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FDA puts hold on esophagitis, H. pylori drug, owing to impurity concerns
The Food and Drug Administration
The FDA approved the company’s two vonoprazan-based treatments for H. pylori infection, Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), last May.
The target action date of the company’s NDA for vonoprazan for the treatment of erosive esophagitis was Jan. 11, 2023.
In a news release, Phathom said it has received complete response letters from the FDA related to its erosive esophagitis NDA and H. pylori postapproval supplement.
Both letters address specifications and controls for a nitrosamine drug substance–related impurity, N-nitroso-vonoprazan (NVP), which was detected in the initial commercial launch materials of both products.
The FDA letters ask Phathom to provide “additional stability data to demonstrate that levels of the impurity previously found in vonoprazan drug product will remain at or below the daily acceptable intake throughout the proposed shelf life of the product,” Phathom said.
Phathom said it has conducted “extensive root cause investigations regarding the trace levels of the impurity since it was detected and has implemented mitigation measures to control the levels of NVP below the acceptable intake.”
The company expects to meet with the FDA before the end of March to discuss a resubmission plan and a timeline for the vonoprazan products.
Owing to the regulatory delays, Phathom said it no longer expects product launches for H. pylori or erosive esophagitis in the first quarter of 2023.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration
The FDA approved the company’s two vonoprazan-based treatments for H. pylori infection, Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), last May.
The target action date of the company’s NDA for vonoprazan for the treatment of erosive esophagitis was Jan. 11, 2023.
In a news release, Phathom said it has received complete response letters from the FDA related to its erosive esophagitis NDA and H. pylori postapproval supplement.
Both letters address specifications and controls for a nitrosamine drug substance–related impurity, N-nitroso-vonoprazan (NVP), which was detected in the initial commercial launch materials of both products.
The FDA letters ask Phathom to provide “additional stability data to demonstrate that levels of the impurity previously found in vonoprazan drug product will remain at or below the daily acceptable intake throughout the proposed shelf life of the product,” Phathom said.
Phathom said it has conducted “extensive root cause investigations regarding the trace levels of the impurity since it was detected and has implemented mitigation measures to control the levels of NVP below the acceptable intake.”
The company expects to meet with the FDA before the end of March to discuss a resubmission plan and a timeline for the vonoprazan products.
Owing to the regulatory delays, Phathom said it no longer expects product launches for H. pylori or erosive esophagitis in the first quarter of 2023.
A version of this article first appeared on Medscape.com.
The Food and Drug Administration
The FDA approved the company’s two vonoprazan-based treatments for H. pylori infection, Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin), last May.
The target action date of the company’s NDA for vonoprazan for the treatment of erosive esophagitis was Jan. 11, 2023.
In a news release, Phathom said it has received complete response letters from the FDA related to its erosive esophagitis NDA and H. pylori postapproval supplement.
Both letters address specifications and controls for a nitrosamine drug substance–related impurity, N-nitroso-vonoprazan (NVP), which was detected in the initial commercial launch materials of both products.
The FDA letters ask Phathom to provide “additional stability data to demonstrate that levels of the impurity previously found in vonoprazan drug product will remain at or below the daily acceptable intake throughout the proposed shelf life of the product,” Phathom said.
Phathom said it has conducted “extensive root cause investigations regarding the trace levels of the impurity since it was detected and has implemented mitigation measures to control the levels of NVP below the acceptable intake.”
The company expects to meet with the FDA before the end of March to discuss a resubmission plan and a timeline for the vonoprazan products.
Owing to the regulatory delays, Phathom said it no longer expects product launches for H. pylori or erosive esophagitis in the first quarter of 2023.
A version of this article first appeared on Medscape.com.
Room for improvement in Barrett esophagus care
, an analysis of U.S. registry data shows.
“As the GI Quality Improvement Consortium (GIQuIC) registry represents the ‘best-case scenario’ for adherence, since sites and endoscopists enrolled in this quality registry are aware that their practices are being monitored, these results indicate that there is still room for improvement and better consistency,” the researchers write.
The study was published online in The American Journal of Gastroenterology.
Quality care in BE, which is a precursor to esophageal adenocarcinoma (EAC), includes adherence to the Seattle biopsy protocol for sampling the BE segment (four-quadrant biopsies every 2 cm) and to a surveillance interval of 3-5 years for patients with nondysplastic BE (NDBE).
Previous studies have found poor adherence to these two QIs, but those studies only provided overall estimates, and individual endoscopists or different sites were not taken into consideration.
Jennifer Kolb, MD, with the University of California, Los Angeles, and colleagues say their study is the first to highlight variation in adherence to these measures at the center and endoscopist levels.
The study is also the first U.S. population–based study to report the dysplasia detection rate (DDR), which is a proposed quality indicator. The findings on this metric also demonstrate marked variability across endoscopists and sites.
Study details
Using the nationwide GIQuIC registry, the researchers evaluated endoscopist and site-based adherence to the Seattle protocol and surveillance interval advice from January 2018 to May 2021.
Among 255 practices with 1,195 endoscopists who performed 20,155 upper endoscopies for suspected or established BE, overall adherence to the Seattle protocol was 86%, which is considerably higher than the 51% reported in a study conducted from 2002 to 2007, Dr. Kolb and colleagues note.
When researchers looked specifically at 572 endoscopists for whom there were at least 10 endoscopy records in the registry, they found high variability in adherence to the Seattle protocol (median, 93.8%; interquartile range, 18.9%).
Adherence to the Seattle protocol was also variable among 153 practices for which there were at least 20 endoscopy records (median, 90%; IQR, 20.1%).
Of the 12,100 upper endoscopies with documented NDBE, 8,517 (70.4%) had a guideline-concordant–recommended surveillance interval of 3-5 years, with variability at both the endoscopist (median, 82.4%; IQR, 36.3%) and site level (median, 77.2%; IQR, 28.9%).
Endoscopist and site adherence to the Seattle protocol and surveillance guidance generally rose along with volume of upper endoscopies performed.
The overall DDR was 3.1%; it varied among endoscopists and sites (mean, 3.3% for both).
The investigators note that the 95% confidence intervals for each provider for DDR were “highly variable” and ranged from –20% to 119.3%. Notably, increasing upper endoscopy volume had an inconsistent effect on adherence rates and DDR by endoscopists and sites.
The investigators saw no correlation between overall DDR and Seattle protocol adherence among sites and only weak but statistically significant negative correlation between DDR and Seattle protocol adherence among individual endoscopists.
Practical approaches to improvement
The researchers say their observations from the GIQuIC database “most accurately represent the real-world experience in Barrett’s endoscopy.”
The results can serve as a “benchmark for quality initiatives and intervention trials aimed at improving outcomes for patients with BE,” they say.
Improving adherence to key QI measures and ensuring more consistent clinical behavior across practice groups and endoscopists are “critical first steps” to ensure high-quality BE care, Dr. Kolb and colleagues say.
To that end, they encourage professional societies to emphasize these metrics to their members and to streamline the reporting systems for QIs within the electronic health records used across various practice settings.
Avenues to improve examination quality may include educational interventions, such as online learning platforms that teach dysplasia detection or that highlight best practices, they add. These educational tools should be easy to use and should emphasize quality improvement measures.
“Future efforts are warranted to identify and extinguish predictors of this variability and to determine whether these interventions can improve DDR and adherence rates to QIs among endoscopists doing these examinations with the goal to improve EAC outcomes,” they conclude.
The study had no financial support. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, an analysis of U.S. registry data shows.
“As the GI Quality Improvement Consortium (GIQuIC) registry represents the ‘best-case scenario’ for adherence, since sites and endoscopists enrolled in this quality registry are aware that their practices are being monitored, these results indicate that there is still room for improvement and better consistency,” the researchers write.
The study was published online in The American Journal of Gastroenterology.
Quality care in BE, which is a precursor to esophageal adenocarcinoma (EAC), includes adherence to the Seattle biopsy protocol for sampling the BE segment (four-quadrant biopsies every 2 cm) and to a surveillance interval of 3-5 years for patients with nondysplastic BE (NDBE).
Previous studies have found poor adherence to these two QIs, but those studies only provided overall estimates, and individual endoscopists or different sites were not taken into consideration.
Jennifer Kolb, MD, with the University of California, Los Angeles, and colleagues say their study is the first to highlight variation in adherence to these measures at the center and endoscopist levels.
The study is also the first U.S. population–based study to report the dysplasia detection rate (DDR), which is a proposed quality indicator. The findings on this metric also demonstrate marked variability across endoscopists and sites.
Study details
Using the nationwide GIQuIC registry, the researchers evaluated endoscopist and site-based adherence to the Seattle protocol and surveillance interval advice from January 2018 to May 2021.
Among 255 practices with 1,195 endoscopists who performed 20,155 upper endoscopies for suspected or established BE, overall adherence to the Seattle protocol was 86%, which is considerably higher than the 51% reported in a study conducted from 2002 to 2007, Dr. Kolb and colleagues note.
When researchers looked specifically at 572 endoscopists for whom there were at least 10 endoscopy records in the registry, they found high variability in adherence to the Seattle protocol (median, 93.8%; interquartile range, 18.9%).
Adherence to the Seattle protocol was also variable among 153 practices for which there were at least 20 endoscopy records (median, 90%; IQR, 20.1%).
Of the 12,100 upper endoscopies with documented NDBE, 8,517 (70.4%) had a guideline-concordant–recommended surveillance interval of 3-5 years, with variability at both the endoscopist (median, 82.4%; IQR, 36.3%) and site level (median, 77.2%; IQR, 28.9%).
Endoscopist and site adherence to the Seattle protocol and surveillance guidance generally rose along with volume of upper endoscopies performed.
The overall DDR was 3.1%; it varied among endoscopists and sites (mean, 3.3% for both).
The investigators note that the 95% confidence intervals for each provider for DDR were “highly variable” and ranged from –20% to 119.3%. Notably, increasing upper endoscopy volume had an inconsistent effect on adherence rates and DDR by endoscopists and sites.
The investigators saw no correlation between overall DDR and Seattle protocol adherence among sites and only weak but statistically significant negative correlation between DDR and Seattle protocol adherence among individual endoscopists.
Practical approaches to improvement
The researchers say their observations from the GIQuIC database “most accurately represent the real-world experience in Barrett’s endoscopy.”
The results can serve as a “benchmark for quality initiatives and intervention trials aimed at improving outcomes for patients with BE,” they say.
Improving adherence to key QI measures and ensuring more consistent clinical behavior across practice groups and endoscopists are “critical first steps” to ensure high-quality BE care, Dr. Kolb and colleagues say.
To that end, they encourage professional societies to emphasize these metrics to their members and to streamline the reporting systems for QIs within the electronic health records used across various practice settings.
Avenues to improve examination quality may include educational interventions, such as online learning platforms that teach dysplasia detection or that highlight best practices, they add. These educational tools should be easy to use and should emphasize quality improvement measures.
“Future efforts are warranted to identify and extinguish predictors of this variability and to determine whether these interventions can improve DDR and adherence rates to QIs among endoscopists doing these examinations with the goal to improve EAC outcomes,” they conclude.
The study had no financial support. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, an analysis of U.S. registry data shows.
“As the GI Quality Improvement Consortium (GIQuIC) registry represents the ‘best-case scenario’ for adherence, since sites and endoscopists enrolled in this quality registry are aware that their practices are being monitored, these results indicate that there is still room for improvement and better consistency,” the researchers write.
The study was published online in The American Journal of Gastroenterology.
Quality care in BE, which is a precursor to esophageal adenocarcinoma (EAC), includes adherence to the Seattle biopsy protocol for sampling the BE segment (four-quadrant biopsies every 2 cm) and to a surveillance interval of 3-5 years for patients with nondysplastic BE (NDBE).
Previous studies have found poor adherence to these two QIs, but those studies only provided overall estimates, and individual endoscopists or different sites were not taken into consideration.
Jennifer Kolb, MD, with the University of California, Los Angeles, and colleagues say their study is the first to highlight variation in adherence to these measures at the center and endoscopist levels.
The study is also the first U.S. population–based study to report the dysplasia detection rate (DDR), which is a proposed quality indicator. The findings on this metric also demonstrate marked variability across endoscopists and sites.
Study details
Using the nationwide GIQuIC registry, the researchers evaluated endoscopist and site-based adherence to the Seattle protocol and surveillance interval advice from January 2018 to May 2021.
Among 255 practices with 1,195 endoscopists who performed 20,155 upper endoscopies for suspected or established BE, overall adherence to the Seattle protocol was 86%, which is considerably higher than the 51% reported in a study conducted from 2002 to 2007, Dr. Kolb and colleagues note.
When researchers looked specifically at 572 endoscopists for whom there were at least 10 endoscopy records in the registry, they found high variability in adherence to the Seattle protocol (median, 93.8%; interquartile range, 18.9%).
Adherence to the Seattle protocol was also variable among 153 practices for which there were at least 20 endoscopy records (median, 90%; IQR, 20.1%).
Of the 12,100 upper endoscopies with documented NDBE, 8,517 (70.4%) had a guideline-concordant–recommended surveillance interval of 3-5 years, with variability at both the endoscopist (median, 82.4%; IQR, 36.3%) and site level (median, 77.2%; IQR, 28.9%).
Endoscopist and site adherence to the Seattle protocol and surveillance guidance generally rose along with volume of upper endoscopies performed.
The overall DDR was 3.1%; it varied among endoscopists and sites (mean, 3.3% for both).
The investigators note that the 95% confidence intervals for each provider for DDR were “highly variable” and ranged from –20% to 119.3%. Notably, increasing upper endoscopy volume had an inconsistent effect on adherence rates and DDR by endoscopists and sites.
The investigators saw no correlation between overall DDR and Seattle protocol adherence among sites and only weak but statistically significant negative correlation between DDR and Seattle protocol adherence among individual endoscopists.
Practical approaches to improvement
The researchers say their observations from the GIQuIC database “most accurately represent the real-world experience in Barrett’s endoscopy.”
The results can serve as a “benchmark for quality initiatives and intervention trials aimed at improving outcomes for patients with BE,” they say.
Improving adherence to key QI measures and ensuring more consistent clinical behavior across practice groups and endoscopists are “critical first steps” to ensure high-quality BE care, Dr. Kolb and colleagues say.
To that end, they encourage professional societies to emphasize these metrics to their members and to streamline the reporting systems for QIs within the electronic health records used across various practice settings.
Avenues to improve examination quality may include educational interventions, such as online learning platforms that teach dysplasia detection or that highlight best practices, they add. These educational tools should be easy to use and should emphasize quality improvement measures.
“Future efforts are warranted to identify and extinguish predictors of this variability and to determine whether these interventions can improve DDR and adherence rates to QIs among endoscopists doing these examinations with the goal to improve EAC outcomes,” they conclude.
The study had no financial support. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE AMERICAN JOURNAL OF GASTROENTEROLOGY
Scant evidence for proton pump inhibitor role in gastric cancer
The available evidence suggests that proton pump inhibitors (PPIs) do not cause gastric cancer, researchers say.
A new study could help resolve a controversy over one of the most serious side effects attributed to the widely used medications.
“Our findings are reassuring, especially to all those patients who have an indication for long-term PPI use and need persistent and effective gastric acid suppression to prevent serious health consequences,” said Daniele Piovani, MSc, PhD, an assistant professor of medical statistics at Humanitas University, Milan, in an email to this news organization.
Previous studies did not take into account the probability that the diseases for which the medications were prescribed might have caused the cancer, Dr. Piovani and colleagues write in Alimentary Pharmacology and Therapeutics.
Researchers have worried about the potential of PPIs to cause cancer after finding that they are associated with enterochromaffin-like cells, gastric atrophy, and changes in gut microbiota and gastric mucosal immunology.
Observational studies and meta-analyses showed a link between PPIs and an increased risk for gastric cancer.
“However, the underlying conditions for which PPIs are prescribed are associated with gastric cancer,” said Dr. Piovani. “This may result in an apparent association between PPIs and gastric cancer.”
Another potential confounding factor is that as-yet undiagnosed cancer might also cause symptoms that are treated with PPIs. Patient behavior also may play a role, she noted.
“Let’s imagine a patient with peptic ulcer who takes PPIs,” said Dr. Piovani. “He may not only have peptic ulcer but also be a heavy smoker. He may drink much more alcohol, have a different dietary pattern, be more likely to be exposed to high levels of stress, etc. in respect to a control [patient] who does not have peptic ulcer and does not take PPIs.”
Comparing two drug classes
More recent studies have compared people taking PPIs to people taking histamine-2 receptor antagonists (H2RAs). H2RAs are often used to treat the same conditions as PPIs, but they are not as strongly linked to hypergastrinemia and are not associated with gastric atrophy, so they might serve as good comparators.
Since results of these studies have been conflicting, Dr. Piovani and colleagues attempted to weigh them together in a systematic review and meta-analysis. They identified two randomized clinical trials and 12 observational studies with a total of over 6 million patients.
One randomized controlled trial involved Helicobacter pylori–negative patients with bleeding ulcers. Researchers assigned 138 to 20 mg daily rabeprazole (a PPI) and 132 to 40 mg famotidine (an H2RA). After a year, no cancer occurred.
The other randomized controlled trial involved H. pylori–negative patients with idiopathic peptic ulcers. Investigators assigned 114 to 30 mg lansoprazole (another PPI) and 114 to 40 mg famotidine. In 2 years, one patient receiving famotidine developed cancer.
The researchers found several methodological problems with these trials. One flaw is that the study periods were not long enough to accurately measure what effects the medications might have on gastric cancers, which are a rare outcome, they note. The evidence from these studies was so weak they could not draw conclusions from the results, the investigators conclude.
Pooling data from the 11 observational trials they were able to combine, the researchers found that PPI users had a one-third higher random relative risk of cancer than H2RA users (95% confidence interval, 1.11-1.59). However, these studies were heterogenous, and five of them did not adjust for age and sex, as well as other potentially confounding covariates.
The remaining six observational studies adjusted for age, sex, and at least two other covariates that could affect the risk for gastric cancer. These studies had a total of 2.5 million patients and 7,372 gastric cancers. Combined, these studies showed an RR of gastric cancer in PPI users, compared with H2RA users of 1.07, which was not statistically significant (95% CI, 0.97-1.19).
The researchers found no clear evidence of a dose-response or of an increased risk with longer-term use of PPIs.
Findings support practice guidance
“I found this relatively reassuring,” Mark Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare, Murray, Utah, told this news organization.
PPIs do dramatically increase the pH of the stomach, stimulating the stomach to try to compensate in a process that can sometimes give rise to tumors, Dr. Lewis said. But these tumors appear to be benign.
Other concerns about PPI use, such as reduction in bone density, remain under investigation, he said.
Some H2RA blockers might actually pose a greater cancer risk than PPIs, said Dr. Lewis, and many clinicians seem to favor PPIs. “I have seen a huge sea change where most patients are on PPIs. And I would say that H2RA blockers are older and increasingly the exception in terms of usage, not the rule.”
The investigators note that observational studies by their nature cannot prove cause and effect, but because gastric cancer is so rare, a randomized controlled trial of PPIs versus H2RAs that is large enough to be definitive may not be feasible.
They conclude that their findings support the American Gastroenterological Association recommendation that “the decision to discontinue PPIs should be based solely on the lack of an indication for use and not because of concern for PPI-associated adverse effects.”
Dr. Piovani and Dr. Lewis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The available evidence suggests that proton pump inhibitors (PPIs) do not cause gastric cancer, researchers say.
A new study could help resolve a controversy over one of the most serious side effects attributed to the widely used medications.
“Our findings are reassuring, especially to all those patients who have an indication for long-term PPI use and need persistent and effective gastric acid suppression to prevent serious health consequences,” said Daniele Piovani, MSc, PhD, an assistant professor of medical statistics at Humanitas University, Milan, in an email to this news organization.
Previous studies did not take into account the probability that the diseases for which the medications were prescribed might have caused the cancer, Dr. Piovani and colleagues write in Alimentary Pharmacology and Therapeutics.
Researchers have worried about the potential of PPIs to cause cancer after finding that they are associated with enterochromaffin-like cells, gastric atrophy, and changes in gut microbiota and gastric mucosal immunology.
Observational studies and meta-analyses showed a link between PPIs and an increased risk for gastric cancer.
“However, the underlying conditions for which PPIs are prescribed are associated with gastric cancer,” said Dr. Piovani. “This may result in an apparent association between PPIs and gastric cancer.”
Another potential confounding factor is that as-yet undiagnosed cancer might also cause symptoms that are treated with PPIs. Patient behavior also may play a role, she noted.
“Let’s imagine a patient with peptic ulcer who takes PPIs,” said Dr. Piovani. “He may not only have peptic ulcer but also be a heavy smoker. He may drink much more alcohol, have a different dietary pattern, be more likely to be exposed to high levels of stress, etc. in respect to a control [patient] who does not have peptic ulcer and does not take PPIs.”
Comparing two drug classes
More recent studies have compared people taking PPIs to people taking histamine-2 receptor antagonists (H2RAs). H2RAs are often used to treat the same conditions as PPIs, but they are not as strongly linked to hypergastrinemia and are not associated with gastric atrophy, so they might serve as good comparators.
Since results of these studies have been conflicting, Dr. Piovani and colleagues attempted to weigh them together in a systematic review and meta-analysis. They identified two randomized clinical trials and 12 observational studies with a total of over 6 million patients.
One randomized controlled trial involved Helicobacter pylori–negative patients with bleeding ulcers. Researchers assigned 138 to 20 mg daily rabeprazole (a PPI) and 132 to 40 mg famotidine (an H2RA). After a year, no cancer occurred.
The other randomized controlled trial involved H. pylori–negative patients with idiopathic peptic ulcers. Investigators assigned 114 to 30 mg lansoprazole (another PPI) and 114 to 40 mg famotidine. In 2 years, one patient receiving famotidine developed cancer.
The researchers found several methodological problems with these trials. One flaw is that the study periods were not long enough to accurately measure what effects the medications might have on gastric cancers, which are a rare outcome, they note. The evidence from these studies was so weak they could not draw conclusions from the results, the investigators conclude.
Pooling data from the 11 observational trials they were able to combine, the researchers found that PPI users had a one-third higher random relative risk of cancer than H2RA users (95% confidence interval, 1.11-1.59). However, these studies were heterogenous, and five of them did not adjust for age and sex, as well as other potentially confounding covariates.
The remaining six observational studies adjusted for age, sex, and at least two other covariates that could affect the risk for gastric cancer. These studies had a total of 2.5 million patients and 7,372 gastric cancers. Combined, these studies showed an RR of gastric cancer in PPI users, compared with H2RA users of 1.07, which was not statistically significant (95% CI, 0.97-1.19).
The researchers found no clear evidence of a dose-response or of an increased risk with longer-term use of PPIs.
Findings support practice guidance
“I found this relatively reassuring,” Mark Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare, Murray, Utah, told this news organization.
PPIs do dramatically increase the pH of the stomach, stimulating the stomach to try to compensate in a process that can sometimes give rise to tumors, Dr. Lewis said. But these tumors appear to be benign.
Other concerns about PPI use, such as reduction in bone density, remain under investigation, he said.
Some H2RA blockers might actually pose a greater cancer risk than PPIs, said Dr. Lewis, and many clinicians seem to favor PPIs. “I have seen a huge sea change where most patients are on PPIs. And I would say that H2RA blockers are older and increasingly the exception in terms of usage, not the rule.”
The investigators note that observational studies by their nature cannot prove cause and effect, but because gastric cancer is so rare, a randomized controlled trial of PPIs versus H2RAs that is large enough to be definitive may not be feasible.
They conclude that their findings support the American Gastroenterological Association recommendation that “the decision to discontinue PPIs should be based solely on the lack of an indication for use and not because of concern for PPI-associated adverse effects.”
Dr. Piovani and Dr. Lewis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The available evidence suggests that proton pump inhibitors (PPIs) do not cause gastric cancer, researchers say.
A new study could help resolve a controversy over one of the most serious side effects attributed to the widely used medications.
“Our findings are reassuring, especially to all those patients who have an indication for long-term PPI use and need persistent and effective gastric acid suppression to prevent serious health consequences,” said Daniele Piovani, MSc, PhD, an assistant professor of medical statistics at Humanitas University, Milan, in an email to this news organization.
Previous studies did not take into account the probability that the diseases for which the medications were prescribed might have caused the cancer, Dr. Piovani and colleagues write in Alimentary Pharmacology and Therapeutics.
Researchers have worried about the potential of PPIs to cause cancer after finding that they are associated with enterochromaffin-like cells, gastric atrophy, and changes in gut microbiota and gastric mucosal immunology.
Observational studies and meta-analyses showed a link between PPIs and an increased risk for gastric cancer.
“However, the underlying conditions for which PPIs are prescribed are associated with gastric cancer,” said Dr. Piovani. “This may result in an apparent association between PPIs and gastric cancer.”
Another potential confounding factor is that as-yet undiagnosed cancer might also cause symptoms that are treated with PPIs. Patient behavior also may play a role, she noted.
“Let’s imagine a patient with peptic ulcer who takes PPIs,” said Dr. Piovani. “He may not only have peptic ulcer but also be a heavy smoker. He may drink much more alcohol, have a different dietary pattern, be more likely to be exposed to high levels of stress, etc. in respect to a control [patient] who does not have peptic ulcer and does not take PPIs.”
Comparing two drug classes
More recent studies have compared people taking PPIs to people taking histamine-2 receptor antagonists (H2RAs). H2RAs are often used to treat the same conditions as PPIs, but they are not as strongly linked to hypergastrinemia and are not associated with gastric atrophy, so they might serve as good comparators.
Since results of these studies have been conflicting, Dr. Piovani and colleagues attempted to weigh them together in a systematic review and meta-analysis. They identified two randomized clinical trials and 12 observational studies with a total of over 6 million patients.
One randomized controlled trial involved Helicobacter pylori–negative patients with bleeding ulcers. Researchers assigned 138 to 20 mg daily rabeprazole (a PPI) and 132 to 40 mg famotidine (an H2RA). After a year, no cancer occurred.
The other randomized controlled trial involved H. pylori–negative patients with idiopathic peptic ulcers. Investigators assigned 114 to 30 mg lansoprazole (another PPI) and 114 to 40 mg famotidine. In 2 years, one patient receiving famotidine developed cancer.
The researchers found several methodological problems with these trials. One flaw is that the study periods were not long enough to accurately measure what effects the medications might have on gastric cancers, which are a rare outcome, they note. The evidence from these studies was so weak they could not draw conclusions from the results, the investigators conclude.
Pooling data from the 11 observational trials they were able to combine, the researchers found that PPI users had a one-third higher random relative risk of cancer than H2RA users (95% confidence interval, 1.11-1.59). However, these studies were heterogenous, and five of them did not adjust for age and sex, as well as other potentially confounding covariates.
The remaining six observational studies adjusted for age, sex, and at least two other covariates that could affect the risk for gastric cancer. These studies had a total of 2.5 million patients and 7,372 gastric cancers. Combined, these studies showed an RR of gastric cancer in PPI users, compared with H2RA users of 1.07, which was not statistically significant (95% CI, 0.97-1.19).
The researchers found no clear evidence of a dose-response or of an increased risk with longer-term use of PPIs.
Findings support practice guidance
“I found this relatively reassuring,” Mark Lewis, MD, director of gastrointestinal oncology at Intermountain Healthcare, Murray, Utah, told this news organization.
PPIs do dramatically increase the pH of the stomach, stimulating the stomach to try to compensate in a process that can sometimes give rise to tumors, Dr. Lewis said. But these tumors appear to be benign.
Other concerns about PPI use, such as reduction in bone density, remain under investigation, he said.
Some H2RA blockers might actually pose a greater cancer risk than PPIs, said Dr. Lewis, and many clinicians seem to favor PPIs. “I have seen a huge sea change where most patients are on PPIs. And I would say that H2RA blockers are older and increasingly the exception in terms of usage, not the rule.”
The investigators note that observational studies by their nature cannot prove cause and effect, but because gastric cancer is so rare, a randomized controlled trial of PPIs versus H2RAs that is large enough to be definitive may not be feasible.
They conclude that their findings support the American Gastroenterological Association recommendation that “the decision to discontinue PPIs should be based solely on the lack of an indication for use and not because of concern for PPI-associated adverse effects.”
Dr. Piovani and Dr. Lewis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ALIMENTARY PHARMACOLOGY AND THERAPEUTICS
PPI use in type 2 diabetes links with cardiovascular events
Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.
During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.
The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.
PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).
The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
Prior observational reports
For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)
And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.
However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.
U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
Long-term PPI use threatens harm
“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”
The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.
The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine2 receptor antagonists, a drug class with indications similar to those for PPIs.
The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.
The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.
During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.
The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.
PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).
The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
Prior observational reports
For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)
And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.
However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.
U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
Long-term PPI use threatens harm
“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”
The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.
The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine2 receptor antagonists, a drug class with indications similar to those for PPIs.
The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.
The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Among people with type 2 diabetes who self-reported regularly using a proton pump inhibitor (PPI), the incidence of cardiovascular disease (CVD) events as well as all-cause death was significantly increased in a study of more than 19,000 people with type 2 diabetes in a prospective U.K. database.
During median follow-up of about 11 years, regular use of a PPI by people with type 2 diabetes was significantly linked with a 27% relative increase in the incidence of coronary artery disease, compared with nonuse of a PPI, after full adjustment for potential confounding variables.
The results also show PPI use was significantly linked after full adjustment with a 34% relative increase in MI, a 35% relative increase in heart failure, and a 30% relative increase in all-cause death, say a team of Chinese researchers in a recent report in the Journal of Clinical Endocrinology and Metabolism.
PPIs are a medication class widely used in both over-the-counter and prescription formulations to reduce acid production in the stomach and to treat gastroesophageal reflux disease and other acid-related disorders. The PPI class includes such widely used agents as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec).
The analyses in this report, which used data collected in the UK Biobank, are “rigorous,” and the findings of “a modest elevation of CVD risk are consistent with a growing number of observational studies in populations with and without diabetes,” commented Mary R. Rooney, PhD, an epidemiologist at Johns Hopkins University, Baltimore, who focuses on diabetes and cardiovascular diseases.
Prior observational reports
For example, a report from a prospective, observational study of more than 4300 U.S. residents published in 2021 that Dr. Rooney coauthored documented that cumulative PPI exposure for more than 5 years was significantly linked with a twofold increase in the rate of CVD events, compared with people who did not use a PPI. (This analysis did not examine a possible effect of diabetes status.)
And in a separate prospective, observational study of more than 1,000 Australians with type 2 diabetes, initiation of PPI treatment was significantly linked with a 3.6-fold increased incidence of CVD events, compared with PPI nonuse.
However, Dr. Rooney cautioned that the role of PPI use in raising CVD events “is still an unresolved question. It is too soon to tell if PPI use in people with diabetes should trigger additional caution.” Findings are needed from prospective, randomized trials to determine more definitively whether PPIs play a causal role in the incidence of CVD events, she said in an interview.
U.S. practice often results in unwarranted prolongation of PPI treatment, said the authors of an editorial that accompanied the 2021 report by Dr. Rooney and coauthors.
Long-term PPI use threatens harm
“The practice of initiating stress ulcer prophylaxis [by administering a PPI] in critical care is common,” wrote the authors of the 2021 editorial, Nitin Malik, MD, and William S. Weintraub, MD. “Although it is data driven and well intentioned, the possibility of causing harm – if it is continued on a long-term basis after resolution of the acute illness – is palpable.”
The new analyses using UK Biobank data included 19,229 adults with type 2 diabetes and no preexisting coronary artery disease, MI, heart failure, or stroke. The cohort included 15,954 people (83%) who did not report using a PPI and 3,275 who currently used PPIs regularly. Study limitations include self-report as the only verification of PPI use and lack of information on type of PPI, dose size, or use duration.
The findings remained consistent in several sensitivity analyses, including a propensity score–matched analysis and after further adjustment for use of histamine2 receptor antagonists, a drug class with indications similar to those for PPIs.
The authors of the report speculated that mechanisms that might link PPI use and increased CVD and mortality risk could include changes to the gut microbiota and possible interactions between PPIs and antiplatelet agents.
The study received no commercial funding. The authors and Dr. Rooney disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
Expert panel forms strategy for eosinophilic esophagitis monitoring
“Follow-up should comprise symptom assessment and periodic or repeated endoscopy with histological assessment in specific EoE settings,” wrote Ulrike von Arnim, MD, from University Hospital Magdeburg (Germany), and an international team of colleagues in Clinical Gastroenterology and Hepatology.
Although medicine and diet can control EoE, there is presently no cure, and long-term management is needed to prevent recurrence and long-term effects such as esophageal remodeling, fibrosis, and stricture, the researchers said. Yet they could find no evidence-based recommendations for clinical monitoring of the condition.
With the participation of The International Gastrointestinal Eosinophil Researchers (TIGER) and the European Consortium for Eosinophilic Diseases of the GI Tract (EUREOS), they assembled a team of 18 gastroenterologists, pathologists, and allergists from the United States and Western Europe with expertise in the condition.
Almost all panelists had more than 10 years of subspecialty EoE care and more than five relevant research publications. All were members of TIGER or EUREOS. The panel met by video conferencing and responded to surveys to develop a consensus about why, by what means, and when to monitor patients with EoE.
The group reached 75% or greater agreement on 11 statements on these subjects.
Regular follow-ups are needed because they enable clinicians to detect whether treatments have stopped working, improve therapy adherence, and introduce patients to any new treatments that become available, while preventing gaps in care that can worsen outcomes, the group wrote.
Symptoms don’t give a precise indication of esophageal healing and shouldn’t be the sole measure for disease activity, the experts wrote. They recommended other approaches to monitoring, including biopsies. They also endorse the Endoscopic Reference Score as an outcome measure.
The panel recommended noninvasive tissue sampling, mentioning the esophageal string test and the Cytosponge as examples, but called for more research on these two techniques.
Blood markers, oral swabs, breath condensates, and stool and urine samples are not recommended as approaches for monitoring EoE, they wrote.
The optimal interval to measure the efficacy of a therapy is more difficult to decide, the panel noted.
“The clinician’s decision should take into account the clinical severity of the disease, estimated risk of imminent subsequent food impaction, presence of stenosis, as well as mode of action and reported outcome of the chosen medical, dietary, or mechanical treatment,” they wrote. Intervals from 6 to 24 weeks may be appropriate.
For diets and topical corticosteroids, they agreed on an interval of 8-12 weeks to confirm remission but say a longer time might be preferred for slower-acting therapies, such as monoclonal antibodies.
The panel had the most trouble reaching a consensus on how often to follow up on patients whose disease is in remission or is stable. They settled on 12 to 24 months after the last endoscopy. Any longer than 2 years risks missing increased disease activity, they wrote.
This follow-up should include assessment of symptoms and a gastrointestinal endoscopy in cases of relapse or suspected stricture, as well as when treatment modification is being considered or when assessment of histological activity is desired, the panel recommended.
Almost all the panelists disclosed financial relationships with pharmaceutical or medical device companies.
A version of this article first appeared on Medscape.com.
“Follow-up should comprise symptom assessment and periodic or repeated endoscopy with histological assessment in specific EoE settings,” wrote Ulrike von Arnim, MD, from University Hospital Magdeburg (Germany), and an international team of colleagues in Clinical Gastroenterology and Hepatology.
Although medicine and diet can control EoE, there is presently no cure, and long-term management is needed to prevent recurrence and long-term effects such as esophageal remodeling, fibrosis, and stricture, the researchers said. Yet they could find no evidence-based recommendations for clinical monitoring of the condition.
With the participation of The International Gastrointestinal Eosinophil Researchers (TIGER) and the European Consortium for Eosinophilic Diseases of the GI Tract (EUREOS), they assembled a team of 18 gastroenterologists, pathologists, and allergists from the United States and Western Europe with expertise in the condition.
Almost all panelists had more than 10 years of subspecialty EoE care and more than five relevant research publications. All were members of TIGER or EUREOS. The panel met by video conferencing and responded to surveys to develop a consensus about why, by what means, and when to monitor patients with EoE.
The group reached 75% or greater agreement on 11 statements on these subjects.
Regular follow-ups are needed because they enable clinicians to detect whether treatments have stopped working, improve therapy adherence, and introduce patients to any new treatments that become available, while preventing gaps in care that can worsen outcomes, the group wrote.
Symptoms don’t give a precise indication of esophageal healing and shouldn’t be the sole measure for disease activity, the experts wrote. They recommended other approaches to monitoring, including biopsies. They also endorse the Endoscopic Reference Score as an outcome measure.
The panel recommended noninvasive tissue sampling, mentioning the esophageal string test and the Cytosponge as examples, but called for more research on these two techniques.
Blood markers, oral swabs, breath condensates, and stool and urine samples are not recommended as approaches for monitoring EoE, they wrote.
The optimal interval to measure the efficacy of a therapy is more difficult to decide, the panel noted.
“The clinician’s decision should take into account the clinical severity of the disease, estimated risk of imminent subsequent food impaction, presence of stenosis, as well as mode of action and reported outcome of the chosen medical, dietary, or mechanical treatment,” they wrote. Intervals from 6 to 24 weeks may be appropriate.
For diets and topical corticosteroids, they agreed on an interval of 8-12 weeks to confirm remission but say a longer time might be preferred for slower-acting therapies, such as monoclonal antibodies.
The panel had the most trouble reaching a consensus on how often to follow up on patients whose disease is in remission or is stable. They settled on 12 to 24 months after the last endoscopy. Any longer than 2 years risks missing increased disease activity, they wrote.
This follow-up should include assessment of symptoms and a gastrointestinal endoscopy in cases of relapse or suspected stricture, as well as when treatment modification is being considered or when assessment of histological activity is desired, the panel recommended.
Almost all the panelists disclosed financial relationships with pharmaceutical or medical device companies.
A version of this article first appeared on Medscape.com.
“Follow-up should comprise symptom assessment and periodic or repeated endoscopy with histological assessment in specific EoE settings,” wrote Ulrike von Arnim, MD, from University Hospital Magdeburg (Germany), and an international team of colleagues in Clinical Gastroenterology and Hepatology.
Although medicine and diet can control EoE, there is presently no cure, and long-term management is needed to prevent recurrence and long-term effects such as esophageal remodeling, fibrosis, and stricture, the researchers said. Yet they could find no evidence-based recommendations for clinical monitoring of the condition.
With the participation of The International Gastrointestinal Eosinophil Researchers (TIGER) and the European Consortium for Eosinophilic Diseases of the GI Tract (EUREOS), they assembled a team of 18 gastroenterologists, pathologists, and allergists from the United States and Western Europe with expertise in the condition.
Almost all panelists had more than 10 years of subspecialty EoE care and more than five relevant research publications. All were members of TIGER or EUREOS. The panel met by video conferencing and responded to surveys to develop a consensus about why, by what means, and when to monitor patients with EoE.
The group reached 75% or greater agreement on 11 statements on these subjects.
Regular follow-ups are needed because they enable clinicians to detect whether treatments have stopped working, improve therapy adherence, and introduce patients to any new treatments that become available, while preventing gaps in care that can worsen outcomes, the group wrote.
Symptoms don’t give a precise indication of esophageal healing and shouldn’t be the sole measure for disease activity, the experts wrote. They recommended other approaches to monitoring, including biopsies. They also endorse the Endoscopic Reference Score as an outcome measure.
The panel recommended noninvasive tissue sampling, mentioning the esophageal string test and the Cytosponge as examples, but called for more research on these two techniques.
Blood markers, oral swabs, breath condensates, and stool and urine samples are not recommended as approaches for monitoring EoE, they wrote.
The optimal interval to measure the efficacy of a therapy is more difficult to decide, the panel noted.
“The clinician’s decision should take into account the clinical severity of the disease, estimated risk of imminent subsequent food impaction, presence of stenosis, as well as mode of action and reported outcome of the chosen medical, dietary, or mechanical treatment,” they wrote. Intervals from 6 to 24 weeks may be appropriate.
For diets and topical corticosteroids, they agreed on an interval of 8-12 weeks to confirm remission but say a longer time might be preferred for slower-acting therapies, such as monoclonal antibodies.
The panel had the most trouble reaching a consensus on how often to follow up on patients whose disease is in remission or is stable. They settled on 12 to 24 months after the last endoscopy. Any longer than 2 years risks missing increased disease activity, they wrote.
This follow-up should include assessment of symptoms and a gastrointestinal endoscopy in cases of relapse or suspected stricture, as well as when treatment modification is being considered or when assessment of histological activity is desired, the panel recommended.
Almost all the panelists disclosed financial relationships with pharmaceutical or medical device companies.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
High rates of inappropriate PPI use in hospitalized patients
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The research was published online in the journal Digestive and Liver Disease.
First author Orly Sneh-Arbib, MD, division of gastroenterology and liver disease, Clalit Health Services, Talpiot, Jerusalem, said in an interview that she and her co-authors were “very surprised” that the rates of inappropriate prescribing remained so high, especially as they had discussed the adverse effects of the drugs numerous times during departmental meetings.
She believes that, for many clinicians, handing out a prescription for PPIs has become a habit, with the thought being: “Just take this; it’s like a vitamin.”
In the paper, the researchers write, “Undoubtedly, more action is needed to raise physicians’ knowledge and attention to the subject while providing automated and standardized technology-based tools to reduce inappropriate PPI use using an acceptable algorithm.”
For the study, Dr. Sneh-Arbib and her colleagues developed an algorithm to assess inappropriate PPI prescribing in almost 4,000 internal medicine patients. To try to limit future overprescribing, their algorithm is now included in the clinical records system.
Consequently, every time a clinician tries to prescribe a PPI, they have to confirm that there is a valid indication for doing so, with the aim of adding an “extra step in the process,” Dr. Sneh-Arbib said.
Clear but complex PPI indications
There are a small, well-defined number of indications for long-term PPI use, the authors write. The indications include prior upper gastrointestinal bleeding, maintenance treatment after healing of erosive esophagitis, Barrett’s esophagus, the use of nonsteroidal anti-inflammatory drugs or antiplatelet agents in patients with increased bleeding risk, and maintenance therapy for symptom control in patients with gastroesophageal reflux disease.
The authors also note that the “appropriateness of PPIs is complex,” with multiple factors to consider for long-term PPI use, including complex drug combinations and medical history.
But having seen patients in their 30s prescribed PPIs “just because of taking steroids or aspirin,” Dr. Sneh-Arbib said she wanted to investigate further.
To examine the rate of inappropriate long-term PPI prescription on discharge from internal medicine departments, the team conducted a retrospective analysis of adults admitted to their institution for the first 6 months of 2014 and the first 6 months of 2017.
They included all patients prescribed PPIs on discharge with a recommendation for long-term use and excluded those who were transferred between departments or who had a hospital stay longer than 3 months.
Information on age, gender, ethnicity, socioeconomic status, current and past diagnoses including all relevant gastrointestinal diagnoses, Charlson comorbidity index, and medications on admission and discharge were recorded.
Guidelines for use of PPIs
To assess inappropriate PPI prescribing, the team searched for published recommendations on long-term use, Dr. Sneh-Arbib said. They developed an algorithm based on the U.K. National Institute for Health and Care Excellence (NICE) clinical guideline, “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management.”
The guideline is “not perfect,” Dr. Sneh-Arbib said, but it was suitable. The team then randomly chose 100 patients from their records to validate the resulting algorithm, finding an accuracy of 96%.
The full analysis included 3,982 patients, of whom 74% were aged 65 years or older, and 50.8% were women. PPIs were first prescribed before hospital admission in 92.4% of cases.
The researchers found that the overall rate of inappropriate PPI prescriptions was 44.3%, a figure that was stable between the two the study periods. In 2014, the rate of inappropriate use was 43.2%, and it was 45.6% in 2017, a nonsignificant difference.
Inappropriate PPIs were higher (68.1%) in patients younger than 65 years, compared with those aged 65 years and older (36%).
The researchers analyzed factors associated with inappropriate PPIs, first excluding 448 patients with clear gastrointestinal indications.
In the majority of cases, the inappropriate PPI prescriptions occurred in patients who were not taking dual antiplatelet treatment (89.4%), in younger patients who were taking aspirin only (8.6%), and in patients receiving a single antiplatelet agent other than aspirin (1.9%), according to multivariate analysis.
Overall, 42.4% of patients classified as inappropriate PPI use were not using aspirin, nonsteroidal anti-inflammatory drugs, antiplatelets, antiaggregants, anticoagulants, or steroids, the researchers found.
They also note that most patients in the study (92.3%) had received PPIs before admission, prescribed by their general practitioner or during a previous hospitalization. This raises concerns about unneeded continuation of the drugs and lack of review by clinicians, they write.
PPI deprescribing
Approached for comment, Adrienna Jirik, MD, a gastroenterologist at the Cleveland Clinic, told this news organization that “PPI overprescription is a common problem worldwide, with the United States being no exception.”
They are “one of the most prescribed medications in the world, with several formulations readily available as an over-the-counter medication,” she added.
Dr. Jirik, who was not involved with the study, said that the algorithm used is “on par with the United States clinical practice guidelines for PPI use” and a “great start to initiate an encounter with a patient on PPIs in the outpatient setting to review the indications and to de-escalate and deprescribe therapy.”
Indeed, the American Gastroenterological Association recently published a clinical practice update on deprescribing PPIs.
“It may be useful to incorporate a version of this algorithm as a ‘hard stop’ on some outpatient EMR [electronic medical record] templates to remind providers to address this issue prior to closing an encounter,” Dr. Jirik added.
She noted, however, that tackling any medication reconciliation is a very important but difficult and time-consuming task.
“Education is definitely key for both primary and subspecialty providers,” Dr. Jirik said. “If patients have been on a long-term PPI, the inpatient provider can suggest a plan for de-escalation based on practice guidelines and arrange proper outpatient follow-up for eventual deprescribing.”
No funding was declared. The authors and Dr. Jirik report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Higher BMI may dampen steroid response in eosinophilic esophagitis
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The higher the patient’s BMI level, the lower the individual’s response to tCS therapy from a symptomatic, endoscopic, and histologic perspective, researchers observed in a retrospective study.
Because there are few clinical predictors of response to topical steroids, clinicians may want to consider BMI in their treatment algorithm and when discussing therapeutic treatment options with patients with EoE, the investigators write in an article published online in Clinical Gastroenterology and Hepatology.
For EoE, current guidelines recommend the use of proton-pump inhibitor (PPI) therapy, topical steroids, and dietary elimination. In addition, the biologic dupilumab (Dupixent) was recently approved in the United States for EoE.
Determining what therapy patients with EoE will respond best to remains a challenge, and obesity’s role in treatment response has been unclear.
To investigate the effect patients’ weight might have on tCS therapy, Evan Dellon, MD, MPH, and colleagues at the University of North Carolina School of Medicine, Chapel Hill, reviewed cases involving 296 adults and adolescents aged 14 years and older who had received topical steroids for EoE.
Baseline characteristics were similar, although heartburn was more common among the 68 patients with obesity than among the non-obese patients (59% vs. 37%; P = .001), and the rate of hiatal hernias detected endoscopically was higher among the patients with obesity (22% vs. 11%; P = .02).
Following tCS treatment, peak eosinophil counts were higher for patients with obesity, compared with non-obese patients (36.1 vs. 21.5; P = .003).
Histologic response was significantly higher in non-obese patients, compared with patients with obesity, at less than 15 eosinophils per high-power field (eos/hpf: 61% vs. 47%; P = .049) and less than or equal to 6 eos/hpf (54% vs. 38%; P = .02).
Among the non-obese patients with EoE, global endoscopic response to tCS was significantly greater than among the patients with obesity (76% vs. 59%; P = .006).
In additon, among non-obese patients, the post-treatment EoE-Endoscopic Reference Score (2.4 vs. 3.2; P = .01) and the endoscopic severity score were significantly lower (2.0 vs. 2.4; P = .05).
Global symptomatic response to tCS was seen in 84% of non-obese patients, versus only 67% of those with obesity (P = .03).
On multivariate analysis, increasing BMI was independently associated with decreased histologic response after accounting for age, heartburn, dilation, and hiatal hernia.
This relationship persisted whether BMI was assessed as a continuous variable (adjusted odds ratio, 0.93 for each unit increase in BMI), as non-obese versus obese (aOR 0.38), as overweight versus normal weight (aOR 0.46), or obese versus normal weight (aOR 0.26).
Different treatment algorithm?
The results remained generally similar when patients were stratified by PPI response status and by continued use of PPIs.
The investigators note that in their cohort, only five patients responded to PPI therapy; all were non-obese. It’s possible, they note, that patients with a higher BMI may benefit from dual PPI/tCS treatment initially, but this strategy would require prospective assessment.
As for the mechanism behind obesity’s apparent negative impact on tCS therapy, the researchers say the low-grade systemic inflammatory state of obesity may make tCS therapy less effective, but they add that studies are needed to pinpoint the exact mechanism.
The study suggests that “a clinician can now add another epidemiologic risk factor for potential poor response to treatment for EoE, specifically steroids,” Philip Katz, MD, professor of medicine, division of gastroenterology and hepatology, Weill Cornell Medicine, New York, said in an interview when reached for comment.
However, it is “difficult, if not impossible, to discern from a retrospective study like this why higher BMI would be a risk factor for poor response,” said Dr. Katz, who was not affiliated with the study.
“The main potential clinical message here is that people who are overweight with EoE perhaps need to be looked at differently and might require a different treatment algorithm or treatment approach than a person who is ideal body weight,” Dr. Katz added.
Also commenting for this article, Shreya Chablaney, MD, a gastroenterologist at NYU Langone Health’s Center for Esophageal Health and clinical instructor at NYU Grossman School of Medicine, noted that predictors of patient response to various treatment options for EoE are not well understood and that more robust data are needed to guide appropriate patient selection when considering them.
“Though this is a relatively small, single-center, retrospective study, it shows an interesting finding, that high BMI is independently associated with a decrease in histologic, symptomatic, and endoscopic response to topical steroids, even when controlling for heartburn and the presence of a hiatal hernia,” she said.
“While these findings may not yet affect current management, it highlights the need for more prospective research to see if dosing adjustment, type of topical steroid, or alternative therapy altogether should be considered in patients who are obese,” Dr. Chablaney said.
Support for the study was provided by the National Institutes of Health. Dr. Dellon is a consultant for Abbott, AbbVie, Adare/ Ellodi, Aimmune, Akesobio, ALK, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eurpaxia, Ferring, GSK, Gossamer Bio, Invea, Landos, LucidDx, Morphic, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, and Target RWE. Dr. Katz is a consultant for Phathom Pharmaceuticals and Sebella Pharmaceuticals and serves on an advisory board for AstraZeneca. Dr. Chablaney reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Vonoprazan promising for erosive esophagitis
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, according to results of the phase 3 PHALCON-EE trial.
Vonoprazan achieved higher rates of healing and maintenance of healing than lansoprazole, with the benefit seen primarily in patients with more severe esophagitis.
The differences in healing rates were evident after 2 weeks of therapy and were maintained throughout the 24-week study, report Loren Laine, MD, Yale University, New Haven, Conn., and colleagues.
The study was published online in Gastroenterology.
More potent acid suppression
Gastroesophageal reflux disease is one of the most common disorders of the gastrointestinal tract, and erosive esophagitis is its most common complication.
Although standard PPI therapy is effective for healing erosive esophagitis, some patients do not achieve success with this conventional treatment.
Studies suggest that lack of healing of erosive esophagitis with 8 weeks of PPI therapy can be expected in roughly 5%-20% of patients, with rates up to 30% reported in patients with more severe esophagitis.
The PCAB vonoprazan provides more potent inhibition of gastric acid than PPIs and is seen as a potential alternative. However, data on its efficacy for erosive esophagitis are limited, the authors note.
The PHALCON-EE trial enrolled 1,024 adults from the United States and Europe with erosive esophagitis without Helicobacter pylori infection or Barrett esophagus.
Participants were randomized to receive once-daily vonoprazan 20 mg or lansoprazole 30 mg for up to 8 weeks in the healing phase.
The 878 patients with healing were then rerandomized to receive once-daily vonoprazan 10 mg, vonoprazan 20 mg, or lansoprazole 15 mg for 24 weeks in the maintenance phase.
For healing by week 8, vonoprazan was noninferior to lansoprazole in the primary analysis and superior to lansoprazole in a predefined exploratory analysis (92.9% vs. 84.6%; P < .0001).
Secondary analyses showed that vonoprazan was noninferior to lansoprazole in mean 24-hour heartburn-free days and superior in healing at week 2 for grade C/D esophagitis (70.2% vs. 52.6%; P = .0008).
For maintenance of healing at week 24, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on secondary analysis of healing (80.7% for vonoprazan 20 mg and 79.2% for vonoprazan 10 mg vs. 72.0% for lansoprazole; P < .0001 for both comparisons).
The most common adverse event reported in the healing phase was diarrhea and in the maintenance phase was COVID-19. Two deaths occurred, both from COVID-19, during the maintenance phase in the vonoprazan 20-mg group.
As expected, serum gastrin increased to a greater extent with vonoprazan than lansoprazole, with levels > 500 pg/mL in 16% of those taking 20 mg at the end of maintenance therapy, the authors report. After stopping vonoprazan, gastrin levels dropped by roughly 60%-65% within 4 weeks.
Promising new option
“PCABs are a promising new option,” Avin Aggarwal, MD, who was not involved in the study, told this news organization.
They have a “more potent acid inhibitory effect” and have shown “superior healing of erosive esophagitis,” said Dr. Aggarwal, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona in Tucson.
The results of the PHALCON-EE trial “validate noninferiority of PCABs compared to standard PPI therapy in the Western population after being proven in multiple Asian studies,” he said.
Dr. Aggarwal noted that PCABs work the same way as PPIs, by blocking the proton pumps, but “the longer half-life of PCABs and action on both active and inactive proton channels result in greater acid inhibition.”
Long-term effects of PCAB therapy from stronger acid inhibition and resulting hypergastrinemia still remain to be determined, he said.
Earlier this year, the U.S. Food and Drug Administration accepted Phathom Pharmaceuticals’ new drug application for vonoprazan for the treatment of erosive esophagitis.
Last May, the FDA approved two vonoprazan-based therapies for the treatment of H. pylori infection.
The study was funded by Phathom Pharmaceuticals. Dr. Laine and several coauthors have disclosed financial relationships with the company. Dr. Aggarwal reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM GASTROENTEROLOGY
Dupilumab improves eosinophilic esophagitis up to 24 weeks
Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.
The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.
In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).
“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”
EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.
Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
Study population difficult to treat
In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.
Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.
On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.
Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.
Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.
The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
Pooled parts A and B findings
Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.
Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.
In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.
Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.
“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”
The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.
Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.
The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.
In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).
“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”
EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.
Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
Study population difficult to treat
In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.
Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.
On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.
Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.
Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.
The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
Pooled parts A and B findings
Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.
Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.
In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.
Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.
“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”
The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.
Dupilumab appears to improve clinical, symptomatic, histologic, and endoscopic aspects of eosinophilic esophagitis (EoE) up to 24 weeks, according to findings presented at the annual meeting of the American College of Gastroenterology.
The drug was also well tolerated, demonstrating consistency with the known dupilumab safety profile, said Evan S. Dellon, MD, a gastroenterologist at the University of North Carolina at Chapel Hill.
In May, the Food and Drug Administration approved dupilumab (Dupixent) for the treatment of EoE in adults and adolescents who are 12 years and older and weigh at least 40 kg (about 88 pounds), based on safety and efficacy data previously presented by Dr. Dellon and colleagues as part of the phase 3 LIBERTY-EoE-TREET study (NCT03633617).
“Dupilumab is now the only medication FDA approved to treat EoE in the U.S.,” Dr. Dellon said. “The findings here are that the pooled efficacy and safety data for parts A and B of the phase 3 trial are consistent with the results of the individual parts of the study that were previously reported, and which led to the drug being approved for EoE.”
EoE is a chronic, progressive, type 2 inflammatory disease of the esophagus, which can lead to symptoms of esophageal dysfunction that affect quality of life. Current treatment options often lack specificity, present adherence challenges, and provide suboptimal long-term disease control, Dr. Dellon said.
Dupilumab, a fully human monoclonal antibody manufactured by Regeneron Pharmaceuticals, blocks the shared receptor component for interleukin-4 and IL-13, which are central drivers of type 2 inflammation in EoE.
Study population difficult to treat
In the three-part, double-blind, placebo-controlled, phase 3 study, dupilumab was administered to 122 patients as 300-mg weekly doses through subcutaneous injection. In parts A and B, dupilumab demonstrated statistically significant and clinically meaningful improvement in adults and adolescents up to 24 weeks. In patients from part A who continued to an extended active treatment period called part C, efficacy was sustained to week 52.
Participants were included if they had EoE that hadn’t responded to high-dose proton pump inhibitors, had baseline esophageal biopsies with a peak intraepithelial eosinophilic count of 15 eosinophils per high-power field (eos/HPF) or higher in two or more esophageal regions, had a history of an average of two or more episodes of dysphagia per week in the 4 weeks prior to screening, had four or more episodes of dysphagia in the 2 weeks prior to randomization with two or more episodes that required liquids or medical attention, and had a baseline Dysphagia Symptom Questionnaire (DSQ) score of 10 or higher.
On the other hand, participants were excluded if they initiated or changed a food-elimination diet regimen or reintroduced a previously eliminated food group in the 6 weeks before screening, had other causes of esophageal eosinophilia, had a history of other inflammatory diseases such as Crohn’s disease or ulcerative colitis, or were treated with swallowed topical corticosteroids within 8 weeks prior to baseline.
Dr. Dellon and colleagues focused on co–primary endpoints: The proportion of patients who achieved peak esophageal intraepithelial eosinophil count of 6 eos/HPF or less, and the absolute change in DSQ score from baseline to week 24.
Key secondary endpoints included percentage change in eos/HPF, absolute change in EoE-Endoscopic Reference Score (EREFS), absolute change in EoE-Histologic Scoring System (EoE-HSS) grade score, and EoE-HSS stage score. Other secondary endpoints included percentage change in DSQ score and proportion of patients achieving less than 15 eos/HPF.
The baseline demographics and clinical characteristics were similar between the treatment and placebo groups. Importantly, about 70% had been treated with topical corticosteroids, and about 40% had a history of esophageal dilation, Dr. Dellon said. The DSQ scores, peak eosinophil counts, and EREFS scores were high, indicating an inflamed, symptomatic, and difficult-to-treat population.
Pooled parts A and B findings
Overall, dupilumab reduced peak esophageal intraepithelial eosinophil counts at week 24. In the dupilumab group, 59% of patients were down to 6 eos/HPF or less, compared with 5.9% in the placebo group. In a secondary endpoint, 77% of dupilumab patients were down to 15 eos/HPF, compared with 7.6% in the placebo group. The dupilumab group saw an 80% drop in baseline change, compared with 1.5% in the placebo group.
Dupilumab also reduced dysphagia symptoms and improved endoscopic features of EoE at week 24. The absolute change in DSQ score was –23.21 in the dupilumab group, compared with –12.69 in the placebo group. The percent change in DSQ score was –65.5% in the dupilumab group, compared with –38.2% in the placebo group. The absolute change in EREFS score was –3.95 in the dupilumab group, compared with –0.41 in the placebo group.
In addition, dupilumab reduced histologic scores at week 24. The absolute change in EoE-HSS grade score was –0.82 in the dupilumab group, compared with –0.1 in the placebo group. The absolute change in EoE-HSS stage score was –0.79 in the dupilumab group, compared with –0.09 in the placebo group.
Dupilumab demonstrated an acceptable safety profile, and no new safety signals were noted, Dr. Dellon said. The most common adverse events was injection-site reaction at 37.5% in the dupilumab group and 33.3% in the placebo group. The severe adverse events were not related to the medication.
“If patients have EoE, dupilumab might be an option for treatment. However, it’s important to realize that, in the phase 3 study, all patients were PPI nonresponders, most had been treated with topical steroids [and many were not responsive], and many had prior esophageal dilation,” Dr. Dellon said. “We don’t have a lot of data in more mild EoE patients, and insurances are currently requiring a series of authorization before patients might be able to get this medication. It’s best to talk to their doctor about whether the medication is a good fit for not.”
The study was sponsored by Sanofi and Regeneron Pharmaceuticals. Three of the authors are employees for and have stock options with Regeneron or Sanofi. The other authors reported consultant roles, advisory roles, and research support from numerous pharmaceutical companies, including Regeneron and Sanofi.
FROM ACG 2022
Risk factors ID’d for acute pancreatitis from weight-loss drugs
CHARLOTTE, N.C. – a new study has found.
Type 2 diabetes, advanced chronic kidney disease, and tobacco use were associated with greater risk for acute pancreatitis, researchers report.
On the other hand, a higher body mass index (BMI) – 36 kg/m2 or higher – appeared to protect people against developing the condition.
“As this class of medications becomes increasingly popular in the United States, it is important for providers to know which patients are at a higher or lower risk of developing acute pancreatitis after being started on them,” said lead study author Robert Postlethwaite, MD, a gastroenterology resident at the University of Texas Southwestern Medical Center, Dallas.
The findings were presented at the annual meeting of the American College of Gastroenterology in Charlotte, N.C., being held in person and virtually.
Popularity comes at a price
The U.S. Food and Drug Administration has approved two GLP-1s for weight management – liraglutide (Victoza) in 2014 and semaglutide (Wegovy) in 2021. They work by targeting areas of the brain that control food intake and appetite. Other GLP-1s approved to treat type 2 diabetes include dulaglutide (Trulicity) and two other formulations of semaglutide (Rybelsus and Ozempic).
The demand for Wegovy has been so great that there is an ongoing shortage of the medication in the United States.
Although GLP-1s demonstrate a favorable side-effect profile, compared with other types of antiobesity medications, acute pancreatitis remains a serious and sometimes life-threatening complication, the researchers note. Some patients require hospitalization.
Dr. Postlethwaite and colleagues performed a retrospective, single-center study of 2,245 patients who attended an academic medical center’s Weight Wellness program from 2015 to 2019. The average age was about 50 years, and 81% were female. The average BMI of all patients was 39.7 kg/m2.
The study only included patients starting GLP-1s for treating obesity, not for diabetes.
Of the 2,245 patients, 49 (2.2%) developed acute pancreatitis after starting a GLP-1.
A history of type 2 diabetes mellitus made acute pancreatitis twice as likely (95% confidence interval, 1.04-3.96; P = .04).
Stage 3 or higher chronic kidney disease increased risk 2.3 times (95% CI, 1.18-4.55; P = .01), while tobacco use upped it 3.3 times (95% CI, 1.70-6.50; P < .001).
In contrast, researchers found those with a BMI of 36-40 kg/m2 were 88% less likely to develop acute pancreatitis (95% CI, 0.07-0.67; P = .007), compared with patients with a BMI of less than or equal to 30 kg/m2. Patients with a BMI of greater than 40 kg/m2 had a 73% lower risk (95% CI, 0.10-0.73; P = .01).
Dr. Postlethwaite and colleagues found no association with age, sex, or history of bariatric surgery or acute pancreatitis.
Because a history of acute pancreatitis was not a risk factor, he advised that clinicians not withhold these medications for this reason, “especially given the significant glycemic, cardiovascular, and weight-loss effects.”
“We hope that we can arm clinicians with evidence in order to risk stratify their patients and determine who is at high risk of developing pancreatitis,” Dr. Postlethwaite said.
“Hopefully, we can prevent the development of pancreatitis in some patients, especially high-risk individuals, or at least allow clinicians to be aware of it in higher-risk patients to identify it early enough to prevent complications of acute pancreatitis,” he added.
Larger studies needed
The study is “promising,” said session comoderator Baharak Moshiree, MD, a gastroenterologist at Atrium Health, Charlotte, N.C., who was not affiliated with the research.
However, because the study was retrospective and relatively small, it needs to be validated in larger, prospective studies, she added.
“With obesity being such a global issue, there are many patients on these GLP-1 agonists,” Dr. Moshiree said.
Generally, these medications are prescribed by endocrinologists, not gastroenterologists, she noted, and she said that gastroenterologists should be aware of the risks associated with them, including minor gastrointestinal side effects, like nausea and vomiting, that can occur because of delayed gastric emptying.
Dr. Postlethwaite noted that being unable to assess how much alcohol or tobacco individuals used was a limitation. The relatively low proportion of people who developed acute pancreatitis in the study also means larger studies are warranted, he added.
Going forward, Dr. Postlethwaite and colleagues want to study the risks for each individual GLP-1 and other therapies used to control high blood sugar in people with type 2 diabetes, such as DPP4 (dipeptidyl-peptidase 4) inhibitors.
The study was independently supported. Dr. Postlethwaite and Dr. Moshiree report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHARLOTTE, N.C. – a new study has found.
Type 2 diabetes, advanced chronic kidney disease, and tobacco use were associated with greater risk for acute pancreatitis, researchers report.
On the other hand, a higher body mass index (BMI) – 36 kg/m2 or higher – appeared to protect people against developing the condition.
“As this class of medications becomes increasingly popular in the United States, it is important for providers to know which patients are at a higher or lower risk of developing acute pancreatitis after being started on them,” said lead study author Robert Postlethwaite, MD, a gastroenterology resident at the University of Texas Southwestern Medical Center, Dallas.
The findings were presented at the annual meeting of the American College of Gastroenterology in Charlotte, N.C., being held in person and virtually.
Popularity comes at a price
The U.S. Food and Drug Administration has approved two GLP-1s for weight management – liraglutide (Victoza) in 2014 and semaglutide (Wegovy) in 2021. They work by targeting areas of the brain that control food intake and appetite. Other GLP-1s approved to treat type 2 diabetes include dulaglutide (Trulicity) and two other formulations of semaglutide (Rybelsus and Ozempic).
The demand for Wegovy has been so great that there is an ongoing shortage of the medication in the United States.
Although GLP-1s demonstrate a favorable side-effect profile, compared with other types of antiobesity medications, acute pancreatitis remains a serious and sometimes life-threatening complication, the researchers note. Some patients require hospitalization.
Dr. Postlethwaite and colleagues performed a retrospective, single-center study of 2,245 patients who attended an academic medical center’s Weight Wellness program from 2015 to 2019. The average age was about 50 years, and 81% were female. The average BMI of all patients was 39.7 kg/m2.
The study only included patients starting GLP-1s for treating obesity, not for diabetes.
Of the 2,245 patients, 49 (2.2%) developed acute pancreatitis after starting a GLP-1.
A history of type 2 diabetes mellitus made acute pancreatitis twice as likely (95% confidence interval, 1.04-3.96; P = .04).
Stage 3 or higher chronic kidney disease increased risk 2.3 times (95% CI, 1.18-4.55; P = .01), while tobacco use upped it 3.3 times (95% CI, 1.70-6.50; P < .001).
In contrast, researchers found those with a BMI of 36-40 kg/m2 were 88% less likely to develop acute pancreatitis (95% CI, 0.07-0.67; P = .007), compared with patients with a BMI of less than or equal to 30 kg/m2. Patients with a BMI of greater than 40 kg/m2 had a 73% lower risk (95% CI, 0.10-0.73; P = .01).
Dr. Postlethwaite and colleagues found no association with age, sex, or history of bariatric surgery or acute pancreatitis.
Because a history of acute pancreatitis was not a risk factor, he advised that clinicians not withhold these medications for this reason, “especially given the significant glycemic, cardiovascular, and weight-loss effects.”
“We hope that we can arm clinicians with evidence in order to risk stratify their patients and determine who is at high risk of developing pancreatitis,” Dr. Postlethwaite said.
“Hopefully, we can prevent the development of pancreatitis in some patients, especially high-risk individuals, or at least allow clinicians to be aware of it in higher-risk patients to identify it early enough to prevent complications of acute pancreatitis,” he added.
Larger studies needed
The study is “promising,” said session comoderator Baharak Moshiree, MD, a gastroenterologist at Atrium Health, Charlotte, N.C., who was not affiliated with the research.
However, because the study was retrospective and relatively small, it needs to be validated in larger, prospective studies, she added.
“With obesity being such a global issue, there are many patients on these GLP-1 agonists,” Dr. Moshiree said.
Generally, these medications are prescribed by endocrinologists, not gastroenterologists, she noted, and she said that gastroenterologists should be aware of the risks associated with them, including minor gastrointestinal side effects, like nausea and vomiting, that can occur because of delayed gastric emptying.
Dr. Postlethwaite noted that being unable to assess how much alcohol or tobacco individuals used was a limitation. The relatively low proportion of people who developed acute pancreatitis in the study also means larger studies are warranted, he added.
Going forward, Dr. Postlethwaite and colleagues want to study the risks for each individual GLP-1 and other therapies used to control high blood sugar in people with type 2 diabetes, such as DPP4 (dipeptidyl-peptidase 4) inhibitors.
The study was independently supported. Dr. Postlethwaite and Dr. Moshiree report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CHARLOTTE, N.C. – a new study has found.
Type 2 diabetes, advanced chronic kidney disease, and tobacco use were associated with greater risk for acute pancreatitis, researchers report.
On the other hand, a higher body mass index (BMI) – 36 kg/m2 or higher – appeared to protect people against developing the condition.
“As this class of medications becomes increasingly popular in the United States, it is important for providers to know which patients are at a higher or lower risk of developing acute pancreatitis after being started on them,” said lead study author Robert Postlethwaite, MD, a gastroenterology resident at the University of Texas Southwestern Medical Center, Dallas.
The findings were presented at the annual meeting of the American College of Gastroenterology in Charlotte, N.C., being held in person and virtually.
Popularity comes at a price
The U.S. Food and Drug Administration has approved two GLP-1s for weight management – liraglutide (Victoza) in 2014 and semaglutide (Wegovy) in 2021. They work by targeting areas of the brain that control food intake and appetite. Other GLP-1s approved to treat type 2 diabetes include dulaglutide (Trulicity) and two other formulations of semaglutide (Rybelsus and Ozempic).
The demand for Wegovy has been so great that there is an ongoing shortage of the medication in the United States.
Although GLP-1s demonstrate a favorable side-effect profile, compared with other types of antiobesity medications, acute pancreatitis remains a serious and sometimes life-threatening complication, the researchers note. Some patients require hospitalization.
Dr. Postlethwaite and colleagues performed a retrospective, single-center study of 2,245 patients who attended an academic medical center’s Weight Wellness program from 2015 to 2019. The average age was about 50 years, and 81% were female. The average BMI of all patients was 39.7 kg/m2.
The study only included patients starting GLP-1s for treating obesity, not for diabetes.
Of the 2,245 patients, 49 (2.2%) developed acute pancreatitis after starting a GLP-1.
A history of type 2 diabetes mellitus made acute pancreatitis twice as likely (95% confidence interval, 1.04-3.96; P = .04).
Stage 3 or higher chronic kidney disease increased risk 2.3 times (95% CI, 1.18-4.55; P = .01), while tobacco use upped it 3.3 times (95% CI, 1.70-6.50; P < .001).
In contrast, researchers found those with a BMI of 36-40 kg/m2 were 88% less likely to develop acute pancreatitis (95% CI, 0.07-0.67; P = .007), compared with patients with a BMI of less than or equal to 30 kg/m2. Patients with a BMI of greater than 40 kg/m2 had a 73% lower risk (95% CI, 0.10-0.73; P = .01).
Dr. Postlethwaite and colleagues found no association with age, sex, or history of bariatric surgery or acute pancreatitis.
Because a history of acute pancreatitis was not a risk factor, he advised that clinicians not withhold these medications for this reason, “especially given the significant glycemic, cardiovascular, and weight-loss effects.”
“We hope that we can arm clinicians with evidence in order to risk stratify their patients and determine who is at high risk of developing pancreatitis,” Dr. Postlethwaite said.
“Hopefully, we can prevent the development of pancreatitis in some patients, especially high-risk individuals, or at least allow clinicians to be aware of it in higher-risk patients to identify it early enough to prevent complications of acute pancreatitis,” he added.
Larger studies needed
The study is “promising,” said session comoderator Baharak Moshiree, MD, a gastroenterologist at Atrium Health, Charlotte, N.C., who was not affiliated with the research.
However, because the study was retrospective and relatively small, it needs to be validated in larger, prospective studies, she added.
“With obesity being such a global issue, there are many patients on these GLP-1 agonists,” Dr. Moshiree said.
Generally, these medications are prescribed by endocrinologists, not gastroenterologists, she noted, and she said that gastroenterologists should be aware of the risks associated with them, including minor gastrointestinal side effects, like nausea and vomiting, that can occur because of delayed gastric emptying.
Dr. Postlethwaite noted that being unable to assess how much alcohol or tobacco individuals used was a limitation. The relatively low proportion of people who developed acute pancreatitis in the study also means larger studies are warranted, he added.
Going forward, Dr. Postlethwaite and colleagues want to study the risks for each individual GLP-1 and other therapies used to control high blood sugar in people with type 2 diabetes, such as DPP4 (dipeptidyl-peptidase 4) inhibitors.
The study was independently supported. Dr. Postlethwaite and Dr. Moshiree report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACG 2022