Upper GI Tract

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

In males but not females, hyperinsulinemia, insulin resistance, and metabolic syndrome are independently associated with a higher risk of Barrett’s esophagus (BE), based on a recent case-control study.

These findings offer some insight into why men have higher rates of BE and esophageal adenocarcinoma than do women, reported lead author Bradley J. Kendall, MBBS, PhD, of the University of Queensland in Brisbane, Australia, and colleagues.

“Esophageal adenocarcinoma (EA) and its precursor lesion, Barrett’s esophagus (BE), are more common in males than females,” the investigators wrote in the Journal of Clinical Gastroenterology. “In contrast, gastroesophageal reflux (GER), the major risk factor for BE and EA occurs at similar frequencies in both sexes. In addition, 10% to 20% of BE and EA cases report no history of GER symptoms. This suggests that non-GER factors are important in the development of BE and EA.”

To examine risk factors more closely, the investigators enrolled 227 patients with BE and 241 age- and sex-matched controls. Data were drawn from self-reported questionnaires, interviews, blood pressure readings, and anthropometric measurements, the latter of which included weight, height, and waist circumference. These patient characteristics were supplemented with fasted blood assays. The investigators looked for associations between BE and insulin level, Homeostatic Model Assessment of Insulin Resistance, metabolic syndrome, type 2 diabetes mellitus, insulin-like growth factors, and interleukin-6 (IL-6).

Across the entire population, independent associations were detected between BE and hyperinsulinemia (highest vs. lowest tertile; odds ratio, 1.9; P = .003), insulin resistance (OR, 1.9; P = .006) and metabolic syndrome (OR, 1.8; P = .004). For those with metabolic syndrome, risk of BE increased by 20% for each additional syndrome criterion (P = .02).

When stratifying by sex, however, all of the above risk factors remained statistically significant in men, but not in women. For male patients, compared with the population as a whole, risks were relatively higher for all three factors: hyperinsulinemia (OR, 2.1; P = .007), insulin resistance (OR, 2.1; P = .01), and metabolic syndrome (OR, 2.3; P = .001). Similarly, for men with metabolic syndrome, each additional syndrome criterion increased risk of BE by 40% (P = .005).

Regardless of sex stratification, the other evaluated characteristics (type 2 diabetes mellitus, insulin-like growth factors, and IL-6) were not associated with BE risk.

The investigators offered some possible mechanistic explanations for their findings.

“Hyperinsulinemia ... can result in increased insulin signaling, increased cellular proliferation, reduced apoptosis, oncogenic pathway activation, and enhanced cellular invasion,” they wrote. “In addition, abdominal obesity, which is the driver of these disorders of insulin homeostasis, also alters adipocytokine profiles and induces a chronic systemic inflammatory state. The inflammatory state can result in oncoprotein activation, angiogenesis, cellular proliferation, apoptosis, and metastasis.”

Concerning the difference between sexes, the investigators pointed to patterns of abdominal obesity. “[A]bdominal obesity and the associated metabolic sequelae are more common in males than females,” they wrote. “These observations give rise to the notion that the metabolic syndrome potentiates the inflammatory effects of the gastric refluxate in the distal esophagus and this may play a role in the male predominance of BE and EA.”

While these findings offer insight into the underlying processes that precipitate BE, the investigators suggested that more research is needed.

“The interactions of obesity hormones, GER, and the cells of the esophageal mucosa warrant further investigation,” they concluded.

The study was funded by the Queensland Cancer Fund, Queensland Government Smart State Fund, and the Princess Alexandra Hospital Research Foundation, and others. The investigators reported no disclosures.

SOURCE: Kendall BJ et al. J Clin Gastroenterol. 2019 Dec 24. doi: 10.1097/MCG.0000000000001307.

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

The American Gastroenterological Association recently released a clinical practice update for endoscopic treatment of Barrett’s esophagus with dysplasia and/or early esophageal adenocarcinoma.

The update offers best practice advice for a range of clinical scenarios based on published evidence, including guidelines and recent systematic reviews, reported lead author Prateek Sharma, MD, of the University of Kansas, Kansas City. Dr. Sharma was accompanied on the authoring review team by three other expert gastroenterologists from the United States and the Netherlands.

Beyond practice advice, the investigators highlighted a research focus for the future.

“Given the expense and time required for careful and continual surveillance after Barrett’s endoscopic therapy, the future must define improved means of risk-stratifying patients for therapy who are at highest risk for cancer development and for risk of recurrence after complete eradication of intestinal metaplasia,” they wrote in Gastroenterology. “Potentially, we may use a panel of patient characteristics (such as the [Progression in Barrett’s] score), preablation tissue characteristics (e.g., baseline grade of dysplasia) and the posttherapy molecular makeup of the epithelium to help risk stratify our patients.”

For now, many of the treatment principles in the update depend upon histologic features.

For instance, either endoscopic therapy or continued surveillance are reasonable options for patients with Barrett’s esophagus who have confirmed and persistent low-grade dysplasia. In contrast, the update recommends that all patients with high-grade dysplasia or esophageal adenocarcinoma (T1a) undergo endoscopic therapy, highlighting that this method is preferred over esophagectomy for patients with T1a cancer. Along the same lines, the investigators noted that endoscopic therapy is a “reasonable alternative” to esophagectomy in cases of T1b esophageal adenocarcinoma in the presence of minimal invasion and good to moderate differentiation, particularly in patients who are poor candidates for surgery.

During the decision-making process, patients with dysplasia should be advised that not undergoing endoscopic therapy may increase cancer risk, the investigators wrote, adding that patients should also be informed about endoscopic therapy–related risks of bleeding and perforation, which occur in less than 1% of patients, and the risk of postprocedural stricture formation, which occurs in approximately 6% of patients.

If endoscopic therapy is elected, the update suggests that the procedure be done by experts who perform at least 10 new cases per year.

Concerning specifics of therapy, the investigators advised that mucosal ablation be applied to all visible esophageal columnar mucosa, 5-10 mm proximal to the squamocolumnar junction, and 5-10 mm distal to the gastroesophageal junction. Ablation should only be performed in cases of flat Barrett’s esophagus in which no visible abnormalities or signs of inflammation are present, the review team wrote.

The investigators went on to lay out some “practical ground rules” for endoscopic therapy, including a potential pitfall.

“Ablation therapy may consist of multiple 2-3 monthly ablation sessions that may extend over a period of more than a year,” the investigators wrote. “The worst adverse outcome during the treatment period is failing to recognize and treat an invasive cancer while continuing the ablation sessions. This occurrence may place the patient outside of the window of opportunity for curative endoscopic treatment. Therefore, every ablation session starts with careful endoscopic inspection using [high-definition white-light endoscopy] and preferably optical chromoendoscopy to exclude the presence of visible abnormalities that require an endoscopic resection instead of the scheduled ablation. Routine biopsies of flat Barrett’s esophagus are not necessary or recommended prior to ablation at these sessions, as the blood may inhibit optimal energy transfer to the tissue.”

Following successfully achieved complete endoscopic and histologic eradication of intestinal metaplasia, the update calls for surveillance endoscopy with biopsies at intervals of 1 and 3 years for cases of low-grade dysplasia and at intervals of 3, 6, and 12 months for high-grade dysplasia or esophageal adenocarcinoma, followed by annual checks thereafter.

The investigators disclosed relationships with Olympus, Ironwood, Erbe, and others.

SOURCE: Sharma P et al. Gastroenterology. 2019 Nov 12. doi: 10.1053/j.gastro.2019.09.051.

A new risk prediction panel based on machine learning may enable routine, noninvasive identification of patients with a high risk of Barrett’s esophagus, according to investigators.

The methods used in the present study could potentially be applied to other conditions to aid in diagnosis and limit low-yield invasive testing, reported lead author Avi Rosenfeld, PhD, of Jerusalem College of Technology in Israel, and colleagues.

“The currently used system for identifying patients with Barrett’s esophagus, or those at risk of esophageal adenocarcinoma, is flawed because it is based on symptoms that trigger expensive and unpleasant invasive tests,” the investigators wrote. Their report is in The Lancet Digital Health.

In an effort to improve early clinical clarity, the investigators turned to machine learning. Algorithm development and testing relied upon data from more than 1,600 patients involved in two case-control trials, BEST2 and BOOST. From BEST2, 1,299 patients were randomized in a 6:4 ratio to generate a training dataset (n = 776) and a testing dataset (n = 523). Data from all 398 patients in the BOOST trial were used for external validation. Barrett’s esophagus was common in both trials, with a prevalence of 68% and 50% in BEST2 and BOOST, respectively.

During the training phase, machine learning identified independent patient characteristics associated with a diagnosis of Barrett’s esophagus. Specific artificial intelligence techniques included information gain and correlation-based feature selection.

“Both information gain and correlation-based feature selection are filter feature selection methods and thus have the advantage of being fast, scalable, and independent of the classifier,” the investigators noted. They explained that independence from the classifier is “crucial,” as this characteristic has been associated with improved interpretability and more stable algorithms than conventional statistical approaches.

The training process revealed eight distinct diagnostic features: sex, age, waist circumference, cigarette smoking, duration of acidic taste, duration of heartburn, frequency of stomach pain, and use of antireflux medication. All of these were directly correlated with Barrett’s esophagus, except for frequency of stomach pain, which had an inverse relationship. The investigators noted that this inverse relationship may initially seem counterintuitive, but a closer look suggests that the relationship is appropriate.

“Most patients with esophageal adenocarcinoma are not identified before cancer develops despite many of them having Barrett’s esophagus,” the investigators wrote. “Indeed, 40% of patients with esophageal adenocarcinoma have not previously had symptomatic reflux and many probably had Barrett’s esophagus. Therefore, Barrett’s esophagus has been hypothesized to not be associated with severity of reflux symptoms; which fits with the model determined from our data.”

To provide a test of the model’s predictive ability, the investigators arbitrarily set sensitivity at 90%. Within this context, logistic regression was used to provide an upper estimate of the model’s predictive ability; this resulted in an area under the receiver-operator curve (AUC) of 0.87 and a specificity of 68%. In the validation phase, these figures decreased slightly. In the testing dataset, AUC was 0.86, while specificity was 65%. External validation was associated with an AUC of 0.81 and a specificity of 58%.

“We have shown that a panel with eight features, including detailed stomach and chest symptoms, can identify the presence of Barrett’s esophagus with high sensitivity and specificity in a case-control population,” the investigators concluded.

“Simple triaging of individuals might be possible on the basis of predictive panels that include variables that are widely available or easy to obtain,” they added. “Patient age and sex, together with medication and smoking history, are routinely captured in primary care systems. Additionally, asking about duration of heartburn and acidic taste, frequency of stomach pain, and measuring waist circumference should be simple for physicians. Alternatively, a patient could do a self-assessment using a web-based app and generate a personalized risk profile for having Barrett’s esophagus.”

The study was funded by the Charles Wolfson Charitable Trust and Guts UK, the National Institute for Health Research Biomedical Research Centre, Cancer Research UK, and the Wellcome/EPSRC Centre for Interventional and Surgical Sciences at University College London. Dr. Fitzgerald reported a relationship with Medtronic via licensing of the cytosponge device.

SOURCE: Rosenfeld A et al. Lancet Digital Health. 2019 Dec 5. doi: 10.1016/S2589-7500(19)30216-X.

A new risk prediction panel based on machine learning may enable routine, noninvasive identification of patients with a high risk of Barrett’s esophagus, according to investigators.

The methods used in the present study could potentially be applied to other conditions to aid in diagnosis and limit low-yield invasive testing, reported lead author Avi Rosenfeld, PhD, of Jerusalem College of Technology in Israel, and colleagues.

“The currently used system for identifying patients with Barrett’s esophagus, or those at risk of esophageal adenocarcinoma, is flawed because it is based on symptoms that trigger expensive and unpleasant invasive tests,” the investigators wrote. Their report is in The Lancet Digital Health.

In an effort to improve early clinical clarity, the investigators turned to machine learning. Algorithm development and testing relied upon data from more than 1,600 patients involved in two case-control trials, BEST2 and BOOST. From BEST2, 1,299 patients were randomized in a 6:4 ratio to generate a training dataset (n = 776) and a testing dataset (n = 523). Data from all 398 patients in the BOOST trial were used for external validation. Barrett’s esophagus was common in both trials, with a prevalence of 68% and 50% in BEST2 and BOOST, respectively.

During the training phase, machine learning identified independent patient characteristics associated with a diagnosis of Barrett’s esophagus. Specific artificial intelligence techniques included information gain and correlation-based feature selection.

“Both information gain and correlation-based feature selection are filter feature selection methods and thus have the advantage of being fast, scalable, and independent of the classifier,” the investigators noted. They explained that independence from the classifier is “crucial,” as this characteristic has been associated with improved interpretability and more stable algorithms than conventional statistical approaches.

The training process revealed eight distinct diagnostic features: sex, age, waist circumference, cigarette smoking, duration of acidic taste, duration of heartburn, frequency of stomach pain, and use of antireflux medication. All of these were directly correlated with Barrett’s esophagus, except for frequency of stomach pain, which had an inverse relationship. The investigators noted that this inverse relationship may initially seem counterintuitive, but a closer look suggests that the relationship is appropriate.

“Most patients with esophageal adenocarcinoma are not identified before cancer develops despite many of them having Barrett’s esophagus,” the investigators wrote. “Indeed, 40% of patients with esophageal adenocarcinoma have not previously had symptomatic reflux and many probably had Barrett’s esophagus. Therefore, Barrett’s esophagus has been hypothesized to not be associated with severity of reflux symptoms; which fits with the model determined from our data.”

To provide a test of the model’s predictive ability, the investigators arbitrarily set sensitivity at 90%. Within this context, logistic regression was used to provide an upper estimate of the model’s predictive ability; this resulted in an area under the receiver-operator curve (AUC) of 0.87 and a specificity of 68%. In the validation phase, these figures decreased slightly. In the testing dataset, AUC was 0.86, while specificity was 65%. External validation was associated with an AUC of 0.81 and a specificity of 58%.

“We have shown that a panel with eight features, including detailed stomach and chest symptoms, can identify the presence of Barrett’s esophagus with high sensitivity and specificity in a case-control population,” the investigators concluded.

“Simple triaging of individuals might be possible on the basis of predictive panels that include variables that are widely available or easy to obtain,” they added. “Patient age and sex, together with medication and smoking history, are routinely captured in primary care systems. Additionally, asking about duration of heartburn and acidic taste, frequency of stomach pain, and measuring waist circumference should be simple for physicians. Alternatively, a patient could do a self-assessment using a web-based app and generate a personalized risk profile for having Barrett’s esophagus.”

The study was funded by the Charles Wolfson Charitable Trust and Guts UK, the National Institute for Health Research Biomedical Research Centre, Cancer Research UK, and the Wellcome/EPSRC Centre for Interventional and Surgical Sciences at University College London. Dr. Fitzgerald reported a relationship with Medtronic via licensing of the cytosponge device.

SOURCE: Rosenfeld A et al. Lancet Digital Health. 2019 Dec 5. doi: 10.1016/S2589-7500(19)30216-X.

A new risk prediction panel based on machine learning may enable routine, noninvasive identification of patients with a high risk of Barrett’s esophagus, according to investigators.

The methods used in the present study could potentially be applied to other conditions to aid in diagnosis and limit low-yield invasive testing, reported lead author Avi Rosenfeld, PhD, of Jerusalem College of Technology in Israel, and colleagues.

“The currently used system for identifying patients with Barrett’s esophagus, or those at risk of esophageal adenocarcinoma, is flawed because it is based on symptoms that trigger expensive and unpleasant invasive tests,” the investigators wrote. Their report is in The Lancet Digital Health.

In an effort to improve early clinical clarity, the investigators turned to machine learning. Algorithm development and testing relied upon data from more than 1,600 patients involved in two case-control trials, BEST2 and BOOST. From BEST2, 1,299 patients were randomized in a 6:4 ratio to generate a training dataset (n = 776) and a testing dataset (n = 523). Data from all 398 patients in the BOOST trial were used for external validation. Barrett’s esophagus was common in both trials, with a prevalence of 68% and 50% in BEST2 and BOOST, respectively.

During the training phase, machine learning identified independent patient characteristics associated with a diagnosis of Barrett’s esophagus. Specific artificial intelligence techniques included information gain and correlation-based feature selection.

“Both information gain and correlation-based feature selection are filter feature selection methods and thus have the advantage of being fast, scalable, and independent of the classifier,” the investigators noted. They explained that independence from the classifier is “crucial,” as this characteristic has been associated with improved interpretability and more stable algorithms than conventional statistical approaches.

The training process revealed eight distinct diagnostic features: sex, age, waist circumference, cigarette smoking, duration of acidic taste, duration of heartburn, frequency of stomach pain, and use of antireflux medication. All of these were directly correlated with Barrett’s esophagus, except for frequency of stomach pain, which had an inverse relationship. The investigators noted that this inverse relationship may initially seem counterintuitive, but a closer look suggests that the relationship is appropriate.

“Most patients with esophageal adenocarcinoma are not identified before cancer develops despite many of them having Barrett’s esophagus,” the investigators wrote. “Indeed, 40% of patients with esophageal adenocarcinoma have not previously had symptomatic reflux and many probably had Barrett’s esophagus. Therefore, Barrett’s esophagus has been hypothesized to not be associated with severity of reflux symptoms; which fits with the model determined from our data.”

To provide a test of the model’s predictive ability, the investigators arbitrarily set sensitivity at 90%. Within this context, logistic regression was used to provide an upper estimate of the model’s predictive ability; this resulted in an area under the receiver-operator curve (AUC) of 0.87 and a specificity of 68%. In the validation phase, these figures decreased slightly. In the testing dataset, AUC was 0.86, while specificity was 65%. External validation was associated with an AUC of 0.81 and a specificity of 58%.

“We have shown that a panel with eight features, including detailed stomach and chest symptoms, can identify the presence of Barrett’s esophagus with high sensitivity and specificity in a case-control population,” the investigators concluded.

“Simple triaging of individuals might be possible on the basis of predictive panels that include variables that are widely available or easy to obtain,” they added. “Patient age and sex, together with medication and smoking history, are routinely captured in primary care systems. Additionally, asking about duration of heartburn and acidic taste, frequency of stomach pain, and measuring waist circumference should be simple for physicians. Alternatively, a patient could do a self-assessment using a web-based app and generate a personalized risk profile for having Barrett’s esophagus.”

The study was funded by the Charles Wolfson Charitable Trust and Guts UK, the National Institute for Health Research Biomedical Research Centre, Cancer Research UK, and the Wellcome/EPSRC Centre for Interventional and Surgical Sciences at University College London. Dr. Fitzgerald reported a relationship with Medtronic via licensing of the cytosponge device.

SOURCE: Rosenfeld A et al. Lancet Digital Health. 2019 Dec 5. doi: 10.1016/S2589-7500(19)30216-X.

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

bjancin@mdedge.com

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

bjancin@mdedge.com

SAN ANTONIO – A wide-area transepithelial sampling (WATS) brush proved superior to standard forceps biopsies for detection of intestinal metaplasia (IM) in the esophagus and gastroesophageal junction in patients with no history of IM who had any visible columnar-lined esophagus on upper endoscopy in a large randomized trial.

Bruce Jancin/MDedge News

“This suggests that WATS should in fact be the preferred method of sampling these patients,” Steven R. DeMeester, MD, commented in presenting the study results at the annual meeting of the American College of Gastroenterology.

With that specific exception, however, the two sampling methods proved similarly effective at detecting IM and dysplasia, suggesting either technology can otherwise reliably be used to detect these conditions, added Dr. DeMeester, a general and thoracic surgeon at the Oregon Clinic, Portland.

This is important new information for clinicians. A prior multicenter, randomized trial by other investigators demonstrated that adding WATS to biopsy sampling improved the detection rate of dysplasia and esophageal adenocarcinoma, compared with biopsies alone (Gastrointest Endosc. 2018 Feb;87[2]:348-55). However, this dual-sampling strategy is too time-consuming for routine use in a busy practice. Given the new evidence that the two sampling methods can reliably be used interchangeably except in patients with no history of IM who have endoscopically visible columnar-lined esophagus, WATS offers a clear advantage in that it’s much quicker, especially in patients with long-segment Barrett’s esophagus, the surgeon said.

Unlike brush cytology, which merely collects surface epithelial cells, the WATS brush collects sheets of esophageal mucosa, which then undergo computer-assisted three-dimensional analysis.

“When done appropriately, a wide area of the esophageal mucosa can be sampled with the WATS brush,” Dr. DeMeester explained.

He reported on 1,002 patients who presented at nine U.S. centers for upper endoscopy for Barrett’s esophagus surveillance or evaluation of foregut symptoms. They were randomized to WATS or forceps biopsies using the Seattle protocol. In the entire group, WATS and forceps biopsies were similarly effective, each finding IM – a potentially premalignant mucosal change – in about 21% of patients, and dysplasia or cancer in 0.8%. Among the 185 patients who underwent endoscopy for follow-up of Barrett’s esophagus or post ablation, the two sampling strategies also performed similarly, detecting IM in roughly 36% of the 151 patients with columnar-lined esophagus shorter than 3 cm and in 56% of those with columnar-lined esophagus of greater length.

However, in the 196 patients with no history of IM who had any length of visible columnar-lined esophagus on endoscopy, the frequency of IM detection was 32.7% with WATS, compared with 15.3% with biopsy.

Dr. DeMeester and coinvestigators were also eager to identify factors associated with detection of IM in the esophagus or gastroesophageal junction in patients undergoing elective endoscopy with no history of IM. They found that whites were at greater risk than blacks, by a margin of 10.1% (17.1% vs. 7%). Moreover, the 23% IM detection rate in patients aged over age 70 years was significantly higher than the 15.5% rate in those under age 70. And to their surprise, there was no significant difference between the IM detection rate in men and women.

Nearly 15% of study participants with no measurable columnar-lined esophagus turned out to have IM. And two patients with low-grade dysplasia and one with adenocarcinoma were found among the group with no history of IM and no visible columnar-lined esophagus on upper endoscopy.

“This demonstrates that the absence of a measurable columnar-lined esophagus does not exclude patients from the risk of having intestinal metaplasia, dysplasia, or cancer at the gastroesophageal junction. Therefore evaluation of the gastroesophageal junction by biopsy or WATS should be considered during upper endoscopy, particularly in patients at increased risk for having intestinal metaplasia,” he concluded.

Dr. DeMeester reported serving as a consultant to BARD and receiving research funding from and serving as a paid speaker for CDx Diagnostics, which funded the trial.

bjancin@mdedge.com

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

SAN ANTONIO – The first new treatment for Helicobacter pylori infection to receive Food and Drug Administration approval in 22 years performed so well in a pivotal phase 3 trial that it is worthy of consideration as best-in-class first-line therapy, David Y. Graham, MD, asserted at the annual meeting of the American College of Gastroenterology.

The drug, recently approved as Talicia, is a rifabutin-based triple therapy. Each capsule contains 50 mg of rifabutin, 1,000 mg of amoxicillin, and 40 mg of omeprazole. As in the pivotal phase 3 trial led by Dr. Graham, the approved treatment regimen calls for adults to take four capsules every 8 hours for 14 days.

The impetus for developing the new therapy centers on the growing problem of resistance to long-standard agents for H. pylori eradication, including metronidazole and clarithromycin. The World Health Organization has declared H. pylori eradication to be a high priority for therapeutic development. Rifabutin resistance is rare: In one study, 413 of 414 strains of H. pylori were sensitive to the antibiotic, noted Dr. Graham, professor of medicine at Baylor College of Medicine, Houston.

He presented the results of the pivotal phase 3, double-blind, multicenter, active comparator trial, known as ERADICATE Hp2, in which 455 participants with confirmed H. pylori infection were randomized to a course of the all-in-one-capsule triple drug combo or to dual therapy with four capsules, each containing 1,000 mg of amoxicillin and 40 mg of omeprazole, every 8 hours for 14 days.

The primary endpoint was H. pylori eradication as documented by a negative urea breath test obtained 4-6 weeks after completing 14 days of treatment. The rate was 84% with the rifabutin-based combo, compared with 58% seen with the high-dose dual therapy. Moreover, in a prespecified secondary analysis restricted to the 391 participants who were confirmed to be actually taking their medication as evidenced by a positive blood level measured on day 13, the eradication rates rose to 90% and 65%, respectively.

The antimicrobial resistance rates documented in this study were eye opening: 17% of patients’ strains were resistant to clarithromycin, 44% to metronidazole, and 10.5% to both. Of concern, 6.4% of participants’ strains were amoxicillin resistant.

“For the first time we saw a low level – but a definite level – of amoxicillin resistance. That’s something we had not seen previously,” Dr. Graham said.

No rifabutin resistance was detected before or after treatment.

The side effect profiles of the two treatment regimens were similar. Diarrhea was reported by 9% of participants, headache by 7%, and nausea by 5%. No serious adverse events occurred in the 14-day study.

The efficacy of the rifabutin-based therapy wasn’t affected by metronidazole or clarithromycin resistance.

The ERADICATE Hp2 trial was sponsored by RedHill Biopharma of Tel Aviv. Dr. Graham reported having no financial conflicts.

bjancin@mdedge.com

Amneal Pharmaceuticals has announced a voluntary recall for both ranitidine tablets and ranitidine syrup because of potential N-nitrosodimethylamine (NDMA) levels above Food and Drug Administration–allowed cutoffs, according to an FDA MedWatch alert.

NDMA, a probable human carcinogen, has been found in several different ranitidine products since an initial FDA announcement in September 2019. Ranitidine, a histamine₂ receptor blocker, is indicated for multiple conditions, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease.

The affected ranitidine products being recalled by Amneal include 60-, 100-, 180-, 500-, and 1,000-count 150-mg tablets; 30-, 100-, 250-, and 1,000-count 300-mg tablets, and a 15-mg/mL syrup. The manufacturer has not received any reports of adverse events confirmed to be directly related to the recall.

Consumers should contact their physicians or health care providers if they have experienced any problems that may be related to the use of this drug product, the FDA said. Adverse reactions or quality problems can be reported to Amneal Drug Safety by phone at 1-877-835-5472.

lfranki@mdedge.com

Amneal Pharmaceuticals has announced a voluntary recall for both ranitidine tablets and ranitidine syrup because of potential N-nitrosodimethylamine (NDMA) levels above Food and Drug Administration–allowed cutoffs, according to an FDA MedWatch alert.

NDMA, a probable human carcinogen, has been found in several different ranitidine products since an initial FDA announcement in September 2019. Ranitidine, a histamine₂ receptor blocker, is indicated for multiple conditions, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease.

The affected ranitidine products being recalled by Amneal include 60-, 100-, 180-, 500-, and 1,000-count 150-mg tablets; 30-, 100-, 250-, and 1,000-count 300-mg tablets, and a 15-mg/mL syrup. The manufacturer has not received any reports of adverse events confirmed to be directly related to the recall.

Consumers should contact their physicians or health care providers if they have experienced any problems that may be related to the use of this drug product, the FDA said. Adverse reactions or quality problems can be reported to Amneal Drug Safety by phone at 1-877-835-5472.

lfranki@mdedge.com

Amneal Pharmaceuticals has announced a voluntary recall for both ranitidine tablets and ranitidine syrup because of potential N-nitrosodimethylamine (NDMA) levels above Food and Drug Administration–allowed cutoffs, according to an FDA MedWatch alert.

NDMA, a probable human carcinogen, has been found in several different ranitidine products since an initial FDA announcement in September 2019. Ranitidine, a histamine₂ receptor blocker, is indicated for multiple conditions, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease.

The affected ranitidine products being recalled by Amneal include 60-, 100-, 180-, 500-, and 1,000-count 150-mg tablets; 30-, 100-, 250-, and 1,000-count 300-mg tablets, and a 15-mg/mL syrup. The manufacturer has not received any reports of adverse events confirmed to be directly related to the recall.

Consumers should contact their physicians or health care providers if they have experienced any problems that may be related to the use of this drug product, the FDA said. Adverse reactions or quality problems can be reported to Amneal Drug Safety by phone at 1-877-835-5472.

lfranki@mdedge.com

SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.

“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.

However, he emphasized a couple of caveats regarding this highly effective intervention.

First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.

Second, there’s a significant learning curve involved in successful use of the clip.

“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.

The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.

The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.

Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.

All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.

One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.

Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.

“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.

The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.

“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.

He reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Jensen DM. ACG 2019, Abstract 8.

SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.

“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.

However, he emphasized a couple of caveats regarding this highly effective intervention.

First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.

Second, there’s a significant learning curve involved in successful use of the clip.

“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.

The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.

The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.

Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.

All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.

One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.

Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.

“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.

The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.

“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.

He reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Jensen DM. ACG 2019, Abstract 8.

SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.

Bruce Jancin/MDedge News

The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.

“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.

However, he emphasized a couple of caveats regarding this highly effective intervention.

First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.

Second, there’s a significant learning curve involved in successful use of the clip.

“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.

The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.

The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.

Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.

All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.

One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.

Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.

“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.

The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.

“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.

He reported having no financial conflicts regarding this study, conducted free of commercial support.

bjancin@mdedge.com

SOURCE: Jensen DM. ACG 2019, Abstract 8.

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

SAN ANTONIO – An investigational muco-adherent swallowed formulation of budesonide developed specifically for treatment of eosinophilic esophagitis aced all primary and secondary endpoints in a pivotal, phase 3, double-blind, placebo-controlled randomized trial, Ikuo Hirano, MD, reported at the annual scientific meeting of the American College of Gastroenterology.

This is welcome news for patients with this chronic immune-mediated disease, for which no Food and Drug Administration–approved drug therapy exists yet.

“This is the first phase 3 trial to demonstrate efficacy using the validated Dysphagia Symptom Questionnaire, the first completed phase 3 trial of any medical therapeutic for eosinophilic esophagitis, and the largest clinical trial for eosinophilic esophagitis conducted to date,” declared Dr. Hirano, professor of medicine at Northwestern University in Chicago.

This was a 12-week induction therapy study including 318 adolescents and adults randomized 2:1 to 2 mg of budesonide oral suspension (BOS) or placebo twice daily. Patients were instructed not to eat or drink anything for 30 minutes afterward to avoid washing away the medication.

This was a severely affected patient population with high-level inflammatory activity: their mean baseline peak eosinophil count was 75 cells per high-power field, well above the diagnostic threshold of 50 eosinophils per high-power field. In keeping with a requirement for study participation, all patients had failed to respond to at least 6 weeks of high-dose proton pump inhibitor therapy. They also had to experience solid food dysphagia on at least 4 days per 2 weeks. More than 40% of subjects had previously undergone esophageal dilation.

One coprimary endpoint addressed histologic response, defined as 6 or fewer eosinophils per high-power field after 12 weeks of double-blind treatment. The histologic response rate was 53% in the BOS group and 1% in placebo-treated controls.

The other coprimary endpoint was symptom response as defined by at least a 30% reduction from baseline in the Dysphagia Symptom Questionnaire score. This was achieved in 53% of patients on BOS and 39% of controls.

The prespecified key secondary endpoint was the absolute reduction in Dysphagia Symptom Questionnaire score through week 12. From a mean baseline score of 30 out of a possible 84, the swallowed steroid recipients experienced a mean 13-point improvement, compared with a 9.1-improvement for those on placebo.

The topical budesonide group also did significantly better than placebo in terms of all other secondary endpoints. Endoscopic improvement as reflected in the mean Eosinophilic Esophagitis Reference Score was greater in the BOS group by a margin of 4 versus 2.2 points. A high-bar histologic response rate of no more than a single eosinophil per high-power field at week 12 was achieved in one-third of the BOS group and zero controls. The overall peak eosinophil count from baseline to week 12 dropped by an average of 55.2 cells per high-power field in the budesonide group, compared to a 7.6-eosinophil decrease in controls. And the proportion of patients with no more than 15 eosinophils per high-power field at week 12 was 62% with BOS, compared with 1% with placebo.

Treatment-emergent adverse events were similar in the two study arms and were mild to moderate in severity. Of note, however, the 3.8% incidence of esophageal candidiasis rate in the topical corticosteroid group was twice that seen in the placebo arm. Adrenal function as assessed by ACTH stimulation testing at baseline and 12 weeks was normal in 88% of the BOS group and 94% of controls.

Dr. Hirano noted that adrenal function will continue to be carefully monitored during an ongoing, phase 3, double-blind, placebo-controlled BOS maintenance study.

He reported receiving research funding from and serving as a consultant to Takeda, the study sponsor, as well as a handful of other pharmaceutical companies.

bjancin@mdedge.com

The Food and Drug Administration has issued an alert to health care providers and patients about voluntary recalls of ranitidine (Zantac) from three separate companies because of the potential of N-nitrosodimethylamine (NDMA) in the medicine.

bankrx/Getty Images

According to the FDA alert, Perrigo is recalling over-the-counter ranitidine tablets of all sizes, Novitium Pharma is recalling all unexpired quantities and lots of ranitidine hydrochloride capsules, and Lannett is recalling all unexpired lots of prescription ranitidine syrup (ranitidine oral solution (15 mg/mL).

Patients who are using over-the-counter ranitidine should consider switching to an alternative, such as famotidine, cimetidine, esomeprazole, lansoprazole, and omeprazole, the FDA noted. None of these medications have shown evidence of containing NDMA.

The alert is the fifth update on ranitidine since the initial FDA announcement that NDMA had been found in ranitidine on Sept. 13, 2019.

The recent FDA safety alerts on ranitidine might be causing concern among your patients about their heartburn treatment. AGA offers key points that you can share with your patients at www.gastro.org/news/talking-to-your-patients-about-ranitidine.

lfranki@mdedge.com

The Food and Drug Administration has issued an alert to health care providers and patients about voluntary recalls of ranitidine (Zantac) from three separate companies because of the potential of N-nitrosodimethylamine (NDMA) in the medicine.

bankrx/Getty Images

According to the FDA alert, Perrigo is recalling over-the-counter ranitidine tablets of all sizes, Novitium Pharma is recalling all unexpired quantities and lots of ranitidine hydrochloride capsules, and Lannett is recalling all unexpired lots of prescription ranitidine syrup (ranitidine oral solution (15 mg/mL).

Patients who are using over-the-counter ranitidine should consider switching to an alternative, such as famotidine, cimetidine, esomeprazole, lansoprazole, and omeprazole, the FDA noted. None of these medications have shown evidence of containing NDMA.

The alert is the fifth update on ranitidine since the initial FDA announcement that NDMA had been found in ranitidine on Sept. 13, 2019.

The recent FDA safety alerts on ranitidine might be causing concern among your patients about their heartburn treatment. AGA offers key points that you can share with your patients at www.gastro.org/news/talking-to-your-patients-about-ranitidine.

lfranki@mdedge.com

The Food and Drug Administration has issued an alert to health care providers and patients about voluntary recalls of ranitidine (Zantac) from three separate companies because of the potential of N-nitrosodimethylamine (NDMA) in the medicine.

bankrx/Getty Images

According to the FDA alert, Perrigo is recalling over-the-counter ranitidine tablets of all sizes, Novitium Pharma is recalling all unexpired quantities and lots of ranitidine hydrochloride capsules, and Lannett is recalling all unexpired lots of prescription ranitidine syrup (ranitidine oral solution (15 mg/mL).

Patients who are using over-the-counter ranitidine should consider switching to an alternative, such as famotidine, cimetidine, esomeprazole, lansoprazole, and omeprazole, the FDA noted. None of these medications have shown evidence of containing NDMA.

The alert is the fifth update on ranitidine since the initial FDA announcement that NDMA had been found in ranitidine on Sept. 13, 2019.

The recent FDA safety alerts on ranitidine might be causing concern among your patients about their heartburn treatment. AGA offers key points that you can share with your patients at www.gastro.org/news/talking-to-your-patients-about-ranitidine.

lfranki@mdedge.com

Guidelines on the management of acute upper gastrointestinal bleeding have been updated, including recommendations on managing patients on antiplatelet or anticoagulant therapy and on use of endoscopy and new therapeutic approaches.

Writing in Annals of Internal Medicine, an international group of experts published an update to the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding, with a focus on resuscitation and risk assessment; pre-endoscopic, endoscopic, and pharmacologic management; and secondary prophylaxis.

Alan N. Barkun, MDCM, MSc, from McGill University, Montreal, and coauthors first recommended that fluid resuscitation should be initiated in patients with acute upper gastrointestinal bleeding and hemodynamic instability to avoid hemorrhagic shock and restore end-organ perfusion and tissue oxygenation while the bleeding is brought under control.

They acknowledged the uncertainty around whether colloid or crystalloid fluid should be used, but suggested routine use of colloids was not justified because they were more expensive and did not appear to increase survival.

On the question of whether the resuscitation should be aggressive or restrictive in its timing and rate, the group said there was not enough evidence to support a recommendation on this. “The important issue in patients with hemorrhagic shock due to trauma or UGIB [upper gastrointestinal bleeding] is to stop the bleeding while minimizing hemodynamic compromise,” they wrote.

They also advised blood transfusions in patients with a hemoglobin level below 80 g/L who did not have underlying cardiovascular disease, but suggested a higher hemoglobin threshold for those with underlying cardiovascular disease.

The second recommendation was that patients with a Glasgow Blatchford score of 1 or less were at very low risk for rebleeding and mortality, and these patients may therefore not need hospitalization or inpatient endoscopy. They advised against using the AIMS65 prognostic score for this purpose because it was designed to identify patients at high risk of death, not those at low risk for safe discharge.

In regard to endoscopic management, they advocated that all patients with acute upper gastrointestinal bleeding – whether low or high risk – undergo endoscopy within 24 hours of presentation. This was even more urgent in patients being treated with anticoagulants. “Because of the recognized benefits of early endoscopy, coagulopathy should be treated as necessary but endoscopy should not be delayed,” they wrote.

Patients with acutely bleeding ulcers with high-risk stigmata should undergo endoscopic therapy preferably with thermocoagulation or sclerosant injection, or with hemoclips depending on the bleeding location and patient characteristics.

The group also included two conditional recommendations, based on very-low-quality evidence, that patients with actively bleeding ulcers receive TC-325 hemostatic powder as temporizing therapy to stop the bleeding if conventional endoscopic therapies aren’t available or fail. However, they stressed that TC-325 should not be used as a single therapeutic strategy.

Because of a lack of efficacy data and low availability of expertise in the technology, the authors said they could not make a recommendation for or against using a Doppler endoscopic probe (DEP) to assess the need for further endoscopic therapy.

“The group generally agreed that although making a recommendation for or against using DEP to manage UGIB is premature, DEP has the potential to alter the usual approach to visually assessing bleeding lesion risk when evaluating the need for, and adequacy of, endoscopic hemostasis.”

The guidelines also addressed the issue of pharmacologic management of acute upper gastrointestinal bleeding. They strongly recommended that patients with bleeding ulcers and high-risk stigmata who have undergone successful endoscopic therapy should then receive an intravenous loading dose of proton pump inhibitor (PPI) therapy, followed by continuous intravenous infusion.

“Cost-effectiveness studies have suggested that high-dose intravenous PPIs after successful endoscopic hemostasis improve outcomes at a modest cost increase relative to non–high-dose intravenous or oral PPI strategies,” they wrote.

A second conditional recommendation, based on very-low-quality evidence, was that patients with a bleeding ulcer who were at high risk for rebleeding be also treated twice-daily with oral PPIs for 2 weeks, then once-daily. They also recommended patients on cardiovascular prophylaxis with single or dual antiplatelet therapy or anticoagulant therapy be given PPIs.

“The consensus group concluded that, for high-risk patients with an ongoing need for anticoagulants, the evidence suggests that the benefits of secondary prophylaxis outweigh the risks.”

The group was supported by a grant from CIHR Institute of Nutrition, Metabolism and Diabetes and from the Saudi Gastroenterology Association. Nine authors declared grants, personal fees, honoraria and other funding from the pharmaceutical and medical device sector outside the submitted work. No other conflicts of interest were declared.

SOURCE: Barkun A et al. Ann Intern Med 2019, October 22. doi: 10.7326/M19-1795.

Guidelines on the management of acute upper gastrointestinal bleeding have been updated, including recommendations on managing patients on antiplatelet or anticoagulant therapy and on use of endoscopy and new therapeutic approaches.

Writing in Annals of Internal Medicine, an international group of experts published an update to the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding, with a focus on resuscitation and risk assessment; pre-endoscopic, endoscopic, and pharmacologic management; and secondary prophylaxis.

Alan N. Barkun, MDCM, MSc, from McGill University, Montreal, and coauthors first recommended that fluid resuscitation should be initiated in patients with acute upper gastrointestinal bleeding and hemodynamic instability to avoid hemorrhagic shock and restore end-organ perfusion and tissue oxygenation while the bleeding is brought under control.

They acknowledged the uncertainty around whether colloid or crystalloid fluid should be used, but suggested routine use of colloids was not justified because they were more expensive and did not appear to increase survival.

On the question of whether the resuscitation should be aggressive or restrictive in its timing and rate, the group said there was not enough evidence to support a recommendation on this. “The important issue in patients with hemorrhagic shock due to trauma or UGIB [upper gastrointestinal bleeding] is to stop the bleeding while minimizing hemodynamic compromise,” they wrote.

They also advised blood transfusions in patients with a hemoglobin level below 80 g/L who did not have underlying cardiovascular disease, but suggested a higher hemoglobin threshold for those with underlying cardiovascular disease.

The second recommendation was that patients with a Glasgow Blatchford score of 1 or less were at very low risk for rebleeding and mortality, and these patients may therefore not need hospitalization or inpatient endoscopy. They advised against using the AIMS65 prognostic score for this purpose because it was designed to identify patients at high risk of death, not those at low risk for safe discharge.

In regard to endoscopic management, they advocated that all patients with acute upper gastrointestinal bleeding – whether low or high risk – undergo endoscopy within 24 hours of presentation. This was even more urgent in patients being treated with anticoagulants. “Because of the recognized benefits of early endoscopy, coagulopathy should be treated as necessary but endoscopy should not be delayed,” they wrote.

Patients with acutely bleeding ulcers with high-risk stigmata should undergo endoscopic therapy preferably with thermocoagulation or sclerosant injection, or with hemoclips depending on the bleeding location and patient characteristics.

The group also included two conditional recommendations, based on very-low-quality evidence, that patients with actively bleeding ulcers receive TC-325 hemostatic powder as temporizing therapy to stop the bleeding if conventional endoscopic therapies aren’t available or fail. However, they stressed that TC-325 should not be used as a single therapeutic strategy.

Because of a lack of efficacy data and low availability of expertise in the technology, the authors said they could not make a recommendation for or against using a Doppler endoscopic probe (DEP) to assess the need for further endoscopic therapy.

“The group generally agreed that although making a recommendation for or against using DEP to manage UGIB is premature, DEP has the potential to alter the usual approach to visually assessing bleeding lesion risk when evaluating the need for, and adequacy of, endoscopic hemostasis.”

The guidelines also addressed the issue of pharmacologic management of acute upper gastrointestinal bleeding. They strongly recommended that patients with bleeding ulcers and high-risk stigmata who have undergone successful endoscopic therapy should then receive an intravenous loading dose of proton pump inhibitor (PPI) therapy, followed by continuous intravenous infusion.

“Cost-effectiveness studies have suggested that high-dose intravenous PPIs after successful endoscopic hemostasis improve outcomes at a modest cost increase relative to non–high-dose intravenous or oral PPI strategies,” they wrote.

A second conditional recommendation, based on very-low-quality evidence, was that patients with a bleeding ulcer who were at high risk for rebleeding be also treated twice-daily with oral PPIs for 2 weeks, then once-daily. They also recommended patients on cardiovascular prophylaxis with single or dual antiplatelet therapy or anticoagulant therapy be given PPIs.

“The consensus group concluded that, for high-risk patients with an ongoing need for anticoagulants, the evidence suggests that the benefits of secondary prophylaxis outweigh the risks.”

The group was supported by a grant from CIHR Institute of Nutrition, Metabolism and Diabetes and from the Saudi Gastroenterology Association. Nine authors declared grants, personal fees, honoraria and other funding from the pharmaceutical and medical device sector outside the submitted work. No other conflicts of interest were declared.

SOURCE: Barkun A et al. Ann Intern Med 2019, October 22. doi: 10.7326/M19-1795.

Guidelines on the management of acute upper gastrointestinal bleeding have been updated, including recommendations on managing patients on antiplatelet or anticoagulant therapy and on use of endoscopy and new therapeutic approaches.

Writing in Annals of Internal Medicine, an international group of experts published an update to the 2010 International Consensus Recommendations on the Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding, with a focus on resuscitation and risk assessment; pre-endoscopic, endoscopic, and pharmacologic management; and secondary prophylaxis.

Alan N. Barkun, MDCM, MSc, from McGill University, Montreal, and coauthors first recommended that fluid resuscitation should be initiated in patients with acute upper gastrointestinal bleeding and hemodynamic instability to avoid hemorrhagic shock and restore end-organ perfusion and tissue oxygenation while the bleeding is brought under control.

They acknowledged the uncertainty around whether colloid or crystalloid fluid should be used, but suggested routine use of colloids was not justified because they were more expensive and did not appear to increase survival.

On the question of whether the resuscitation should be aggressive or restrictive in its timing and rate, the group said there was not enough evidence to support a recommendation on this. “The important issue in patients with hemorrhagic shock due to trauma or UGIB [upper gastrointestinal bleeding] is to stop the bleeding while minimizing hemodynamic compromise,” they wrote.

They also advised blood transfusions in patients with a hemoglobin level below 80 g/L who did not have underlying cardiovascular disease, but suggested a higher hemoglobin threshold for those with underlying cardiovascular disease.

The second recommendation was that patients with a Glasgow Blatchford score of 1 or less were at very low risk for rebleeding and mortality, and these patients may therefore not need hospitalization or inpatient endoscopy. They advised against using the AIMS65 prognostic score for this purpose because it was designed to identify patients at high risk of death, not those at low risk for safe discharge.

In regard to endoscopic management, they advocated that all patients with acute upper gastrointestinal bleeding – whether low or high risk – undergo endoscopy within 24 hours of presentation. This was even more urgent in patients being treated with anticoagulants. “Because of the recognized benefits of early endoscopy, coagulopathy should be treated as necessary but endoscopy should not be delayed,” they wrote.

Patients with acutely bleeding ulcers with high-risk stigmata should undergo endoscopic therapy preferably with thermocoagulation or sclerosant injection, or with hemoclips depending on the bleeding location and patient characteristics.

The group also included two conditional recommendations, based on very-low-quality evidence, that patients with actively bleeding ulcers receive TC-325 hemostatic powder as temporizing therapy to stop the bleeding if conventional endoscopic therapies aren’t available or fail. However, they stressed that TC-325 should not be used as a single therapeutic strategy.

Because of a lack of efficacy data and low availability of expertise in the technology, the authors said they could not make a recommendation for or against using a Doppler endoscopic probe (DEP) to assess the need for further endoscopic therapy.

“The group generally agreed that although making a recommendation for or against using DEP to manage UGIB is premature, DEP has the potential to alter the usual approach to visually assessing bleeding lesion risk when evaluating the need for, and adequacy of, endoscopic hemostasis.”

The guidelines also addressed the issue of pharmacologic management of acute upper gastrointestinal bleeding. They strongly recommended that patients with bleeding ulcers and high-risk stigmata who have undergone successful endoscopic therapy should then receive an intravenous loading dose of proton pump inhibitor (PPI) therapy, followed by continuous intravenous infusion.

“Cost-effectiveness studies have suggested that high-dose intravenous PPIs after successful endoscopic hemostasis improve outcomes at a modest cost increase relative to non–high-dose intravenous or oral PPI strategies,” they wrote.

A second conditional recommendation, based on very-low-quality evidence, was that patients with a bleeding ulcer who were at high risk for rebleeding be also treated twice-daily with oral PPIs for 2 weeks, then once-daily. They also recommended patients on cardiovascular prophylaxis with single or dual antiplatelet therapy or anticoagulant therapy be given PPIs.

“The consensus group concluded that, for high-risk patients with an ongoing need for anticoagulants, the evidence suggests that the benefits of secondary prophylaxis outweigh the risks.”

The group was supported by a grant from CIHR Institute of Nutrition, Metabolism and Diabetes and from the Saudi Gastroenterology Association. Nine authors declared grants, personal fees, honoraria and other funding from the pharmaceutical and medical device sector outside the submitted work. No other conflicts of interest were declared.

SOURCE: Barkun A et al. Ann Intern Med 2019, October 22. doi: 10.7326/M19-1795.