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AI detects hidden, potentially curable pancreatic cancers
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
TOPLINE:
new research suggests.
METHODOLOGY:
- The researchers utilized a diverse dataset of 3,014 CT scans: 1,105 diagnostic CT scans with pancreatic ductal adenocarcinoma (PDA) and 1,909 control CT scans.
- Of the total, 696 diagnostic CT scans with PDA and 1,080 control CT scans were used as an AI model training subset, and 409 CT scans with PDA and 829 control CT scans were used as an intramural hold-out test subset.
- The model was also tested on a simulated cohort that evaluated the risk for PDA in new-onset diabetes; multicenter public datasets (194 CT scans with PDA and 80 controls); and a cohort of 100 prediagnostic CT scans, incidentally acquired 3-36 months prior to PDA being diagnosed, and 134 controls.
TAKEAWAY:
- The model correctly classified 360 CT scans with PDA (88%) and 783 control CT scans (94%) in the intramural test subset. The mean accuracy was 0.92, the area under the receiver operating characteristic curve was 0.97, sensitivity was 0.88, and specificity was 0.95.
- On heat maps, activation areas overlapped with the tumor in 350 of 360 CT scans (97%).
- Performance was high across tumor stages, with sensitivities of 0.80, 0.87, 0.95, and 1.0 on T1 through T4 stages, respectively. Performance was comparable for hypodense versus isodense tumors (sensitivity of 0.90 vs. 0.82, respectively), patient demographics, CT slice thicknesses, and vendors.
- Findings were generalizable on both the simulated cohort (accuracy, 0.95; area under the ROC curve, 0.97) and public datasets (accuracy, 0.86; AUROC, 0.9).
- Occult PDA was detected on prediagnostic CT scans at a median 475 days before clinical diagnosis. Accuracy was 0.84, AUROC was 0.91, sensitivity was 0.75, and specificity was 0.9.
IN PRACTICE:
“Artificial intelligence model could mitigate the inadequacies of imaging and the diagnostic errors in interpretation, which often contribute to delayed diagnosis of pancreas cancer. In combination with emerging blood-based biomarkers, such a model could be evaluated to screen for sporadic cancer in ongoing trials of high-risk cohorts such as the Early Detection Initiative (NCT04662879).”
SOURCE:
Panagiotis Korfiatis, PhD, of Mayo Clinic, Rochester, Minn., led the study, which was published online in Gastroenterology.
LIMITATIONS:
The retrospective design is prone to selection bias. Results are presented dichotomously as either cancer or control. These are preliminary insights, and prospective clinical trials that incorporate epidemiological risk factors and emerging blood-based biomarkers are needed to further evaluate the model’s performance.
DISCLOSURES:
The research was supported by the National Cancer Institute, the Centene Charitable Foundation, and the Champions for Hope Pancreatic Cancer Research Program of the Funk Zitiello Foundation. One author received an institutional research grant from Sofie Biosciences and Clovis Oncology, is on the BlueStar Genomics advisory board (ad hoc), and is a consultant for Bayer Healthcare, Candel Therapeutics, and UWorld. The remaining authors reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
GLP-1 agonists linked to higher risk for rare but serious GI complications
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
Patients taking either of these glucagonlike peptide-1 (GLP-1) receptor agonists had a 9-fold elevation in risk for pancreatitis. They were also 4 times more likely to develop bowel obstruction and over 3.5 times more likely to experience gastroparesis.
The research letter was published online in JAMA.
Investigators say their findings are not about scaring people off the weight-loss drugs, but instead about increasing awareness that these potential adverse outcomes can happen.
“Given the wide use of these drugs, these adverse events, although rare, must be considered by patients thinking about using them for weight loss,” said lead author Mohit Sodhi, MSc, in a news release about the study. Mr. Sodhi is a graduate of the experimental medicine program at the University of British Columbia in Vancouver, and also a 4th-year medical student at UBC.
People taking a GLP-1 agonist to treat diabetes might be more willing to accept the risks, given their potential advantages, especially that of lowering the risk for heart problems, said Mahyar Etminan, PharmD, MSc, the study’s senior author and an expert in drug safety and pharmacoepidemiology at UBC. “But those who are otherwise healthy and just taking them for weight loss might want to be more careful in weighing the risk–benefit equation.”
People taking these drugs for weight loss have an approximately 1%-2% chance of experiencing these events, including a 1% risk for gastroparesis, Dr. Etminan said.
Key findings
The study included 4,144 people taking liraglutide, 613 taking semaglutide, and 654 taking naltrexone/bupropion based on medical records between 2006 and 2020.
They included patients with a recent history of obesity but excluded those with diabetes or who had been prescribed another diabetes medication.
The use of GLP-1 agonists, compared with naltrexone/bupropion, was associated with an increased risk for pancreatitis (adjusted hazard ratio, 9.09; 95% confidence interval, 1.25-66.00), bowel obstruction (HR, 4.22; 95% CI, 1.02-17.40), and gastroparesis (HR, 3.67; 95% CI, 1.15-11.90).
The study also found a higher incidence of biliary disease, but the difference was not statistically significant (HR, 1.50; 95% CI, 0.89-2.53). The incidence of biliary disease (per 1,000 person-years) was 11.7 for semaglutide, 18.6 for liraglutide, and 12.6 for naltrexone/bupropion.
Not the first report of GI issues
“This important paper confirms the safety signals hinted at in previous randomized controlled trials,” said Carel Le Roux, MBChB, PhD, professor of metabolic medicine, Ulster University, Coleraine, Ireland, and professor of experimental pathology at University College Dublin.
“The limitations of the paper are acknowledged but do not detract from the value of the robust data,” Dr. Le Roux said. “Patients should be informed of the low risk of serious complications, such as pancreatitis, gastroparesis, and bowel obstruction, before they start semaglutide or liraglutide.”
This is not the first report of GI issues associated with GLP-1 agonists, but it’s one of the largest. Most reports have been anecdotal. The U.S. Food and Drug Administration announced on Sept. 28 that it would require manufacturers to include a warning about gastrointestinal ileus on the Ozempic (semaglutide) label.
“The results from this study highlight how important it is that patients access these drugs only through trusted medical professionals, and only with ongoing support and monitoring,” noted Simon Cork, PhD, senior lecturer in physiology, Anglia Ruskin University in Cambridge, England.
Dr. Cork added that “it’s important to look at this in the proper context.” Obesity significantly increases the risk for developing cardiovascular disease, type 2 diabetes, cancer, gallbladder disease, and stroke, risks that fall dramatically with clinically meaningful and sustained weight loss, he said.
“For the overwhelming majority of patients for whom these drugs are targeted (those with the most severe forms of obesity), the benefits of weight loss far outweigh the risks,” Dr. Cork said.
The study was independently supported. Mr. Sodhi, Dr. Etminan, and Dr. Cork report no relevant financial relationships. Dr. Le Roux is a consultant and has received research funding and reimbursement of travel expenses from Novo Nordisk.
A version of this article first appeared on Medscape.com.
FROM JAMA
What the first authorized DNA cancer risk test can and can’t tell you
A novel DNA test system that assesses a person’s genetic predisposition for certain cancers – the first of its kind granted marketing authorization by the Food and Drug Administration – may become a valuable new public health tool.
The Common Hereditary Cancers Panel (Invitae) was approved late September following FDA review under the De Novo process, a regulatory pathway for new types of low- to moderate-risk devices.
Validation of the prescription-only in vitro test was based on assessments of more than 9,000 clinical samples, which demonstrated accuracy of at least 99% for all tested variants in 47 genes known to be associated with an increased risk of developing certain cancers, including breast, ovarian, uterine, prostate, colorectal, gastric, pancreatic as well as melanoma.
How the test system works
Next-generation sequencing assesses germline human genomic DNA extracted from a single blood sample collected at the point of care, such as a doctor’s office, and is sent to a laboratory for analysis.
Specifically, the system aims to detect substitutions, small insertion and deletion alterations, and copy number variants in the panel of 47 targeted genes.
Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological health, explained in an FDA press release announcing the marketing authorization.
Clinical interpretation is based on evidence from the published literature, prediction programs, public databases, and Invitae’s own variants database, the FDA statement explained.
What the test can do
Not only can the Common Hereditary Cancer Panel identify genetic variants that increase an individual’s risk of certain cancers, the panel can also help identify potential cancer-related hereditary variants in patients already diagnosed with cancer.
The most clinically significant genes the test system can detect include BRCA1 and BRCA2, which have known associations with hereditary breast and ovarian cancer syndrome; Lynch syndrome–associated genes including MLH1, MSH2, MSH6, PMS2, and EPCAM; CDH1, which is largely associated with hereditary diffuse gastric cancer and lobular breast cancer; and STK11, which is associated with Peutz-Jeghers syndrome.
“Patients should speak with a health care professional, such as a genetic counselor, to discuss any personal/family history of cancer, as such information can be helpful in interpreting test results,” the FDA advised.
What the test can’t do
The test is not intended to identify or evaluate all known genes tied to a person’s potential predisposition for cancer. The test is also not intended for cancer screening or prenatal testing.
For these reasons, and because genetics are not the only factor associated with developing cancer, negative test results could lead to misunderstanding among some patients about their cancer risk.
“Results are intended to be interpreted within the context of additional laboratory results, family history, and clinical findings,” the company wrote in a statement.
Test safety
Risks associated with the test include the possibility of false positive and false negative results and the potential for people to misunderstand what the results mean about their risk for cancer.
A false sense of assurance after a false negative result might, for instance, lead patients to forgo recommended surveillance or clinical management, whereas false positive test results could lead to inappropriate decision-making and undesirable consequences.
“These risks are mitigated by the analytical performance validation, clinical validation, and appropriate labeling of this test,” the agency explained.
Along with the De Novo authorization, the FDA is establishing special controls to define requirements for these tests. For instance, accuracy must be 99% or higher for positive agreement and at least 99.9% for negative agreement with a validated, independent method.
Public health implications
The information gleaned from this tool can “help guide physicians to provide appropriate monitoring and potential therapy, based on discovered variants,” Dr. Shuren said.
The marketing authorization of Invitae’s test established a new regulatory category, which “means that subsequent devices of the same type with the same intended use may go through FDA’s 510(k) premarket process,” the FDA explained.
A version of this article first appeared on Medscape.com.
A novel DNA test system that assesses a person’s genetic predisposition for certain cancers – the first of its kind granted marketing authorization by the Food and Drug Administration – may become a valuable new public health tool.
The Common Hereditary Cancers Panel (Invitae) was approved late September following FDA review under the De Novo process, a regulatory pathway for new types of low- to moderate-risk devices.
Validation of the prescription-only in vitro test was based on assessments of more than 9,000 clinical samples, which demonstrated accuracy of at least 99% for all tested variants in 47 genes known to be associated with an increased risk of developing certain cancers, including breast, ovarian, uterine, prostate, colorectal, gastric, pancreatic as well as melanoma.
How the test system works
Next-generation sequencing assesses germline human genomic DNA extracted from a single blood sample collected at the point of care, such as a doctor’s office, and is sent to a laboratory for analysis.
Specifically, the system aims to detect substitutions, small insertion and deletion alterations, and copy number variants in the panel of 47 targeted genes.
Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological health, explained in an FDA press release announcing the marketing authorization.
Clinical interpretation is based on evidence from the published literature, prediction programs, public databases, and Invitae’s own variants database, the FDA statement explained.
What the test can do
Not only can the Common Hereditary Cancer Panel identify genetic variants that increase an individual’s risk of certain cancers, the panel can also help identify potential cancer-related hereditary variants in patients already diagnosed with cancer.
The most clinically significant genes the test system can detect include BRCA1 and BRCA2, which have known associations with hereditary breast and ovarian cancer syndrome; Lynch syndrome–associated genes including MLH1, MSH2, MSH6, PMS2, and EPCAM; CDH1, which is largely associated with hereditary diffuse gastric cancer and lobular breast cancer; and STK11, which is associated with Peutz-Jeghers syndrome.
“Patients should speak with a health care professional, such as a genetic counselor, to discuss any personal/family history of cancer, as such information can be helpful in interpreting test results,” the FDA advised.
What the test can’t do
The test is not intended to identify or evaluate all known genes tied to a person’s potential predisposition for cancer. The test is also not intended for cancer screening or prenatal testing.
For these reasons, and because genetics are not the only factor associated with developing cancer, negative test results could lead to misunderstanding among some patients about their cancer risk.
“Results are intended to be interpreted within the context of additional laboratory results, family history, and clinical findings,” the company wrote in a statement.
Test safety
Risks associated with the test include the possibility of false positive and false negative results and the potential for people to misunderstand what the results mean about their risk for cancer.
A false sense of assurance after a false negative result might, for instance, lead patients to forgo recommended surveillance or clinical management, whereas false positive test results could lead to inappropriate decision-making and undesirable consequences.
“These risks are mitigated by the analytical performance validation, clinical validation, and appropriate labeling of this test,” the agency explained.
Along with the De Novo authorization, the FDA is establishing special controls to define requirements for these tests. For instance, accuracy must be 99% or higher for positive agreement and at least 99.9% for negative agreement with a validated, independent method.
Public health implications
The information gleaned from this tool can “help guide physicians to provide appropriate monitoring and potential therapy, based on discovered variants,” Dr. Shuren said.
The marketing authorization of Invitae’s test established a new regulatory category, which “means that subsequent devices of the same type with the same intended use may go through FDA’s 510(k) premarket process,” the FDA explained.
A version of this article first appeared on Medscape.com.
A novel DNA test system that assesses a person’s genetic predisposition for certain cancers – the first of its kind granted marketing authorization by the Food and Drug Administration – may become a valuable new public health tool.
The Common Hereditary Cancers Panel (Invitae) was approved late September following FDA review under the De Novo process, a regulatory pathway for new types of low- to moderate-risk devices.
Validation of the prescription-only in vitro test was based on assessments of more than 9,000 clinical samples, which demonstrated accuracy of at least 99% for all tested variants in 47 genes known to be associated with an increased risk of developing certain cancers, including breast, ovarian, uterine, prostate, colorectal, gastric, pancreatic as well as melanoma.
How the test system works
Next-generation sequencing assesses germline human genomic DNA extracted from a single blood sample collected at the point of care, such as a doctor’s office, and is sent to a laboratory for analysis.
Specifically, the system aims to detect substitutions, small insertion and deletion alterations, and copy number variants in the panel of 47 targeted genes.
Jeff Shuren, MD, JD, director of the FDA’s Center for Devices and Radiological health, explained in an FDA press release announcing the marketing authorization.
Clinical interpretation is based on evidence from the published literature, prediction programs, public databases, and Invitae’s own variants database, the FDA statement explained.
What the test can do
Not only can the Common Hereditary Cancer Panel identify genetic variants that increase an individual’s risk of certain cancers, the panel can also help identify potential cancer-related hereditary variants in patients already diagnosed with cancer.
The most clinically significant genes the test system can detect include BRCA1 and BRCA2, which have known associations with hereditary breast and ovarian cancer syndrome; Lynch syndrome–associated genes including MLH1, MSH2, MSH6, PMS2, and EPCAM; CDH1, which is largely associated with hereditary diffuse gastric cancer and lobular breast cancer; and STK11, which is associated with Peutz-Jeghers syndrome.
“Patients should speak with a health care professional, such as a genetic counselor, to discuss any personal/family history of cancer, as such information can be helpful in interpreting test results,” the FDA advised.
What the test can’t do
The test is not intended to identify or evaluate all known genes tied to a person’s potential predisposition for cancer. The test is also not intended for cancer screening or prenatal testing.
For these reasons, and because genetics are not the only factor associated with developing cancer, negative test results could lead to misunderstanding among some patients about their cancer risk.
“Results are intended to be interpreted within the context of additional laboratory results, family history, and clinical findings,” the company wrote in a statement.
Test safety
Risks associated with the test include the possibility of false positive and false negative results and the potential for people to misunderstand what the results mean about their risk for cancer.
A false sense of assurance after a false negative result might, for instance, lead patients to forgo recommended surveillance or clinical management, whereas false positive test results could lead to inappropriate decision-making and undesirable consequences.
“These risks are mitigated by the analytical performance validation, clinical validation, and appropriate labeling of this test,” the agency explained.
Along with the De Novo authorization, the FDA is establishing special controls to define requirements for these tests. For instance, accuracy must be 99% or higher for positive agreement and at least 99.9% for negative agreement with a validated, independent method.
Public health implications
The information gleaned from this tool can “help guide physicians to provide appropriate monitoring and potential therapy, based on discovered variants,” Dr. Shuren said.
The marketing authorization of Invitae’s test established a new regulatory category, which “means that subsequent devices of the same type with the same intended use may go through FDA’s 510(k) premarket process,” the FDA explained.
A version of this article first appeared on Medscape.com.
Alert! A decade of type 2 diabetes shortens life by 3.5 years
researchers estimate on the basis of data from studies conducted in 19 high-income countries.
They estimated that, among 50-year-olds, life expectancy of those diagnosed with type 2 diabetes at age 30 is 14 years shorter than that of their peers without diabetes. Among those diagnosed at age 50, life expectancy is 6 years shorter.
The study was recently published in The Lancet – Diabetes and Endocrinology.
The team analyzed data from the Emerging Risk Factors Collaboration and the UK Biobank. The data were from 97 long-term, prospective cohorts and involved 1.5 million participants who were followed for 23.1 million person-years.
“The strongest associations with earlier age at diagnosis of diabetes were for vascular (for example, myocardial infarction and stroke) and other causes of death – mainly respiratory, neurological, and infectious diseases and external causes,” they reported.
Their findings are consistent with previous studies that suggested that younger individuals who develop type 2 diabetes might have higher body mass index (BMI), blood pressure, and lipid levels and that they might experience faster deterioration in glycemic control than individuals who develop diabetes later, potentially leading to premature mortality.
Asked to comment, Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, who was not involved with this study, said: “We’ve long known that diabetes reduces life expectancy, and the younger you get it the more years you lose. However, this study was from a broader and larger population base than prior studies.
“In this study, the major reason for death was vascular disease, and undertreatment of cardiovascular risk factors may have occurred in the younger individuals. We also don’t know about glucose control.
“I personally think the findings show that we should treat cardiovascular risk factors more aggressively in people diagnosed with [type 2] diabetes in their 30s and 40s,” urged Dr. Peters.
High priority should be given to prevention globally
“Type 2 diabetes used to be seen as a disease that affected older adults, but we’re increasingly seeing people diagnosed earlier in life,” senior author Emanuele Di Angelantonio, MD, PhD, from the University of Cambridge (England), explained in a press release. “As we’ve shown, this means they are at risk of a much shorter life expectancy than they would otherwise have.”
The findings suggest that “high priority should be given to developing and implementing interventions that prevent or delay the onset of [type 2 diabetes], especially as its prevalence among younger age groups is increasing globally,” the study authors wrote.
The results “support the idea that the younger an individual is when they develop type 2 diabetes, the more damage their body accumulates from its impaired metabolism,” added co–senior author Naveed Sattar, MD, PhD, of the University of Glasgow,
Dr. Peters agreed: “People who develop type 2 diabetes at a younger age might have a different, potentially more aggressive type of type 2 diabetes and perhaps need treatment targets that are lower than people who develop type 2 diabetes when they are older.”
“The findings ... suggest that early detection of diabetes by screening followed by intensive glucose management could help prevent long-term complications from the condition,” Dr. Sattar said.
Dr. Peters added: “An issue for some is pregnancy. ... Many of the medications taken for management of CVD [cardiovascular disease] risk factors are contraindicated in pregnancy (as are many of the medications [for treating type 2 diabetes]).
“We need to be careful to risk reduce but take care of the ‘whole person,’ and if of childbearing age, consider the safest approaches to healthy management,” she emphasized.
Study results: Type 2 diabetes diagnosed at age 30, 40, and 50
Previous studies estimated that adults with type 2 diabetes die 6 years earlier on average in comparison with their counterparts who do not have diabetes, but it was not known how diabetes duration affects life span.
To investigate this, the team analyzed individual records from the Emerging Risk Factors Collaboration and the UK Biobank. The primary outcome was all-cause mortality. Other outcomes were deaths from CVD, cancer, and other causes.
Over a median follow-up of 12.5 years, there were 246,670 deaths: 84,443 from cardiovascular causes, 150, 972 from noncardiovascular causes, and 11,255 from unknown/ill-defined causes.
Compared with participants who did not have a history of type 2 diabetes, the hazard ratios for all-cause mortality, adjusted for age and sex, were 2.69 for participants diagnosed at age 30-39, 2.26 for those diagnosed aged 40-49, 1.84 aged 50-59, 1.57 for those aged 60-69, and 1.39 for those diagnosed 70 and older.
These hazard ratios were similar after adjusting for BMI, systolic blood pressure, and total cholesterol, but they were substantially attenuated after further adjusting for fasting glucose or hemoglobin A1c level.
Similar patterns were observed for cause-specific mortality.
“Every decade of earlier diagnosis of diabetes was associated with about 3-4 years of lower life expectancy, highlighting the need to develop and implement interventions that prevent or delay the onset of diabetes and to intensify the treatment of risk factors among young adults diagnosed with diabetes,” the researchers wrote.
The study was funded the British Heart Foundation, the Medical Research Council, the National Institute for Health and Care Research, and Health Data Research UK. Dr. Peters is on advisory boards for Vertex, Eli Lilly, and Medscape, receives research funding from Abbott Diabetes Care and Insulet, and has stock options for Omada Health.
A version of this article first appeared on Medscape.com.
researchers estimate on the basis of data from studies conducted in 19 high-income countries.
They estimated that, among 50-year-olds, life expectancy of those diagnosed with type 2 diabetes at age 30 is 14 years shorter than that of their peers without diabetes. Among those diagnosed at age 50, life expectancy is 6 years shorter.
The study was recently published in The Lancet – Diabetes and Endocrinology.
The team analyzed data from the Emerging Risk Factors Collaboration and the UK Biobank. The data were from 97 long-term, prospective cohorts and involved 1.5 million participants who were followed for 23.1 million person-years.
“The strongest associations with earlier age at diagnosis of diabetes were for vascular (for example, myocardial infarction and stroke) and other causes of death – mainly respiratory, neurological, and infectious diseases and external causes,” they reported.
Their findings are consistent with previous studies that suggested that younger individuals who develop type 2 diabetes might have higher body mass index (BMI), blood pressure, and lipid levels and that they might experience faster deterioration in glycemic control than individuals who develop diabetes later, potentially leading to premature mortality.
Asked to comment, Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, who was not involved with this study, said: “We’ve long known that diabetes reduces life expectancy, and the younger you get it the more years you lose. However, this study was from a broader and larger population base than prior studies.
“In this study, the major reason for death was vascular disease, and undertreatment of cardiovascular risk factors may have occurred in the younger individuals. We also don’t know about glucose control.
“I personally think the findings show that we should treat cardiovascular risk factors more aggressively in people diagnosed with [type 2] diabetes in their 30s and 40s,” urged Dr. Peters.
High priority should be given to prevention globally
“Type 2 diabetes used to be seen as a disease that affected older adults, but we’re increasingly seeing people diagnosed earlier in life,” senior author Emanuele Di Angelantonio, MD, PhD, from the University of Cambridge (England), explained in a press release. “As we’ve shown, this means they are at risk of a much shorter life expectancy than they would otherwise have.”
The findings suggest that “high priority should be given to developing and implementing interventions that prevent or delay the onset of [type 2 diabetes], especially as its prevalence among younger age groups is increasing globally,” the study authors wrote.
The results “support the idea that the younger an individual is when they develop type 2 diabetes, the more damage their body accumulates from its impaired metabolism,” added co–senior author Naveed Sattar, MD, PhD, of the University of Glasgow,
Dr. Peters agreed: “People who develop type 2 diabetes at a younger age might have a different, potentially more aggressive type of type 2 diabetes and perhaps need treatment targets that are lower than people who develop type 2 diabetes when they are older.”
“The findings ... suggest that early detection of diabetes by screening followed by intensive glucose management could help prevent long-term complications from the condition,” Dr. Sattar said.
Dr. Peters added: “An issue for some is pregnancy. ... Many of the medications taken for management of CVD [cardiovascular disease] risk factors are contraindicated in pregnancy (as are many of the medications [for treating type 2 diabetes]).
“We need to be careful to risk reduce but take care of the ‘whole person,’ and if of childbearing age, consider the safest approaches to healthy management,” she emphasized.
Study results: Type 2 diabetes diagnosed at age 30, 40, and 50
Previous studies estimated that adults with type 2 diabetes die 6 years earlier on average in comparison with their counterparts who do not have diabetes, but it was not known how diabetes duration affects life span.
To investigate this, the team analyzed individual records from the Emerging Risk Factors Collaboration and the UK Biobank. The primary outcome was all-cause mortality. Other outcomes were deaths from CVD, cancer, and other causes.
Over a median follow-up of 12.5 years, there were 246,670 deaths: 84,443 from cardiovascular causes, 150, 972 from noncardiovascular causes, and 11,255 from unknown/ill-defined causes.
Compared with participants who did not have a history of type 2 diabetes, the hazard ratios for all-cause mortality, adjusted for age and sex, were 2.69 for participants diagnosed at age 30-39, 2.26 for those diagnosed aged 40-49, 1.84 aged 50-59, 1.57 for those aged 60-69, and 1.39 for those diagnosed 70 and older.
These hazard ratios were similar after adjusting for BMI, systolic blood pressure, and total cholesterol, but they were substantially attenuated after further adjusting for fasting glucose or hemoglobin A1c level.
Similar patterns were observed for cause-specific mortality.
“Every decade of earlier diagnosis of diabetes was associated with about 3-4 years of lower life expectancy, highlighting the need to develop and implement interventions that prevent or delay the onset of diabetes and to intensify the treatment of risk factors among young adults diagnosed with diabetes,” the researchers wrote.
The study was funded the British Heart Foundation, the Medical Research Council, the National Institute for Health and Care Research, and Health Data Research UK. Dr. Peters is on advisory boards for Vertex, Eli Lilly, and Medscape, receives research funding from Abbott Diabetes Care and Insulet, and has stock options for Omada Health.
A version of this article first appeared on Medscape.com.
researchers estimate on the basis of data from studies conducted in 19 high-income countries.
They estimated that, among 50-year-olds, life expectancy of those diagnosed with type 2 diabetes at age 30 is 14 years shorter than that of their peers without diabetes. Among those diagnosed at age 50, life expectancy is 6 years shorter.
The study was recently published in The Lancet – Diabetes and Endocrinology.
The team analyzed data from the Emerging Risk Factors Collaboration and the UK Biobank. The data were from 97 long-term, prospective cohorts and involved 1.5 million participants who were followed for 23.1 million person-years.
“The strongest associations with earlier age at diagnosis of diabetes were for vascular (for example, myocardial infarction and stroke) and other causes of death – mainly respiratory, neurological, and infectious diseases and external causes,” they reported.
Their findings are consistent with previous studies that suggested that younger individuals who develop type 2 diabetes might have higher body mass index (BMI), blood pressure, and lipid levels and that they might experience faster deterioration in glycemic control than individuals who develop diabetes later, potentially leading to premature mortality.
Asked to comment, Anne Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, who was not involved with this study, said: “We’ve long known that diabetes reduces life expectancy, and the younger you get it the more years you lose. However, this study was from a broader and larger population base than prior studies.
“In this study, the major reason for death was vascular disease, and undertreatment of cardiovascular risk factors may have occurred in the younger individuals. We also don’t know about glucose control.
“I personally think the findings show that we should treat cardiovascular risk factors more aggressively in people diagnosed with [type 2] diabetes in their 30s and 40s,” urged Dr. Peters.
High priority should be given to prevention globally
“Type 2 diabetes used to be seen as a disease that affected older adults, but we’re increasingly seeing people diagnosed earlier in life,” senior author Emanuele Di Angelantonio, MD, PhD, from the University of Cambridge (England), explained in a press release. “As we’ve shown, this means they are at risk of a much shorter life expectancy than they would otherwise have.”
The findings suggest that “high priority should be given to developing and implementing interventions that prevent or delay the onset of [type 2 diabetes], especially as its prevalence among younger age groups is increasing globally,” the study authors wrote.
The results “support the idea that the younger an individual is when they develop type 2 diabetes, the more damage their body accumulates from its impaired metabolism,” added co–senior author Naveed Sattar, MD, PhD, of the University of Glasgow,
Dr. Peters agreed: “People who develop type 2 diabetes at a younger age might have a different, potentially more aggressive type of type 2 diabetes and perhaps need treatment targets that are lower than people who develop type 2 diabetes when they are older.”
“The findings ... suggest that early detection of diabetes by screening followed by intensive glucose management could help prevent long-term complications from the condition,” Dr. Sattar said.
Dr. Peters added: “An issue for some is pregnancy. ... Many of the medications taken for management of CVD [cardiovascular disease] risk factors are contraindicated in pregnancy (as are many of the medications [for treating type 2 diabetes]).
“We need to be careful to risk reduce but take care of the ‘whole person,’ and if of childbearing age, consider the safest approaches to healthy management,” she emphasized.
Study results: Type 2 diabetes diagnosed at age 30, 40, and 50
Previous studies estimated that adults with type 2 diabetes die 6 years earlier on average in comparison with their counterparts who do not have diabetes, but it was not known how diabetes duration affects life span.
To investigate this, the team analyzed individual records from the Emerging Risk Factors Collaboration and the UK Biobank. The primary outcome was all-cause mortality. Other outcomes were deaths from CVD, cancer, and other causes.
Over a median follow-up of 12.5 years, there were 246,670 deaths: 84,443 from cardiovascular causes, 150, 972 from noncardiovascular causes, and 11,255 from unknown/ill-defined causes.
Compared with participants who did not have a history of type 2 diabetes, the hazard ratios for all-cause mortality, adjusted for age and sex, were 2.69 for participants diagnosed at age 30-39, 2.26 for those diagnosed aged 40-49, 1.84 aged 50-59, 1.57 for those aged 60-69, and 1.39 for those diagnosed 70 and older.
These hazard ratios were similar after adjusting for BMI, systolic blood pressure, and total cholesterol, but they were substantially attenuated after further adjusting for fasting glucose or hemoglobin A1c level.
Similar patterns were observed for cause-specific mortality.
“Every decade of earlier diagnosis of diabetes was associated with about 3-4 years of lower life expectancy, highlighting the need to develop and implement interventions that prevent or delay the onset of diabetes and to intensify the treatment of risk factors among young adults diagnosed with diabetes,” the researchers wrote.
The study was funded the British Heart Foundation, the Medical Research Council, the National Institute for Health and Care Research, and Health Data Research UK. Dr. Peters is on advisory boards for Vertex, Eli Lilly, and Medscape, receives research funding from Abbott Diabetes Care and Insulet, and has stock options for Omada Health.
A version of this article first appeared on Medscape.com.
FROM THE LANCET – DIABETES AND ENDOCRINOLOGY
Confirmed: Intermittent use of benzodiazepines is the safest option
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
BARCELONA – results of a large-scale study show.
Investigators matched more than 57,000 chronic benzodiazepine users with nearly 114,000 intermittent users and found that, at 1 year, chronic users had an 8% increased risk for emergency department visits and/or hospitalizations for falls.
Chronic users also had a 25% increased risk for hip fracture, a 4% raised risk for ED visits and/or hospitalizations for any reason, and a 23% increased risk for death.
Study investigator Simon J.C. Davies, MD, PhD, MSc, Centre for Addiction & Mental Health, Toronto, said that the research shows that, where possible, patients older than 65 years with anxiety or insomnia who are taking benzodiazepines should not stay on these medications continuously.
However, he acknowledged that, “in practical terms, there will be some who can’t change or do not want to change” their treatment.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology.
Wide range of adverse outcomes
The authors noted that benzodiazepines are used to treat anxiety and insomnia but are associated with a range of adverse outcomes, including falls, fractures, cognitive impairment, and mortality as well as tolerance and dose escalation.
“These risks are especially relevant in older adults,” they added, noting that some guidelines recommend avoiding the drugs in this population, whereas other suggest short-term benzodiazepine use for a maximum of 4 weeks.
Despite this, “benzodiazepines are widely prescribed in older adults.” One study showed that almost 15% of adults aged 65 years or older received at least one benzodiazepine prescription.
Moreover, chronic use is more common in older versus younger patients.
Benzodiazepine use among older adults “used to be higher,” Dr. Davies said in an interview, at around 20%, but the “numbers have come down,” partly because of the introduction of benzodiazepine-like sleep medications but also because of educational efforts.
“There are certainly campaigns in Ontario to educate physicians,” Dr. Davies said, “but I think more broadly people are aware of the activity of these drugs, and the tolerance and other issues.”
To compare the risk associated with chronic versus intermittent use of benzodiazepines in older adults, the team performed a population-based cohort study using linked health care databases in Ontario.
They focused on adults aged 65 years or older with a first benzodiazepine prescription after at least 1 year without taking the drugs.
Chronic benzodiazepine use was defined as 120 days of prescriptions over the first 180 days after the index prescription. Patients who met these criteria were matched with intermittent users in a 2:1 ratio by age and sex.
Patients were then propensity matched using 24 variables, including health system use in the year prior to the index prescription, clinical diagnoses, prior psychiatric health system use, falls, and income level.
The team identified 57,072 chronic benzodiazepine users and 312,468 intermittent users, of whom, 57,041 and 113,839, respectively, were propensity matched.
As expected, chronic users were prescribed benzodiazepines for more days than were the intermittent users over both the initial 180-day exposure period, at 141 days versus 33 days, and again during a further 180-day follow-up period, at 181 days versus 19 days.
Over the follow-up period, the daily lorazepam dose-equivalents of chronic users four times that of intermittent users.
Hospitalizations and/or ED visits for falls were higher among patients in the chronic benzodiazepine group, at 4.6% versus 3.2% in those who took the drugs intermittently.
After adjusting for benzodiazepine dose, the team found that chronic benzodiazepine use was associated with a significant increase in the risk for falls leading to hospital presentation over the 360-day study period, compared with intermittent use (hazard ratio, 1.08; P = .0124).
Sex differences
In addition, chronic use was linked to a significantly increased risk for hip fracture (HR, 1.25; P = .0095), and long-term care admission (HR, 1.32; P < .0001).
There was also a significant increase in ED visits and/or hospitalizations for any reason with chronic benzodiazepine use versus intermittent use (HR, 1.04; P = .0007), and an increase in the risk for death (HR, 1.23; P < .0001).
A nonsignificant increased risk for wrist fracture was also associated with chronic use of benzodiazepines (HR, 1.02; P = .8683).
Further analysis revealed some sex differences. For instance, men had a marked increase in the risk for hip fracture with chronic use (HR, 1.50; P = .0154), whereas the risk was not significant in women (HR, 1.16; P = .1332). In addition, mortality risk associated with chronic use was higher in men than in women (HR, 1.39; P < .0001 vs. HR, 1.10; P = .2245).
The decision to discontinue chronic benzodiazepine use can be challenging, said Dr. Davies. “If you’re advising people to stop, what happens to the treatment of their anxiety?”
He said that there are many other treatment options for anxiety that don’t come with tolerance or risk for addiction.
“My position would be that intermittent use is perfectly acceptable while you bide your time to explore other treatments. They may be pharmacological; they may, of course, be lifestyle changes, psychotherapies, and so on,” said Dr. Davies.
If, however, patients feel that chronic benzodiazepine use is their only option, this research informs that decision by quantifying the risks.
“We’ve always known that there was a problem, but there haven’t been high-quality epidemiological studies like this that allowed us to say what the numbers are,” said Dr. Davies.
Confirmatory research
In a comment, Christoph U. Correll, MD, professor of psychiatry at Hofstra University, Hempstead, N.Y., noted that the risk associated with benzodiazepine use, especially in older people, has been demonstrated repeatedly.
“In that context, it is not surprising that less continuous exposure to an established risk factor attenuates the risk for these adverse outcomes,” he said.
Dr. Correll, who was not involved in the study pointed out there is nevertheless a “risk of residual confounding by indication.”
In other words, “people with intermittent benzodiazepine use may have less severe underlying illness and better healthy lifestyle behaviors than those requiring chronic benzodiazepine administration.”
Also commenting on the research, Christian Vinkers, MD, PhD, psychiatrist and professor of stress and resilience, Amsterdam University Medical Centre, said that it confirms “once again that long-term benzodiazepine use should not be encouraged.”
“The risk of falls, as well as cognitive side effects and impaired driving skills, with the risk of road accidents, make chronic overuse of benzodiazepines a public health issue. Of course, there is a small group of patients who should have access to long-term use, but it is reasonable to assume that this group is currently too large,” he added.
The study was funded through a grant from the University of Toronto Department of Psychiatry Excellence Funds. No relevant financial relationships were declared.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Esketamine bests quetiapine for severe depression in head-to-head trial
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
BARCELONA – (TRD), results of a large, multicenter, head-to-head phase 3 trial show.
Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission, compared with quetiapine.
More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI).
Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates.
The findings were presented at the annual meeting of the European College of Neuropsychopharmacology and were published online in the New England Journal of Medicine.
New hope
The results provide “some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer,” said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP.
“These patients are not resistant, they just have resistance to monoaminergic drugs,” he added. Esketamine, he said, is a “new weapon in our armamentarium.”
Dr. Reif said TRD is a serious condition that affects approximately 20%-30% of those with major depressive disorder and has “substantial impact” on patients’ lives, including quality of life and level of functioning.
“We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment,” Dr. Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was “urgently needed.”
For the trial, patients from 171 sites in 24 countries with TRD, defined as a less than 25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy.
Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery-Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32.
Dr. Reif said the study population was representative of a typical TRD population.
The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30.
Key findings
Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8, compared with those treated with quetiapine (27.1% vs. 17.6%; P = .003). This equated to an adjusted odds ratio for remission of 1.74 (P = .003).
Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% vs. 14.1% with quetiapine; odds ratio, 1.72; P = .008).
At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, versus 37.0% (P < .001).
Dr. Reif noted that the definition of remission used in the study was a MADRS score of less than or equal to 10, but if the “more lenient” definition of less than or equal to 12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, versus 46.7%.
Dr. Reif also presented results on functional remission rates beyond 32 weeks – data that were not included in the study as published in NEJM.
While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs. 25.0%; OR, 1.88; P < .001).
The safety data revealed no new signals, Dr. Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs. 11.0% with quetiapine.
Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover.
Dr. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it “greatly improves patients’ functional impairment” while achieving “generally lower” adverse event rates.
He added that they are currently running a significant number of secondary analyses “to give us a better grasp of which patient benefits most” from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection.
‘Tremendous advance’
Session co-chair Mark Weiser, MD, chairman at the department of psychiatry, Tel Aviv (Israel) University, said in an interview that the results are “very exciting” and offer “further proof of a tremendous advance in our field.”
Dr. Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key.
“It’s great to improve symptoms,” he said, “but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that’s of extreme importance and makes us feel very optimistic about the future.”
Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, welcomed the findings.
“The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine,” he said in a release. “This gives people with treatment-resistant depression more safe treatment options.”
The study was funded by Janssen EMEA. Dr. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry.
A version of this article first appeared on Medscape.com.
AT ECNP 2023
Proton pump inhibitors linked to increased dementia risk
TOPLINE:
and was highest among those diagnosed before age 70 years regardless of when PPI treatment was initiated.
METHODOLOGY:
- Researchers used four Danish registries to collect data on dementia diagnoses and prescription PPI use among 1,983,785 individuals aged 60-75 years between 2000 and 2018.
- The median follow-up time was 10.3 years.
TAKEAWAY:
- There were 99,384 (5.0%) cases of all-cause dementia during follow-up, with a median age of diagnosis of 79 years.
- Twenty-one-point-two percent of dementia cases and 18.9% of controls reported a history of PPI use.
- Risk for all-cause dementia before age 90 years was 36% higher with PPI use in people aged 60-69 years at baseline (adjusted incidence rate ratio, 1.36; 95% confidence interval, 1.29-1.43) and 6% higher in those who were age 80-89 years at baseline (aIRR, 1.06; 95% CI, 1.03-1.09).
- Investigators found significant increased dementia risk before age 90 years with PPI use regardless of when PPI treatment began and found no link between PPI use and dementia diagnoses after age 90 years.
IN PRACTICE:
“The association between PPI use and dementia was unambiguously largest among the youngest cases of dementia, potentially suggestive of a critical window of exposure where midlife PPI use affects dementia risk to a larger degree compared to late-life use,” the authors wrote. “Further, the finding could signify a declining impact of individual risk factors with advancing age owing to lengthy ongoing neuropathological processes.”
SOURCE:
Lead author of the study was Nelsan Pourhadi, MD, Danish Dementia Research Centre, department of neurology, Copenhagen University Hospital–Rigshospitalet. It was published online in Alzheimer’s and Dementia.
LIMITATIONS:
The study did not include data on PPI prescriptions before 1995, over-the-counter PPI use, and in-hospital intravenous use of PPI during the study period.
DISCLOSURES:
The study was funded by the Danish Ministry of Health. The authors reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
TOPLINE:
and was highest among those diagnosed before age 70 years regardless of when PPI treatment was initiated.
METHODOLOGY:
- Researchers used four Danish registries to collect data on dementia diagnoses and prescription PPI use among 1,983,785 individuals aged 60-75 years between 2000 and 2018.
- The median follow-up time was 10.3 years.
TAKEAWAY:
- There were 99,384 (5.0%) cases of all-cause dementia during follow-up, with a median age of diagnosis of 79 years.
- Twenty-one-point-two percent of dementia cases and 18.9% of controls reported a history of PPI use.
- Risk for all-cause dementia before age 90 years was 36% higher with PPI use in people aged 60-69 years at baseline (adjusted incidence rate ratio, 1.36; 95% confidence interval, 1.29-1.43) and 6% higher in those who were age 80-89 years at baseline (aIRR, 1.06; 95% CI, 1.03-1.09).
- Investigators found significant increased dementia risk before age 90 years with PPI use regardless of when PPI treatment began and found no link between PPI use and dementia diagnoses after age 90 years.
IN PRACTICE:
“The association between PPI use and dementia was unambiguously largest among the youngest cases of dementia, potentially suggestive of a critical window of exposure where midlife PPI use affects dementia risk to a larger degree compared to late-life use,” the authors wrote. “Further, the finding could signify a declining impact of individual risk factors with advancing age owing to lengthy ongoing neuropathological processes.”
SOURCE:
Lead author of the study was Nelsan Pourhadi, MD, Danish Dementia Research Centre, department of neurology, Copenhagen University Hospital–Rigshospitalet. It was published online in Alzheimer’s and Dementia.
LIMITATIONS:
The study did not include data on PPI prescriptions before 1995, over-the-counter PPI use, and in-hospital intravenous use of PPI during the study period.
DISCLOSURES:
The study was funded by the Danish Ministry of Health. The authors reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
TOPLINE:
and was highest among those diagnosed before age 70 years regardless of when PPI treatment was initiated.
METHODOLOGY:
- Researchers used four Danish registries to collect data on dementia diagnoses and prescription PPI use among 1,983,785 individuals aged 60-75 years between 2000 and 2018.
- The median follow-up time was 10.3 years.
TAKEAWAY:
- There were 99,384 (5.0%) cases of all-cause dementia during follow-up, with a median age of diagnosis of 79 years.
- Twenty-one-point-two percent of dementia cases and 18.9% of controls reported a history of PPI use.
- Risk for all-cause dementia before age 90 years was 36% higher with PPI use in people aged 60-69 years at baseline (adjusted incidence rate ratio, 1.36; 95% confidence interval, 1.29-1.43) and 6% higher in those who were age 80-89 years at baseline (aIRR, 1.06; 95% CI, 1.03-1.09).
- Investigators found significant increased dementia risk before age 90 years with PPI use regardless of when PPI treatment began and found no link between PPI use and dementia diagnoses after age 90 years.
IN PRACTICE:
“The association between PPI use and dementia was unambiguously largest among the youngest cases of dementia, potentially suggestive of a critical window of exposure where midlife PPI use affects dementia risk to a larger degree compared to late-life use,” the authors wrote. “Further, the finding could signify a declining impact of individual risk factors with advancing age owing to lengthy ongoing neuropathological processes.”
SOURCE:
Lead author of the study was Nelsan Pourhadi, MD, Danish Dementia Research Centre, department of neurology, Copenhagen University Hospital–Rigshospitalet. It was published online in Alzheimer’s and Dementia.
LIMITATIONS:
The study did not include data on PPI prescriptions before 1995, over-the-counter PPI use, and in-hospital intravenous use of PPI during the study period.
DISCLOSURES:
The study was funded by the Danish Ministry of Health. The authors reported no relevant conflicts.
A version of this article first appeared on Medscape.com.
Breast, GYN Cancers Diagnosed at Lower Ages in VA Than Community
CHICAGO—A new report offers a picture of patients seeking care for breast and gynecological cancers within the US Department of Veterans Affairs (VA) health care system: They are somewhat younger than their counterparts in the general population, and those with breast cancer are much more likely to be men.
It is not clear whether these numbers are purely a reflection of the unique population within the VA or whether there is a more complicated explanation. Researchers also found that more than half of those with newly diagnosed breast, cervical, and ovarian cancers lived in the South compared with few (8%-13%) who lived in the Northeast.
The study findings were released in a poster at the 2023 annual meeting of the Association of VA Hematology/Oncology. Sarah Colonna, MD, study coauthor and medical director of breast oncology for the national VA, said in an interview that it is important to understand statistics regarding breast and gynecological cancer within the VA, especially as the system focuses more on patients with the conditions. And, she said, the wave of women who joined the military in recent decades are getting older and more likely to need oncology care. “We know women veterans are coming: They’re aging, and they’re going to get cancer.”
Colonna and colleagues examined statistics from the VA Corporate Data Warehouse to determine how many veterans were newly diagnosed with breast, uterine, ovarian, cervical, and vulvovaginal cancer in 2021 and 2022. The researchers compared their findings with 2020 statistics about the general population from the SEER database.
Within the VA, there were 3304 cases of breast cancer (mean age, 59 years; range, 23-99; mean body mass index [BMI], 31), 344 cases of cervical cancer (mean age, 46 years; range, 22-90; mean BMI, 29), 177 cases of ovarian cancer (mean age, 57 years; range, 24-80; mean BMI, 29), 365 cases of uterine cancer (mean age, 60 years; range, 24-85; mean BMI, 35), and 32 cases of vaginal/vulvar cancer (mean age, 56 years; range, 24-75; mean BMI, 31).
In contrast, the mean ages at diagnosis for the general population were slightly higher at 63 years for breast cancer, 50 years for cervical cancer, 63 years for ovarian cancer, and 63 years for uterine cancer. Vaginal/vulvar cancer was a bit of an outlier at mean age 69 years for the general population vs 56 years for the VA population; however, the number of cases in the latter group was quite low at 32 patients.
Overall, gynecological cancers were diagnosed at an average age of 55 years among the VA population vs 61 years among the general population. Men made up 11% of breast cancer cases in the VA vs 1% in the general population. “Of course, we have 10 times the proportion of men than in the outside,” said Colonna, an oncologist with the Huntsman Cancer Institute/Wahlen VA Medical Center in Utah. That may explain the difference, “but nobody knows for sure,” she said.
Patients Within the VA with the following cancers were more likely to be Black veterans than in the general population: breast, 30% vs 12%; cervical, 20% vs 14%; ovarian, 28% vs 10%; uterine, 25% vs 12%; and vaginal/vulvar, 44% vs 10%. This could reflect the fact that 30% of women treated within the VA are Black women vs 12% in the general population, Colonna said. Unfortunately, she said, “black women with breast cancer, tend to do really poorly. They tend to get it young, and they tend to die.”
As for the geographic distribution of cases, Colonna said it represents the high numbers of veterans who live in the South, suggesting that more VA oncology resources may be needed there.
In an interview, Aditi Hazra, PhD, MPH, an assistant professor of medicine at Harvard Medical School, said the new analysis is “very valuable”: “Women are a growing proportion of the veterans who serve, and we need more data to understand the risk factors and incidents of disease in this population.” Hazra said the next step will be to control the data for risk factors and “tease out what is driving the rates in the VA.”
There is no study funding, and the authors have no disclosures. Dr. Hazra discloses that she works for the VA and has collaborated with one of the study authors.
CHICAGO—A new report offers a picture of patients seeking care for breast and gynecological cancers within the US Department of Veterans Affairs (VA) health care system: They are somewhat younger than their counterparts in the general population, and those with breast cancer are much more likely to be men.
It is not clear whether these numbers are purely a reflection of the unique population within the VA or whether there is a more complicated explanation. Researchers also found that more than half of those with newly diagnosed breast, cervical, and ovarian cancers lived in the South compared with few (8%-13%) who lived in the Northeast.
The study findings were released in a poster at the 2023 annual meeting of the Association of VA Hematology/Oncology. Sarah Colonna, MD, study coauthor and medical director of breast oncology for the national VA, said in an interview that it is important to understand statistics regarding breast and gynecological cancer within the VA, especially as the system focuses more on patients with the conditions. And, she said, the wave of women who joined the military in recent decades are getting older and more likely to need oncology care. “We know women veterans are coming: They’re aging, and they’re going to get cancer.”
Colonna and colleagues examined statistics from the VA Corporate Data Warehouse to determine how many veterans were newly diagnosed with breast, uterine, ovarian, cervical, and vulvovaginal cancer in 2021 and 2022. The researchers compared their findings with 2020 statistics about the general population from the SEER database.
Within the VA, there were 3304 cases of breast cancer (mean age, 59 years; range, 23-99; mean body mass index [BMI], 31), 344 cases of cervical cancer (mean age, 46 years; range, 22-90; mean BMI, 29), 177 cases of ovarian cancer (mean age, 57 years; range, 24-80; mean BMI, 29), 365 cases of uterine cancer (mean age, 60 years; range, 24-85; mean BMI, 35), and 32 cases of vaginal/vulvar cancer (mean age, 56 years; range, 24-75; mean BMI, 31).
In contrast, the mean ages at diagnosis for the general population were slightly higher at 63 years for breast cancer, 50 years for cervical cancer, 63 years for ovarian cancer, and 63 years for uterine cancer. Vaginal/vulvar cancer was a bit of an outlier at mean age 69 years for the general population vs 56 years for the VA population; however, the number of cases in the latter group was quite low at 32 patients.
Overall, gynecological cancers were diagnosed at an average age of 55 years among the VA population vs 61 years among the general population. Men made up 11% of breast cancer cases in the VA vs 1% in the general population. “Of course, we have 10 times the proportion of men than in the outside,” said Colonna, an oncologist with the Huntsman Cancer Institute/Wahlen VA Medical Center in Utah. That may explain the difference, “but nobody knows for sure,” she said.
Patients Within the VA with the following cancers were more likely to be Black veterans than in the general population: breast, 30% vs 12%; cervical, 20% vs 14%; ovarian, 28% vs 10%; uterine, 25% vs 12%; and vaginal/vulvar, 44% vs 10%. This could reflect the fact that 30% of women treated within the VA are Black women vs 12% in the general population, Colonna said. Unfortunately, she said, “black women with breast cancer, tend to do really poorly. They tend to get it young, and they tend to die.”
As for the geographic distribution of cases, Colonna said it represents the high numbers of veterans who live in the South, suggesting that more VA oncology resources may be needed there.
In an interview, Aditi Hazra, PhD, MPH, an assistant professor of medicine at Harvard Medical School, said the new analysis is “very valuable”: “Women are a growing proportion of the veterans who serve, and we need more data to understand the risk factors and incidents of disease in this population.” Hazra said the next step will be to control the data for risk factors and “tease out what is driving the rates in the VA.”
There is no study funding, and the authors have no disclosures. Dr. Hazra discloses that she works for the VA and has collaborated with one of the study authors.
CHICAGO—A new report offers a picture of patients seeking care for breast and gynecological cancers within the US Department of Veterans Affairs (VA) health care system: They are somewhat younger than their counterparts in the general population, and those with breast cancer are much more likely to be men.
It is not clear whether these numbers are purely a reflection of the unique population within the VA or whether there is a more complicated explanation. Researchers also found that more than half of those with newly diagnosed breast, cervical, and ovarian cancers lived in the South compared with few (8%-13%) who lived in the Northeast.
The study findings were released in a poster at the 2023 annual meeting of the Association of VA Hematology/Oncology. Sarah Colonna, MD, study coauthor and medical director of breast oncology for the national VA, said in an interview that it is important to understand statistics regarding breast and gynecological cancer within the VA, especially as the system focuses more on patients with the conditions. And, she said, the wave of women who joined the military in recent decades are getting older and more likely to need oncology care. “We know women veterans are coming: They’re aging, and they’re going to get cancer.”
Colonna and colleagues examined statistics from the VA Corporate Data Warehouse to determine how many veterans were newly diagnosed with breast, uterine, ovarian, cervical, and vulvovaginal cancer in 2021 and 2022. The researchers compared their findings with 2020 statistics about the general population from the SEER database.
Within the VA, there were 3304 cases of breast cancer (mean age, 59 years; range, 23-99; mean body mass index [BMI], 31), 344 cases of cervical cancer (mean age, 46 years; range, 22-90; mean BMI, 29), 177 cases of ovarian cancer (mean age, 57 years; range, 24-80; mean BMI, 29), 365 cases of uterine cancer (mean age, 60 years; range, 24-85; mean BMI, 35), and 32 cases of vaginal/vulvar cancer (mean age, 56 years; range, 24-75; mean BMI, 31).
In contrast, the mean ages at diagnosis for the general population were slightly higher at 63 years for breast cancer, 50 years for cervical cancer, 63 years for ovarian cancer, and 63 years for uterine cancer. Vaginal/vulvar cancer was a bit of an outlier at mean age 69 years for the general population vs 56 years for the VA population; however, the number of cases in the latter group was quite low at 32 patients.
Overall, gynecological cancers were diagnosed at an average age of 55 years among the VA population vs 61 years among the general population. Men made up 11% of breast cancer cases in the VA vs 1% in the general population. “Of course, we have 10 times the proportion of men than in the outside,” said Colonna, an oncologist with the Huntsman Cancer Institute/Wahlen VA Medical Center in Utah. That may explain the difference, “but nobody knows for sure,” she said.
Patients Within the VA with the following cancers were more likely to be Black veterans than in the general population: breast, 30% vs 12%; cervical, 20% vs 14%; ovarian, 28% vs 10%; uterine, 25% vs 12%; and vaginal/vulvar, 44% vs 10%. This could reflect the fact that 30% of women treated within the VA are Black women vs 12% in the general population, Colonna said. Unfortunately, she said, “black women with breast cancer, tend to do really poorly. They tend to get it young, and they tend to die.”
As for the geographic distribution of cases, Colonna said it represents the high numbers of veterans who live in the South, suggesting that more VA oncology resources may be needed there.
In an interview, Aditi Hazra, PhD, MPH, an assistant professor of medicine at Harvard Medical School, said the new analysis is “very valuable”: “Women are a growing proportion of the veterans who serve, and we need more data to understand the risk factors and incidents of disease in this population.” Hazra said the next step will be to control the data for risk factors and “tease out what is driving the rates in the VA.”
There is no study funding, and the authors have no disclosures. Dr. Hazra discloses that she works for the VA and has collaborated with one of the study authors.
Growing ‘tranq’ threat poses challenges for PCPs
The widening threat of the animal tranquilizer xylazine, otherwise known as tranq, which has been found in illegally manufactured fentanyl, necessitates wider testing, a better understanding of its effects, and more research on treatment options, according to a narrative review published in the Annals of Internal Medicine.
“A lot of doctors and providers are asking about this drug,” said Joseph D’Orazio, MD, an addiction medicine specialist and medical toxicologist at Cooper University Healthcare, Camden, N.J., who led the review.
Xylazine is believed to prolong or intensify the effects of opioids, making it a popular additive to illegally produced opioids, particularly fentanyl, according to the Drug Enforcement Administration. Users end up in a zombie-like state with slowed breathing, and they sometimes develop skin ulcers. Because xylazine is not an opioid, common antidotes such as naloxone are ineffective. The White House has called the fentanyl-xylazine combo an “emerging threat.”
“Xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier,” said DEA administrator Anne Milgram, in a statement on the agency’s website. “DEA has seized xylazine and fentanyl mixtures in 48 of 50 States. The DEA Laboratory System is reporting that in 2022 approximately 23% of fentanyl powder and 7% of fentanyl pills seized by the DEA contained xylazine.”
Dr. D’Orazio paired clinical experience with available research to provide guidance on the care of patients exposed to xylazine.
He and his team issued a call for more research on the drug’s effects, including more details on dependency and withdrawal.
Testing a patient who may have been exposed to xylazine requires forensic lab capabilities, which makes testing complicated and costly. The review found no evidence of the origin of the drug or why it causes open sores.
The review calls for more education of providers, including primary care physicians, on the treatment and care of patients who have used xylazine and fentanyl. The authors also call for expanding standard urine analysis to test for xylazine and for intensifying surveillance of the drug supply and distribution of xylazine test strips.
The authors of an editorial that accompanied the journal article urged the health care community to get ahead of xylazine before the crisis worsens.
“Not testing for xylazine in current unaffected areas and populations may lead to delays in responding if and when the drug becomes prevalent in the drug supply,” the authors wrote.
Xylazine was detected in 90% of street opioid samples tested in Philadelphia in 2021, and a toxic surveillance study of drug paraphernalia in Maryland found xylazine in 80% of samples tested between 2021 and 2022.
Dr. D’Orazio stressed that although Narcan is ineffective in treating xylazine, because the sedative is almost always mixed with fentanyl or another opiate, the opioid antagonist should still be used in emergencies.
Angelique Campen, MD, an emergency medicine physician at Providence St. Joseph Medical Center, Burbank, Calif., said she has seen an increase in patients entering the emergency department under the influence of what seems like fentanyl or heroin, but standard treatments such as Narcan have a limited effect. These patients remain in a prolonged period of sedation.
Recently, she admitted to her hospital’s intensive care unit a patient suspected of a xylazine overdose who was not responding to treatment.
Dr. Campen said that patients are screened for fentanyl, but because no test is available for xylazine, she presumed xylazine was causing the complication.
“It makes perfect medical sense to me that that’s what was going on,” Dr. Campen, who has worked at St. Joseph’s for 25 years, said. “I’m hoping with physicians being more aware of it that we can have that part of our regular urine drug screen.”
Dr. Campen also said she hopes an antidote is soon developed.
“If we can just keep delivering that message, hopefully, [to] more and more people, it will get through to them,” she said. “Every time you’re taking this, even though you may have taken it a week before and been fine, you never know: The next dose you take may be the lethal dose.”
A review author reports being awarded $1,000 to cover travel cost for Best Overall Abstract at the American Society of Addiction Medicine 2023 Annual Meeting. Another author reports receiving payments for training conducted as part of a NJDMAHS training grant to educate on substance use disorders. Dr. D’Orazio reports a $500 honorarium for a one-time lecture on xylazine at Yale; and a $500 honorarium for speaking one to three times per year on various topics regarding opioid use disorder at the Health Federation of Philadelphia. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
The widening threat of the animal tranquilizer xylazine, otherwise known as tranq, which has been found in illegally manufactured fentanyl, necessitates wider testing, a better understanding of its effects, and more research on treatment options, according to a narrative review published in the Annals of Internal Medicine.
“A lot of doctors and providers are asking about this drug,” said Joseph D’Orazio, MD, an addiction medicine specialist and medical toxicologist at Cooper University Healthcare, Camden, N.J., who led the review.
Xylazine is believed to prolong or intensify the effects of opioids, making it a popular additive to illegally produced opioids, particularly fentanyl, according to the Drug Enforcement Administration. Users end up in a zombie-like state with slowed breathing, and they sometimes develop skin ulcers. Because xylazine is not an opioid, common antidotes such as naloxone are ineffective. The White House has called the fentanyl-xylazine combo an “emerging threat.”
“Xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier,” said DEA administrator Anne Milgram, in a statement on the agency’s website. “DEA has seized xylazine and fentanyl mixtures in 48 of 50 States. The DEA Laboratory System is reporting that in 2022 approximately 23% of fentanyl powder and 7% of fentanyl pills seized by the DEA contained xylazine.”
Dr. D’Orazio paired clinical experience with available research to provide guidance on the care of patients exposed to xylazine.
He and his team issued a call for more research on the drug’s effects, including more details on dependency and withdrawal.
Testing a patient who may have been exposed to xylazine requires forensic lab capabilities, which makes testing complicated and costly. The review found no evidence of the origin of the drug or why it causes open sores.
The review calls for more education of providers, including primary care physicians, on the treatment and care of patients who have used xylazine and fentanyl. The authors also call for expanding standard urine analysis to test for xylazine and for intensifying surveillance of the drug supply and distribution of xylazine test strips.
The authors of an editorial that accompanied the journal article urged the health care community to get ahead of xylazine before the crisis worsens.
“Not testing for xylazine in current unaffected areas and populations may lead to delays in responding if and when the drug becomes prevalent in the drug supply,” the authors wrote.
Xylazine was detected in 90% of street opioid samples tested in Philadelphia in 2021, and a toxic surveillance study of drug paraphernalia in Maryland found xylazine in 80% of samples tested between 2021 and 2022.
Dr. D’Orazio stressed that although Narcan is ineffective in treating xylazine, because the sedative is almost always mixed with fentanyl or another opiate, the opioid antagonist should still be used in emergencies.
Angelique Campen, MD, an emergency medicine physician at Providence St. Joseph Medical Center, Burbank, Calif., said she has seen an increase in patients entering the emergency department under the influence of what seems like fentanyl or heroin, but standard treatments such as Narcan have a limited effect. These patients remain in a prolonged period of sedation.
Recently, she admitted to her hospital’s intensive care unit a patient suspected of a xylazine overdose who was not responding to treatment.
Dr. Campen said that patients are screened for fentanyl, but because no test is available for xylazine, she presumed xylazine was causing the complication.
“It makes perfect medical sense to me that that’s what was going on,” Dr. Campen, who has worked at St. Joseph’s for 25 years, said. “I’m hoping with physicians being more aware of it that we can have that part of our regular urine drug screen.”
Dr. Campen also said she hopes an antidote is soon developed.
“If we can just keep delivering that message, hopefully, [to] more and more people, it will get through to them,” she said. “Every time you’re taking this, even though you may have taken it a week before and been fine, you never know: The next dose you take may be the lethal dose.”
A review author reports being awarded $1,000 to cover travel cost for Best Overall Abstract at the American Society of Addiction Medicine 2023 Annual Meeting. Another author reports receiving payments for training conducted as part of a NJDMAHS training grant to educate on substance use disorders. Dr. D’Orazio reports a $500 honorarium for a one-time lecture on xylazine at Yale; and a $500 honorarium for speaking one to three times per year on various topics regarding opioid use disorder at the Health Federation of Philadelphia. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
The widening threat of the animal tranquilizer xylazine, otherwise known as tranq, which has been found in illegally manufactured fentanyl, necessitates wider testing, a better understanding of its effects, and more research on treatment options, according to a narrative review published in the Annals of Internal Medicine.
“A lot of doctors and providers are asking about this drug,” said Joseph D’Orazio, MD, an addiction medicine specialist and medical toxicologist at Cooper University Healthcare, Camden, N.J., who led the review.
Xylazine is believed to prolong or intensify the effects of opioids, making it a popular additive to illegally produced opioids, particularly fentanyl, according to the Drug Enforcement Administration. Users end up in a zombie-like state with slowed breathing, and they sometimes develop skin ulcers. Because xylazine is not an opioid, common antidotes such as naloxone are ineffective. The White House has called the fentanyl-xylazine combo an “emerging threat.”
“Xylazine is making the deadliest drug threat our country has ever faced, fentanyl, even deadlier,” said DEA administrator Anne Milgram, in a statement on the agency’s website. “DEA has seized xylazine and fentanyl mixtures in 48 of 50 States. The DEA Laboratory System is reporting that in 2022 approximately 23% of fentanyl powder and 7% of fentanyl pills seized by the DEA contained xylazine.”
Dr. D’Orazio paired clinical experience with available research to provide guidance on the care of patients exposed to xylazine.
He and his team issued a call for more research on the drug’s effects, including more details on dependency and withdrawal.
Testing a patient who may have been exposed to xylazine requires forensic lab capabilities, which makes testing complicated and costly. The review found no evidence of the origin of the drug or why it causes open sores.
The review calls for more education of providers, including primary care physicians, on the treatment and care of patients who have used xylazine and fentanyl. The authors also call for expanding standard urine analysis to test for xylazine and for intensifying surveillance of the drug supply and distribution of xylazine test strips.
The authors of an editorial that accompanied the journal article urged the health care community to get ahead of xylazine before the crisis worsens.
“Not testing for xylazine in current unaffected areas and populations may lead to delays in responding if and when the drug becomes prevalent in the drug supply,” the authors wrote.
Xylazine was detected in 90% of street opioid samples tested in Philadelphia in 2021, and a toxic surveillance study of drug paraphernalia in Maryland found xylazine in 80% of samples tested between 2021 and 2022.
Dr. D’Orazio stressed that although Narcan is ineffective in treating xylazine, because the sedative is almost always mixed with fentanyl or another opiate, the opioid antagonist should still be used in emergencies.
Angelique Campen, MD, an emergency medicine physician at Providence St. Joseph Medical Center, Burbank, Calif., said she has seen an increase in patients entering the emergency department under the influence of what seems like fentanyl or heroin, but standard treatments such as Narcan have a limited effect. These patients remain in a prolonged period of sedation.
Recently, she admitted to her hospital’s intensive care unit a patient suspected of a xylazine overdose who was not responding to treatment.
Dr. Campen said that patients are screened for fentanyl, but because no test is available for xylazine, she presumed xylazine was causing the complication.
“It makes perfect medical sense to me that that’s what was going on,” Dr. Campen, who has worked at St. Joseph’s for 25 years, said. “I’m hoping with physicians being more aware of it that we can have that part of our regular urine drug screen.”
Dr. Campen also said she hopes an antidote is soon developed.
“If we can just keep delivering that message, hopefully, [to] more and more people, it will get through to them,” she said. “Every time you’re taking this, even though you may have taken it a week before and been fine, you never know: The next dose you take may be the lethal dose.”
A review author reports being awarded $1,000 to cover travel cost for Best Overall Abstract at the American Society of Addiction Medicine 2023 Annual Meeting. Another author reports receiving payments for training conducted as part of a NJDMAHS training grant to educate on substance use disorders. Dr. D’Orazio reports a $500 honorarium for a one-time lecture on xylazine at Yale; and a $500 honorarium for speaking one to three times per year on various topics regarding opioid use disorder at the Health Federation of Philadelphia. No other disclosures were reported.
A version of this article first appeared on Medscape.com.
This is how you get patients back for follow-up cancer testing
according to authors of a new study published in the Journal of the American Medical Association.
Results from the clustered, randomized clinical trial indicate that systems-based interventions, such as automating reminders in electronic health records (EHRs), outreach in the form of phone calls or letters, and assistance with barriers to health care, such as housing insecurity, can increase the number of patients who complete appropriate diagnostic follow-up after an abnormal result.
Patients who received an EHR reminder, outreach call or letter, and additional calls to screen for and assist with nine barriers to health care – housing insecurity, food insecurity, paying for basic utilities, family caregiving, legal issues, transportation, financial compensation for treatment, education, and employment – completed follow-up within 120 days of study enrollment at a rate of 31.4%. The follow-up rate was 31% for those who received only an EHR reminder and outreach, 22.7% for those who received only an EHR reminder, and 22.9% for those who received usual care.
“The benefits of cancer screening won’t be fully realized without systems to ensure timely follow-up of abnormal results,” said Anna Tosteson, ScD, director of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, N.H., a coauthor of the study.
Current payment incentives and quality-of-care indicators focus on getting people in for screening but should also address completion of screening – meaning timely and appropriate follow-up of results that could be indicative of cancer, Dr. Tosteson said.
“There’s a disconnect if you have screening rates that are high but once people have an abnormal result, which is potentially one step closer to a cancer diagnosis, there are no systems in place to help clinicians track them,” said study coauthor Jennifer Haas, MD, director of the Center for Primary Care Research at Massachusetts General Hospital in Boston.
In a 2016 study, researchers found that follow-up rates after abnormal cancer screenings varied widely. While 95.6% of patients with abnormal breast cancer screenings underwent timely follow-up testing, only 68.1% of patients with colorectal abnormalities and 44.8% of patients with cervical abnormalities did so.
Researchers for the new study used guideline recommendations and specialist input to create automated EHR algorithms that determined a follow-up period and diagnostic test.
They put the algorithm into practice with 11,980 patients who were part of 44 primary care practices within three health networks between August 2020 and December 2021. All patients had received abnormal test results for colorectal, breast, cervical, or lung cancer in varying risk categories.
All patients received usual care from their providers, which consisted of a “hodgepodge of whatever their clinic usually does,” Dr. Haas said. Without standards and systems in place for follow-up, the burden of testing and tracking patients with abnormal results typically falls on the primary care provider.
The researchers intervened only when patients were overdue for completion of follow-up. They then staggered the interventions sequentially.
All study participants received an automated, algorithm-triggered EHR reminder for follow-up in their patient portal along with routine health maintenance reminders. To view the reminder, patients had to log into their portal. Participants in the outreach and outreach and navigation groups also received a phone call, an EHR message, or a physical letter 2 weeks after receiving an EHR notification if they hadn’t completed follow-up. Research assistants performed the outreach after having been prompted by the algorithm.
After another 4 weeks, those in the EHR, outreach, and navigation group received a call from a patient navigator who helped them address nine barriers to health care, chiefly by providing them with referrals to free resources.
Among patients who received navigation, outcomes were not significantly better than among those who received EHR and outreach, indicating social determinants of health did not significantly affect the population studied or that the modest approach to navigation and the resources provided were insufficient, Dr. Haas said.
The complexity of an automated platform that encompasses many types of cancers, test results, and other data elements could prove difficult to apply in settings with less infrastructure, said Steven Atlas, MD, MPH, director of the Practice-Based Research and Quality Improvement Network in the division of general internal medicine at Mass General.
“I think there’s a role for the federal government to take on these initiatives,” Dr. Atlas said. Government intervention could help create “national IT systems to create standards for creating code for what an abnormal result is and how it should be followed,” he said.
While interventions improved patient follow-up, the overall rates were still low.
“What concerns me is that despite the various interventions implemented to encourage and support patients to return for follow-up testing, over 60% of patients still did not return for the recommended testing,” said Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles. Dr. Elmore was not involved with the study.
The research took place during the COVID-19 pandemic, which may have reduced follow-up, the study authors wrote. Still, given that previous research has shown that follow-up tends to be low, the rates highlight “the need to understand factors associated with not completing follow-up that go beyond reminder effort,” they wrote. These include a need for patient education about the meaning of test results and what follow-up procedures involve.
The study was supported by the National Cancer Institute and the American Cancer Society. The authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
according to authors of a new study published in the Journal of the American Medical Association.
Results from the clustered, randomized clinical trial indicate that systems-based interventions, such as automating reminders in electronic health records (EHRs), outreach in the form of phone calls or letters, and assistance with barriers to health care, such as housing insecurity, can increase the number of patients who complete appropriate diagnostic follow-up after an abnormal result.
Patients who received an EHR reminder, outreach call or letter, and additional calls to screen for and assist with nine barriers to health care – housing insecurity, food insecurity, paying for basic utilities, family caregiving, legal issues, transportation, financial compensation for treatment, education, and employment – completed follow-up within 120 days of study enrollment at a rate of 31.4%. The follow-up rate was 31% for those who received only an EHR reminder and outreach, 22.7% for those who received only an EHR reminder, and 22.9% for those who received usual care.
“The benefits of cancer screening won’t be fully realized without systems to ensure timely follow-up of abnormal results,” said Anna Tosteson, ScD, director of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, N.H., a coauthor of the study.
Current payment incentives and quality-of-care indicators focus on getting people in for screening but should also address completion of screening – meaning timely and appropriate follow-up of results that could be indicative of cancer, Dr. Tosteson said.
“There’s a disconnect if you have screening rates that are high but once people have an abnormal result, which is potentially one step closer to a cancer diagnosis, there are no systems in place to help clinicians track them,” said study coauthor Jennifer Haas, MD, director of the Center for Primary Care Research at Massachusetts General Hospital in Boston.
In a 2016 study, researchers found that follow-up rates after abnormal cancer screenings varied widely. While 95.6% of patients with abnormal breast cancer screenings underwent timely follow-up testing, only 68.1% of patients with colorectal abnormalities and 44.8% of patients with cervical abnormalities did so.
Researchers for the new study used guideline recommendations and specialist input to create automated EHR algorithms that determined a follow-up period and diagnostic test.
They put the algorithm into practice with 11,980 patients who were part of 44 primary care practices within three health networks between August 2020 and December 2021. All patients had received abnormal test results for colorectal, breast, cervical, or lung cancer in varying risk categories.
All patients received usual care from their providers, which consisted of a “hodgepodge of whatever their clinic usually does,” Dr. Haas said. Without standards and systems in place for follow-up, the burden of testing and tracking patients with abnormal results typically falls on the primary care provider.
The researchers intervened only when patients were overdue for completion of follow-up. They then staggered the interventions sequentially.
All study participants received an automated, algorithm-triggered EHR reminder for follow-up in their patient portal along with routine health maintenance reminders. To view the reminder, patients had to log into their portal. Participants in the outreach and outreach and navigation groups also received a phone call, an EHR message, or a physical letter 2 weeks after receiving an EHR notification if they hadn’t completed follow-up. Research assistants performed the outreach after having been prompted by the algorithm.
After another 4 weeks, those in the EHR, outreach, and navigation group received a call from a patient navigator who helped them address nine barriers to health care, chiefly by providing them with referrals to free resources.
Among patients who received navigation, outcomes were not significantly better than among those who received EHR and outreach, indicating social determinants of health did not significantly affect the population studied or that the modest approach to navigation and the resources provided were insufficient, Dr. Haas said.
The complexity of an automated platform that encompasses many types of cancers, test results, and other data elements could prove difficult to apply in settings with less infrastructure, said Steven Atlas, MD, MPH, director of the Practice-Based Research and Quality Improvement Network in the division of general internal medicine at Mass General.
“I think there’s a role for the federal government to take on these initiatives,” Dr. Atlas said. Government intervention could help create “national IT systems to create standards for creating code for what an abnormal result is and how it should be followed,” he said.
While interventions improved patient follow-up, the overall rates were still low.
“What concerns me is that despite the various interventions implemented to encourage and support patients to return for follow-up testing, over 60% of patients still did not return for the recommended testing,” said Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles. Dr. Elmore was not involved with the study.
The research took place during the COVID-19 pandemic, which may have reduced follow-up, the study authors wrote. Still, given that previous research has shown that follow-up tends to be low, the rates highlight “the need to understand factors associated with not completing follow-up that go beyond reminder effort,” they wrote. These include a need for patient education about the meaning of test results and what follow-up procedures involve.
The study was supported by the National Cancer Institute and the American Cancer Society. The authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
according to authors of a new study published in the Journal of the American Medical Association.
Results from the clustered, randomized clinical trial indicate that systems-based interventions, such as automating reminders in electronic health records (EHRs), outreach in the form of phone calls or letters, and assistance with barriers to health care, such as housing insecurity, can increase the number of patients who complete appropriate diagnostic follow-up after an abnormal result.
Patients who received an EHR reminder, outreach call or letter, and additional calls to screen for and assist with nine barriers to health care – housing insecurity, food insecurity, paying for basic utilities, family caregiving, legal issues, transportation, financial compensation for treatment, education, and employment – completed follow-up within 120 days of study enrollment at a rate of 31.4%. The follow-up rate was 31% for those who received only an EHR reminder and outreach, 22.7% for those who received only an EHR reminder, and 22.9% for those who received usual care.
“The benefits of cancer screening won’t be fully realized without systems to ensure timely follow-up of abnormal results,” said Anna Tosteson, ScD, director of the Dartmouth Institute for Health Policy and Clinical Practice in Lebanon, N.H., a coauthor of the study.
Current payment incentives and quality-of-care indicators focus on getting people in for screening but should also address completion of screening – meaning timely and appropriate follow-up of results that could be indicative of cancer, Dr. Tosteson said.
“There’s a disconnect if you have screening rates that are high but once people have an abnormal result, which is potentially one step closer to a cancer diagnosis, there are no systems in place to help clinicians track them,” said study coauthor Jennifer Haas, MD, director of the Center for Primary Care Research at Massachusetts General Hospital in Boston.
In a 2016 study, researchers found that follow-up rates after abnormal cancer screenings varied widely. While 95.6% of patients with abnormal breast cancer screenings underwent timely follow-up testing, only 68.1% of patients with colorectal abnormalities and 44.8% of patients with cervical abnormalities did so.
Researchers for the new study used guideline recommendations and specialist input to create automated EHR algorithms that determined a follow-up period and diagnostic test.
They put the algorithm into practice with 11,980 patients who were part of 44 primary care practices within three health networks between August 2020 and December 2021. All patients had received abnormal test results for colorectal, breast, cervical, or lung cancer in varying risk categories.
All patients received usual care from their providers, which consisted of a “hodgepodge of whatever their clinic usually does,” Dr. Haas said. Without standards and systems in place for follow-up, the burden of testing and tracking patients with abnormal results typically falls on the primary care provider.
The researchers intervened only when patients were overdue for completion of follow-up. They then staggered the interventions sequentially.
All study participants received an automated, algorithm-triggered EHR reminder for follow-up in their patient portal along with routine health maintenance reminders. To view the reminder, patients had to log into their portal. Participants in the outreach and outreach and navigation groups also received a phone call, an EHR message, or a physical letter 2 weeks after receiving an EHR notification if they hadn’t completed follow-up. Research assistants performed the outreach after having been prompted by the algorithm.
After another 4 weeks, those in the EHR, outreach, and navigation group received a call from a patient navigator who helped them address nine barriers to health care, chiefly by providing them with referrals to free resources.
Among patients who received navigation, outcomes were not significantly better than among those who received EHR and outreach, indicating social determinants of health did not significantly affect the population studied or that the modest approach to navigation and the resources provided were insufficient, Dr. Haas said.
The complexity of an automated platform that encompasses many types of cancers, test results, and other data elements could prove difficult to apply in settings with less infrastructure, said Steven Atlas, MD, MPH, director of the Practice-Based Research and Quality Improvement Network in the division of general internal medicine at Mass General.
“I think there’s a role for the federal government to take on these initiatives,” Dr. Atlas said. Government intervention could help create “national IT systems to create standards for creating code for what an abnormal result is and how it should be followed,” he said.
While interventions improved patient follow-up, the overall rates were still low.
“What concerns me is that despite the various interventions implemented to encourage and support patients to return for follow-up testing, over 60% of patients still did not return for the recommended testing,” said Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles. Dr. Elmore was not involved with the study.
The research took place during the COVID-19 pandemic, which may have reduced follow-up, the study authors wrote. Still, given that previous research has shown that follow-up tends to be low, the rates highlight “the need to understand factors associated with not completing follow-up that go beyond reminder effort,” they wrote. These include a need for patient education about the meaning of test results and what follow-up procedures involve.
The study was supported by the National Cancer Institute and the American Cancer Society. The authors have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM JAMA