Upper GI Tract

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

A new international consensus paper is recommending that eosinophilic GI diseases (EGIDs) should be named according to more specific criteria. The paper seeks to update nomenclature to improve research and bolster clinical clarity.

The involved part of the GI tract should be specifically named, and the abbreviation “Eo” should be used. Furthermore, the umbrella term should be EGID instead of the currently used “eosinophilic gastroenteritis,” according to the statement published in Clinical Gastroenterology and Hepatology. The statement included 91 authors from five continents who filled out two rounds of surveys. In total, 93% completed the first and 90% completed the second. The paper produced 22 statements, with a consensus reached on all but 2.

EGIDs are chronic, immune-driven disorders that produce gastrointestinal symptoms and are characterized by eosinophil-dominant inflammation in specific GI regions. Although eosinophilic esophagitis (EoE) is the most well known of these conditions, other EGIDs have become more commonly recognized in recent years and are the subject of intense study. Other affected areas include the stomach, small bowel, and colon, where it can occur individually or in combination.

Efforts are underway to develop guidelines for diagnosis and treatment of EGIDs, but there was initial confusion surrounding the term eosinophilic gastroenteritis since its definition varied significantly in different clinical and research settings, according to the authors. That term varyingly referred to stomach alone, small bowel alone, stomach and small bowel, or any region of the GI tract.

“This nonstandardized use of nomenclature highlighted a need for a common language for non-EoE eosinophilic GI disease names, not only for clinical practice, but also for the consistent data collection required for research to continue to advance the field,” co–first authors Evan S. Dellon, MD, MPH, AGAF, from the University of North Carolina at Chapel Hill, and Nirmala Gonsalves, MD, from Northwestern University, Chicago, and colleagues wrote. “This step, while seemingly rudimentary, was essential to inform the guideline efforts that are now underway.”

After responses to the surveys were analyzed, respondents participated in one of two scheduled meetings held on a video conferencing platform in May 2021. Feedback from these meetings was then used to create a second round of 29 statements which were again distributed, and participants were asked to either agree or disagree with each statement. Agreement was set a priori at 70%. In all, 38% of the participants were women, and 91% worked in academic or university settings.

In routine clinical practice, conditions with eosinophil-dominant inflammation in the absence of secondary causes outside of the esophagus can collectively be referred to clinically as non-EoE EGID. Stomach involvement should be called eosinophilic gastritis (EoG), small bowel involvement eosinophilic enteritis (EoN), and colon involvement eosinophilic colitis (EoC).

For research use, and clinical use if desired, the authors called for greater granularity in description of the conditions, with each location named. For example, if the stomach and small bowel are both involved, the condition should be termed eosinophilic gastritis and enteritis. The authors could not reach a consensus for terminology when the esophagus is also involved, leading to the recommendation that it can be included using the phrase “with esophageal involvement” or by using EoE, although they note that this could be confusing since EoE is the current term for eosinophilia isolated in the esophagus.

The authors came to universal agreement in many areas, but there were exceptions that mostly centered on how to name conditions that affect multiple areas of the GI tract. It remains uncertain whether eosinophilia in different regions is caused by the same pathogenesis. Some experts felt that a “primary” location of EGID should be identified using predominant symptoms, endoscopic features, and complications. However, the authors anticipate that this nomenclature will change over time.

The authors noted that the clinical manifestation of the disease should remain the driving factor behind classification. Testing should be driven by clinically relevant questions and overtesting should be avoided. More details on this are likely to be forthcoming in future guidelines.

The consensus statement is limited by the fact that most participants were from academic settings. These recommendations do not apply to eosinophilic disorders of gallbladder, liver, or pancreas. Application of the recommendations to the small bowel may be too general or specific, but are meant primarily as a starting point for further refinement.

These limitations should help to drive further research. For example, molecular and pathogenic data could help distinguish EoE from “esophageal involvement” by determining if pathogenic mechanisms are the same or different, which would in turn lead to lumping the conditions into a single term or keeping them separate.

“The iterative and collaborative process led to agreement on nearly all aspects of the proposed nomenclature framework, and has identified future research directions. It is expected that as more data are collected, the nomenclature will again be updated to reflect best practices and the underlying pathogenesis of these disorders,” the authors concluded.

The authors disclosed relationships with various industry companies, include AstraZeneca, Celgene, GlaxoSmithKline, Regeneron, Sanofi, and Takeda.

Eosinophilic gastrointestinal diseases (EGIDs) are characterized by GI signs or symptoms occurring along with tissue eosinophilia. Eosinophilic esophagitis (EoE) is the more commonly recognized EGID as endoscopic and histopathologic diagnostic criteria have long been established. Because of a lack of consensus on biopsy protocols, poorly understood histopathologic diagnostic criteria, and vague, nonspecific gastrointestinal complaints, patients with non-EoE EGIDs go unrecognized for years. Because of this, there is increasing emphasis on better defining rare, distal eosinophilic gastrointestinal diseases (i.e., eosinophilic gastritis, enteritis, and colitis).

EGID nomenclature was standardized in 2022 in part to minimize vague terminology (i.e., eosinophilic gastroenteritis) and to provide more specific information about the location of eosinophilic disease. The 2022 nomenclature suggest that EGID be used as the umbrella term for all GI luminal eosinophilia (without a known cause) but with emphasis on the site of specific eosinophilic involvement (i.e., eosinophilic gastritis or eosinophilic gastritis and colitis). Importantly, there is much work to be done to adequately identify patients suffering from EGIDs. Symptoms are variable, ranging from abdominal pain, bloating, and nausea seen in proximal disease to loose stools and hematochezia in more distal involvement. Signs of disease, such as iron or other nutrient deficiencies and protein loss, may also occur. Endoscopic findings can vary from erythema, granularity, erosions, ulcerations, and blunting to even normal-appearing tissue. In eosinophilic gastritis, Ikuo Hirano, MD, and colleagues demonstrated that increasing endoscopic inflammatory findings in the stomach correlate with assessment of disease severity. Regardless of endoscopic findings, numerous biopsies are needed for the diagnosis of EGIDs because, as already established in EoE, eosinophil involvement is patchy. Nirmala Gonsalves, MD, and Evan Dellon, MD, found that a minimum of four biopsies each in the gastric antrum, gastric body, and small bowel are needed to detect disease. Optimal biopsy patterns have not yet been determined for eosinophilic ileitis or colitis.

Despite these advances, there is more work to be performed. Although these disease states are termed “eosinophilic,” the immunopathology driving these diseases is multifactorial, involving lymphocytes and mast cells and creating different phenotypes of disease in a similar fashion to inflammatory bowel disease. Current therapies being studied include eosinophil-depleting medications along with others targeting T2 immune pathways. Patients may need multiple therapeutic options, and personalized medicine will soon play a larger role in defining treatments. For now, researchers are fervently working on improved methods to identify, phenotype, and treat these morbid disorders.
 

Dr. Peterson is associate professor of gastroenterology at University of Utah Health, Salt Lake City. She has no relevant conflicts of interest. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Eosinophilic gastrointestinal diseases (EGIDs) are characterized by GI signs or symptoms occurring along with tissue eosinophilia. Eosinophilic esophagitis (EoE) is the more commonly recognized EGID as endoscopic and histopathologic diagnostic criteria have long been established. Because of a lack of consensus on biopsy protocols, poorly understood histopathologic diagnostic criteria, and vague, nonspecific gastrointestinal complaints, patients with non-EoE EGIDs go unrecognized for years. Because of this, there is increasing emphasis on better defining rare, distal eosinophilic gastrointestinal diseases (i.e., eosinophilic gastritis, enteritis, and colitis).

EGID nomenclature was standardized in 2022 in part to minimize vague terminology (i.e., eosinophilic gastroenteritis) and to provide more specific information about the location of eosinophilic disease. The 2022 nomenclature suggest that EGID be used as the umbrella term for all GI luminal eosinophilia (without a known cause) but with emphasis on the site of specific eosinophilic involvement (i.e., eosinophilic gastritis or eosinophilic gastritis and colitis). Importantly, there is much work to be done to adequately identify patients suffering from EGIDs. Symptoms are variable, ranging from abdominal pain, bloating, and nausea seen in proximal disease to loose stools and hematochezia in more distal involvement. Signs of disease, such as iron or other nutrient deficiencies and protein loss, may also occur. Endoscopic findings can vary from erythema, granularity, erosions, ulcerations, and blunting to even normal-appearing tissue. In eosinophilic gastritis, Ikuo Hirano, MD, and colleagues demonstrated that increasing endoscopic inflammatory findings in the stomach correlate with assessment of disease severity. Regardless of endoscopic findings, numerous biopsies are needed for the diagnosis of EGIDs because, as already established in EoE, eosinophil involvement is patchy. Nirmala Gonsalves, MD, and Evan Dellon, MD, found that a minimum of four biopsies each in the gastric antrum, gastric body, and small bowel are needed to detect disease. Optimal biopsy patterns have not yet been determined for eosinophilic ileitis or colitis.

Despite these advances, there is more work to be performed. Although these disease states are termed “eosinophilic,” the immunopathology driving these diseases is multifactorial, involving lymphocytes and mast cells and creating different phenotypes of disease in a similar fashion to inflammatory bowel disease. Current therapies being studied include eosinophil-depleting medications along with others targeting T2 immune pathways. Patients may need multiple therapeutic options, and personalized medicine will soon play a larger role in defining treatments. For now, researchers are fervently working on improved methods to identify, phenotype, and treat these morbid disorders.
 

Dr. Peterson is associate professor of gastroenterology at University of Utah Health, Salt Lake City. She has no relevant conflicts of interest. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Eosinophilic gastrointestinal diseases (EGIDs) are characterized by GI signs or symptoms occurring along with tissue eosinophilia. Eosinophilic esophagitis (EoE) is the more commonly recognized EGID as endoscopic and histopathologic diagnostic criteria have long been established. Because of a lack of consensus on biopsy protocols, poorly understood histopathologic diagnostic criteria, and vague, nonspecific gastrointestinal complaints, patients with non-EoE EGIDs go unrecognized for years. Because of this, there is increasing emphasis on better defining rare, distal eosinophilic gastrointestinal diseases (i.e., eosinophilic gastritis, enteritis, and colitis).

EGID nomenclature was standardized in 2022 in part to minimize vague terminology (i.e., eosinophilic gastroenteritis) and to provide more specific information about the location of eosinophilic disease. The 2022 nomenclature suggest that EGID be used as the umbrella term for all GI luminal eosinophilia (without a known cause) but with emphasis on the site of specific eosinophilic involvement (i.e., eosinophilic gastritis or eosinophilic gastritis and colitis). Importantly, there is much work to be done to adequately identify patients suffering from EGIDs. Symptoms are variable, ranging from abdominal pain, bloating, and nausea seen in proximal disease to loose stools and hematochezia in more distal involvement. Signs of disease, such as iron or other nutrient deficiencies and protein loss, may also occur. Endoscopic findings can vary from erythema, granularity, erosions, ulcerations, and blunting to even normal-appearing tissue. In eosinophilic gastritis, Ikuo Hirano, MD, and colleagues demonstrated that increasing endoscopic inflammatory findings in the stomach correlate with assessment of disease severity. Regardless of endoscopic findings, numerous biopsies are needed for the diagnosis of EGIDs because, as already established in EoE, eosinophil involvement is patchy. Nirmala Gonsalves, MD, and Evan Dellon, MD, found that a minimum of four biopsies each in the gastric antrum, gastric body, and small bowel are needed to detect disease. Optimal biopsy patterns have not yet been determined for eosinophilic ileitis or colitis.

Despite these advances, there is more work to be performed. Although these disease states are termed “eosinophilic,” the immunopathology driving these diseases is multifactorial, involving lymphocytes and mast cells and creating different phenotypes of disease in a similar fashion to inflammatory bowel disease. Current therapies being studied include eosinophil-depleting medications along with others targeting T2 immune pathways. Patients may need multiple therapeutic options, and personalized medicine will soon play a larger role in defining treatments. For now, researchers are fervently working on improved methods to identify, phenotype, and treat these morbid disorders.
 

Dr. Peterson is associate professor of gastroenterology at University of Utah Health, Salt Lake City. She has no relevant conflicts of interest. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Warfarin is associated with higher rates of upper gastrointestinal bleeding but not overall or lower GI bleeding rates, compared with direct oral anticoagulants (DOACs), according to a new nationwide report from Iceland.

In addition, warfarin is associated with higher rates of major GI bleeding, compared with apixaban.

“Although there has been a myriad of studies comparing GI bleeding rates between warfarin and DOACs, very few studies have compared upper and lower GI bleeding rates specifically,” Arnar Ingason, MD, PhD, a gastroenterology resident at the University of Iceland and Landspitali University Hospital, Reykjavik, said in an interview.

“Knowing whether the risk of upper and lower GI bleeding differs between warfarin and DOACs is important, as it can help guide oral anticoagulant selection,” he said.

“Given that warfarin was associated with higher rates of upper GI bleeding compared to DOACs in our study, warfarin may not be optimal for patients with high risk of upper GI bleeding, such as patients with previous history of upper GI bleeding,” Dr. Ingason added.

The study was published online in Clinical Gastroenterology and Hepatology.
 

Analyzing bleed rates

Dr. Ingason and colleagues analyzed data from electronic medical records for more than 7,000 patients in Iceland who began a prescription for oral anticoagulants between 2014 and 2019. They used inverse probability weighting to yield balanced study groups and calculate the rates of overall, major, upper, and lower GI bleeding. All events of gastrointestinal bleeding were manually confirmed by chart review.

Clinically relevant GI bleeding was defined as bleeding that led to medical intervention, unscheduled physician contact, or temporary cessation of treatment. Upper GI bleeding was defined as hematemesis or a confirmed upper GI bleed site on endoscopy, whereas lower gastrointestinal bleeding was defined as hematochezia or a confirmed lower GI bleed site on endoscopy. Patients with melena and uncertain bleeding site on endoscopy were classified as having a gastrointestinal bleed of unknown location.

Major bleeding was defined as a drop in hemoglobin of at least 20 g/L, transfusion of two or more packs of red blood cells, or bleeding into a closed compartment such as the retroperitoneum.

In total, 295 gastrointestinal bleed events were identified, with 150 events (51%) classified as lower, 105 events (36%) classified as upper, and 40 events (14%) of an unknown location. About 71% required hospitalization, and 63% met the criteria for major bleeding. Five patients died, including three taking warfarin and the other two taking apixaban and rivaroxaban.

Overall, warfarin was associated with double the rate of upper GI bleeding, with 1.7 events per 100 person-years, compared with 0.8 events per 100 person-years for DOACs. The rates of lower GI bleeding were similar for the drugs.

Specifically, warfarin was associated with nearly 5.5 times higher rates of upper gastrointestinal bleeding, compared with dabigatran (Pradaxa, Boehringer Ingelheim), 2.6 times higher than apixaban (Eliquis, Bristol-Myers Squibb), and 1.7 times higher than rivaroxaban (Xarelto, Janssen). The risk for upper GI bleeding also was higher in men taking warfarin.

Warfarin was associated with higher rates of major bleeding, compared with apixaban, with 2.3 events per 100 person-years versus 1.5 events per 100 person-years. Otherwise, overall and major bleed rates were similar for users of warfarin and DOACs.

“GI bleeding among cardiac patients on anticoagulants and antiplatelets is the fastest growing group of GI bleeders,” Neena Abraham, MD, professor of medicine and a gastroenterologist at the Mayo Clinic in Scottsdale, Ariz., said in an interview.

Dr. Abraham, who wasn’t involved with this study, runs a dedicated cardiogastroenterology practice and has studied these patients’ bleeding risk for 20 years.

“This is a group that is ever increasing with aging baby boomers,” she said. “It is anticipated by 2040 that more than 40% of the U.S. adult population will have one or more cardiovascular conditions requiring the chronic prescription of anticoagulant or antiplatelet drugs.”
 

Considering future research

In this study, peptic ulcer disease was a proportionally less common cause of upper GI bleeding for warfarin at 18%, compared with DOACs at 39%. At the same time, the absolute propensity-weighted incidence rates of peptic ulcer–induced bleeding were similar, with 0.3 events per 100 person-years for both groups.

“As warfarin is not thought to induce peptic ulcer disease but rather promote bleeding from pre-existing lesions, one explanation may be that peptic ulcer disease almost always leads to overt bleeding in anticoagulated patients, while other lesions, such as mucosal erosions and angiodysplasias, may be more likely to lead to overt bleeding in warfarin patients due to a potentially more intense anticoagulation,” Dr. Ingason said.

Dr. Ingason and colleagues now plan to compare GI bleeding severity between warfarin and DOACs. Previous studies have suggested that GI bleeding may be more severe in patients receiving warfarin than in those receiving DOACs, he said.

In addition, large studies with manual verification of GI bleed events could better estimate the potential differences in the sources of upper and lower bleeding between warfarin and DOACs, Dr. Ingason noted.

“Some DOACs, specifically dabigatran, are known to have a mucosal effect on the luminal GI tract, as well as a systemic effect,” Dr. Abraham said. “This pharmacologic effect may contribute to an increase in lower gastrointestinal bleeding in the setting of colonic diverticulosis or mucosal injuries from inflammatory processes.”

Ongoing research should also look at different ways to reduce anticoagulant-related GI bleeding among cardiac patients, she noted.

“Our research group continues to study the risk of cardiac and bleeding adverse events in patients prescribed to DOACs compared to those patients who receive a left atrial appendage occlusion device,” Dr. Abraham said. “This device often permits patients at high risk of GI bleeding to transition off anticoagulant and antiplatelet drugs.”

The study was funded by the Icelandic Centre for Research and the Landspitali University Hospital Research Fund. The funders had no role in the design, conduct, or reporting of the study. The authors declared no competing interests. Dr. Abraham reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

It takes at least 10 years for one-third of patients with eosinophilic esophagitis (EoE) to receive a diagnosis and a median of 4 years for patients overall to get their diagnosis – numbers that haven’t budged in 3 decades, according to a study published online in the American Journal of Gastroenterology.

This delay has persisted despite more than 2,000 publications on the condition since 2014 and a variety of educational events about it, reported Fritz R. Murray, MD, of the department of gastroenterology and hepatology at University Hospital Zurich and his colleagues.

“Bearing in mind that eosinophilic esophagitis is a chronic and progressive disease, that, if left untreated, leads to esophageal structuring ultimately causing food impaction, the results of our analysis are a cause for concern,” the authors wrote.

“Substantial efforts are warranted to increase awareness for eosinophilic esophagitis and its hallmark symptom, solid-food dysphagia, as an age-independent red-flag symptom … in order to lower risk of long-term complications,” they added.

The researchers retrospectively analyzed prospectively collected data from 1,152 patients in a Swiss database. The patients (74% male; median age, 38 years) had all been diagnosed with EoE according to established criteria. The authors calculated the diagnostic delay from 1989 to 2021 and at three key time points: 1993 – first description of the condition, 2007 – first consensus recommendations, and 2011 – updated consensus recommendations

The median diagnostic delay over the 3 decades studied was 4 years overall and was at least 10 years in nearly one-third (32%) of the population. Diagnostic delay did not significantly change throughout the study period, year by year, or at or after any of the milestones included in the analysis, retaining the minimum 10-year delay in about one-third of all patients.

The median age at symptom onset was 30 years, with 51% of patients first experiencing symptoms between 10 and 30 years of age.

“Age at diagnosis showed a normal distribution with its peak between 30 and 40 years with 25% of the study population being diagnosed with EoE during that period,” the authors reported.

Although diagnostic delay did not differ between sexes, the length of time before diagnosis did vary on the basis of the patient’s age at diagnosis, increasing from a median of 0 years for those aged 10 years or younger to 5 years for those aged 31-40 years.

“When examining variation in diagnostic delay based on age at symptom onset, we observed an inverse association of age at symptom onset and diagnostic delay, with longest diagnostic delay observed in children,” they wrote.

Diagnostic delay was longer in those who needed an endoscopic disimpaction – a median of 6 years – before being diagnosed, compared with those who did not require this procedure, who had a median delay of 3 years. Nearly one-third (31%) of participants had at least one food impaction requiring endoscopic removal before receiving their diagnosis.

Three in four participants (74%) had a confirmed atopic condition besides eosinophilic esophagitis, with 13% not having an atopic comorbidity and another 13% lacking information on whether they did or didn’t. Those with atopic conditions were younger (median age, 29 years) when symptoms began than were those without atopic conditions (median age, 34 years).

Similarly, those with atopic conditions were younger (median age, 38 years) than those without these conditions (median age, 41 years) at the time of diagnosis. Diagnostic delay was a median 2 years shorter – 3 years vs. 5 years – for patients with concomitant atopic conditions.

“Importantly, the length of diagnosis delay (untreated disease) directly correlates with the occurrence of esophageal strictures,” the authors wrote, citing previous research finding that the prevalence of strictures rose from 17% in patients with a delay of up to 2 years to 71% in patients with a delay of more than 20 years.

“Esophageal strictures were present in around 38% of patients with a delay between 8-11 years” in that study, “a delay that is prevalent in about one third of our study population,” the authors wrote. “However, even a median delay of 4 years resulted in strictures in around 31% of untreated patients.”

Other research has found that the risk for esophageal strictures increases an estimated 9% each year that eosinophilic esophagitis goes untreated.

The authors suggested that patients’ denying symptoms or attempting to address their symptoms with changes in diet or eating behavior may be one reason for the long diagnostic delay, given other findings showing that patient-dependent delay was 18 months, compared with 6 months for physician-dependent delay. Although the authors didn’t have the information in their dataset to assess patient- vs. physician-dependent delay, a subgroup analysis revealed that patients and nongastroenterologist doctors combined made up the largest proportion of diagnosis delay.

“This fact indicates that future efforts should target the general population, and potentially primary physicians, to strengthen the awareness for eosinophilic esophagitis as a potential underlying condition in patients with dysphagia,” the authors wrote.

“A change in eating behavior, especially in cases with prolonged chewing, slow swallowing or even the necessity of drinking fluids after swallowing of solid food, should raise suspicion also in the general population,” they added.

Dr. Murray received travel support from Janssen, and 9 of the other 11 authors reported consulting, speaking, research and/or travel fees from 23 various pharmaceutical and related companies.

A version of this article first appeared on Medscape.com.

It takes at least 10 years for one-third of patients with eosinophilic esophagitis (EoE) to receive a diagnosis and a median of 4 years for patients overall to get their diagnosis – numbers that haven’t budged in 3 decades, according to a study published online in the American Journal of Gastroenterology.

This delay has persisted despite more than 2,000 publications on the condition since 2014 and a variety of educational events about it, reported Fritz R. Murray, MD, of the department of gastroenterology and hepatology at University Hospital Zurich and his colleagues.

“Bearing in mind that eosinophilic esophagitis is a chronic and progressive disease, that, if left untreated, leads to esophageal structuring ultimately causing food impaction, the results of our analysis are a cause for concern,” the authors wrote.

“Substantial efforts are warranted to increase awareness for eosinophilic esophagitis and its hallmark symptom, solid-food dysphagia, as an age-independent red-flag symptom … in order to lower risk of long-term complications,” they added.

The researchers retrospectively analyzed prospectively collected data from 1,152 patients in a Swiss database. The patients (74% male; median age, 38 years) had all been diagnosed with EoE according to established criteria. The authors calculated the diagnostic delay from 1989 to 2021 and at three key time points: 1993 – first description of the condition, 2007 – first consensus recommendations, and 2011 – updated consensus recommendations

The median diagnostic delay over the 3 decades studied was 4 years overall and was at least 10 years in nearly one-third (32%) of the population. Diagnostic delay did not significantly change throughout the study period, year by year, or at or after any of the milestones included in the analysis, retaining the minimum 10-year delay in about one-third of all patients.

The median age at symptom onset was 30 years, with 51% of patients first experiencing symptoms between 10 and 30 years of age.

“Age at diagnosis showed a normal distribution with its peak between 30 and 40 years with 25% of the study population being diagnosed with EoE during that period,” the authors reported.

Although diagnostic delay did not differ between sexes, the length of time before diagnosis did vary on the basis of the patient’s age at diagnosis, increasing from a median of 0 years for those aged 10 years or younger to 5 years for those aged 31-40 years.

“When examining variation in diagnostic delay based on age at symptom onset, we observed an inverse association of age at symptom onset and diagnostic delay, with longest diagnostic delay observed in children,” they wrote.

Diagnostic delay was longer in those who needed an endoscopic disimpaction – a median of 6 years – before being diagnosed, compared with those who did not require this procedure, who had a median delay of 3 years. Nearly one-third (31%) of participants had at least one food impaction requiring endoscopic removal before receiving their diagnosis.

Three in four participants (74%) had a confirmed atopic condition besides eosinophilic esophagitis, with 13% not having an atopic comorbidity and another 13% lacking information on whether they did or didn’t. Those with atopic conditions were younger (median age, 29 years) when symptoms began than were those without atopic conditions (median age, 34 years).

Similarly, those with atopic conditions were younger (median age, 38 years) than those without these conditions (median age, 41 years) at the time of diagnosis. Diagnostic delay was a median 2 years shorter – 3 years vs. 5 years – for patients with concomitant atopic conditions.

“Importantly, the length of diagnosis delay (untreated disease) directly correlates with the occurrence of esophageal strictures,” the authors wrote, citing previous research finding that the prevalence of strictures rose from 17% in patients with a delay of up to 2 years to 71% in patients with a delay of more than 20 years.

“Esophageal strictures were present in around 38% of patients with a delay between 8-11 years” in that study, “a delay that is prevalent in about one third of our study population,” the authors wrote. “However, even a median delay of 4 years resulted in strictures in around 31% of untreated patients.”

Other research has found that the risk for esophageal strictures increases an estimated 9% each year that eosinophilic esophagitis goes untreated.

The authors suggested that patients’ denying symptoms or attempting to address their symptoms with changes in diet or eating behavior may be one reason for the long diagnostic delay, given other findings showing that patient-dependent delay was 18 months, compared with 6 months for physician-dependent delay. Although the authors didn’t have the information in their dataset to assess patient- vs. physician-dependent delay, a subgroup analysis revealed that patients and nongastroenterologist doctors combined made up the largest proportion of diagnosis delay.

“This fact indicates that future efforts should target the general population, and potentially primary physicians, to strengthen the awareness for eosinophilic esophagitis as a potential underlying condition in patients with dysphagia,” the authors wrote.

“A change in eating behavior, especially in cases with prolonged chewing, slow swallowing or even the necessity of drinking fluids after swallowing of solid food, should raise suspicion also in the general population,” they added.

Dr. Murray received travel support from Janssen, and 9 of the other 11 authors reported consulting, speaking, research and/or travel fees from 23 various pharmaceutical and related companies.

A version of this article first appeared on Medscape.com.

It takes at least 10 years for one-third of patients with eosinophilic esophagitis (EoE) to receive a diagnosis and a median of 4 years for patients overall to get their diagnosis – numbers that haven’t budged in 3 decades, according to a study published online in the American Journal of Gastroenterology.

This delay has persisted despite more than 2,000 publications on the condition since 2014 and a variety of educational events about it, reported Fritz R. Murray, MD, of the department of gastroenterology and hepatology at University Hospital Zurich and his colleagues.

“Bearing in mind that eosinophilic esophagitis is a chronic and progressive disease, that, if left untreated, leads to esophageal structuring ultimately causing food impaction, the results of our analysis are a cause for concern,” the authors wrote.

“Substantial efforts are warranted to increase awareness for eosinophilic esophagitis and its hallmark symptom, solid-food dysphagia, as an age-independent red-flag symptom … in order to lower risk of long-term complications,” they added.

The researchers retrospectively analyzed prospectively collected data from 1,152 patients in a Swiss database. The patients (74% male; median age, 38 years) had all been diagnosed with EoE according to established criteria. The authors calculated the diagnostic delay from 1989 to 2021 and at three key time points: 1993 – first description of the condition, 2007 – first consensus recommendations, and 2011 – updated consensus recommendations

The median diagnostic delay over the 3 decades studied was 4 years overall and was at least 10 years in nearly one-third (32%) of the population. Diagnostic delay did not significantly change throughout the study period, year by year, or at or after any of the milestones included in the analysis, retaining the minimum 10-year delay in about one-third of all patients.

The median age at symptom onset was 30 years, with 51% of patients first experiencing symptoms between 10 and 30 years of age.

“Age at diagnosis showed a normal distribution with its peak between 30 and 40 years with 25% of the study population being diagnosed with EoE during that period,” the authors reported.

Although diagnostic delay did not differ between sexes, the length of time before diagnosis did vary on the basis of the patient’s age at diagnosis, increasing from a median of 0 years for those aged 10 years or younger to 5 years for those aged 31-40 years.

“When examining variation in diagnostic delay based on age at symptom onset, we observed an inverse association of age at symptom onset and diagnostic delay, with longest diagnostic delay observed in children,” they wrote.

Diagnostic delay was longer in those who needed an endoscopic disimpaction – a median of 6 years – before being diagnosed, compared with those who did not require this procedure, who had a median delay of 3 years. Nearly one-third (31%) of participants had at least one food impaction requiring endoscopic removal before receiving their diagnosis.

Three in four participants (74%) had a confirmed atopic condition besides eosinophilic esophagitis, with 13% not having an atopic comorbidity and another 13% lacking information on whether they did or didn’t. Those with atopic conditions were younger (median age, 29 years) when symptoms began than were those without atopic conditions (median age, 34 years).

Similarly, those with atopic conditions were younger (median age, 38 years) than those without these conditions (median age, 41 years) at the time of diagnosis. Diagnostic delay was a median 2 years shorter – 3 years vs. 5 years – for patients with concomitant atopic conditions.

“Importantly, the length of diagnosis delay (untreated disease) directly correlates with the occurrence of esophageal strictures,” the authors wrote, citing previous research finding that the prevalence of strictures rose from 17% in patients with a delay of up to 2 years to 71% in patients with a delay of more than 20 years.

“Esophageal strictures were present in around 38% of patients with a delay between 8-11 years” in that study, “a delay that is prevalent in about one third of our study population,” the authors wrote. “However, even a median delay of 4 years resulted in strictures in around 31% of untreated patients.”

Other research has found that the risk for esophageal strictures increases an estimated 9% each year that eosinophilic esophagitis goes untreated.

The authors suggested that patients’ denying symptoms or attempting to address their symptoms with changes in diet or eating behavior may be one reason for the long diagnostic delay, given other findings showing that patient-dependent delay was 18 months, compared with 6 months for physician-dependent delay. Although the authors didn’t have the information in their dataset to assess patient- vs. physician-dependent delay, a subgroup analysis revealed that patients and nongastroenterologist doctors combined made up the largest proportion of diagnosis delay.

“This fact indicates that future efforts should target the general population, and potentially primary physicians, to strengthen the awareness for eosinophilic esophagitis as a potential underlying condition in patients with dysphagia,” the authors wrote.

“A change in eating behavior, especially in cases with prolonged chewing, slow swallowing or even the necessity of drinking fluids after swallowing of solid food, should raise suspicion also in the general population,” they added.

Dr. Murray received travel support from Janssen, and 9 of the other 11 authors reported consulting, speaking, research and/or travel fees from 23 various pharmaceutical and related companies.

A version of this article first appeared on Medscape.com.

Approximately 30% of U.S. adults experience troublesome reflux symptoms of heartburn, regurgitation and noncardiac chest pain. Because the mechanisms driving symptoms vary across patients, phenotyping patients via a step-wise diagnostic framework effectively guides personalized management in GERD.

For instance, PPI trials are appropriate when esophageal symptoms are present, whereas up-front reflux monitoring rather than empiric PPI trials are recommended for evaluation of isolated extra-esophageal symptoms. All patients undergoing evaluation for GERD should receive counseling on weight management and lifestyle modifications as well as the brain-gut axis relationship. In the common scenario of inadequate symptom response to PPIs, upper GI endoscopy is recommended to assess for erosive reflux disease (which confirms a diagnosis of GERD) as well as the anti-reflux barrier integrity. For instance, the presence of a large hiatal hernia and/or grade III/IV gastro-esophageal flap valve may point to mechanical gastro-esophageal reflux as a driver of symptoms and lower the threshold for surgical referral. In the absence of erosive reflux disease the next recommended step is ambulatory reflux monitoring off PPI therapy, either as prolonged wireless telemetry (which can be done concurrently with index endoscopy as long as PPI was discontinued > 7 days) or 24-hour transnasal pH-impedance catheter-based testing. Studies suggest that 96-hour monitoring is optimal for diagnostic accuracy and to guide therapeutic strategies.

Patients without evidence of GERD on endoscopy or ambulatory reflux monitoring likely have a functional esophageal disorder for which therapy hinges on pharmacologic neuromodulation or behavioral interventions as well as PPI cessation.

Alternatively, management for GERD (erosive or nonerosive) aims to optimize lifestyle, PPI therapy and the individualized use of adjunctive therapy, which include H2-receptor antagonists, alginate antacids, GABA agonists, neuromodulation and/or behavioral interventions. Surgical or endoscopic antireflux interventions are also an option for refractory GERD. Prior to intervention, achalasia must be excluded (typically with esophageal manometry), and confirmation of PPI refractory GERD on pH-impedance monitoring on PPI is of value, particularly when the phenotype is unclear. Again, the choice of antireflux intervention (e.g., laparoscopic fundoplication, magnetic sphincter augmentation, transoral incisionless fundoplication, Roux-en-Y gastric bypass) should be individualized to the patient’s anatomy, physiology, and clinical profile.

A multitude of treatment options are available to manage GERD, including behavioral interventions, lifestyle modifications, pharmacotherapy, and endoscopic/surgical interventions. However, not every treatment strategy is appropriate for every patient. Data gathered from the step-down diagnostic approach, which starts with clinical presentation, then endoscopy, then reflux monitoring, then esophageal physiologic testing, helps determine the GERD phenotype and effectively guide therapy.
 

Dr. Yadlapati is associate professor of clinical medicine, and medical director, UCSD Center for Esophageal Diseases; director, GI Motility Lab, division of gastroenterology, University of California San Diego, La Jolla, Calif. She disclosed ties with Medtronic, Phathom Pharmaceuticals, StatLinkMD, Medscape, Ironwood Pharmaceuticals, and RJS Mediagnostix. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Approximately 30% of U.S. adults experience troublesome reflux symptoms of heartburn, regurgitation and noncardiac chest pain. Because the mechanisms driving symptoms vary across patients, phenotyping patients via a step-wise diagnostic framework effectively guides personalized management in GERD.

For instance, PPI trials are appropriate when esophageal symptoms are present, whereas up-front reflux monitoring rather than empiric PPI trials are recommended for evaluation of isolated extra-esophageal symptoms. All patients undergoing evaluation for GERD should receive counseling on weight management and lifestyle modifications as well as the brain-gut axis relationship. In the common scenario of inadequate symptom response to PPIs, upper GI endoscopy is recommended to assess for erosive reflux disease (which confirms a diagnosis of GERD) as well as the anti-reflux barrier integrity. For instance, the presence of a large hiatal hernia and/or grade III/IV gastro-esophageal flap valve may point to mechanical gastro-esophageal reflux as a driver of symptoms and lower the threshold for surgical referral. In the absence of erosive reflux disease the next recommended step is ambulatory reflux monitoring off PPI therapy, either as prolonged wireless telemetry (which can be done concurrently with index endoscopy as long as PPI was discontinued > 7 days) or 24-hour transnasal pH-impedance catheter-based testing. Studies suggest that 96-hour monitoring is optimal for diagnostic accuracy and to guide therapeutic strategies.

Patients without evidence of GERD on endoscopy or ambulatory reflux monitoring likely have a functional esophageal disorder for which therapy hinges on pharmacologic neuromodulation or behavioral interventions as well as PPI cessation.

Alternatively, management for GERD (erosive or nonerosive) aims to optimize lifestyle, PPI therapy and the individualized use of adjunctive therapy, which include H2-receptor antagonists, alginate antacids, GABA agonists, neuromodulation and/or behavioral interventions. Surgical or endoscopic antireflux interventions are also an option for refractory GERD. Prior to intervention, achalasia must be excluded (typically with esophageal manometry), and confirmation of PPI refractory GERD on pH-impedance monitoring on PPI is of value, particularly when the phenotype is unclear. Again, the choice of antireflux intervention (e.g., laparoscopic fundoplication, magnetic sphincter augmentation, transoral incisionless fundoplication, Roux-en-Y gastric bypass) should be individualized to the patient’s anatomy, physiology, and clinical profile.

A multitude of treatment options are available to manage GERD, including behavioral interventions, lifestyle modifications, pharmacotherapy, and endoscopic/surgical interventions. However, not every treatment strategy is appropriate for every patient. Data gathered from the step-down diagnostic approach, which starts with clinical presentation, then endoscopy, then reflux monitoring, then esophageal physiologic testing, helps determine the GERD phenotype and effectively guide therapy.
 

Dr. Yadlapati is associate professor of clinical medicine, and medical director, UCSD Center for Esophageal Diseases; director, GI Motility Lab, division of gastroenterology, University of California San Diego, La Jolla, Calif. She disclosed ties with Medtronic, Phathom Pharmaceuticals, StatLinkMD, Medscape, Ironwood Pharmaceuticals, and RJS Mediagnostix. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Approximately 30% of U.S. adults experience troublesome reflux symptoms of heartburn, regurgitation and noncardiac chest pain. Because the mechanisms driving symptoms vary across patients, phenotyping patients via a step-wise diagnostic framework effectively guides personalized management in GERD.

For instance, PPI trials are appropriate when esophageal symptoms are present, whereas up-front reflux monitoring rather than empiric PPI trials are recommended for evaluation of isolated extra-esophageal symptoms. All patients undergoing evaluation for GERD should receive counseling on weight management and lifestyle modifications as well as the brain-gut axis relationship. In the common scenario of inadequate symptom response to PPIs, upper GI endoscopy is recommended to assess for erosive reflux disease (which confirms a diagnosis of GERD) as well as the anti-reflux barrier integrity. For instance, the presence of a large hiatal hernia and/or grade III/IV gastro-esophageal flap valve may point to mechanical gastro-esophageal reflux as a driver of symptoms and lower the threshold for surgical referral. In the absence of erosive reflux disease the next recommended step is ambulatory reflux monitoring off PPI therapy, either as prolonged wireless telemetry (which can be done concurrently with index endoscopy as long as PPI was discontinued > 7 days) or 24-hour transnasal pH-impedance catheter-based testing. Studies suggest that 96-hour monitoring is optimal for diagnostic accuracy and to guide therapeutic strategies.

Patients without evidence of GERD on endoscopy or ambulatory reflux monitoring likely have a functional esophageal disorder for which therapy hinges on pharmacologic neuromodulation or behavioral interventions as well as PPI cessation.

Alternatively, management for GERD (erosive or nonerosive) aims to optimize lifestyle, PPI therapy and the individualized use of adjunctive therapy, which include H2-receptor antagonists, alginate antacids, GABA agonists, neuromodulation and/or behavioral interventions. Surgical or endoscopic antireflux interventions are also an option for refractory GERD. Prior to intervention, achalasia must be excluded (typically with esophageal manometry), and confirmation of PPI refractory GERD on pH-impedance monitoring on PPI is of value, particularly when the phenotype is unclear. Again, the choice of antireflux intervention (e.g., laparoscopic fundoplication, magnetic sphincter augmentation, transoral incisionless fundoplication, Roux-en-Y gastric bypass) should be individualized to the patient’s anatomy, physiology, and clinical profile.

A multitude of treatment options are available to manage GERD, including behavioral interventions, lifestyle modifications, pharmacotherapy, and endoscopic/surgical interventions. However, not every treatment strategy is appropriate for every patient. Data gathered from the step-down diagnostic approach, which starts with clinical presentation, then endoscopy, then reflux monitoring, then esophageal physiologic testing, helps determine the GERD phenotype and effectively guide therapy.
 

Dr. Yadlapati is associate professor of clinical medicine, and medical director, UCSD Center for Esophageal Diseases; director, GI Motility Lab, division of gastroenterology, University of California San Diego, La Jolla, Calif. She disclosed ties with Medtronic, Phathom Pharmaceuticals, StatLinkMD, Medscape, Ironwood Pharmaceuticals, and RJS Mediagnostix. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). The rationale for early detection of BE rests on the premise that, after the diagnosis of BE, patients can be placed under endoscopic surveillance to detect prevalent and incident dysplasia and EAC. Randomized controlled trials have demonstrated that endoscopic eradication therapy (EET) of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) can reduce progression to EAC. Guidelines support endoscopic screening for BE in those with multiple (three or more) risk factors.

However, endoscopy is expensive, invasive, and not widely utilized (less than 10% of those eligible are screened). Most patients with BE are unaware of their diagnosis and hence not under surveillance. Nonendoscopic techniques of BE detection – swallowed cell collection devices providing rich esophageal cytology specimens combined with biomarkers – are being developed. Case-control studies have shown promising accuracy and a recent UK pragmatic primary care study showed the ability of this technology to increase BE detection safely.

Detection of dysplasia in endoscopic surveillance is critical and the neoplasia detection rate (NDR) has been recently proposed as a quality marker. The NDR is the ratio of HGD+EAC detected to all patients with BE undergoing their first surveillance endoscopy. A recent systematic review and meta-analysis showed an inverse association between NDR and postendoscopy BE neoplasia. Additional and prospective studies are required to further correlate NDR values to clinically relevant outcomes similar to the association between adenoma detection rate and postcolonoscopy colorectal cancer.

Detection of dysplasia with endoscopic surveillance is challenging because of sampling error inherent in the Seattle protocol. A recent technology, Wide Area Transepithelial Sampling–3D (WATS), combines the concept of increased sampling of the BE mucosa by using a stiff endoscopic brush followed by use of artificial intelligence neural network enabled selection of abnormal cells, which are presented to a pathologist. This technology has been shown to increase dysplasia and HGD detection, compared to endoscopic surveillance, in a systematic review and meta-analysis. However, WATS is negative in a substantial proportion of cases in which endoscopic Seattle protocol reveals dysplasia. In addition, only limited data are available on the natural history of WATS LGD or HGD. Confirmation of WATS-only dysplasia (LGD, HGD, or EAC) by endoscopic histology is also recommended before the institution of EET. Finally, assessment of progression risk in those with BE is critical to enable more personalized follow up recommendations. Clinical risk scores integrating age, sex, smoking history, and LGD have been proposed and validated. A recent tissue systems pathology test has been shown in multiple case-control studies to identify a subset of BE patients who are at higher risk of progression, independent of LGD. This test is highly specific but only modestly sensitive in identifying progressors.

Dr. Iyer is professor of medicine, director of the Esophageal Interest Group, and codirector of the Advanced Esophageal Fellowship at the Mayo Clinic College of Medicine and Science, Rochester, Minn. He reports relationships with Exact Sciences, Pentax Medical, and others. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). The rationale for early detection of BE rests on the premise that, after the diagnosis of BE, patients can be placed under endoscopic surveillance to detect prevalent and incident dysplasia and EAC. Randomized controlled trials have demonstrated that endoscopic eradication therapy (EET) of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) can reduce progression to EAC. Guidelines support endoscopic screening for BE in those with multiple (three or more) risk factors.

However, endoscopy is expensive, invasive, and not widely utilized (less than 10% of those eligible are screened). Most patients with BE are unaware of their diagnosis and hence not under surveillance. Nonendoscopic techniques of BE detection – swallowed cell collection devices providing rich esophageal cytology specimens combined with biomarkers – are being developed. Case-control studies have shown promising accuracy and a recent UK pragmatic primary care study showed the ability of this technology to increase BE detection safely.

Detection of dysplasia in endoscopic surveillance is critical and the neoplasia detection rate (NDR) has been recently proposed as a quality marker. The NDR is the ratio of HGD+EAC detected to all patients with BE undergoing their first surveillance endoscopy. A recent systematic review and meta-analysis showed an inverse association between NDR and postendoscopy BE neoplasia. Additional and prospective studies are required to further correlate NDR values to clinically relevant outcomes similar to the association between adenoma detection rate and postcolonoscopy colorectal cancer.

Detection of dysplasia with endoscopic surveillance is challenging because of sampling error inherent in the Seattle protocol. A recent technology, Wide Area Transepithelial Sampling–3D (WATS), combines the concept of increased sampling of the BE mucosa by using a stiff endoscopic brush followed by use of artificial intelligence neural network enabled selection of abnormal cells, which are presented to a pathologist. This technology has been shown to increase dysplasia and HGD detection, compared to endoscopic surveillance, in a systematic review and meta-analysis. However, WATS is negative in a substantial proportion of cases in which endoscopic Seattle protocol reveals dysplasia. In addition, only limited data are available on the natural history of WATS LGD or HGD. Confirmation of WATS-only dysplasia (LGD, HGD, or EAC) by endoscopic histology is also recommended before the institution of EET. Finally, assessment of progression risk in those with BE is critical to enable more personalized follow up recommendations. Clinical risk scores integrating age, sex, smoking history, and LGD have been proposed and validated. A recent tissue systems pathology test has been shown in multiple case-control studies to identify a subset of BE patients who are at higher risk of progression, independent of LGD. This test is highly specific but only modestly sensitive in identifying progressors.

Dr. Iyer is professor of medicine, director of the Esophageal Interest Group, and codirector of the Advanced Esophageal Fellowship at the Mayo Clinic College of Medicine and Science, Rochester, Minn. He reports relationships with Exact Sciences, Pentax Medical, and others. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC). The rationale for early detection of BE rests on the premise that, after the diagnosis of BE, patients can be placed under endoscopic surveillance to detect prevalent and incident dysplasia and EAC. Randomized controlled trials have demonstrated that endoscopic eradication therapy (EET) of low-grade dysplasia (LGD) and high-grade dysplasia (HGD) can reduce progression to EAC. Guidelines support endoscopic screening for BE in those with multiple (three or more) risk factors.

However, endoscopy is expensive, invasive, and not widely utilized (less than 10% of those eligible are screened). Most patients with BE are unaware of their diagnosis and hence not under surveillance. Nonendoscopic techniques of BE detection – swallowed cell collection devices providing rich esophageal cytology specimens combined with biomarkers – are being developed. Case-control studies have shown promising accuracy and a recent UK pragmatic primary care study showed the ability of this technology to increase BE detection safely.

Detection of dysplasia in endoscopic surveillance is critical and the neoplasia detection rate (NDR) has been recently proposed as a quality marker. The NDR is the ratio of HGD+EAC detected to all patients with BE undergoing their first surveillance endoscopy. A recent systematic review and meta-analysis showed an inverse association between NDR and postendoscopy BE neoplasia. Additional and prospective studies are required to further correlate NDR values to clinically relevant outcomes similar to the association between adenoma detection rate and postcolonoscopy colorectal cancer.

Detection of dysplasia with endoscopic surveillance is challenging because of sampling error inherent in the Seattle protocol. A recent technology, Wide Area Transepithelial Sampling–3D (WATS), combines the concept of increased sampling of the BE mucosa by using a stiff endoscopic brush followed by use of artificial intelligence neural network enabled selection of abnormal cells, which are presented to a pathologist. This technology has been shown to increase dysplasia and HGD detection, compared to endoscopic surveillance, in a systematic review and meta-analysis. However, WATS is negative in a substantial proportion of cases in which endoscopic Seattle protocol reveals dysplasia. In addition, only limited data are available on the natural history of WATS LGD or HGD. Confirmation of WATS-only dysplasia (LGD, HGD, or EAC) by endoscopic histology is also recommended before the institution of EET. Finally, assessment of progression risk in those with BE is critical to enable more personalized follow up recommendations. Clinical risk scores integrating age, sex, smoking history, and LGD have been proposed and validated. A recent tissue systems pathology test has been shown in multiple case-control studies to identify a subset of BE patients who are at higher risk of progression, independent of LGD. This test is highly specific but only modestly sensitive in identifying progressors.

Dr. Iyer is professor of medicine, director of the Esophageal Interest Group, and codirector of the Advanced Esophageal Fellowship at the Mayo Clinic College of Medicine and Science, Rochester, Minn. He reports relationships with Exact Sciences, Pentax Medical, and others. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2022.

Folic acid supplementation can improve histopathologic aspects of gastric precancerous conditions (GPC), including gastric mucosal atrophy and intestinal metaplasia, according to results of a meta-analysis of relevant research.

The results, say the authors, provide evidence for the potential clinical use of folic acid in the management of GPC.

“We believe doctors can try to use folic acid to halt or reverse progression of gastric precancerous conditions, thereby reducing the incidence rate of gastric cancer,” investigator Jinhao Zeng, PhD, with Hospital of Chengdu University of Traditional Chinese Medicine, said in an interview.

Dr. Zeng cautioned, however, that the number of relevant studies “remains relatively inadequate, and the results should be interpreted with caution.”

David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, who wasn’t involved in the study, also urged caution in interpreting the results.

“Overall, folate supplementation is unlikely to be harmful, but these data should not be used as justification for risk reduction,” Dr. Johnson said in an interview.

The study was published online in BMC Gastroenterology.
 

Examining prevention, treatment effects

The study is believed to be the first meta-analysis to examine the effects of folic acid on prevention and treatment for patients with GPC. The analysis included 13 randomized controlled trials that had a total of 1,252 adults with GPC living in China.

A meta-analysis of five studies showed a statistically significant positive treatment effect of folic acid supplementation on gastric mucosal atrophy (relative risk, 1.61; 95% confidence interval 1.07 – 2.41), Dr. Zeng and colleagues reported.

A meta-analysis of two trials showed a statistically significant effect of folic acid on reversal of intestinal metaplasia (RR, 1.77; 95% CI, 1.32-2.37), they also found.

“Our study indicates that folic acid has a beneficial effect in the treatment of pathological changes of GPC when the dose was maintained at 20-30 mg/d and the duration of treatment was maintained at 3-6 months,” they wrote.

Folic acid supplementation did not appear to be effective for GPC symptom relief.

The authors said that, in a separate analysis, they confirmed that folic acid can inhibit development of gastric mucosal carcinogenesis by affecting the levels of gastrin and pepsinogen.
 

More study needed

Commenting on the study, Judith Kim, MD, division of gastroenterology and hepatology, New York University Langone Health, said prior studies have evaluated whether folic acid supplementation is associated with a lower risk of gastric cancer, but the results have been “mixed and inconclusive.”

“While there have been prior meta-analyses on folic acid and gastric cancer, this study is noteworthy, as it evaluated the impact of folic acid on precancerous lesions, for which there is no current treatment,” Dr. Kim said.

“Currently, there is no recommendation for folic acid supplementation for the treatment or prevention of GPC and gastric cancer,” Dr. Kim said. “There has been interest in folic acid as a chemopreventive agent, given its potential protective role against DNA damage, but randomized control trials have yet to confirm these benefits.”

The analysis by Dr. Zeng and colleagues “supports the need for larger randomized controlled trials to further study this association,” Dr. Kim said.

“Given the study’s small size and limitation to a Chinese population (who have a higher incidence of precancerous lesions and gastric cancer than the general US population), I would caution against folic acid use for the sole purpose of GPC prevention, as there could be negative side effects of supplementation,” she advised.

The study was supported by the National Natural Science Foundation of China, the Hospital of Chengdu University of Traditional Chinese Medicine, and Project of Sichuan Administration of Traditional Chinese Medicine. Dr. Zeng, Dr. Johnson, and Dr. Kim reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Folic acid supplementation can improve histopathologic aspects of gastric precancerous conditions (GPC), including gastric mucosal atrophy and intestinal metaplasia, according to results of a meta-analysis of relevant research.

The results, say the authors, provide evidence for the potential clinical use of folic acid in the management of GPC.

“We believe doctors can try to use folic acid to halt or reverse progression of gastric precancerous conditions, thereby reducing the incidence rate of gastric cancer,” investigator Jinhao Zeng, PhD, with Hospital of Chengdu University of Traditional Chinese Medicine, said in an interview.

Dr. Zeng cautioned, however, that the number of relevant studies “remains relatively inadequate, and the results should be interpreted with caution.”

David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, who wasn’t involved in the study, also urged caution in interpreting the results.

“Overall, folate supplementation is unlikely to be harmful, but these data should not be used as justification for risk reduction,” Dr. Johnson said in an interview.

The study was published online in BMC Gastroenterology.
 

Examining prevention, treatment effects

The study is believed to be the first meta-analysis to examine the effects of folic acid on prevention and treatment for patients with GPC. The analysis included 13 randomized controlled trials that had a total of 1,252 adults with GPC living in China.

A meta-analysis of five studies showed a statistically significant positive treatment effect of folic acid supplementation on gastric mucosal atrophy (relative risk, 1.61; 95% confidence interval 1.07 – 2.41), Dr. Zeng and colleagues reported.

A meta-analysis of two trials showed a statistically significant effect of folic acid on reversal of intestinal metaplasia (RR, 1.77; 95% CI, 1.32-2.37), they also found.

“Our study indicates that folic acid has a beneficial effect in the treatment of pathological changes of GPC when the dose was maintained at 20-30 mg/d and the duration of treatment was maintained at 3-6 months,” they wrote.

Folic acid supplementation did not appear to be effective for GPC symptom relief.

The authors said that, in a separate analysis, they confirmed that folic acid can inhibit development of gastric mucosal carcinogenesis by affecting the levels of gastrin and pepsinogen.
 

More study needed

Commenting on the study, Judith Kim, MD, division of gastroenterology and hepatology, New York University Langone Health, said prior studies have evaluated whether folic acid supplementation is associated with a lower risk of gastric cancer, but the results have been “mixed and inconclusive.”

“While there have been prior meta-analyses on folic acid and gastric cancer, this study is noteworthy, as it evaluated the impact of folic acid on precancerous lesions, for which there is no current treatment,” Dr. Kim said.

“Currently, there is no recommendation for folic acid supplementation for the treatment or prevention of GPC and gastric cancer,” Dr. Kim said. “There has been interest in folic acid as a chemopreventive agent, given its potential protective role against DNA damage, but randomized control trials have yet to confirm these benefits.”

The analysis by Dr. Zeng and colleagues “supports the need for larger randomized controlled trials to further study this association,” Dr. Kim said.

“Given the study’s small size and limitation to a Chinese population (who have a higher incidence of precancerous lesions and gastric cancer than the general US population), I would caution against folic acid use for the sole purpose of GPC prevention, as there could be negative side effects of supplementation,” she advised.

The study was supported by the National Natural Science Foundation of China, the Hospital of Chengdu University of Traditional Chinese Medicine, and Project of Sichuan Administration of Traditional Chinese Medicine. Dr. Zeng, Dr. Johnson, and Dr. Kim reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Folic acid supplementation can improve histopathologic aspects of gastric precancerous conditions (GPC), including gastric mucosal atrophy and intestinal metaplasia, according to results of a meta-analysis of relevant research.

The results, say the authors, provide evidence for the potential clinical use of folic acid in the management of GPC.

“We believe doctors can try to use folic acid to halt or reverse progression of gastric precancerous conditions, thereby reducing the incidence rate of gastric cancer,” investigator Jinhao Zeng, PhD, with Hospital of Chengdu University of Traditional Chinese Medicine, said in an interview.

Dr. Zeng cautioned, however, that the number of relevant studies “remains relatively inadequate, and the results should be interpreted with caution.”

David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, who wasn’t involved in the study, also urged caution in interpreting the results.

“Overall, folate supplementation is unlikely to be harmful, but these data should not be used as justification for risk reduction,” Dr. Johnson said in an interview.

The study was published online in BMC Gastroenterology.
 

Examining prevention, treatment effects

The study is believed to be the first meta-analysis to examine the effects of folic acid on prevention and treatment for patients with GPC. The analysis included 13 randomized controlled trials that had a total of 1,252 adults with GPC living in China.

A meta-analysis of five studies showed a statistically significant positive treatment effect of folic acid supplementation on gastric mucosal atrophy (relative risk, 1.61; 95% confidence interval 1.07 – 2.41), Dr. Zeng and colleagues reported.

A meta-analysis of two trials showed a statistically significant effect of folic acid on reversal of intestinal metaplasia (RR, 1.77; 95% CI, 1.32-2.37), they also found.

“Our study indicates that folic acid has a beneficial effect in the treatment of pathological changes of GPC when the dose was maintained at 20-30 mg/d and the duration of treatment was maintained at 3-6 months,” they wrote.

Folic acid supplementation did not appear to be effective for GPC symptom relief.

The authors said that, in a separate analysis, they confirmed that folic acid can inhibit development of gastric mucosal carcinogenesis by affecting the levels of gastrin and pepsinogen.
 

More study needed

Commenting on the study, Judith Kim, MD, division of gastroenterology and hepatology, New York University Langone Health, said prior studies have evaluated whether folic acid supplementation is associated with a lower risk of gastric cancer, but the results have been “mixed and inconclusive.”

“While there have been prior meta-analyses on folic acid and gastric cancer, this study is noteworthy, as it evaluated the impact of folic acid on precancerous lesions, for which there is no current treatment,” Dr. Kim said.

“Currently, there is no recommendation for folic acid supplementation for the treatment or prevention of GPC and gastric cancer,” Dr. Kim said. “There has been interest in folic acid as a chemopreventive agent, given its potential protective role against DNA damage, but randomized control trials have yet to confirm these benefits.”

The analysis by Dr. Zeng and colleagues “supports the need for larger randomized controlled trials to further study this association,” Dr. Kim said.

“Given the study’s small size and limitation to a Chinese population (who have a higher incidence of precancerous lesions and gastric cancer than the general US population), I would caution against folic acid use for the sole purpose of GPC prevention, as there could be negative side effects of supplementation,” she advised.

The study was supported by the National Natural Science Foundation of China, the Hospital of Chengdu University of Traditional Chinese Medicine, and Project of Sichuan Administration of Traditional Chinese Medicine. Dr. Zeng, Dr. Johnson, and Dr. Kim reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Vonoprazan, a potassium-competitive acid blocker, appears to be superior to standard proton pump inhibitor–based therapy in clarithromycin-resistant Helicobacter pylori strains, as well as noninferior to standard care in nonresistant infections, according to a recent study that supported a Food and Drug Administration approval of vonoprazan dual and triple therapies in May 2022.

For decades, H. pylori has been mostly treated by proton pump inhibitor–based triple therapy, which includes a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. However, eradication rates have dropped below 80% in the United States and Europe, according to the authors, mainly because of rising rates of clarithromycin resistance.

Since H. pylori is a leading cause of peptic ulcer, gastric adenocarcinoma, and gastric mucosa–associated lymphoid tissue lymphoma, better eradication methods should be highlighted, researchers led by William Chey, MD, professor of medicine and director of the GI Physiology Laboratory at Michigan Medicine in Ann Arbor, wrote in Gastroenterology.

In a multicenter, randomized, controlled, phase 3 trial, the research team studied 1,046 treatment-naive adults with H. pylori infection at 103 sites in the U.S., the U.K., Bulgaria, the Czech Republic, Hungary, and Poland between December 2019 and January 2021.

The patients were randomized to receive open-label vonoprazan dual therapy or a double-blind triple therapy twice a day for 14 days. The vonoprazan dual therapy consisted of 20 mg of vonoprazan twice daily and 1 gram of amoxicillin three times per day. The triple therapy consisted of 20 mg of vonoprazan or 30 mg of lansoprazole (standard care), each given with 1 gram of amoxicillin and 500 mg of clarithromycin.

The primary outcome assessed noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains, with a noninferiority margin of 10%. Secondary outcomes assessed the superiority in eradication rates in clarithromycin-resistant infections, as well as in all patients.

Eradication rates for nonresistant strains were 84.7% for vonoprazan triple therapy and 78.5% for vonoprazan dual therapy, compared with 78.8% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered noninferior to standard therapy.

The eradication rates in clarithromycin-resistant infections were 65.8% for vonoprazan triple therapy and 69.6% in vonoprazan dual therapy, compared with 31.9% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior to standard therapy, with a difference of 33.9 percentage points for triple therapy and 37.7 percentage points for dual therapy.

In all patients, the eradication rates were 80.8% for vonoprazan triple therapy and 77.2% for vonoprazan dual therapy, compared with 68.5% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior, with a difference of 12.3 percentage points for triple therapy and 8.7 percentage points for dual therapy.

Treatment-emergent adverse events were reported in 34.1% of patients in the vonoprazan triple therapy group and 29.9% of patients in the vonoprazan dual therapy group, compared with 34.5% in the lansoprazole triple-therapy group. Most adverse events were mild to moderate.

Serious adverse events occurred in 1.3% of the overall study population, including 1.7% of the vonoprazan triple therapy group, 1.4% of the vonoprazan dual therapy group, and 0.9% of the lansoprazole triple therapy group. None were considered related to the study drugs.

Vonoprazan was approved for the treatment of H. pylori infections by the FDA in May 2022, and had already been approved for treatment of H. pylori infections and other acid-related diseases in several other countries. It decreases intragastric pH and maintains it to a greater degree than that of proton pump inhibitors, which has been associated with higher eradication rates, the authors wrote.

“Optimizing current regimens offers the potential to increase eradication rates and reduce additional antibiotic usage, thereby promoting and improving antimicrobial stewardship,” the study authors wrote.

The study was funded by Phathom Pharmaceuticals, which contributed to the design and conduct of the trial, collection and interpretation of the data, preparation and review of the manuscript, and the decision to submit the manuscript for publication. The study authors declared various conflicts of interest, including some who have received compensation as a consultant, advisory committee member, or employee for Phathom Pharmaceuticals.

Vonoprazan, a potassium-competitive acid blocker, appears to be superior to standard proton pump inhibitor–based therapy in clarithromycin-resistant Helicobacter pylori strains, as well as noninferior to standard care in nonresistant infections, according to a recent study that supported a Food and Drug Administration approval of vonoprazan dual and triple therapies in May 2022.

For decades, H. pylori has been mostly treated by proton pump inhibitor–based triple therapy, which includes a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. However, eradication rates have dropped below 80% in the United States and Europe, according to the authors, mainly because of rising rates of clarithromycin resistance.

Since H. pylori is a leading cause of peptic ulcer, gastric adenocarcinoma, and gastric mucosa–associated lymphoid tissue lymphoma, better eradication methods should be highlighted, researchers led by William Chey, MD, professor of medicine and director of the GI Physiology Laboratory at Michigan Medicine in Ann Arbor, wrote in Gastroenterology.

In a multicenter, randomized, controlled, phase 3 trial, the research team studied 1,046 treatment-naive adults with H. pylori infection at 103 sites in the U.S., the U.K., Bulgaria, the Czech Republic, Hungary, and Poland between December 2019 and January 2021.

The patients were randomized to receive open-label vonoprazan dual therapy or a double-blind triple therapy twice a day for 14 days. The vonoprazan dual therapy consisted of 20 mg of vonoprazan twice daily and 1 gram of amoxicillin three times per day. The triple therapy consisted of 20 mg of vonoprazan or 30 mg of lansoprazole (standard care), each given with 1 gram of amoxicillin and 500 mg of clarithromycin.

The primary outcome assessed noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains, with a noninferiority margin of 10%. Secondary outcomes assessed the superiority in eradication rates in clarithromycin-resistant infections, as well as in all patients.

Eradication rates for nonresistant strains were 84.7% for vonoprazan triple therapy and 78.5% for vonoprazan dual therapy, compared with 78.8% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered noninferior to standard therapy.

The eradication rates in clarithromycin-resistant infections were 65.8% for vonoprazan triple therapy and 69.6% in vonoprazan dual therapy, compared with 31.9% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior to standard therapy, with a difference of 33.9 percentage points for triple therapy and 37.7 percentage points for dual therapy.

In all patients, the eradication rates were 80.8% for vonoprazan triple therapy and 77.2% for vonoprazan dual therapy, compared with 68.5% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior, with a difference of 12.3 percentage points for triple therapy and 8.7 percentage points for dual therapy.

Treatment-emergent adverse events were reported in 34.1% of patients in the vonoprazan triple therapy group and 29.9% of patients in the vonoprazan dual therapy group, compared with 34.5% in the lansoprazole triple-therapy group. Most adverse events were mild to moderate.

Serious adverse events occurred in 1.3% of the overall study population, including 1.7% of the vonoprazan triple therapy group, 1.4% of the vonoprazan dual therapy group, and 0.9% of the lansoprazole triple therapy group. None were considered related to the study drugs.

Vonoprazan was approved for the treatment of H. pylori infections by the FDA in May 2022, and had already been approved for treatment of H. pylori infections and other acid-related diseases in several other countries. It decreases intragastric pH and maintains it to a greater degree than that of proton pump inhibitors, which has been associated with higher eradication rates, the authors wrote.

“Optimizing current regimens offers the potential to increase eradication rates and reduce additional antibiotic usage, thereby promoting and improving antimicrobial stewardship,” the study authors wrote.

The study was funded by Phathom Pharmaceuticals, which contributed to the design and conduct of the trial, collection and interpretation of the data, preparation and review of the manuscript, and the decision to submit the manuscript for publication. The study authors declared various conflicts of interest, including some who have received compensation as a consultant, advisory committee member, or employee for Phathom Pharmaceuticals.

Vonoprazan, a potassium-competitive acid blocker, appears to be superior to standard proton pump inhibitor–based therapy in clarithromycin-resistant Helicobacter pylori strains, as well as noninferior to standard care in nonresistant infections, according to a recent study that supported a Food and Drug Administration approval of vonoprazan dual and triple therapies in May 2022.

For decades, H. pylori has been mostly treated by proton pump inhibitor–based triple therapy, which includes a proton pump inhibitor, clarithromycin, and amoxicillin or metronidazole. However, eradication rates have dropped below 80% in the United States and Europe, according to the authors, mainly because of rising rates of clarithromycin resistance.

Since H. pylori is a leading cause of peptic ulcer, gastric adenocarcinoma, and gastric mucosa–associated lymphoid tissue lymphoma, better eradication methods should be highlighted, researchers led by William Chey, MD, professor of medicine and director of the GI Physiology Laboratory at Michigan Medicine in Ann Arbor, wrote in Gastroenterology.

In a multicenter, randomized, controlled, phase 3 trial, the research team studied 1,046 treatment-naive adults with H. pylori infection at 103 sites in the U.S., the U.K., Bulgaria, the Czech Republic, Hungary, and Poland between December 2019 and January 2021.

The patients were randomized to receive open-label vonoprazan dual therapy or a double-blind triple therapy twice a day for 14 days. The vonoprazan dual therapy consisted of 20 mg of vonoprazan twice daily and 1 gram of amoxicillin three times per day. The triple therapy consisted of 20 mg of vonoprazan or 30 mg of lansoprazole (standard care), each given with 1 gram of amoxicillin and 500 mg of clarithromycin.

The primary outcome assessed noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains, with a noninferiority margin of 10%. Secondary outcomes assessed the superiority in eradication rates in clarithromycin-resistant infections, as well as in all patients.

Eradication rates for nonresistant strains were 84.7% for vonoprazan triple therapy and 78.5% for vonoprazan dual therapy, compared with 78.8% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered noninferior to standard therapy.

The eradication rates in clarithromycin-resistant infections were 65.8% for vonoprazan triple therapy and 69.6% in vonoprazan dual therapy, compared with 31.9% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior to standard therapy, with a difference of 33.9 percentage points for triple therapy and 37.7 percentage points for dual therapy.

In all patients, the eradication rates were 80.8% for vonoprazan triple therapy and 77.2% for vonoprazan dual therapy, compared with 68.5% for lansoprazole triple therapy. The rates for both vonoprazan therapies were considered superior, with a difference of 12.3 percentage points for triple therapy and 8.7 percentage points for dual therapy.

Treatment-emergent adverse events were reported in 34.1% of patients in the vonoprazan triple therapy group and 29.9% of patients in the vonoprazan dual therapy group, compared with 34.5% in the lansoprazole triple-therapy group. Most adverse events were mild to moderate.

Serious adverse events occurred in 1.3% of the overall study population, including 1.7% of the vonoprazan triple therapy group, 1.4% of the vonoprazan dual therapy group, and 0.9% of the lansoprazole triple therapy group. None were considered related to the study drugs.

Vonoprazan was approved for the treatment of H. pylori infections by the FDA in May 2022, and had already been approved for treatment of H. pylori infections and other acid-related diseases in several other countries. It decreases intragastric pH and maintains it to a greater degree than that of proton pump inhibitors, which has been associated with higher eradication rates, the authors wrote.

“Optimizing current regimens offers the potential to increase eradication rates and reduce additional antibiotic usage, thereby promoting and improving antimicrobial stewardship,” the study authors wrote.

The study was funded by Phathom Pharmaceuticals, which contributed to the design and conduct of the trial, collection and interpretation of the data, preparation and review of the manuscript, and the decision to submit the manuscript for publication. The study authors declared various conflicts of interest, including some who have received compensation as a consultant, advisory committee member, or employee for Phathom Pharmaceuticals.

In a novel analysis accounting for protopathic bias, proton pump inhibitor (PPI) therapy was not associated with increased risk for death due to digestive disease, cancer, cardiovascular disease (CVD), or any cause, although the jury is out on renal disease.

“There have been several studies suggesting that PPIs can cause long-term health problems and may be associated with increased mortality,” Andrew T. Chan, MD, MPH, gastroenterologist and professor of medicine, Massachusetts General Hospital and Harvard Medical School, both in Boston, told this news organization.

“We conducted this study to examine this issue using data that were better able to account for potential biases in those prior studies. We found that PPIs were generally not associated with an increased risk of mortality,” Dr. Chan said.

The study was published online in Gastroenterology.
 

‘Reassuring’ data

The findings are based on data collected between 2004 and 2018 from 50,156 women enrolled in the Nurses’ Health Study and 21,731 men enrolled from the Health Professionals Follow-up Study.

During the study period, 10,998 women (21.9%) and 2,945 men (13.6%) initiated PPI therapy, and PPI use increased over the study period from 6.1% to 10.0% in women and from 2.5% to 7.0% in men.

The mean age at baseline was 68.9 years for women and 68.0 years for men. During a median follow-up of 13.8 years, a total of 22,125 participants died – 4,592 of cancer, 5,404 of CVD, and 12,129 of other causes.

Unlike other studies, the researchers used a modified lag-time approach to minimize reverse causation (protopathic bias).

“Using this approach, any increased PPI use during the excluded period, which could be due to comorbid conditions prior to death, will not be considered in the quantification of the exposure, and thus, protopathic bias would be avoided,” they explain.

In the initial analysis that did not take into account lag times, PPI users had significantly higher risks for all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, compared with nonusers.

However, when applying lag times of up to 6 years, the associations were largely attenuated and no longer statistically significant, which “highlights the importance of carefully controlling for the influence of protopathic bias,” the researchers write.

However, despite applying lag times, PPI users remained at a significantly increased risk for mortality due to renal diseases (hazard ratio, 2.45; 95% confidence interval, 1.59-3.78).

The researchers caution, however, that they did not have reliable data on renal diseases and therefore could not adjust for confounding in the models. They call for further studies examining the risk for mortality due to renal diseases in patients using PPI therapy.

The researchers also looked at duration of PPI use and all-cause and cause-specific mortality.

For all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, the greatest risks were seen mostly in those who reported PPI use for 1-2 years. Longer duration of PPI use did not confer higher risk for mortality for these endpoints.

In contrast, a potential trend toward greater risk with longer duration of PPI use was observed for mortality due to renal disease. The hazard ratio was 1.68 (95% CI, 1.19-2.38) for 1 to 2 years of use and gradually increased to 2.42 (95% CI, 1.23-4.77) for 7 or more years of use.

Notably, when mortality risks were compared among PPI users and histamine H2 receptor antagonist (H2RA) users without lag time, PPI users were at increased risk for all-cause mortality and mortality due to causes other than cancer and CVD, compared with H2RA users.

But again, the strength of the associations decreased after lag time was introduced.

“This confirmed our main findings and suggested PPIs might be preferred over H2RAs in sicker patients with comorbid conditions,” the researchers write.
 

‘Generally safe’ when needed

Summing up, Dr. Chan said, “We think our results should be reassuring to clinicians that recommending PPIs to patients with appropriate indications will not increase their risk of death. These are generally safe drugs that when used appropriately can be very beneficial.”

Offering perspective on the study, David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, noted that a “major continuing criticism of the allegations of harm by PPIs has been that these most commonly come from retrospective analyses of databases that were not constructed to evaluate these endpoints of harm.”

“Accordingly, these reports have multiple potentials for stratification bias and typically have low odds ratios for supporting the purported causality,” Dr. Johnson told this news organization.

“This is a well-done study design with a prospective database analysis that uses a modified lag-time approach to minimize reverse causation, that is, protopathic bias, which can occur when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected,” Dr. Johnson explained.

Echoing Dr. Chan, Dr. Johnson said the finding that PPI use was not associated with higher risk for all-cause mortality and mortality due to major causes is “reassuring.”

“Recognizably, too many people are taking PPIs chronically when they are not needed. If needed and appropriate, these data on continued use are reassuring,” Dr. Johnson added.

This work was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. Dr. Chan has consulted for OM1, Bayer Pharma AG, and Pfizer for topics unrelated to this study, as well as Boehringer Ingelheim for litigation related to ranitidine and cancer. Dr. Johnson reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a novel analysis accounting for protopathic bias, proton pump inhibitor (PPI) therapy was not associated with increased risk for death due to digestive disease, cancer, cardiovascular disease (CVD), or any cause, although the jury is out on renal disease.

“There have been several studies suggesting that PPIs can cause long-term health problems and may be associated with increased mortality,” Andrew T. Chan, MD, MPH, gastroenterologist and professor of medicine, Massachusetts General Hospital and Harvard Medical School, both in Boston, told this news organization.

“We conducted this study to examine this issue using data that were better able to account for potential biases in those prior studies. We found that PPIs were generally not associated with an increased risk of mortality,” Dr. Chan said.

The study was published online in Gastroenterology.
 

‘Reassuring’ data

The findings are based on data collected between 2004 and 2018 from 50,156 women enrolled in the Nurses’ Health Study and 21,731 men enrolled from the Health Professionals Follow-up Study.

During the study period, 10,998 women (21.9%) and 2,945 men (13.6%) initiated PPI therapy, and PPI use increased over the study period from 6.1% to 10.0% in women and from 2.5% to 7.0% in men.

The mean age at baseline was 68.9 years for women and 68.0 years for men. During a median follow-up of 13.8 years, a total of 22,125 participants died – 4,592 of cancer, 5,404 of CVD, and 12,129 of other causes.

Unlike other studies, the researchers used a modified lag-time approach to minimize reverse causation (protopathic bias).

“Using this approach, any increased PPI use during the excluded period, which could be due to comorbid conditions prior to death, will not be considered in the quantification of the exposure, and thus, protopathic bias would be avoided,” they explain.

In the initial analysis that did not take into account lag times, PPI users had significantly higher risks for all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, compared with nonusers.

However, when applying lag times of up to 6 years, the associations were largely attenuated and no longer statistically significant, which “highlights the importance of carefully controlling for the influence of protopathic bias,” the researchers write.

However, despite applying lag times, PPI users remained at a significantly increased risk for mortality due to renal diseases (hazard ratio, 2.45; 95% confidence interval, 1.59-3.78).

The researchers caution, however, that they did not have reliable data on renal diseases and therefore could not adjust for confounding in the models. They call for further studies examining the risk for mortality due to renal diseases in patients using PPI therapy.

The researchers also looked at duration of PPI use and all-cause and cause-specific mortality.

For all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, the greatest risks were seen mostly in those who reported PPI use for 1-2 years. Longer duration of PPI use did not confer higher risk for mortality for these endpoints.

In contrast, a potential trend toward greater risk with longer duration of PPI use was observed for mortality due to renal disease. The hazard ratio was 1.68 (95% CI, 1.19-2.38) for 1 to 2 years of use and gradually increased to 2.42 (95% CI, 1.23-4.77) for 7 or more years of use.

Notably, when mortality risks were compared among PPI users and histamine H2 receptor antagonist (H2RA) users without lag time, PPI users were at increased risk for all-cause mortality and mortality due to causes other than cancer and CVD, compared with H2RA users.

But again, the strength of the associations decreased after lag time was introduced.

“This confirmed our main findings and suggested PPIs might be preferred over H2RAs in sicker patients with comorbid conditions,” the researchers write.
 

‘Generally safe’ when needed

Summing up, Dr. Chan said, “We think our results should be reassuring to clinicians that recommending PPIs to patients with appropriate indications will not increase their risk of death. These are generally safe drugs that when used appropriately can be very beneficial.”

Offering perspective on the study, David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, noted that a “major continuing criticism of the allegations of harm by PPIs has been that these most commonly come from retrospective analyses of databases that were not constructed to evaluate these endpoints of harm.”

“Accordingly, these reports have multiple potentials for stratification bias and typically have low odds ratios for supporting the purported causality,” Dr. Johnson told this news organization.

“This is a well-done study design with a prospective database analysis that uses a modified lag-time approach to minimize reverse causation, that is, protopathic bias, which can occur when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected,” Dr. Johnson explained.

Echoing Dr. Chan, Dr. Johnson said the finding that PPI use was not associated with higher risk for all-cause mortality and mortality due to major causes is “reassuring.”

“Recognizably, too many people are taking PPIs chronically when they are not needed. If needed and appropriate, these data on continued use are reassuring,” Dr. Johnson added.

This work was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. Dr. Chan has consulted for OM1, Bayer Pharma AG, and Pfizer for topics unrelated to this study, as well as Boehringer Ingelheim for litigation related to ranitidine and cancer. Dr. Johnson reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In a novel analysis accounting for protopathic bias, proton pump inhibitor (PPI) therapy was not associated with increased risk for death due to digestive disease, cancer, cardiovascular disease (CVD), or any cause, although the jury is out on renal disease.

“There have been several studies suggesting that PPIs can cause long-term health problems and may be associated with increased mortality,” Andrew T. Chan, MD, MPH, gastroenterologist and professor of medicine, Massachusetts General Hospital and Harvard Medical School, both in Boston, told this news organization.

“We conducted this study to examine this issue using data that were better able to account for potential biases in those prior studies. We found that PPIs were generally not associated with an increased risk of mortality,” Dr. Chan said.

The study was published online in Gastroenterology.
 

‘Reassuring’ data

The findings are based on data collected between 2004 and 2018 from 50,156 women enrolled in the Nurses’ Health Study and 21,731 men enrolled from the Health Professionals Follow-up Study.

During the study period, 10,998 women (21.9%) and 2,945 men (13.6%) initiated PPI therapy, and PPI use increased over the study period from 6.1% to 10.0% in women and from 2.5% to 7.0% in men.

The mean age at baseline was 68.9 years for women and 68.0 years for men. During a median follow-up of 13.8 years, a total of 22,125 participants died – 4,592 of cancer, 5,404 of CVD, and 12,129 of other causes.

Unlike other studies, the researchers used a modified lag-time approach to minimize reverse causation (protopathic bias).

“Using this approach, any increased PPI use during the excluded period, which could be due to comorbid conditions prior to death, will not be considered in the quantification of the exposure, and thus, protopathic bias would be avoided,” they explain.

In the initial analysis that did not take into account lag times, PPI users had significantly higher risks for all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, compared with nonusers.

However, when applying lag times of up to 6 years, the associations were largely attenuated and no longer statistically significant, which “highlights the importance of carefully controlling for the influence of protopathic bias,” the researchers write.

However, despite applying lag times, PPI users remained at a significantly increased risk for mortality due to renal diseases (hazard ratio, 2.45; 95% confidence interval, 1.59-3.78).

The researchers caution, however, that they did not have reliable data on renal diseases and therefore could not adjust for confounding in the models. They call for further studies examining the risk for mortality due to renal diseases in patients using PPI therapy.

The researchers also looked at duration of PPI use and all-cause and cause-specific mortality.

For all-cause mortality and mortality due to cancer, CVD, respiratory diseases, and digestive diseases, the greatest risks were seen mostly in those who reported PPI use for 1-2 years. Longer duration of PPI use did not confer higher risk for mortality for these endpoints.

In contrast, a potential trend toward greater risk with longer duration of PPI use was observed for mortality due to renal disease. The hazard ratio was 1.68 (95% CI, 1.19-2.38) for 1 to 2 years of use and gradually increased to 2.42 (95% CI, 1.23-4.77) for 7 or more years of use.

Notably, when mortality risks were compared among PPI users and histamine H2 receptor antagonist (H2RA) users without lag time, PPI users were at increased risk for all-cause mortality and mortality due to causes other than cancer and CVD, compared with H2RA users.

But again, the strength of the associations decreased after lag time was introduced.

“This confirmed our main findings and suggested PPIs might be preferred over H2RAs in sicker patients with comorbid conditions,” the researchers write.
 

‘Generally safe’ when needed

Summing up, Dr. Chan said, “We think our results should be reassuring to clinicians that recommending PPIs to patients with appropriate indications will not increase their risk of death. These are generally safe drugs that when used appropriately can be very beneficial.”

Offering perspective on the study, David Johnson, MD, professor of medicine and chief of gastroenterology at the Eastern Virginia School of Medicine, Norfolk, noted that a “major continuing criticism of the allegations of harm by PPIs has been that these most commonly come from retrospective analyses of databases that were not constructed to evaluate these endpoints of harm.”

“Accordingly, these reports have multiple potentials for stratification bias and typically have low odds ratios for supporting the purported causality,” Dr. Johnson told this news organization.

“This is a well-done study design with a prospective database analysis that uses a modified lag-time approach to minimize reverse causation, that is, protopathic bias, which can occur when a pharmaceutical agent is inadvertently prescribed for an early manifestation of a disease that has not yet been diagnostically detected,” Dr. Johnson explained.

Echoing Dr. Chan, Dr. Johnson said the finding that PPI use was not associated with higher risk for all-cause mortality and mortality due to major causes is “reassuring.”

“Recognizably, too many people are taking PPIs chronically when they are not needed. If needed and appropriate, these data on continued use are reassuring,” Dr. Johnson added.

This work was supported by the National Institutes of Health and the Crohn’s and Colitis Foundation. Dr. Chan has consulted for OM1, Bayer Pharma AG, and Pfizer for topics unrelated to this study, as well as Boehringer Ingelheim for litigation related to ranitidine and cancer. Dr. Johnson reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Four days is an optimal time for wireless reflux monitoring to determine which patients can stop taking proton pump inhibitors (PPIs) and which ones need long-term antireflux therapy, researchers report.

“This first-of-its kind double-blinded clinical trial demonstrates the comparable, and in some cases better, performance of a simple assessment of daily acid exposure from multiple days of recording compared to other composite or complex assessments,” write Rena Yadlapati, MD, with the Division of Gastroenterology at the University of California, San Diego, and her coauthors.

Their findings were published online in the American Journal of Gastroenterology.

A substantial percentage of patients who have esophageal reflux symptoms do not have gastroesophageal reflux disease (GERD) and can stop taking PPIs.

Wireless reflux monitoring performed while patients are not taking PPIs is the gold standard for determining whether a patient has abnormal acid from GERD, but the optimal daily acid exposure time (AET) and the optimal duration of monitoring have not been well studied.

Aiming to fill this knowledge gap, Dr. Yadlapati and her colleagues conducted a single-arm, double-blinded clinical trial over 4 years at two tertiary care centers. They enrolled adult patients who had demonstrated an inadequate response to more than 8 weeks’ treatment with PPIs.

Study participants were asked to stop taking their PPI for 3 weeks in order for the investigators to determine the rate of relapse after PPI use and establish the study reference standard to discontinue therapy. During the 3-week period, after having stopped taking PPIs for at least a week, patients underwent 96-hour wireless reflux monitoring. They were then told to continue not taking PPIs for an additional 2 weeks. They could use over-the-counter antacids for symptom relief.

The primary outcome was whether PPIs could be successfully discontinued or restarted within 3 weeks. Of the 132 patients, 30% were able to stop taking PPIs.
 

AET less than 4.0% best discontinuation predictor

The team came to two key conclusions.

They found that acid exposure time of less than 4.0% was the best predictor of when stopping PPIs will be effective without worsening symptoms (odds ratio, 2.9; 95% confidence interval, 1.4-6.4). Comparatively, 45% (22 of 49 patients) with total AET of 4.0% or less discontinued taking PPIs, versus 22% (18 of 83 patients) with total AET of more than 4.0%.

Additionally, the investigators concluded that 96 hours of monitoring was better than 48 hours or fewer in predicting whether patients could stop taking PPIs (area under curve [AUC] for 96 hours, 0.63, versus AUC for 48 hours, 0.57).

Dr. Yadlapati told this news organization that the findings should be practice-changing.

“You really need to test for 4 days,” she said. She noted that the battery life of the monitor is 96 hours, and clinicians commonly only test for 2 days.

With only 1-2 days of monitoring, there is too much variability in how much acid is in the esophagus from one day to another. Monitoring over a 4-day period gives a clearer picture of acid exposure burden, she said.

Her advice: “If you have a patient with heartburn or chest pain and you think it might be from reflux, and they’re not responding to a trial of PPI, get the reflux monitoring. Don’t wait.”

After 4 days of monitoring, if exposure to acid is low, “they should really be taken off their PPI therapy,” she said.

They likely have a condition that requires a different therapy, she added.

“It is very consistent with what we have thought to be the case and what some lower-quality studies have shown,” she said. “It just hadn’t been done in a clinical trial with a large patient population and with a full outcome.”
 

PPI often used inappropriately

Interest is high both in discontinuing PPI in light of widespread and often inappropriate use and in not starting treatment with PPIs for patients who need a different therapy.

As this news organization has reported, some studies have linked long-term PPI use with intestinal infections, pneumonia, stomach cancer, osteoporosis-related bone fractures, chronic kidney disease, vitamin deficiencies, heart attacks, strokes, dementia, and early death.

Avin Aggarwal, MD, a gastroenterologist and medical director of Banner Health’s South Campus endoscopy services and clinical assistant professor at the University of Arizona, Tucson, said in an interview that this study provides the evidence needed to push for practice change.

He said his center has been using 48-hour reflux monitoring. He said that anecdotally, they had gotten better data with 4-day monitoring, but evidence was not directly tied to a measurable outcome such as this study provides.

With 4-day monitoring, “we get way more symptoms on the recorder to actually correlate them with reflux or not,” he said.

He said he will now push for the 96-hour monitoring in his clinic.

He added that part of the problem is in assuming patients have GERD and initiating PPIs in the first place without a specific diagnosis of acid reflux.

Patients, he said, are often aware of the long-term side effects of PPIs and are approaching their physicians to see whether they can discontinue them.

The data from this study, he said, will help guide physicians on when it is appropriate to discontinue treatment.

Dr. Yadlapati is a consultant for Medtronic, Phathom Pharmaceuticals, and StatLinkMD and receives research support from Ironwood Pharmaceuticals. She is on the advisory board with stock options for RJS Mediagnostix. Other study coauthors report ties to Medtronic, Diversatek, Ironwood, Iso-Thrive, Quintiles, Johnson & Johnson, Reckitt, Phathom Pharmaceuticals, Daewood, Takeda, and Crospon. Study coauthor Michael F. Vaezi, MD, PHD, holds a patent on mucosal integrity by Vanderbilt. Dr. Aggarwal reports no relevant financial relationships.

A version of this article first appeared on Medscape.com.