel cleansing or antibiotics can alter the baseline gut microbiome, but no previous human research explored the impact of both triggers at once.

The present study involved individuals 50 years or older from the OptumInsight Clinformatics database who underwent screening colonoscopy between 2000 and 2016. Those with preexisting gastrointestinal conditions or symptoms within 180 days leading up to colonoscopy were excluded, leaving 402,259 individuals in the final cohort. From this group, individuals were identified who had exposure to antibiotics within 14 days before and/or after colonoscopy.

The primary outcome was a diagnosis of IBS in the 180 days following the antibiotic exposure window. Secondary outcomes included newly diagnosed diarrhea, change in bowel habits, and abdominal pain. A variety of covariates were tested through multivariable logistical regression, including gastrointestinal infections, medical comorbidities, and demographic factors, with only sex and age remaining in the final model.

Across the cohort, 2% of patients received antibiotics either before or after colonoscopy, while 1% had exposure both before and after. A total of 1,002 individuals (0.2%) were diagnosed with IBS within a median time frame of 112 days.

Multivariate analysis revealed that individuals exposed to antibiotics in the 14 days following colonoscopy had a 77% increased risk of developing IBS (adjusted odds ratio, 1.77; 95% confidence interval, 1.31-2.39). To a lesser degree, and not quite achieving statistical significance, trends toward an association were found for antibiotic exposure before colonoscopy (aOR, 1.38; 95% CI, 0.99-1.92), and for antibiotic exposure both before and after colonoscopy (aOR, 1.41; 95% CI, 0.97-2.04).

Dr. Vajravelu said that these preliminary findings are currently undergoing further analysis.

“In particular, we are interested in determining whether antibiotics that target gram-negative bacteria, which are abundant in the gut, have a greater association with subsequent IBS,” Dr. Vajravelu said.

In addition, they are taking steps to eliminate other confounding factors.

“The main objective of these new analyses is to ensure that the association between bowel cleanse and antibiotics with subsequent IBS is not related to the reasons antibiotics were prescribed initially,” Dr. Vajravelu said. “For example, someone experiencing diarrhea could receive a trial of empiric antibiotics and then receive a colonoscopy when the diarrhea does not resolve. In [the present analysis], we avoided including individuals like this by including only those who underwent screening colonoscopy, and therefore did not have any prior documented GI symptoms. In our [ongoing] analyses, we are including additional restrictions to strengthen the findings.”

If the findings do hold, Dr. Vajravelu suggested that they may have clinical implications.

“[I]t may be important to review whether patients scheduled for colonoscopy have received recent antibiotics and warn them to avoid antibiotics after colonoscopy, if possible,” Dr. Vajravelu said. “Additionally, for gastroenterologists, these data may underscore the importance of adhering to preprocedural antibiotic prophylaxis guidelines put forth by GI societies.”The investigators disclosed relationships with Merck, Pfizer, Gilead, and others.

SOURCE: Vajravelu R et al. DDW 2020. Abstract 404.

The implantable defibrillator with subcutaneous leads, designed in part to minimize the risk for potentially serious lead-related complications, has reached a milestone by turning in a “noninferior” performance when it was compared with transvenous-lead devices in a first-of-its-kind head-to-head study.

Patients implanted with the subcutaneous-lead S-ICD (Boston Scientific) defibrillator showed a 4-year risk for inappropriate shocks or device-related complications similar to that seen with standard transvenous-lead implantable cardioverter defibrillators (ICD) in a randomized comparison.

At the same time, the S-ICD did its job by showing a highly significant three-fourths reduction in risk for lead-related complications, compared with ICDs with standard leads, in the trial with more than 800 patients, called PRAETORIAN.

The study population represented a mix of patients seen in “real-world” practice who have an ICD indication, of whom about two-thirds had ischemic cardiomyopathy, said Reinoud Knops, MD, PhD, Academic Medical Center, Hilversum, the Netherlands. About 80% received the devices for primary prevention.

Knops, the trial’s principal investigator, presented the results online May 8 as one of the Heart Rhythm Society 2020 Scientific Sessions virtual presentations.

“I think the PRAETORIAN trial has really shown now, in a conventional ICD population – the real-world patients that we treat with ICD therapy, the single-chamber ICD cohort – that the S-ICD is a really good alternative option,” he said to reporters during a media briefing.

“The main conclusion is that the S-ICD should be considered in all patients who need an ICD who do not have a pacing indication,” Knops said.

This latter part is critical, because the S-ICD does not provide pacing therapy, including antitachycardia pacing (ATP) and cardiac resynchronization therapy (CRT), and the trial did not enter patients considered likely to benefit from it. For example, it excluded anyone with bradycardia or treatment-refractory monomorphic ventricular tachycardia (VT) and patients considered appropriate for CRT.

In fact, there are a lot reasons clinicians might prefer a transvenous-lead ICD over the S-ICD, observed Anne B. Curtis, MD, University at Buffalo, State University of New York, who is not associated with PRAETORIAN.

A transvenous-lead system might be preferred in older patients, those with heart failure, and those with a lot of comorbidities. “A lot of these patients already have cardiomyopathies, so they’re more likely to develop atrial fibrillation or a need for CRT,” conditions that might make a transvenous-lead system the better choice, Curtis told theheart.org | Medscape Cardiology.

“For a lot of patients, you’re always thinking that you may have a need for that kind of therapy.”

In contrast, younger patients who perhaps have survived cardiac arrest and probably don’t have heart failure, and so may be less likely to benefit from pacing therapy, Curtis said, “are the kind of patient who you would probably lean very strongly toward for an S-ICD rather than a transvenous ICD.”

Remaining patients, those who might be considered candidates for either kind of device, are actually “a fairly limited subset,” she said.

The trial randomized 849 patients in Europe and the United States, from March 2011 to January 2017, who had a class I or IIa indication for an ICD but no bradycardia or need for CRT or ATP, to be implanted with an S-ICD or a transvenous-lead ICD.

The rates of the primary end point, a composite of device-related complications and inappropriate shocks at a median follow-up of 4 years, were comparable, at 15.1% in the S-ICD group and 15.7% for those with transvenous-lead ICDs.

The incidence of device-related complications numerically favored the S-ICD group, and the incidence of inappropriate shocks numerically favored the transvenous-lead group, but neither difference reached significance.

Knops said the PRAETORIAN researchers are seeking addition funding to extend the follow-up to 8 years. “We will get more insight into the durability of the S-ICD when we follow these patients longer,” he told theheart.org | Medscape Cardiology.

The investigator-initiated trial received support from Boston Scientific. Knops discloses receiving consultancy fees and research grants from Abbott, Boston Scientific, Medtronic, and Cairdac, and holding stock options from AtaCor Medical.
 

This article first appeared on Medscape.com.

The implantable defibrillator with subcutaneous leads, designed in part to minimize the risk for potentially serious lead-related complications, has reached a milestone by turning in a “noninferior” performance when it was compared with transvenous-lead devices in a first-of-its-kind head-to-head study.

Patients implanted with the subcutaneous-lead S-ICD (Boston Scientific) defibrillator showed a 4-year risk for inappropriate shocks or device-related complications similar to that seen with standard transvenous-lead implantable cardioverter defibrillators (ICD) in a randomized comparison.

At the same time, the S-ICD did its job by showing a highly significant three-fourths reduction in risk for lead-related complications, compared with ICDs with standard leads, in the trial with more than 800 patients, called PRAETORIAN.

The study population represented a mix of patients seen in “real-world” practice who have an ICD indication, of whom about two-thirds had ischemic cardiomyopathy, said Reinoud Knops, MD, PhD, Academic Medical Center, Hilversum, the Netherlands. About 80% received the devices for primary prevention.

Knops, the trial’s principal investigator, presented the results online May 8 as one of the Heart Rhythm Society 2020 Scientific Sessions virtual presentations.

“I think the PRAETORIAN trial has really shown now, in a conventional ICD population – the real-world patients that we treat with ICD therapy, the single-chamber ICD cohort – that the S-ICD is a really good alternative option,” he said to reporters during a media briefing.

“The main conclusion is that the S-ICD should be considered in all patients who need an ICD who do not have a pacing indication,” Knops said.

This latter part is critical, because the S-ICD does not provide pacing therapy, including antitachycardia pacing (ATP) and cardiac resynchronization therapy (CRT), and the trial did not enter patients considered likely to benefit from it. For example, it excluded anyone with bradycardia or treatment-refractory monomorphic ventricular tachycardia (VT) and patients considered appropriate for CRT.

In fact, there are a lot reasons clinicians might prefer a transvenous-lead ICD over the S-ICD, observed Anne B. Curtis, MD, University at Buffalo, State University of New York, who is not associated with PRAETORIAN.

A transvenous-lead system might be preferred in older patients, those with heart failure, and those with a lot of comorbidities. “A lot of these patients already have cardiomyopathies, so they’re more likely to develop atrial fibrillation or a need for CRT,” conditions that might make a transvenous-lead system the better choice, Curtis told theheart.org | Medscape Cardiology.

“For a lot of patients, you’re always thinking that you may have a need for that kind of therapy.”

In contrast, younger patients who perhaps have survived cardiac arrest and probably don’t have heart failure, and so may be less likely to benefit from pacing therapy, Curtis said, “are the kind of patient who you would probably lean very strongly toward for an S-ICD rather than a transvenous ICD.”

Remaining patients, those who might be considered candidates for either kind of device, are actually “a fairly limited subset,” she said.

The trial randomized 849 patients in Europe and the United States, from March 2011 to January 2017, who had a class I or IIa indication for an ICD but no bradycardia or need for CRT or ATP, to be implanted with an S-ICD or a transvenous-lead ICD.

The rates of the primary end point, a composite of device-related complications and inappropriate shocks at a median follow-up of 4 years, were comparable, at 15.1% in the S-ICD group and 15.7% for those with transvenous-lead ICDs.

The incidence of device-related complications numerically favored the S-ICD group, and the incidence of inappropriate shocks numerically favored the transvenous-lead group, but neither difference reached significance.

Knops said the PRAETORIAN researchers are seeking addition funding to extend the follow-up to 8 years. “We will get more insight into the durability of the S-ICD when we follow these patients longer,” he told theheart.org | Medscape Cardiology.

The investigator-initiated trial received support from Boston Scientific. Knops discloses receiving consultancy fees and research grants from Abbott, Boston Scientific, Medtronic, and Cairdac, and holding stock options from AtaCor Medical.
 

This article first appeared on Medscape.com.

The implantable defibrillator with subcutaneous leads, designed in part to minimize the risk for potentially serious lead-related complications, has reached a milestone by turning in a “noninferior” performance when it was compared with transvenous-lead devices in a first-of-its-kind head-to-head study.

Patients implanted with the subcutaneous-lead S-ICD (Boston Scientific) defibrillator showed a 4-year risk for inappropriate shocks or device-related complications similar to that seen with standard transvenous-lead implantable cardioverter defibrillators (ICD) in a randomized comparison.

At the same time, the S-ICD did its job by showing a highly significant three-fourths reduction in risk for lead-related complications, compared with ICDs with standard leads, in the trial with more than 800 patients, called PRAETORIAN.

The study population represented a mix of patients seen in “real-world” practice who have an ICD indication, of whom about two-thirds had ischemic cardiomyopathy, said Reinoud Knops, MD, PhD, Academic Medical Center, Hilversum, the Netherlands. About 80% received the devices for primary prevention.

Knops, the trial’s principal investigator, presented the results online May 8 as one of the Heart Rhythm Society 2020 Scientific Sessions virtual presentations.

“I think the PRAETORIAN trial has really shown now, in a conventional ICD population – the real-world patients that we treat with ICD therapy, the single-chamber ICD cohort – that the S-ICD is a really good alternative option,” he said to reporters during a media briefing.

“The main conclusion is that the S-ICD should be considered in all patients who need an ICD who do not have a pacing indication,” Knops said.

This latter part is critical, because the S-ICD does not provide pacing therapy, including antitachycardia pacing (ATP) and cardiac resynchronization therapy (CRT), and the trial did not enter patients considered likely to benefit from it. For example, it excluded anyone with bradycardia or treatment-refractory monomorphic ventricular tachycardia (VT) and patients considered appropriate for CRT.

In fact, there are a lot reasons clinicians might prefer a transvenous-lead ICD over the S-ICD, observed Anne B. Curtis, MD, University at Buffalo, State University of New York, who is not associated with PRAETORIAN.

A transvenous-lead system might be preferred in older patients, those with heart failure, and those with a lot of comorbidities. “A lot of these patients already have cardiomyopathies, so they’re more likely to develop atrial fibrillation or a need for CRT,” conditions that might make a transvenous-lead system the better choice, Curtis told theheart.org | Medscape Cardiology.

“For a lot of patients, you’re always thinking that you may have a need for that kind of therapy.”

In contrast, younger patients who perhaps have survived cardiac arrest and probably don’t have heart failure, and so may be less likely to benefit from pacing therapy, Curtis said, “are the kind of patient who you would probably lean very strongly toward for an S-ICD rather than a transvenous ICD.”

Remaining patients, those who might be considered candidates for either kind of device, are actually “a fairly limited subset,” she said.

The trial randomized 849 patients in Europe and the United States, from March 2011 to January 2017, who had a class I or IIa indication for an ICD but no bradycardia or need for CRT or ATP, to be implanted with an S-ICD or a transvenous-lead ICD.

The rates of the primary end point, a composite of device-related complications and inappropriate shocks at a median follow-up of 4 years, were comparable, at 15.1% in the S-ICD group and 15.7% for those with transvenous-lead ICDs.

The incidence of device-related complications numerically favored the S-ICD group, and the incidence of inappropriate shocks numerically favored the transvenous-lead group, but neither difference reached significance.

Knops said the PRAETORIAN researchers are seeking addition funding to extend the follow-up to 8 years. “We will get more insight into the durability of the S-ICD when we follow these patients longer,” he told theheart.org | Medscape Cardiology.

The investigator-initiated trial received support from Boston Scientific. Knops discloses receiving consultancy fees and research grants from Abbott, Boston Scientific, Medtronic, and Cairdac, and holding stock options from AtaCor Medical.
 

This article first appeared on Medscape.com.

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

And in a recent potential treatment advance, Janus kinase inhibition shows promise as a novel therapy for ILD in patients with juvenile dermatomyositis (JDM), added Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 3 (12%) of 25 patients with juvenile polymyositis and in 8 (18%) of 44 youths with juvenile connective tissue disease–myositis overlap. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: namely, 9% of the cohort were positive for anti–melanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl-tRNA synthetase (anti-Jo-1) autoantibodies were present in 4%.

Thirty-three of the 371 juvenile myositis patients had ILD based upon CT imaging, chest x-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo1. After controlling for the presence of these other myositis-specific autoantibodies, anti-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52 and anti-Jo1 positive (Ann Rheum Dis. 2019 Jul;78[7]:988-95).

Patients with anti-Ro autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, IVIG, and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation–syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody–positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody–positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals (Brain. 2019 Nov 1;142[11]:e59).

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody–positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms (Rheumatology [Oxford]. 2019 Nov 22. doi: 10.1093/rheumatology/kez525. [Epub ahead of print]).

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

And in a recent potential treatment advance, Janus kinase inhibition shows promise as a novel therapy for ILD in patients with juvenile dermatomyositis (JDM), added Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 3 (12%) of 25 patients with juvenile polymyositis and in 8 (18%) of 44 youths with juvenile connective tissue disease–myositis overlap. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: namely, 9% of the cohort were positive for anti–melanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl-tRNA synthetase (anti-Jo-1) autoantibodies were present in 4%.

Thirty-three of the 371 juvenile myositis patients had ILD based upon CT imaging, chest x-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo1. After controlling for the presence of these other myositis-specific autoantibodies, anti-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52 and anti-Jo1 positive (Ann Rheum Dis. 2019 Jul;78[7]:988-95).

Patients with anti-Ro autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, IVIG, and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation–syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody–positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody–positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals (Brain. 2019 Nov 1;142[11]:e59).

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody–positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms (Rheumatology [Oxford]. 2019 Nov 22. doi: 10.1093/rheumatology/kez525. [Epub ahead of print]).

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

And in a recent potential treatment advance, Janus kinase inhibition shows promise as a novel therapy for ILD in patients with juvenile dermatomyositis (JDM), added Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 3 (12%) of 25 patients with juvenile polymyositis and in 8 (18%) of 44 youths with juvenile connective tissue disease–myositis overlap. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: namely, 9% of the cohort were positive for anti–melanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl-tRNA synthetase (anti-Jo-1) autoantibodies were present in 4%.

Thirty-three of the 371 juvenile myositis patients had ILD based upon CT imaging, chest x-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo1. After controlling for the presence of these other myositis-specific autoantibodies, anti-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52 and anti-Jo1 positive (Ann Rheum Dis. 2019 Jul;78[7]:988-95).

Patients with anti-Ro autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, IVIG, and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation–syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody–positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody–positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals (Brain. 2019 Nov 1;142[11]:e59).

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody–positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms (Rheumatology [Oxford]. 2019 Nov 22. doi: 10.1093/rheumatology/kez525. [Epub ahead of print]).

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

Patients with atrial fibrillation, even those on oral anticoagulant therapy, developed clinically silent brain infarctions at a striking rate of close to 3% per year, according to results from SWISS-AF, a prospective of study of 1,227 Swiss patients followed with serial MR brain scans over a 2 year period.

The results also showed that these brain infarctions – which occurred in 68 (5.5%) of the atrial fibrillation (AFib) patients, including 58 (85%) who did not have any strokes or transient ischemic attacks during follow-up – appeared to represent enough pathology to link with a small but statistically significant decline in three separate cognitive measures, compared with patients who did not develop brain infarctions during follow-up.

“Cognitive decline may go unrecognized for a long time in clinical practice because usually no one tests for it,” plus “the absolute declines were small and probably not appreciable” in the everyday behavior of affected patients, David Conen, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. But “we were surprised to see a significant change after just 2 years. We expect much larger effects to develop over time,” he said during a press briefing.

Another key finding was that roughly half the patients had large cortical or noncortical infarcts, which usually have a thromboembolic cause, but the other half had small noncortical infarcts that likely have a different etiology involving the microvasculature. Causes for those small infarcts might include localized atherosclerotic disease or amyloidosis, proposed Dr. Conen, a cardiologist at McMaster University, Hamilton, Ont.

This finding also suggests that, as a consequence, anticoagulation alone may not be enough to prevent this brain damage in Afib patients. “It calls for a more comprehensive approach to prevention,” with attention to atherosclerotic cardiovascular disease risk factors in AFib patients, including interventions that address hypertension, diabetes, hyperlipidemia, and smoking cessation. “Anticoagulation in AFib patients is critical, but it also is not enough,” Dr. Conen said.

These data “are very important. The two pillars for taking care of AFib patients have traditionally been to manage the patient’s stroke risk and to treat symptoms. Dr. Conen’s data suggest that simply starting anticoagulation is not sufficient, and it stresses the importance of continued management of hypertension, diabetes, and other medical and social issues,” commented Fred Kusumoto, MD, director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla.

“The risk factors associated with the development of cardiovascular disease are similar to those associated with the development of AFib and heart failure. It is important to understand the importance of managing hypertension, diabetes, and obesity; encouraging exercise and a healthy diet; and stopping smoking in all AFib patients as well as in the general population. Many clinicians have not emphasized the importance of continually addressing these behaviors,” Dr. Kusumoto said in an interview.

The SWISS-AF (Swiss Atrial Fibrillation Cohort) study enrolled 2,415 AFib patients at 14 Swiss centers during 2014-2017, and obtained both a baseline brain MR scan and baseline cognitive-test results for 1,737 patients (J Am Coll Cardiol. 2019 Mar;73[9]:989-99). Patients retook the cognitive tests annually, and 1,227 had a second MR brain scan after 2 years in the study, the cohort that supplied the data Dr. Conen presented. At baseline, these patients averaged 71 years of age, just over a quarter were women, and 90% were on an oral anticoagulant, with 84% on an oral anticoagulant at 2-year follow-up. Treatment split roughly equally between direct-acting oral anticoagulants and vitamin K antagonists like warfarin.

Among the 68 patients with evidence for an incident brain infarct after 2 years, 59 (87%) were on treatment with an OAC, and 51 (75%) who were both on treatment with a direct-acting oral anticoagulant and developed their brain infarct without also having a stroke or transient ischemic attack, which Dr. Conen called a “silent event.” The cognitive tests that showed statistically significant declines after 2 years in the patients with silent brain infarcts compared with those without a new infarct were the Trail Making Test parts A and B, and the animal-naming verbal fluency test. The two other tests applied were the Montreal Cognitive Assessment and the Digital Symbol Substitution Test.

Results from several prior studies also indicated a relationship between AFib and cognitive decline, but SWISS-AF is “the largest study to rigorously examine the incidence of silent brain infarcts in AFib patients,” commented Christine M. Albert, MD, chair of cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles. “Silent infarcts could be the cause, at least in part, for the cognitive decline and dementia associated with AFib,” she noted. But divining the therapeutic implications of the finding will require further investigation that looks at factors such as the impact of anticoagulant type, other treatment that addresses AFib such as ablation and rate control, the duration and type of AFib, and the prevalence of hypertension and other stroke risk factors, she said as a designated discussant for Dr. Conen’s report.

SWISS-AF received no commercial funding. Dr. Conen has been a speaker on behalf of Servier. Dr. Kusumoto had no disclosures. Dr. Albert has been a consultant to Roche Diagnostics and has received research funding from Abbott, Roche Diagnostics, and St. Jude Medical.

mzoler@mdedge.com

Patients with atrial fibrillation, even those on oral anticoagulant therapy, developed clinically silent brain infarctions at a striking rate of close to 3% per year, according to results from SWISS-AF, a prospective of study of 1,227 Swiss patients followed with serial MR brain scans over a 2 year period.

The results also showed that these brain infarctions – which occurred in 68 (5.5%) of the atrial fibrillation (AFib) patients, including 58 (85%) who did not have any strokes or transient ischemic attacks during follow-up – appeared to represent enough pathology to link with a small but statistically significant decline in three separate cognitive measures, compared with patients who did not develop brain infarctions during follow-up.

“Cognitive decline may go unrecognized for a long time in clinical practice because usually no one tests for it,” plus “the absolute declines were small and probably not appreciable” in the everyday behavior of affected patients, David Conen, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. But “we were surprised to see a significant change after just 2 years. We expect much larger effects to develop over time,” he said during a press briefing.

Another key finding was that roughly half the patients had large cortical or noncortical infarcts, which usually have a thromboembolic cause, but the other half had small noncortical infarcts that likely have a different etiology involving the microvasculature. Causes for those small infarcts might include localized atherosclerotic disease or amyloidosis, proposed Dr. Conen, a cardiologist at McMaster University, Hamilton, Ont.

This finding also suggests that, as a consequence, anticoagulation alone may not be enough to prevent this brain damage in Afib patients. “It calls for a more comprehensive approach to prevention,” with attention to atherosclerotic cardiovascular disease risk factors in AFib patients, including interventions that address hypertension, diabetes, hyperlipidemia, and smoking cessation. “Anticoagulation in AFib patients is critical, but it also is not enough,” Dr. Conen said.

These data “are very important. The two pillars for taking care of AFib patients have traditionally been to manage the patient’s stroke risk and to treat symptoms. Dr. Conen’s data suggest that simply starting anticoagulation is not sufficient, and it stresses the importance of continued management of hypertension, diabetes, and other medical and social issues,” commented Fred Kusumoto, MD, director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla.

“The risk factors associated with the development of cardiovascular disease are similar to those associated with the development of AFib and heart failure. It is important to understand the importance of managing hypertension, diabetes, and obesity; encouraging exercise and a healthy diet; and stopping smoking in all AFib patients as well as in the general population. Many clinicians have not emphasized the importance of continually addressing these behaviors,” Dr. Kusumoto said in an interview.

The SWISS-AF (Swiss Atrial Fibrillation Cohort) study enrolled 2,415 AFib patients at 14 Swiss centers during 2014-2017, and obtained both a baseline brain MR scan and baseline cognitive-test results for 1,737 patients (J Am Coll Cardiol. 2019 Mar;73[9]:989-99). Patients retook the cognitive tests annually, and 1,227 had a second MR brain scan after 2 years in the study, the cohort that supplied the data Dr. Conen presented. At baseline, these patients averaged 71 years of age, just over a quarter were women, and 90% were on an oral anticoagulant, with 84% on an oral anticoagulant at 2-year follow-up. Treatment split roughly equally between direct-acting oral anticoagulants and vitamin K antagonists like warfarin.

Among the 68 patients with evidence for an incident brain infarct after 2 years, 59 (87%) were on treatment with an OAC, and 51 (75%) who were both on treatment with a direct-acting oral anticoagulant and developed their brain infarct without also having a stroke or transient ischemic attack, which Dr. Conen called a “silent event.” The cognitive tests that showed statistically significant declines after 2 years in the patients with silent brain infarcts compared with those without a new infarct were the Trail Making Test parts A and B, and the animal-naming verbal fluency test. The two other tests applied were the Montreal Cognitive Assessment and the Digital Symbol Substitution Test.

Results from several prior studies also indicated a relationship between AFib and cognitive decline, but SWISS-AF is “the largest study to rigorously examine the incidence of silent brain infarcts in AFib patients,” commented Christine M. Albert, MD, chair of cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles. “Silent infarcts could be the cause, at least in part, for the cognitive decline and dementia associated with AFib,” she noted. But divining the therapeutic implications of the finding will require further investigation that looks at factors such as the impact of anticoagulant type, other treatment that addresses AFib such as ablation and rate control, the duration and type of AFib, and the prevalence of hypertension and other stroke risk factors, she said as a designated discussant for Dr. Conen’s report.

SWISS-AF received no commercial funding. Dr. Conen has been a speaker on behalf of Servier. Dr. Kusumoto had no disclosures. Dr. Albert has been a consultant to Roche Diagnostics and has received research funding from Abbott, Roche Diagnostics, and St. Jude Medical.

mzoler@mdedge.com

Patients with atrial fibrillation, even those on oral anticoagulant therapy, developed clinically silent brain infarctions at a striking rate of close to 3% per year, according to results from SWISS-AF, a prospective of study of 1,227 Swiss patients followed with serial MR brain scans over a 2 year period.

The results also showed that these brain infarctions – which occurred in 68 (5.5%) of the atrial fibrillation (AFib) patients, including 58 (85%) who did not have any strokes or transient ischemic attacks during follow-up – appeared to represent enough pathology to link with a small but statistically significant decline in three separate cognitive measures, compared with patients who did not develop brain infarctions during follow-up.

“Cognitive decline may go unrecognized for a long time in clinical practice because usually no one tests for it,” plus “the absolute declines were small and probably not appreciable” in the everyday behavior of affected patients, David Conen, MD, said at the annual scientific sessions of the Heart Rhythm Society, held online because of COVID-19. But “we were surprised to see a significant change after just 2 years. We expect much larger effects to develop over time,” he said during a press briefing.

Another key finding was that roughly half the patients had large cortical or noncortical infarcts, which usually have a thromboembolic cause, but the other half had small noncortical infarcts that likely have a different etiology involving the microvasculature. Causes for those small infarcts might include localized atherosclerotic disease or amyloidosis, proposed Dr. Conen, a cardiologist at McMaster University, Hamilton, Ont.

This finding also suggests that, as a consequence, anticoagulation alone may not be enough to prevent this brain damage in Afib patients. “It calls for a more comprehensive approach to prevention,” with attention to atherosclerotic cardiovascular disease risk factors in AFib patients, including interventions that address hypertension, diabetes, hyperlipidemia, and smoking cessation. “Anticoagulation in AFib patients is critical, but it also is not enough,” Dr. Conen said.

These data “are very important. The two pillars for taking care of AFib patients have traditionally been to manage the patient’s stroke risk and to treat symptoms. Dr. Conen’s data suggest that simply starting anticoagulation is not sufficient, and it stresses the importance of continued management of hypertension, diabetes, and other medical and social issues,” commented Fred Kusumoto, MD, director of heart rhythm services at the Mayo Clinic in Jacksonville, Fla.

“The risk factors associated with the development of cardiovascular disease are similar to those associated with the development of AFib and heart failure. It is important to understand the importance of managing hypertension, diabetes, and obesity; encouraging exercise and a healthy diet; and stopping smoking in all AFib patients as well as in the general population. Many clinicians have not emphasized the importance of continually addressing these behaviors,” Dr. Kusumoto said in an interview.

The SWISS-AF (Swiss Atrial Fibrillation Cohort) study enrolled 2,415 AFib patients at 14 Swiss centers during 2014-2017, and obtained both a baseline brain MR scan and baseline cognitive-test results for 1,737 patients (J Am Coll Cardiol. 2019 Mar;73[9]:989-99). Patients retook the cognitive tests annually, and 1,227 had a second MR brain scan after 2 years in the study, the cohort that supplied the data Dr. Conen presented. At baseline, these patients averaged 71 years of age, just over a quarter were women, and 90% were on an oral anticoagulant, with 84% on an oral anticoagulant at 2-year follow-up. Treatment split roughly equally between direct-acting oral anticoagulants and vitamin K antagonists like warfarin.

Among the 68 patients with evidence for an incident brain infarct after 2 years, 59 (87%) were on treatment with an OAC, and 51 (75%) who were both on treatment with a direct-acting oral anticoagulant and developed their brain infarct without also having a stroke or transient ischemic attack, which Dr. Conen called a “silent event.” The cognitive tests that showed statistically significant declines after 2 years in the patients with silent brain infarcts compared with those without a new infarct were the Trail Making Test parts A and B, and the animal-naming verbal fluency test. The two other tests applied were the Montreal Cognitive Assessment and the Digital Symbol Substitution Test.

Results from several prior studies also indicated a relationship between AFib and cognitive decline, but SWISS-AF is “the largest study to rigorously examine the incidence of silent brain infarcts in AFib patients,” commented Christine M. Albert, MD, chair of cardiology at the Smidt Heart Institute of Cedars-Sinai Medical Center in Los Angeles. “Silent infarcts could be the cause, at least in part, for the cognitive decline and dementia associated with AFib,” she noted. But divining the therapeutic implications of the finding will require further investigation that looks at factors such as the impact of anticoagulant type, other treatment that addresses AFib such as ablation and rate control, the duration and type of AFib, and the prevalence of hypertension and other stroke risk factors, she said as a designated discussant for Dr. Conen’s report.

SWISS-AF received no commercial funding. Dr. Conen has been a speaker on behalf of Servier. Dr. Kusumoto had no disclosures. Dr. Albert has been a consultant to Roche Diagnostics and has received research funding from Abbott, Roche Diagnostics, and St. Jude Medical.

mzoler@mdedge.com

Individuals who sleep more or less than average report significantly more constipation, compared with normal sleepers, based on data from 14,590 adults.

“Normal sleep duration is thought to be essential for healthy bowel function; however, the effect of either limited or excessive sleep duration on bowel patterns is poorly understood,” Adeyinka Adejumo, MD, of North Shore Medical Center, Salem, Mass., and colleagues wrote in an abstract released as part of the annual Digestive Disease Week^®, which was canceled because of COVID-19.

To examine the association between sleep duration and bowel function, the researchers identified 14,590 adults aged 20 years and older who completed questionnaires on sleep and bowel health as part of the National Health and Nutrition Examination Survey (NHANES) during 2005-2010.

Sleep was divided into three categories based on standards from the National Sleep Foundation: short (less than 7 hours), normal (7-8 hours) and long (more than 8 hours).

Overall, constipation rates were significantly lower among normal sleepers (8.3%) compared with both short and long sleepers (11.0% and 12.5%, respectively; P < .0001 for both).

Bowel function was defined as normal, constipation, or diarrhea based on stool form and bowel movements per week. After controlling for demographic, lifestyle, and dietary factors, long sleepers and short sleepers were 61% and 38% more likely, respectively, to report constipation, compared with normal sleepers.

However, sleep duration was not related to diarrhea, the researchers noted. In addition, “A sensitivity analysis revealed that sleep duration did not mediate the relationship between comorbid factors (such as overall health, poverty index, obesity, and body mass index) and constipation,” they wrote.

The results suggest that decreased sleep is associated with constipation among adults in the United States, the researchers said. However, “further studies are needed to evaluate the physiologic mechanisms driving the impact of sleep duration on bowel function to determine whether sleep disorders or their underlying causes affect constipation,” they concluded.

“This study was necessary because up to 50% of Americans suffer from sleep disorders, out of which abnormal sleep duration is one of the most common and underdiagnosed, and associated with other diseases such as hypertension and diabetes,” Dr. Adejumo said in an interview. “However, disorders of bowel function (constipation and diarrhea), which affect almost 10%-15% of the population and result in significant health care burden, such as higher cost, hospital visits, abdominal discomfort, have not been studied among individuals with suboptimal sleep duration.”

Dr. Adejumo said he and his colleagues were surprised by their findings. “Although, based on our hypothesis, we thought that sleeping too long may be associated with constipation, we were shocked to note similar results among people who also sleep for short durations,” he noted.

“Previous studies had suggested that bowel contraction slows down considerably during sleep. It, therefore, will make sense that sleeping for too long may result in suppressed bowel motility and decreased bowel movement,” he said. “However, our results showed similar findings among short sleepers. We do not know the exact mechanism of these results. It may be that short sleep resulted in inadequate bowel rest, bowel muscle fatigue, and, subsequently, decreased bowel movement,” said Dr. Adejumo. “Or it may also be that brain-gut signaling pathways are disrupted among short sleepers, as is seen among IBS patients after a poor night sleep, resulting in higher constipation,” he added.

Clinicians should be aware of the impact of both short and long sleep on constipation, said Dr. Adejumo. “Individuals who are unable to have adequate periods of sleep due to other diseases, including insomnia, disrupted job schedules, or conditions with too long sleep, such as narcolepsy, may all additionally suffer from constipation. Such patients may need regular evaluation and treatment for constipation to improve their discomfort,” he said.

“To confirm our findings, other clinical studies with more granular data on sleep and constipation, are needed, as well as translational research to uncover the potential mechanisms of these findings,” he emphasized.

The researchers had no financial conflicts to disclose.
 

SOURCE: Adejumo A et al. DDW 2020. Abstract Sa1711.

Individuals who sleep more or less than average report significantly more constipation, compared with normal sleepers, based on data from 14,590 adults.

“Normal sleep duration is thought to be essential for healthy bowel function; however, the effect of either limited or excessive sleep duration on bowel patterns is poorly understood,” Adeyinka Adejumo, MD, of North Shore Medical Center, Salem, Mass., and colleagues wrote in an abstract released as part of the annual Digestive Disease Week^®, which was canceled because of COVID-19.

To examine the association between sleep duration and bowel function, the researchers identified 14,590 adults aged 20 years and older who completed questionnaires on sleep and bowel health as part of the National Health and Nutrition Examination Survey (NHANES) during 2005-2010.

Sleep was divided into three categories based on standards from the National Sleep Foundation: short (less than 7 hours), normal (7-8 hours) and long (more than 8 hours).

Overall, constipation rates were significantly lower among normal sleepers (8.3%) compared with both short and long sleepers (11.0% and 12.5%, respectively; P < .0001 for both).

Bowel function was defined as normal, constipation, or diarrhea based on stool form and bowel movements per week. After controlling for demographic, lifestyle, and dietary factors, long sleepers and short sleepers were 61% and 38% more likely, respectively, to report constipation, compared with normal sleepers.

However, sleep duration was not related to diarrhea, the researchers noted. In addition, “A sensitivity analysis revealed that sleep duration did not mediate the relationship between comorbid factors (such as overall health, poverty index, obesity, and body mass index) and constipation,” they wrote.

The results suggest that decreased sleep is associated with constipation among adults in the United States, the researchers said. However, “further studies are needed to evaluate the physiologic mechanisms driving the impact of sleep duration on bowel function to determine whether sleep disorders or their underlying causes affect constipation,” they concluded.

“This study was necessary because up to 50% of Americans suffer from sleep disorders, out of which abnormal sleep duration is one of the most common and underdiagnosed, and associated with other diseases such as hypertension and diabetes,” Dr. Adejumo said in an interview. “However, disorders of bowel function (constipation and diarrhea), which affect almost 10%-15% of the population and result in significant health care burden, such as higher cost, hospital visits, abdominal discomfort, have not been studied among individuals with suboptimal sleep duration.”

Dr. Adejumo said he and his colleagues were surprised by their findings. “Although, based on our hypothesis, we thought that sleeping too long may be associated with constipation, we were shocked to note similar results among people who also sleep for short durations,” he noted.

“Previous studies had suggested that bowel contraction slows down considerably during sleep. It, therefore, will make sense that sleeping for too long may result in suppressed bowel motility and decreased bowel movement,” he said. “However, our results showed similar findings among short sleepers. We do not know the exact mechanism of these results. It may be that short sleep resulted in inadequate bowel rest, bowel muscle fatigue, and, subsequently, decreased bowel movement,” said Dr. Adejumo. “Or it may also be that brain-gut signaling pathways are disrupted among short sleepers, as is seen among IBS patients after a poor night sleep, resulting in higher constipation,” he added.

Clinicians should be aware of the impact of both short and long sleep on constipation, said Dr. Adejumo. “Individuals who are unable to have adequate periods of sleep due to other diseases, including insomnia, disrupted job schedules, or conditions with too long sleep, such as narcolepsy, may all additionally suffer from constipation. Such patients may need regular evaluation and treatment for constipation to improve their discomfort,” he said.

“To confirm our findings, other clinical studies with more granular data on sleep and constipation, are needed, as well as translational research to uncover the potential mechanisms of these findings,” he emphasized.

The researchers had no financial conflicts to disclose.
 

SOURCE: Adejumo A et al. DDW 2020. Abstract Sa1711.

Individuals who sleep more or less than average report significantly more constipation, compared with normal sleepers, based on data from 14,590 adults.

“Normal sleep duration is thought to be essential for healthy bowel function; however, the effect of either limited or excessive sleep duration on bowel patterns is poorly understood,” Adeyinka Adejumo, MD, of North Shore Medical Center, Salem, Mass., and colleagues wrote in an abstract released as part of the annual Digestive Disease Week^®, which was canceled because of COVID-19.

To examine the association between sleep duration and bowel function, the researchers identified 14,590 adults aged 20 years and older who completed questionnaires on sleep and bowel health as part of the National Health and Nutrition Examination Survey (NHANES) during 2005-2010.

Sleep was divided into three categories based on standards from the National Sleep Foundation: short (less than 7 hours), normal (7-8 hours) and long (more than 8 hours).

Overall, constipation rates were significantly lower among normal sleepers (8.3%) compared with both short and long sleepers (11.0% and 12.5%, respectively; P < .0001 for both).

Bowel function was defined as normal, constipation, or diarrhea based on stool form and bowel movements per week. After controlling for demographic, lifestyle, and dietary factors, long sleepers and short sleepers were 61% and 38% more likely, respectively, to report constipation, compared with normal sleepers.

However, sleep duration was not related to diarrhea, the researchers noted. In addition, “A sensitivity analysis revealed that sleep duration did not mediate the relationship between comorbid factors (such as overall health, poverty index, obesity, and body mass index) and constipation,” they wrote.

The results suggest that decreased sleep is associated with constipation among adults in the United States, the researchers said. However, “further studies are needed to evaluate the physiologic mechanisms driving the impact of sleep duration on bowel function to determine whether sleep disorders or their underlying causes affect constipation,” they concluded.

“This study was necessary because up to 50% of Americans suffer from sleep disorders, out of which abnormal sleep duration is one of the most common and underdiagnosed, and associated with other diseases such as hypertension and diabetes,” Dr. Adejumo said in an interview. “However, disorders of bowel function (constipation and diarrhea), which affect almost 10%-15% of the population and result in significant health care burden, such as higher cost, hospital visits, abdominal discomfort, have not been studied among individuals with suboptimal sleep duration.”

Dr. Adejumo said he and his colleagues were surprised by their findings. “Although, based on our hypothesis, we thought that sleeping too long may be associated with constipation, we were shocked to note similar results among people who also sleep for short durations,” he noted.

“Previous studies had suggested that bowel contraction slows down considerably during sleep. It, therefore, will make sense that sleeping for too long may result in suppressed bowel motility and decreased bowel movement,” he said. “However, our results showed similar findings among short sleepers. We do not know the exact mechanism of these results. It may be that short sleep resulted in inadequate bowel rest, bowel muscle fatigue, and, subsequently, decreased bowel movement,” said Dr. Adejumo. “Or it may also be that brain-gut signaling pathways are disrupted among short sleepers, as is seen among IBS patients after a poor night sleep, resulting in higher constipation,” he added.

Clinicians should be aware of the impact of both short and long sleep on constipation, said Dr. Adejumo. “Individuals who are unable to have adequate periods of sleep due to other diseases, including insomnia, disrupted job schedules, or conditions with too long sleep, such as narcolepsy, may all additionally suffer from constipation. Such patients may need regular evaluation and treatment for constipation to improve their discomfort,” he said.

“To confirm our findings, other clinical studies with more granular data on sleep and constipation, are needed, as well as translational research to uncover the potential mechanisms of these findings,” he emphasized.

The researchers had no financial conflicts to disclose.
 

SOURCE: Adejumo A et al. DDW 2020. Abstract Sa1711.