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Report of potential interaction between PPIs, clopidogrel
The January 2009 issue of GI & Hepatology News (GIHN) featured an article on the potential drug interaction between proton pump inhibitors (PPIs) and clopidogrel.
In the study of interest, researchers retrospectively reviewed 16,000 patients prescribed clopidogrel after percutaneous coronary intervention (PCI) and found that those patients also on a PPI were 1.5 times as likely to suffer from a myocardial infarction, stroke, or be hospitalized for angina as those not on a PPI. A second study mentioned in the GIHN article, a post hoc analysis of the CREDO trial, found a higher rate of ischemic events in patients on a PPI, but this increase was seen whether the patient was on clopidogrel or not. The conflicting data presented a management challenge for cardiologists and gastroenterologists alike.
Multiple subsequent studies, including a large randomized trial, COGENT (N Engl J Med. 2010;363:1909-17), comparing omeprazole with placebo in patients on clopidogrel, found no significant interaction. A consensus document published in December 2010 acknowledged the potential risks from pharmacodynamic studies but suggested that the clinical data were unclear.
This story speaks to the power of research to change practice, the importance of effectively communicating research findings to the public, and the fact that the practice of medicine is often an exercise in balancing conflicting data on behalf of our patients.
Ziad Gellad, MD, MPH, is associate professor of medicine in the division of gastroenterology, Duke University Medical Center, Durham, N.C.; a faculty member at the Duke Clinical Research Institute; and an Associate Editor of GI & Hepatology News.
The January 2009 issue of GI & Hepatology News (GIHN) featured an article on the potential drug interaction between proton pump inhibitors (PPIs) and clopidogrel.
In the study of interest, researchers retrospectively reviewed 16,000 patients prescribed clopidogrel after percutaneous coronary intervention (PCI) and found that those patients also on a PPI were 1.5 times as likely to suffer from a myocardial infarction, stroke, or be hospitalized for angina as those not on a PPI. A second study mentioned in the GIHN article, a post hoc analysis of the CREDO trial, found a higher rate of ischemic events in patients on a PPI, but this increase was seen whether the patient was on clopidogrel or not. The conflicting data presented a management challenge for cardiologists and gastroenterologists alike.
Multiple subsequent studies, including a large randomized trial, COGENT (N Engl J Med. 2010;363:1909-17), comparing omeprazole with placebo in patients on clopidogrel, found no significant interaction. A consensus document published in December 2010 acknowledged the potential risks from pharmacodynamic studies but suggested that the clinical data were unclear.
This story speaks to the power of research to change practice, the importance of effectively communicating research findings to the public, and the fact that the practice of medicine is often an exercise in balancing conflicting data on behalf of our patients.
Ziad Gellad, MD, MPH, is associate professor of medicine in the division of gastroenterology, Duke University Medical Center, Durham, N.C.; a faculty member at the Duke Clinical Research Institute; and an Associate Editor of GI & Hepatology News.
The January 2009 issue of GI & Hepatology News (GIHN) featured an article on the potential drug interaction between proton pump inhibitors (PPIs) and clopidogrel.
In the study of interest, researchers retrospectively reviewed 16,000 patients prescribed clopidogrel after percutaneous coronary intervention (PCI) and found that those patients also on a PPI were 1.5 times as likely to suffer from a myocardial infarction, stroke, or be hospitalized for angina as those not on a PPI. A second study mentioned in the GIHN article, a post hoc analysis of the CREDO trial, found a higher rate of ischemic events in patients on a PPI, but this increase was seen whether the patient was on clopidogrel or not. The conflicting data presented a management challenge for cardiologists and gastroenterologists alike.
Multiple subsequent studies, including a large randomized trial, COGENT (N Engl J Med. 2010;363:1909-17), comparing omeprazole with placebo in patients on clopidogrel, found no significant interaction. A consensus document published in December 2010 acknowledged the potential risks from pharmacodynamic studies but suggested that the clinical data were unclear.
This story speaks to the power of research to change practice, the importance of effectively communicating research findings to the public, and the fact that the practice of medicine is often an exercise in balancing conflicting data on behalf of our patients.
Ziad Gellad, MD, MPH, is associate professor of medicine in the division of gastroenterology, Duke University Medical Center, Durham, N.C.; a faculty member at the Duke Clinical Research Institute; and an Associate Editor of GI & Hepatology News.
BOS beat placebo for eosinophilic esophagitis
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
Budesonide oral suspension (BOS) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis, according to a first-in-kind, multicenter, randomized, double-blind, phase II trial presented in the March issue of Gastroenterology (doi: 10.1053/j.gastro.2016.11.021).
The novel topical corticosteroid formulation yielded a significant histologic response and was associated with 3 fewer days of dysphagia over 2 weeks compared with placebo, reported Evan S. Dellon, MD, MPH, of University of North Carolina, Chapel Hill, and his associates. “There were no unexpected safety signals, and compliance with medication was high, suggesting that this formulation can be reliably used,” they wrote. Their findings earned BOS (SHP621) an FDA Breakthrough Therapy Designation in June 2016. Although corticosteroids are first-line therapy for eosinophilic esophagitis, symptom response in other studies has been mixed, and the Food and Drug Administration had approved neither fluticasone nor budesonide for this disease, the researchers noted. They formulated BOS to adhere better to the esophageal mucosa in order to enhance esophageal delivery while decreasing unwanted pulmonary deposition.
For the study, they randomly assigned 93 patients aged 11-40 years with eosinophilic esophagitis to receive either placebo or 2 mg BOS twice daily. By week 12, Dysphagia Symptom Questionnaire scores had fallen by 14.3 points with BOS group and by 7.5 points with placebo (P = .001). Endoscopic severity scores dropped by 3.8 points with BOS and rose by 0.4 points with placebo (P less than .0001). Rates of histologic response were 39% and 3%, respectively (P less than .0001). Nonresponders averaged 10 kg more body weight than responders, and had been diagnosed about 21 months earlier (average disease duration, 46 months and 25 months, respectively).
Rates of reported adverse effects were similar with BOS (47%) and placebo (50%). Individual rates of nasopharyngitis, upper respiratory infections, and oropharyngeal pain also were comparable between groups, but one patient stopped BOS after developing dyspnea, nausea, and vomiting that were considered treatment related. Esophageal candidiasis developed in two BOS recipients – a rate similar rate to that in a prior study of BOS (Clin Gastroenterol Hepatol. 2015 Jan 13. doi: 10.1016/j.cgh.2014.05.02), and a lower percentage than in other studies of topical steroids for eosinophilic esophagitis, according to the researchers. Morning cortisol levels were similar between groups, and there were no adverse laboratory effects, they added.
Patients in this trial had severe symptoms and histology and were highly compliant with treatment. They filled out at least 70% of their symptom diary, had at least 15 eosinophils per high-power frame from at least two esophageal levels on screening endoscopy, and reported at least 4 days of dysphagia during the second half of a 4-week, blinded placebo run-in period. Researchers should consider using these strict inclusion criteria in future trials of eosinophilic esophagitis, especially because previous studies have failed to show a treatment benefit for topical steroid therapy, the investigators noted.
Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
FROM GASTROENTEROLOGY
Key clinical point: Budesonide oral suspension (BOS) (2 mg twice daily) was safe and significantly outperformed placebo on validated measures of eosinophilic esophagitis.
Major finding: Dysphagia Symptom Questionnaire scores decreased by 14.3 points with BOS and by 7.5 points with placebo (P = .001). Endoscopic severity scores decreased by 3.8 points and rose by 0.4 points, respectively (P less than .0001).
Data source: A 12-week, double-blind, placebo-controlled, parallel-group, phase II trial of 93 adolescents and adults with eosinophilic esophagitis.
Disclosures: Meritage Pharma, which is now a part of the Shire group, makes budesonide oral suspension and sponsored the study. Dr. Dellon disclosed ties to Meritage, Receptos, Regeneron, Aptalis, Banner Life Sciences, Novartis, and Roche. All five coinvestigators disclosed ties to industry, including Meritage, Shire, Receptos, Regeneron, and Biogen Idec.
VIDEO: No difference between PPI and H2RA for low-dose aspirin gastroprotection
Among patients on low-dose aspirin at risk for recurrent GI bleeding, there were slightly fewer GI bleeds or ulcers when patients were on the proton pump inhibitor rabeprazole (Aciphex) instead of the histamine2-receptor antagonist famotidine (Pepcid), but the difference was not statistically significant according to a study reported in the January issue of Gastroenterology.
SOURCE: American Gastroenterological Association
In a 270-subject, double-blind, randomized trial in Hong Kong and Japan led by Francis Chan, MD, of the Chinese University of Hong Kong, investigators found, “Among high-risk aspirin users, the incidence of recurrent bleeding is comparable with either use of PPI [proton pump inhibitor] or H2RA [H2-receptor antagonist].” However, “since a small difference in efficacy cannot be excluded, PPI probably remains the preferred treatment for long-term protection against upper GI bleeding in high-risk aspirin users” (Gastroenterology. 2016 Sep 15. doi: 10.1053/j.gastro.2016.09.006).
Even so, “our findings suggest that famotidine may be a reasonable alternative option for aspirin users who disfavor long-term PPI therapy,” they said.
Because of concerns about the long-term safety of PPIs, including the association between PPIs and increased risk of serious cardiovascular events in patients on clopidogrel (Plavix), clinicians have been looking for alternatives. The findings reassure that H2RAs are a reasonable choice; many clinicians have already turned to them.
All 270 subjects had previously had endoscopically confirmed ulcer bleeding while on low-dose aspirin (325 mg or less per day). “Considering clinicians will be most concerned with the adequacy of gastroprotective treatment effect in aspirin users with the highest risk, we exclusively enrolled patients with endoscopy-proven upper GI bleeding,” Dr. Chan and his colleagues said.
After the ulcers healed, the subjects resumed aspirin (80 mg) daily and were randomized to either famotidine 40 mg once daily (n = 132) or rabeprazole 20 mg daily (n = 138) for up to 12 months. Helicobacter pylori was eradicated prior to randomization in patients who tested positive. Subjects were evaluated every 2 months, with repeat endoscopy for symptoms of upper GI bleeding or significant drops in hemoglobin, as well as at the end of the study.
During the 12-month study period, upper GI bleeding recurred in one patient receiving rabeprazole (0.7%) and four receiving famotidine (3.1%; P = .16). The composite endpoint of recurrent bleeding or endoscopic ulcers at month 12 was reached by nine patients in the rabeprazole group (7.9%) and 13 receiving famotidine (12.4%; P = .26).
“Our findings indicate that both treatments are comparable in preventing recurrent upper GI bleeding in high-risk aspirin users, although a small difference in efficacy cannot be excluded,” the investigators said.
Over two-thirds of the subjects were men, and the mean age was 73 years. About a quarter in the PPI group and almost 40% in the H2RA group had H. pylori cleared before randomization.
The Research Grant Council of Hong Kong funded the work. Dr. Chan has served as a consultant to Pfizer, Eisai, Takeda, and Otsuka, and has received research grants from Pfizer and lecture fees from Pfizer, AstraZeneca, and Takeda. Several other authors reported similar industry disclosures.
Aspirin is widely used for primary and secondary prophylaxis of cardiovascular disease. Dr. Chan and colleagues present a randomized, controlled trial comparing rabeprazole 20 mg once a day to famotidine 40 mg once a day in preventing recurrent GI hemorrhage and endoscopic ulcers in low-dose (less than 325 mg) aspirin users. The authors conclude that no statistical difference was found between the two agents. The study contrasts with another study from Hong Kong, which found that proton pump inhibitors were more effective.
The authors are to be complimented on this important addition to the literature but the reader should not conclude that H2-receptor antagonists and proton pump inhibitors are equivalent in preventing recurrent bleeding from aspirin-induced ulcers.
Nimish Vakil, MD, AGAF, is clinical professor of medicine at the University of Wisconsin–Madison. He has consulted for Ironwood and AstraZeneca.
Aspirin is widely used for primary and secondary prophylaxis of cardiovascular disease. Dr. Chan and colleagues present a randomized, controlled trial comparing rabeprazole 20 mg once a day to famotidine 40 mg once a day in preventing recurrent GI hemorrhage and endoscopic ulcers in low-dose (less than 325 mg) aspirin users. The authors conclude that no statistical difference was found between the two agents. The study contrasts with another study from Hong Kong, which found that proton pump inhibitors were more effective.
The authors are to be complimented on this important addition to the literature but the reader should not conclude that H2-receptor antagonists and proton pump inhibitors are equivalent in preventing recurrent bleeding from aspirin-induced ulcers.
Nimish Vakil, MD, AGAF, is clinical professor of medicine at the University of Wisconsin–Madison. He has consulted for Ironwood and AstraZeneca.
Aspirin is widely used for primary and secondary prophylaxis of cardiovascular disease. Dr. Chan and colleagues present a randomized, controlled trial comparing rabeprazole 20 mg once a day to famotidine 40 mg once a day in preventing recurrent GI hemorrhage and endoscopic ulcers in low-dose (less than 325 mg) aspirin users. The authors conclude that no statistical difference was found between the two agents. The study contrasts with another study from Hong Kong, which found that proton pump inhibitors were more effective.
The authors are to be complimented on this important addition to the literature but the reader should not conclude that H2-receptor antagonists and proton pump inhibitors are equivalent in preventing recurrent bleeding from aspirin-induced ulcers.
Nimish Vakil, MD, AGAF, is clinical professor of medicine at the University of Wisconsin–Madison. He has consulted for Ironwood and AstraZeneca.
Among patients on low-dose aspirin at risk for recurrent GI bleeding, there were slightly fewer GI bleeds or ulcers when patients were on the proton pump inhibitor rabeprazole (Aciphex) instead of the histamine2-receptor antagonist famotidine (Pepcid), but the difference was not statistically significant according to a study reported in the January issue of Gastroenterology.
SOURCE: American Gastroenterological Association
In a 270-subject, double-blind, randomized trial in Hong Kong and Japan led by Francis Chan, MD, of the Chinese University of Hong Kong, investigators found, “Among high-risk aspirin users, the incidence of recurrent bleeding is comparable with either use of PPI [proton pump inhibitor] or H2RA [H2-receptor antagonist].” However, “since a small difference in efficacy cannot be excluded, PPI probably remains the preferred treatment for long-term protection against upper GI bleeding in high-risk aspirin users” (Gastroenterology. 2016 Sep 15. doi: 10.1053/j.gastro.2016.09.006).
Even so, “our findings suggest that famotidine may be a reasonable alternative option for aspirin users who disfavor long-term PPI therapy,” they said.
Because of concerns about the long-term safety of PPIs, including the association between PPIs and increased risk of serious cardiovascular events in patients on clopidogrel (Plavix), clinicians have been looking for alternatives. The findings reassure that H2RAs are a reasonable choice; many clinicians have already turned to them.
All 270 subjects had previously had endoscopically confirmed ulcer bleeding while on low-dose aspirin (325 mg or less per day). “Considering clinicians will be most concerned with the adequacy of gastroprotective treatment effect in aspirin users with the highest risk, we exclusively enrolled patients with endoscopy-proven upper GI bleeding,” Dr. Chan and his colleagues said.
After the ulcers healed, the subjects resumed aspirin (80 mg) daily and were randomized to either famotidine 40 mg once daily (n = 132) or rabeprazole 20 mg daily (n = 138) for up to 12 months. Helicobacter pylori was eradicated prior to randomization in patients who tested positive. Subjects were evaluated every 2 months, with repeat endoscopy for symptoms of upper GI bleeding or significant drops in hemoglobin, as well as at the end of the study.
During the 12-month study period, upper GI bleeding recurred in one patient receiving rabeprazole (0.7%) and four receiving famotidine (3.1%; P = .16). The composite endpoint of recurrent bleeding or endoscopic ulcers at month 12 was reached by nine patients in the rabeprazole group (7.9%) and 13 receiving famotidine (12.4%; P = .26).
“Our findings indicate that both treatments are comparable in preventing recurrent upper GI bleeding in high-risk aspirin users, although a small difference in efficacy cannot be excluded,” the investigators said.
Over two-thirds of the subjects were men, and the mean age was 73 years. About a quarter in the PPI group and almost 40% in the H2RA group had H. pylori cleared before randomization.
The Research Grant Council of Hong Kong funded the work. Dr. Chan has served as a consultant to Pfizer, Eisai, Takeda, and Otsuka, and has received research grants from Pfizer and lecture fees from Pfizer, AstraZeneca, and Takeda. Several other authors reported similar industry disclosures.
Among patients on low-dose aspirin at risk for recurrent GI bleeding, there were slightly fewer GI bleeds or ulcers when patients were on the proton pump inhibitor rabeprazole (Aciphex) instead of the histamine2-receptor antagonist famotidine (Pepcid), but the difference was not statistically significant according to a study reported in the January issue of Gastroenterology.
SOURCE: American Gastroenterological Association
In a 270-subject, double-blind, randomized trial in Hong Kong and Japan led by Francis Chan, MD, of the Chinese University of Hong Kong, investigators found, “Among high-risk aspirin users, the incidence of recurrent bleeding is comparable with either use of PPI [proton pump inhibitor] or H2RA [H2-receptor antagonist].” However, “since a small difference in efficacy cannot be excluded, PPI probably remains the preferred treatment for long-term protection against upper GI bleeding in high-risk aspirin users” (Gastroenterology. 2016 Sep 15. doi: 10.1053/j.gastro.2016.09.006).
Even so, “our findings suggest that famotidine may be a reasonable alternative option for aspirin users who disfavor long-term PPI therapy,” they said.
Because of concerns about the long-term safety of PPIs, including the association between PPIs and increased risk of serious cardiovascular events in patients on clopidogrel (Plavix), clinicians have been looking for alternatives. The findings reassure that H2RAs are a reasonable choice; many clinicians have already turned to them.
All 270 subjects had previously had endoscopically confirmed ulcer bleeding while on low-dose aspirin (325 mg or less per day). “Considering clinicians will be most concerned with the adequacy of gastroprotective treatment effect in aspirin users with the highest risk, we exclusively enrolled patients with endoscopy-proven upper GI bleeding,” Dr. Chan and his colleagues said.
After the ulcers healed, the subjects resumed aspirin (80 mg) daily and were randomized to either famotidine 40 mg once daily (n = 132) or rabeprazole 20 mg daily (n = 138) for up to 12 months. Helicobacter pylori was eradicated prior to randomization in patients who tested positive. Subjects were evaluated every 2 months, with repeat endoscopy for symptoms of upper GI bleeding or significant drops in hemoglobin, as well as at the end of the study.
During the 12-month study period, upper GI bleeding recurred in one patient receiving rabeprazole (0.7%) and four receiving famotidine (3.1%; P = .16). The composite endpoint of recurrent bleeding or endoscopic ulcers at month 12 was reached by nine patients in the rabeprazole group (7.9%) and 13 receiving famotidine (12.4%; P = .26).
“Our findings indicate that both treatments are comparable in preventing recurrent upper GI bleeding in high-risk aspirin users, although a small difference in efficacy cannot be excluded,” the investigators said.
Over two-thirds of the subjects were men, and the mean age was 73 years. About a quarter in the PPI group and almost 40% in the H2RA group had H. pylori cleared before randomization.
The Research Grant Council of Hong Kong funded the work. Dr. Chan has served as a consultant to Pfizer, Eisai, Takeda, and Otsuka, and has received research grants from Pfizer and lecture fees from Pfizer, AstraZeneca, and Takeda. Several other authors reported similar industry disclosures.
FROM GASTROENTEROLOGY
Key clinical point:
Major finding: During the 12-month study period, upper GI bleeding recurred in one patient receiving rabeprazole (0.7%) and four receiving famotidine (3.1%; P = .16). The composite endpoint of recurrent bleeding or endoscopic ulcers at month 12 was reached by nine patients in the rabeprazole group (7.9%) and 13 receiving famotidine (12.4%; P = .26).
Data source: A 270-subject, double-blind, randomized trial in Hong Kong and Japan.
Disclosures: The Research Grant Council of Hong Kong funded the work. The lead investigator has served as a consultant to Pfizer, Eisai, Takeda, and Otsuka, and has received research grants from Pfizer and lecture fees from Pfizer, AstraZeneca, and Takeda. Several other authors reported similar industry disclosures.
Increased death rate with platelets for aspirin/clopidogrel GI bleed
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
The management of patients with gastrointestinal bleeding on antithrombotic drugs is a major challenge for gastroenterologists. Unfortunately, the use of aspirin alone has been shown to increase the risk of GI bleed twofold, and the addition of a thienopyridine additionally increases the risk of bleeding twofold. Furthermore, there is no available agent to reverse antiplatelet affects of these drugs, which irreversibly block platelet function for the life of the platelet (8-10 days). Current recommendations for the management of severe GI bleeding in patients receiving antithrombotic therapy include platelet transfusion, including those with a normal platelet count. However, this comes with a price as reversal of platelet function may increase the rate of cardiovascular events.
Zakko et al. performed a retrospective case-control study evaluating the role of platelet transfusion in patients presenting with GI bleeding. Patients were matched by age, sex, and the location of the GI bleed. Most patients included in the study were on low-dose aspirin and almost a third of the patients were taking both aspirin and a thienopyridine. Patients receiving platelet transfusions appeared to have more severe GI bleeding compared with matched controls, as patients receiving transfusion were more likely to have been hypotensive, tachycardic, have a low hemoglobin level, and require treatment in the intensive care unit (72% vs. 28%, P less than .0001). Patients receiving platelet transfusions were also more likely than matched controls to have recurrent GI bleeding as well as major cardiovascular adverse events, including myocardial infarction and inpatient death. After adjusting for patient characteristics, patients receiving platelet transfusions were more likely to have an increased risk of death (adjusted OR, 5.57; 95% CI, 1.52-27.1). The authors conclude that “the use of platelet transfusions in patients with GI bleeding who are taking antiplatelet agents without thrombocytopenia did not reduce rebleeding but was associated with higher mortality.”
Currently, there is no convincing evidence to support platelet transfusion in patients with bleeding on aspirin and/or a thienopyridine. Because the majority of the deaths were due to GI bleeding and not cardiovascular events, the observed increase in adverse events in patients receiving platelet transfusions likely reflects more severe GI bleeding in patients receiving platelet transfusions than in controls. We should avoid platelet transfusions and focus our management on achieving adequate resuscitation, use of proton pump inhibitors for patients with high-risk ulcers, and early endoscopy with endoscopic therapy for high-risk lesions.
John R. Saltzman, MD, AGAF, is director of endoscopy, Brigham and Women’s Hospital, professor of medicine, Harvard Medical School, Boston. He has no conflicts of interest.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
Patients with normal platelet counts who have a GI bleed while on antiplatelets were almost six times more likely to die in the hospital if they had a platelet transfusion in a retrospective cohort study from the Yale University in New Haven, Conn.
Ten of the 14 deaths in the 204 transfused patients – versus none of the 3 deaths in the 204 nontransfused patients - were due to bleeding, so it’s possible that the mortality difference was simply because patients with worse bleeding were more likely to get transfused. “On the other hand, the adjusted [odds ratios] for mortality (4.5-6.8 with different sensitivity analyses) [were] large, increasing the likelihood of a cause-and-effect relationship,” said investigators led by gastroenterologist Liam Zakko, MD, now at the Mayo Clinic in Rochester, Minn. (Clin Gastroenterol Hepatol. 2016 Jul 25. doi: 10.1016/j.cgh.2016.07.017).
Current guidelines suggest platelet transfusions are an option for antiplatelet patients with serious GI bleeds, but the Yale team found that they did not reduce rebleeding. “The observation of increased mortality without documentation of clinical benefit suggests a very cautious approach to the use of platelet transfusion. ... We do not support the use of platelet transfusions in patients with GI [bleeds] who are taking antiplatelet agents,” the investigators wrote.
Subjects in the two groups were matched for sex, age, and GI bleed location, and all had platelet counts above 100 × 109/L. Almost everyone was on aspirin for cardiovascular protection, and 30% were on also on clopidogrel.
Just over half in both groups had upper GI bleeds, and about 40% in each group had colonic bleeds. Transfused patients had more-severe bleeding, with overall lower blood pressure and lower hemoglobin; a larger proportion was admitted to the ICU.
On univariate analyses, platelet patients had more cardiovascular events (23% vs. 13%) while in the hospital. They were also more likely to stay in the hospital for more than 4 days (47% vs. 33%) and more likely to die while there (7% vs. 1%). On multivariable analysis, only the greater risk for death during admission remained statistically significant (odds ratio, 5.57; 95% confidence interval, 1.52-27.1). The adjusted odds ratio for recurrent bleeding was not significant.
Four patients in the platelet group died from cardiovascular causes. One patient in the control group had a fatal cardiovascular event.
Although counterintuitive, the authors said that it’s possible that platelet transfusions might actually increase the risk of severe and fatal GI bleeding. “Mechanisms by which platelet transfusion would increase mortality or [GI bleeding]–related mortality are not clear,” but “platelet transfusions are reported to be proinflammatory and alter recipient immunity,” they said.
At least for now, “the most prudent way to manage patients on antiplatelet agents with [GI bleeding] is to follow current evidence-based recommendations,” including early endoscopy, endoscopic hemostatic therapy for high-risk lesions, and intensive proton pump inhibitor therapy in patients with ulcers and high-risk endoscopic features.
“Although not based on high-quality evidence, we believe that hemostatic techniques that do not cause significant tissue damage (e.g., clips rather than thermal devices or sclerosants) should be used in patients on antiplatelet agents, especially if patients are expected to remain on these agents in the future,” they said.
The mean age in the study was 74 years, and about two-thirds of the subjects were men.
The authors had no disclosures.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Compared with those not transfused, the risk for death during admission remained statistically significant on multivariate analysis (OR, 5.57; 95% CI, 1.52-27.1).
Data source: Retrospective cohort study of 408 GI bleed patients
Disclosures: The authors had no disclosures.
PPIs may boost ischemic stroke risk
NEW ORLEANS – The use of proton pump inhibitors (PPIs) was associated with significantly increased risk of having a first ischemic stroke in a large nationwide Danish cohort study, Thomas S. Sehested, MD, reported at the American Heart Association scientific sessions.
The relationship was dose dependent. At the lowest available dose of each of the four PPIs studied there was no significantly increased risk. At the intermediate doses of three of the four PPIs studied, the increased risk of ischemic stroke became statistically significant. And the highest dose of each drug was associated with the greatest ischemic stroke risk.
In Denmark, for instance, where most PPIs are prescription only and use is easily trackable, it’s estimated that, at any given time, 7% of the adult population is taking a PPI, often not as directed in the labeling.
The impetus for this study, Dr. Sehested explained, was the mounting evidence that PPIs may constitute an independent risk factor for acute MI and other cardiovascular events. For example, a recent meta-analysis of 17 randomized controlled trials totaling 7,540 participants published through mid-2015 concluded that the use of PPIs was associated with a 70% increase in cardiovascular risk (Neurogastroenterol Motil. 2016 Aug 30. doi: 10.1111/nmo.12926).
He reported on 245,676 Danes above age 30 who were free of prior MI or stroke when they underwent elective GI endoscopy during 1997-2012. After a 30-day postendoscopy grace period during which 1,476 patients had a first MI, stroke, or died of any cause, the final study population was 244,200, of whom 43.7% were PPI users during the grace period and beyond.
During a median 5.8 years of follow-up, 9,489 subjects (3.9%) had a first ischemic stroke. Because of the comprehensive nature of Denmark’s interlocking birth to death registries, there was virtually no loss to follow-up in this study.
The unadjusted incidence of ischemic stroke in PPI nonusers was 55.7 per 10,000 person-years, compared with 88.9 per 10,000 in PPI users.
The PPI users were slightly older than nonusers by roughly 3 years. They were also an absolute 5% more likely to be hypertensive and an absolute 1.7% more likely to be regular users of NSAIDs. All of these differences, while modest, were statistically significant because of the large patient numbers involved.
In a multivariate analysis adjusted for age, sex, calendar year, comorbid diabetes, hypertension, alcohol use disorder, heart failure, peptic ulcer, peripheral artery disease, kidney disease, aspirin, oral anticoagulants and other medications, and socioeconomic status, current users of PPIs were 19% more likely to have a first ischemic stroke than nonusers. That difference is statistically significant and clinically meaningful, Dr. Sehested said.
In contrast, when the same sort of nationwide analysis was repeated, comparing current users of histamine-2 receptor antagonists to nonusers of those drugs or PPIs, there was no difference in ischemic stroke risk between the two groups.
The message, according to Dr. Sehested, is that physicians should encourage more cautious use of PPIs. And especially in the United States, where most PPIs are available over the counter, it’s prudent during office visits to ask what nonprescription drugs a patient is taking.
Dr. Sehested presented his study findings in a session devoted to original research in cardiovascular epidemiology. Many top American epidemiologists were present in the audience, and several rose to congratulate him on his presentation of the latest elegant epidemiologic study to come out of Denmark, the only place in the world where this sort of nationwide comprehensive research is possible.
“Wow! I just love the work you do in Denmark. It’s really inspiring,” commented David Siscovick, MD, senior vice president for research at the New York Academy of Medicine and professor emeritus of medicine and epidemiology at the University of Washington in Seattle.
He had a question: “Did you deal with PPI starters and stoppers and compliance in any way?”
Dr. Sehested replied that he and his coinvestigators were able to see who was on a PPI at any given point in the study, and they accounted for that. One issue the researchers plan to examine but haven’t yet had a chance to, however, is the relationship between duration of PPI therapy and ischemic stroke risk. It’s likely that some patients had already been on a PPI for a lengthy time at elective endoscopy, which is when the study in its current form began.
“I think that would strengthen the study,” he said.
Comoderator Jorge Kizer, MD, of Albert Einstein College of Medicine in New York, commented, “Confounding by indication is clearly the elephant in the room. The guidelines actually recommend adding a PPI if a patient is on dual-antiplatelet therapy and has an NSAID added. Did you adjust for that? It would boost confidence that the results are actually due to the PPI.”
Dr. Sehested answered that the great majority of individuals with cardiovascular disease at baseline were excluded from the analysis.
“I don’t think we had that many on dual-antiplatelet therapy,” he added.
Preclinical studies suggest a possible mechanism by which PPIs may harm cardiovascular health. The drugs reduce nitric oxide synthase levels, with resultant endothelial dysfunction, he said.
Dr. Sehested is employed at the Danish Heart Foundation, which funded the study.
A growing number of retrospective studies have associated proton pump inhibitors with a host of serious adverse effects. These include chronic kidney disease, dementia, osteoporosis, cardiovascular events, pneumonia, enteric infections, and others. The authors of this large, retrospective Danish study have now added ischemic stroke to the list.
Nonetheless, this study should serve as wake-up call to closely examine the risks and benefits of ongoing PPI use for each individual patient. For example, guidelines clearly advocate the use of PPIs in patients at high risk for peptic ulcer disease (for example, use of aspirin and warfarin together), and these patients should continue PPIs unless more convincing evidence of serious side effects emerge. On the other hand, several studies have shown that many patients with uncomplicated gastroesophageal reflux disease symptoms can achieve symptom control with substitution of histamine2 blockers, p.r.n. dosing of PPIs, or without acid-reducing medications entirely. Still, many patients with confirmed pathologic acid reflux are likely to require ongoing PPIs. For patients who continue PPIs, they should use the lowest effective dose.
Surely, physicians will be discussing PPI adverse effects with increasing numbers of patients. Until higher-quality evidence in the form of a randomized controlled trial emerges, physicians should get used to explaining the principles of epidemiology.
Jacob Kurlander, MD, is a clinical lecturer in the division of gastroenterology, University of Michigan, Ann Arbor. He has received research funding from Ironwood Pharmaceuticals.
A growing number of retrospective studies have associated proton pump inhibitors with a host of serious adverse effects. These include chronic kidney disease, dementia, osteoporosis, cardiovascular events, pneumonia, enteric infections, and others. The authors of this large, retrospective Danish study have now added ischemic stroke to the list.
Nonetheless, this study should serve as wake-up call to closely examine the risks and benefits of ongoing PPI use for each individual patient. For example, guidelines clearly advocate the use of PPIs in patients at high risk for peptic ulcer disease (for example, use of aspirin and warfarin together), and these patients should continue PPIs unless more convincing evidence of serious side effects emerge. On the other hand, several studies have shown that many patients with uncomplicated gastroesophageal reflux disease symptoms can achieve symptom control with substitution of histamine2 blockers, p.r.n. dosing of PPIs, or without acid-reducing medications entirely. Still, many patients with confirmed pathologic acid reflux are likely to require ongoing PPIs. For patients who continue PPIs, they should use the lowest effective dose.
Surely, physicians will be discussing PPI adverse effects with increasing numbers of patients. Until higher-quality evidence in the form of a randomized controlled trial emerges, physicians should get used to explaining the principles of epidemiology.
Jacob Kurlander, MD, is a clinical lecturer in the division of gastroenterology, University of Michigan, Ann Arbor. He has received research funding from Ironwood Pharmaceuticals.
A growing number of retrospective studies have associated proton pump inhibitors with a host of serious adverse effects. These include chronic kidney disease, dementia, osteoporosis, cardiovascular events, pneumonia, enteric infections, and others. The authors of this large, retrospective Danish study have now added ischemic stroke to the list.
Nonetheless, this study should serve as wake-up call to closely examine the risks and benefits of ongoing PPI use for each individual patient. For example, guidelines clearly advocate the use of PPIs in patients at high risk for peptic ulcer disease (for example, use of aspirin and warfarin together), and these patients should continue PPIs unless more convincing evidence of serious side effects emerge. On the other hand, several studies have shown that many patients with uncomplicated gastroesophageal reflux disease symptoms can achieve symptom control with substitution of histamine2 blockers, p.r.n. dosing of PPIs, or without acid-reducing medications entirely. Still, many patients with confirmed pathologic acid reflux are likely to require ongoing PPIs. For patients who continue PPIs, they should use the lowest effective dose.
Surely, physicians will be discussing PPI adverse effects with increasing numbers of patients. Until higher-quality evidence in the form of a randomized controlled trial emerges, physicians should get used to explaining the principles of epidemiology.
Jacob Kurlander, MD, is a clinical lecturer in the division of gastroenterology, University of Michigan, Ann Arbor. He has received research funding from Ironwood Pharmaceuticals.
NEW ORLEANS – The use of proton pump inhibitors (PPIs) was associated with significantly increased risk of having a first ischemic stroke in a large nationwide Danish cohort study, Thomas S. Sehested, MD, reported at the American Heart Association scientific sessions.
The relationship was dose dependent. At the lowest available dose of each of the four PPIs studied there was no significantly increased risk. At the intermediate doses of three of the four PPIs studied, the increased risk of ischemic stroke became statistically significant. And the highest dose of each drug was associated with the greatest ischemic stroke risk.
In Denmark, for instance, where most PPIs are prescription only and use is easily trackable, it’s estimated that, at any given time, 7% of the adult population is taking a PPI, often not as directed in the labeling.
The impetus for this study, Dr. Sehested explained, was the mounting evidence that PPIs may constitute an independent risk factor for acute MI and other cardiovascular events. For example, a recent meta-analysis of 17 randomized controlled trials totaling 7,540 participants published through mid-2015 concluded that the use of PPIs was associated with a 70% increase in cardiovascular risk (Neurogastroenterol Motil. 2016 Aug 30. doi: 10.1111/nmo.12926).
He reported on 245,676 Danes above age 30 who were free of prior MI or stroke when they underwent elective GI endoscopy during 1997-2012. After a 30-day postendoscopy grace period during which 1,476 patients had a first MI, stroke, or died of any cause, the final study population was 244,200, of whom 43.7% were PPI users during the grace period and beyond.
During a median 5.8 years of follow-up, 9,489 subjects (3.9%) had a first ischemic stroke. Because of the comprehensive nature of Denmark’s interlocking birth to death registries, there was virtually no loss to follow-up in this study.
The unadjusted incidence of ischemic stroke in PPI nonusers was 55.7 per 10,000 person-years, compared with 88.9 per 10,000 in PPI users.
The PPI users were slightly older than nonusers by roughly 3 years. They were also an absolute 5% more likely to be hypertensive and an absolute 1.7% more likely to be regular users of NSAIDs. All of these differences, while modest, were statistically significant because of the large patient numbers involved.
In a multivariate analysis adjusted for age, sex, calendar year, comorbid diabetes, hypertension, alcohol use disorder, heart failure, peptic ulcer, peripheral artery disease, kidney disease, aspirin, oral anticoagulants and other medications, and socioeconomic status, current users of PPIs were 19% more likely to have a first ischemic stroke than nonusers. That difference is statistically significant and clinically meaningful, Dr. Sehested said.
In contrast, when the same sort of nationwide analysis was repeated, comparing current users of histamine-2 receptor antagonists to nonusers of those drugs or PPIs, there was no difference in ischemic stroke risk between the two groups.
The message, according to Dr. Sehested, is that physicians should encourage more cautious use of PPIs. And especially in the United States, where most PPIs are available over the counter, it’s prudent during office visits to ask what nonprescription drugs a patient is taking.
Dr. Sehested presented his study findings in a session devoted to original research in cardiovascular epidemiology. Many top American epidemiologists were present in the audience, and several rose to congratulate him on his presentation of the latest elegant epidemiologic study to come out of Denmark, the only place in the world where this sort of nationwide comprehensive research is possible.
“Wow! I just love the work you do in Denmark. It’s really inspiring,” commented David Siscovick, MD, senior vice president for research at the New York Academy of Medicine and professor emeritus of medicine and epidemiology at the University of Washington in Seattle.
He had a question: “Did you deal with PPI starters and stoppers and compliance in any way?”
Dr. Sehested replied that he and his coinvestigators were able to see who was on a PPI at any given point in the study, and they accounted for that. One issue the researchers plan to examine but haven’t yet had a chance to, however, is the relationship between duration of PPI therapy and ischemic stroke risk. It’s likely that some patients had already been on a PPI for a lengthy time at elective endoscopy, which is when the study in its current form began.
“I think that would strengthen the study,” he said.
Comoderator Jorge Kizer, MD, of Albert Einstein College of Medicine in New York, commented, “Confounding by indication is clearly the elephant in the room. The guidelines actually recommend adding a PPI if a patient is on dual-antiplatelet therapy and has an NSAID added. Did you adjust for that? It would boost confidence that the results are actually due to the PPI.”
Dr. Sehested answered that the great majority of individuals with cardiovascular disease at baseline were excluded from the analysis.
“I don’t think we had that many on dual-antiplatelet therapy,” he added.
Preclinical studies suggest a possible mechanism by which PPIs may harm cardiovascular health. The drugs reduce nitric oxide synthase levels, with resultant endothelial dysfunction, he said.
Dr. Sehested is employed at the Danish Heart Foundation, which funded the study.
NEW ORLEANS – The use of proton pump inhibitors (PPIs) was associated with significantly increased risk of having a first ischemic stroke in a large nationwide Danish cohort study, Thomas S. Sehested, MD, reported at the American Heart Association scientific sessions.
The relationship was dose dependent. At the lowest available dose of each of the four PPIs studied there was no significantly increased risk. At the intermediate doses of three of the four PPIs studied, the increased risk of ischemic stroke became statistically significant. And the highest dose of each drug was associated with the greatest ischemic stroke risk.
In Denmark, for instance, where most PPIs are prescription only and use is easily trackable, it’s estimated that, at any given time, 7% of the adult population is taking a PPI, often not as directed in the labeling.
The impetus for this study, Dr. Sehested explained, was the mounting evidence that PPIs may constitute an independent risk factor for acute MI and other cardiovascular events. For example, a recent meta-analysis of 17 randomized controlled trials totaling 7,540 participants published through mid-2015 concluded that the use of PPIs was associated with a 70% increase in cardiovascular risk (Neurogastroenterol Motil. 2016 Aug 30. doi: 10.1111/nmo.12926).
He reported on 245,676 Danes above age 30 who were free of prior MI or stroke when they underwent elective GI endoscopy during 1997-2012. After a 30-day postendoscopy grace period during which 1,476 patients had a first MI, stroke, or died of any cause, the final study population was 244,200, of whom 43.7% were PPI users during the grace period and beyond.
During a median 5.8 years of follow-up, 9,489 subjects (3.9%) had a first ischemic stroke. Because of the comprehensive nature of Denmark’s interlocking birth to death registries, there was virtually no loss to follow-up in this study.
The unadjusted incidence of ischemic stroke in PPI nonusers was 55.7 per 10,000 person-years, compared with 88.9 per 10,000 in PPI users.
The PPI users were slightly older than nonusers by roughly 3 years. They were also an absolute 5% more likely to be hypertensive and an absolute 1.7% more likely to be regular users of NSAIDs. All of these differences, while modest, were statistically significant because of the large patient numbers involved.
In a multivariate analysis adjusted for age, sex, calendar year, comorbid diabetes, hypertension, alcohol use disorder, heart failure, peptic ulcer, peripheral artery disease, kidney disease, aspirin, oral anticoagulants and other medications, and socioeconomic status, current users of PPIs were 19% more likely to have a first ischemic stroke than nonusers. That difference is statistically significant and clinically meaningful, Dr. Sehested said.
In contrast, when the same sort of nationwide analysis was repeated, comparing current users of histamine-2 receptor antagonists to nonusers of those drugs or PPIs, there was no difference in ischemic stroke risk between the two groups.
The message, according to Dr. Sehested, is that physicians should encourage more cautious use of PPIs. And especially in the United States, where most PPIs are available over the counter, it’s prudent during office visits to ask what nonprescription drugs a patient is taking.
Dr. Sehested presented his study findings in a session devoted to original research in cardiovascular epidemiology. Many top American epidemiologists were present in the audience, and several rose to congratulate him on his presentation of the latest elegant epidemiologic study to come out of Denmark, the only place in the world where this sort of nationwide comprehensive research is possible.
“Wow! I just love the work you do in Denmark. It’s really inspiring,” commented David Siscovick, MD, senior vice president for research at the New York Academy of Medicine and professor emeritus of medicine and epidemiology at the University of Washington in Seattle.
He had a question: “Did you deal with PPI starters and stoppers and compliance in any way?”
Dr. Sehested replied that he and his coinvestigators were able to see who was on a PPI at any given point in the study, and they accounted for that. One issue the researchers plan to examine but haven’t yet had a chance to, however, is the relationship between duration of PPI therapy and ischemic stroke risk. It’s likely that some patients had already been on a PPI for a lengthy time at elective endoscopy, which is when the study in its current form began.
“I think that would strengthen the study,” he said.
Comoderator Jorge Kizer, MD, of Albert Einstein College of Medicine in New York, commented, “Confounding by indication is clearly the elephant in the room. The guidelines actually recommend adding a PPI if a patient is on dual-antiplatelet therapy and has an NSAID added. Did you adjust for that? It would boost confidence that the results are actually due to the PPI.”
Dr. Sehested answered that the great majority of individuals with cardiovascular disease at baseline were excluded from the analysis.
“I don’t think we had that many on dual-antiplatelet therapy,” he added.
Preclinical studies suggest a possible mechanism by which PPIs may harm cardiovascular health. The drugs reduce nitric oxide synthase levels, with resultant endothelial dysfunction, he said.
Dr. Sehested is employed at the Danish Heart Foundation, which funded the study.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Current use of a proton pump inhibitor was independently associated with a 19% increased risk of a first ischemic stroke, and the risk was greater at the top approved doses.
Data source: This retrospective nationwide Danish study involved 244,200 adults age 30 or older followed for a median of nearly 6 years following elective GI endoscopy.
Disclosures: The presenter is employed at the Danish Heart Foundation, which funded the study.
Treating upper GI diseases: Where do we go from here?
WASHINGTON – The American Gastroenterological Association, the Food and Drug Administration, pharmaceutical companies, and patient advocacy groups came together for a first-of-its-kind meeting, a program of the AGA Center for Diagnostics and Therapeutics, to discuss new and emerging drugs for the treatment of four key GI diseases, highlighting the promise that these treatments show and the hurdles they face to gain approval.
“If we look at the AGA’s Burden of GI Disease Survey, published a few years ago in Gastroenterology, [you] can see that there are millions of visits to primary care and specialists for a variety of upper gastrointestinal symptoms, so clearly upper GI disorders still pose a major burden to our health care environment,” explained Colin W. Howden, MD, AGAF, chair of the AGA Center for Diagnostics and Therapeutics from the University of Tennessee in Memphis.
While proton pump inhibitors (PPIs) continue to be the first line of management for GERD, severe cases often require a stronger approach. Alternatives that are being investigated include potassium-competitive acid blockers, for which there have been clinical trials. However, no advantage over PPIs was demonstrated in any trials. Another alternative is bile salt binders, for which at least one trial is currently underway. Dr. Vela was unable to say when findings are expected to be published.
Another approach to managing GERD is to treat the acid pocket itself by using alginate. A randomized study by Rohof et al. investigated this in 2013, comparing Gaviscon and antacid; although the population size was small (n = 16), investigators concluded that “alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux [making it] an appropriate therapy for postprandial acid reflux.”
Another new drug is lesogaberan, a GABA-B agonist that was examined in a 2010 randomized, double-blind crossover study by Boeckxstaens et al. While also a small trial (n = 21), the findings indicated that the drug is a good option for those with only partial response to PPIs, as it decreased the number of transient lower esophageal sphincter relaxations (TLESRs) and reflux episodes, and increased LES pressure [in] patients with reflux symptoms. Work to inhibit transient LES relaxations also is being done, but so far lesogaberan, arbaclofen, and ADX 10059 (an mGluR5 modulator) programs have all been halted because of side effects or insufficient efficacy findings.
Prokinetics are also being looked at, with drugs such as metoclopramide being examined for efficacy, although to this point, the drug has shown “no improvement in acid exposure or esophageal clearance [when] compared to placebo,” according to Dr. Vela. Other drugs that are available outside the United States include domperidone, itopride, and mosapride, but Dr. Vela, who led a 2014 report on these therapies, stated that benefits offered by these are modest, and studies investigating them are limited in number.
Also being looked at are rebamipide, which can be used a cytoprotective agent that increases prostaglandin production. A 2010 study by Yoshida et al. found that lansoprazole (15 mg/day), combined with 300 mg/day of rebamipide, was significantly better at preventing relapse within a year than was just the former medication taken on its own. Additionally, there are conceptual studies examining topical protection to maintain mucosal integrity, nociceptor blockades, and imipramine.
Regarding trials for GERD, Robyn Carson, director of health economics & outcomes research at Allergan stated that the company recently redefined what constitutes GERD in order to help refocus what its drugs were trying to do.
“I think we’ve operationalized it very recently in terms of exclusion and GERD,” she explained. “The way we define it is ‘active GERD’ with two or more episodes a week of heartburn, so it was very much focused on the heartburn and PPI use was acceptable.”
Following the GERD discussion, panelists talked about what’s coming up in the realm of EoE. Stuart J. Spechler, MD, of the University of Texas Southwestern in Dallas, discussed ongoing research into treating EoE as an antigen-driven disorder, noting that about half of all EoE patients have a history of atopic disease – such as rhinitis, asthma, and atopic dermatitis – and exhibit sensitization to food or other aeroallergens. Furthermore, about 3% of patients who undergo oral immunotherapy to treat a food allergy develop EoE.
But in terms of what to take EoE research forward, Dr. Spechler called for a shift away from trying to distinguish between EoE and GERD, arguing that GERD contributes to EoE pathogenesis, and vice versa. PPIs can and should be used in EoE for the same reasons that they’re used to treat GERD, he explained.
“We need a shift in focus [because] I don’t think it’s likely to be that productive a line of research,” Dr. Spechler said. “The two diseases often coexist.”
To attack gastroparesis, P. Jay Pasricha, MD explained that a number of trials examining several drugs have shown that they are either ineffective or “do not correlate with improvement in gastric emptying.” These drugs include cisapride, tegaserod, botulinum toxin, mitemcinal, camcinal, TZP 102, and relamorelin.
“I’m not going to talk about emerging biomarkers because there isn’t a lot to talk about with biomarkers that hasn’t already been said,” stated Dr. Pasricha of Johns Hopkins University in Baltimore adding that his focus would largely be focused on emerging therapies and treatment targets.
A 2013 study by Parkman et al. investigated the effects of nortriptyline on mitigating idiopathic gastroparesis symptoms, finding that there was no significant difference in symptoms among patients who took the drug, versus those who took a placebo. In terms of using antinauseants to alleviate symptoms, dopamine receptor antagonists continue to be commonly prescribed, but they have their limitations. Metoclopramide, though approved since 1986, can be used for only 12 weeks, has acute and chronic side effects such as mood and irreversible movement disorders, and a black box warning imposed on it by the FDA in 2009 for tardive dyskinesia. One drug approved in India, though not by the FDA, is domperidone, which has no side effects to the central nervous system but does raise cardiovascular concerns in patients with “mild hERG affinity.”
Currently, the APRON trial is investigating the efficacy of aprepitant to relieve chronic nausea and vomiting in gastroparesis patients. Those enrolled in the study are all at least 18 years old, have undergone gastric-emptying scintigraphy, and either a normal upper endoscopy or an upper GI series within the 2 years prior to enrollment, have symptoms of chronic nausea or vomiting consistent with a functional gastric disorder for at least 6 months before enrollment, and nausea defined as “significant” by a visual analog scale score of at least 25 mm.
“Continuing to focus solely on accelerating gastric emptying is a failed strategy,” said Dr. Pasricha, adding that research needs to focus on the unique aspects of the disease’s biology, including pathogenic similarities with functional dyspepsia.
To that end, the final disease covered was functional dyspepsia. In terms of ongoing or planned clinical studies, Jan Tack, MD, from the University of Leuven (Belgium), mentioned three. Two of them are multicenter controlled trials investigating acotiamide, one in Europe and the other in India, for the management of functional dyspepsia and postprandial distress syndrome, while the other is a multicenter study examining rikkunshito, a traditional Japanese medicine. Additionally, ongoing or planned mechanistic studies include single-center controlled trials in Belgium on the efficacy of acotiamide and rikkunshito for intragastric pressure, as well as another Belgian study analyzing the impact of monoacylglycerol lipase inhibitors on intragastric pressure in patients that have functional dyspepsia with “impaired accommodation.”
Meal-related symptoms, nutrient challenge tests, and intragastric pressure measurements should all become short-term pathophysiology and efficacy markers, said Dr. Tack, adding that it’s also important for new therapeutic targets to include gastric emptying, hypersensitivity, and duodenal alterations, if necessary.
Hurdles persist in getting drugs through the approval process, however. Juli Tomaino, MD, of the FDA’s Center for Drug Evaluation and Research, explained where many proposed drugs run into issues in the regulatory process.
“We really have to know what we’re diagnosing, so the regulatory pathway to any of these approvals will really depend on the independent patient population, it will depend on the mechanism of action of the drug, what the drug is able to do and not do, and how you’re going to design that trial to target whatever that drug can do,” Dr. Tomaino said.
The issue of labeling also factors in, according to her. “We know that patients with acid-mediated heartburn do well on PPIs, but if they’re having different symptoms due to different mechanisms of action, then you have to design that drug with that patient population in mind, and that’s what the labeling would look like,” she explained. “So I’m not saying that it would necessarily have to list all the enrollment criteria, all the enrichment techniques that we use in that trial, but it would be a description of the intended patient population and what the drug would do.”
Mrs. Carson also chimed in on the topic of trial difficulties, saying that “[Irritable bowel syndrome] and [chronic idiopathic constipation] became quite an impediment to recruitment, and I think as we get farther away from the complete overlapping conditions, I think that’s where in discussions with the [Qualification Review Team] at FDA, they recognize that [we should] track that and let this evidence drive the next step,” adding that “we’ll have data on that shortly.”
The AGA Center for Diagnostics and Therapeutics will be issuing white papers on each of the four upper GI disorders discussed at the meeting.
Dr. Howden disclosed that he is a consultant for Aralez, Ironwood, Allergan, Otsuka, and SynteractHCR; an expert witness for Allergan; and coeditor of Alimentary Pharmacology & Therapeutics. Dr. Spechler disclosed that he is a consultant for Interpace Diagnostics, Takeda Pharmaceuticals, and Ironwood Pharmaceuticals. Dr. Pasricha disclosed that he is the cofounder of Neurogastrx, OrphoMed, and ETX Pharma, and is a consultant for Vanda and Allergan. Dr. Tack disclosed that he is a consultant for Abide, Allergan, AstraZeneca, Danone, El Pharma, Menarini, Novartis, Ono, Shire, Takeda, Theravance, Tsumura, and Zeria, as well as being on several of their advisory boards and speakers bureaus. Dr. Vela is a consultant for Medtronic and Torax.*
*Additions were made to the story on 11/8/2016 and 11/18/2016.
WASHINGTON – The American Gastroenterological Association, the Food and Drug Administration, pharmaceutical companies, and patient advocacy groups came together for a first-of-its-kind meeting, a program of the AGA Center for Diagnostics and Therapeutics, to discuss new and emerging drugs for the treatment of four key GI diseases, highlighting the promise that these treatments show and the hurdles they face to gain approval.
“If we look at the AGA’s Burden of GI Disease Survey, published a few years ago in Gastroenterology, [you] can see that there are millions of visits to primary care and specialists for a variety of upper gastrointestinal symptoms, so clearly upper GI disorders still pose a major burden to our health care environment,” explained Colin W. Howden, MD, AGAF, chair of the AGA Center for Diagnostics and Therapeutics from the University of Tennessee in Memphis.
While proton pump inhibitors (PPIs) continue to be the first line of management for GERD, severe cases often require a stronger approach. Alternatives that are being investigated include potassium-competitive acid blockers, for which there have been clinical trials. However, no advantage over PPIs was demonstrated in any trials. Another alternative is bile salt binders, for which at least one trial is currently underway. Dr. Vela was unable to say when findings are expected to be published.
Another approach to managing GERD is to treat the acid pocket itself by using alginate. A randomized study by Rohof et al. investigated this in 2013, comparing Gaviscon and antacid; although the population size was small (n = 16), investigators concluded that “alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux [making it] an appropriate therapy for postprandial acid reflux.”
Another new drug is lesogaberan, a GABA-B agonist that was examined in a 2010 randomized, double-blind crossover study by Boeckxstaens et al. While also a small trial (n = 21), the findings indicated that the drug is a good option for those with only partial response to PPIs, as it decreased the number of transient lower esophageal sphincter relaxations (TLESRs) and reflux episodes, and increased LES pressure [in] patients with reflux symptoms. Work to inhibit transient LES relaxations also is being done, but so far lesogaberan, arbaclofen, and ADX 10059 (an mGluR5 modulator) programs have all been halted because of side effects or insufficient efficacy findings.
Prokinetics are also being looked at, with drugs such as metoclopramide being examined for efficacy, although to this point, the drug has shown “no improvement in acid exposure or esophageal clearance [when] compared to placebo,” according to Dr. Vela. Other drugs that are available outside the United States include domperidone, itopride, and mosapride, but Dr. Vela, who led a 2014 report on these therapies, stated that benefits offered by these are modest, and studies investigating them are limited in number.
Also being looked at are rebamipide, which can be used a cytoprotective agent that increases prostaglandin production. A 2010 study by Yoshida et al. found that lansoprazole (15 mg/day), combined with 300 mg/day of rebamipide, was significantly better at preventing relapse within a year than was just the former medication taken on its own. Additionally, there are conceptual studies examining topical protection to maintain mucosal integrity, nociceptor blockades, and imipramine.
Regarding trials for GERD, Robyn Carson, director of health economics & outcomes research at Allergan stated that the company recently redefined what constitutes GERD in order to help refocus what its drugs were trying to do.
“I think we’ve operationalized it very recently in terms of exclusion and GERD,” she explained. “The way we define it is ‘active GERD’ with two or more episodes a week of heartburn, so it was very much focused on the heartburn and PPI use was acceptable.”
Following the GERD discussion, panelists talked about what’s coming up in the realm of EoE. Stuart J. Spechler, MD, of the University of Texas Southwestern in Dallas, discussed ongoing research into treating EoE as an antigen-driven disorder, noting that about half of all EoE patients have a history of atopic disease – such as rhinitis, asthma, and atopic dermatitis – and exhibit sensitization to food or other aeroallergens. Furthermore, about 3% of patients who undergo oral immunotherapy to treat a food allergy develop EoE.
But in terms of what to take EoE research forward, Dr. Spechler called for a shift away from trying to distinguish between EoE and GERD, arguing that GERD contributes to EoE pathogenesis, and vice versa. PPIs can and should be used in EoE for the same reasons that they’re used to treat GERD, he explained.
“We need a shift in focus [because] I don’t think it’s likely to be that productive a line of research,” Dr. Spechler said. “The two diseases often coexist.”
To attack gastroparesis, P. Jay Pasricha, MD explained that a number of trials examining several drugs have shown that they are either ineffective or “do not correlate with improvement in gastric emptying.” These drugs include cisapride, tegaserod, botulinum toxin, mitemcinal, camcinal, TZP 102, and relamorelin.
“I’m not going to talk about emerging biomarkers because there isn’t a lot to talk about with biomarkers that hasn’t already been said,” stated Dr. Pasricha of Johns Hopkins University in Baltimore adding that his focus would largely be focused on emerging therapies and treatment targets.
A 2013 study by Parkman et al. investigated the effects of nortriptyline on mitigating idiopathic gastroparesis symptoms, finding that there was no significant difference in symptoms among patients who took the drug, versus those who took a placebo. In terms of using antinauseants to alleviate symptoms, dopamine receptor antagonists continue to be commonly prescribed, but they have their limitations. Metoclopramide, though approved since 1986, can be used for only 12 weeks, has acute and chronic side effects such as mood and irreversible movement disorders, and a black box warning imposed on it by the FDA in 2009 for tardive dyskinesia. One drug approved in India, though not by the FDA, is domperidone, which has no side effects to the central nervous system but does raise cardiovascular concerns in patients with “mild hERG affinity.”
Currently, the APRON trial is investigating the efficacy of aprepitant to relieve chronic nausea and vomiting in gastroparesis patients. Those enrolled in the study are all at least 18 years old, have undergone gastric-emptying scintigraphy, and either a normal upper endoscopy or an upper GI series within the 2 years prior to enrollment, have symptoms of chronic nausea or vomiting consistent with a functional gastric disorder for at least 6 months before enrollment, and nausea defined as “significant” by a visual analog scale score of at least 25 mm.
“Continuing to focus solely on accelerating gastric emptying is a failed strategy,” said Dr. Pasricha, adding that research needs to focus on the unique aspects of the disease’s biology, including pathogenic similarities with functional dyspepsia.
To that end, the final disease covered was functional dyspepsia. In terms of ongoing or planned clinical studies, Jan Tack, MD, from the University of Leuven (Belgium), mentioned three. Two of them are multicenter controlled trials investigating acotiamide, one in Europe and the other in India, for the management of functional dyspepsia and postprandial distress syndrome, while the other is a multicenter study examining rikkunshito, a traditional Japanese medicine. Additionally, ongoing or planned mechanistic studies include single-center controlled trials in Belgium on the efficacy of acotiamide and rikkunshito for intragastric pressure, as well as another Belgian study analyzing the impact of monoacylglycerol lipase inhibitors on intragastric pressure in patients that have functional dyspepsia with “impaired accommodation.”
Meal-related symptoms, nutrient challenge tests, and intragastric pressure measurements should all become short-term pathophysiology and efficacy markers, said Dr. Tack, adding that it’s also important for new therapeutic targets to include gastric emptying, hypersensitivity, and duodenal alterations, if necessary.
Hurdles persist in getting drugs through the approval process, however. Juli Tomaino, MD, of the FDA’s Center for Drug Evaluation and Research, explained where many proposed drugs run into issues in the regulatory process.
“We really have to know what we’re diagnosing, so the regulatory pathway to any of these approvals will really depend on the independent patient population, it will depend on the mechanism of action of the drug, what the drug is able to do and not do, and how you’re going to design that trial to target whatever that drug can do,” Dr. Tomaino said.
The issue of labeling also factors in, according to her. “We know that patients with acid-mediated heartburn do well on PPIs, but if they’re having different symptoms due to different mechanisms of action, then you have to design that drug with that patient population in mind, and that’s what the labeling would look like,” she explained. “So I’m not saying that it would necessarily have to list all the enrollment criteria, all the enrichment techniques that we use in that trial, but it would be a description of the intended patient population and what the drug would do.”
Mrs. Carson also chimed in on the topic of trial difficulties, saying that “[Irritable bowel syndrome] and [chronic idiopathic constipation] became quite an impediment to recruitment, and I think as we get farther away from the complete overlapping conditions, I think that’s where in discussions with the [Qualification Review Team] at FDA, they recognize that [we should] track that and let this evidence drive the next step,” adding that “we’ll have data on that shortly.”
The AGA Center for Diagnostics and Therapeutics will be issuing white papers on each of the four upper GI disorders discussed at the meeting.
Dr. Howden disclosed that he is a consultant for Aralez, Ironwood, Allergan, Otsuka, and SynteractHCR; an expert witness for Allergan; and coeditor of Alimentary Pharmacology & Therapeutics. Dr. Spechler disclosed that he is a consultant for Interpace Diagnostics, Takeda Pharmaceuticals, and Ironwood Pharmaceuticals. Dr. Pasricha disclosed that he is the cofounder of Neurogastrx, OrphoMed, and ETX Pharma, and is a consultant for Vanda and Allergan. Dr. Tack disclosed that he is a consultant for Abide, Allergan, AstraZeneca, Danone, El Pharma, Menarini, Novartis, Ono, Shire, Takeda, Theravance, Tsumura, and Zeria, as well as being on several of their advisory boards and speakers bureaus. Dr. Vela is a consultant for Medtronic and Torax.*
*Additions were made to the story on 11/8/2016 and 11/18/2016.
WASHINGTON – The American Gastroenterological Association, the Food and Drug Administration, pharmaceutical companies, and patient advocacy groups came together for a first-of-its-kind meeting, a program of the AGA Center for Diagnostics and Therapeutics, to discuss new and emerging drugs for the treatment of four key GI diseases, highlighting the promise that these treatments show and the hurdles they face to gain approval.
“If we look at the AGA’s Burden of GI Disease Survey, published a few years ago in Gastroenterology, [you] can see that there are millions of visits to primary care and specialists for a variety of upper gastrointestinal symptoms, so clearly upper GI disorders still pose a major burden to our health care environment,” explained Colin W. Howden, MD, AGAF, chair of the AGA Center for Diagnostics and Therapeutics from the University of Tennessee in Memphis.
While proton pump inhibitors (PPIs) continue to be the first line of management for GERD, severe cases often require a stronger approach. Alternatives that are being investigated include potassium-competitive acid blockers, for which there have been clinical trials. However, no advantage over PPIs was demonstrated in any trials. Another alternative is bile salt binders, for which at least one trial is currently underway. Dr. Vela was unable to say when findings are expected to be published.
Another approach to managing GERD is to treat the acid pocket itself by using alginate. A randomized study by Rohof et al. investigated this in 2013, comparing Gaviscon and antacid; although the population size was small (n = 16), investigators concluded that “alginate-antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux [making it] an appropriate therapy for postprandial acid reflux.”
Another new drug is lesogaberan, a GABA-B agonist that was examined in a 2010 randomized, double-blind crossover study by Boeckxstaens et al. While also a small trial (n = 21), the findings indicated that the drug is a good option for those with only partial response to PPIs, as it decreased the number of transient lower esophageal sphincter relaxations (TLESRs) and reflux episodes, and increased LES pressure [in] patients with reflux symptoms. Work to inhibit transient LES relaxations also is being done, but so far lesogaberan, arbaclofen, and ADX 10059 (an mGluR5 modulator) programs have all been halted because of side effects or insufficient efficacy findings.
Prokinetics are also being looked at, with drugs such as metoclopramide being examined for efficacy, although to this point, the drug has shown “no improvement in acid exposure or esophageal clearance [when] compared to placebo,” according to Dr. Vela. Other drugs that are available outside the United States include domperidone, itopride, and mosapride, but Dr. Vela, who led a 2014 report on these therapies, stated that benefits offered by these are modest, and studies investigating them are limited in number.
Also being looked at are rebamipide, which can be used a cytoprotective agent that increases prostaglandin production. A 2010 study by Yoshida et al. found that lansoprazole (15 mg/day), combined with 300 mg/day of rebamipide, was significantly better at preventing relapse within a year than was just the former medication taken on its own. Additionally, there are conceptual studies examining topical protection to maintain mucosal integrity, nociceptor blockades, and imipramine.
Regarding trials for GERD, Robyn Carson, director of health economics & outcomes research at Allergan stated that the company recently redefined what constitutes GERD in order to help refocus what its drugs were trying to do.
“I think we’ve operationalized it very recently in terms of exclusion and GERD,” she explained. “The way we define it is ‘active GERD’ with two or more episodes a week of heartburn, so it was very much focused on the heartburn and PPI use was acceptable.”
Following the GERD discussion, panelists talked about what’s coming up in the realm of EoE. Stuart J. Spechler, MD, of the University of Texas Southwestern in Dallas, discussed ongoing research into treating EoE as an antigen-driven disorder, noting that about half of all EoE patients have a history of atopic disease – such as rhinitis, asthma, and atopic dermatitis – and exhibit sensitization to food or other aeroallergens. Furthermore, about 3% of patients who undergo oral immunotherapy to treat a food allergy develop EoE.
But in terms of what to take EoE research forward, Dr. Spechler called for a shift away from trying to distinguish between EoE and GERD, arguing that GERD contributes to EoE pathogenesis, and vice versa. PPIs can and should be used in EoE for the same reasons that they’re used to treat GERD, he explained.
“We need a shift in focus [because] I don’t think it’s likely to be that productive a line of research,” Dr. Spechler said. “The two diseases often coexist.”
To attack gastroparesis, P. Jay Pasricha, MD explained that a number of trials examining several drugs have shown that they are either ineffective or “do not correlate with improvement in gastric emptying.” These drugs include cisapride, tegaserod, botulinum toxin, mitemcinal, camcinal, TZP 102, and relamorelin.
“I’m not going to talk about emerging biomarkers because there isn’t a lot to talk about with biomarkers that hasn’t already been said,” stated Dr. Pasricha of Johns Hopkins University in Baltimore adding that his focus would largely be focused on emerging therapies and treatment targets.
A 2013 study by Parkman et al. investigated the effects of nortriptyline on mitigating idiopathic gastroparesis symptoms, finding that there was no significant difference in symptoms among patients who took the drug, versus those who took a placebo. In terms of using antinauseants to alleviate symptoms, dopamine receptor antagonists continue to be commonly prescribed, but they have their limitations. Metoclopramide, though approved since 1986, can be used for only 12 weeks, has acute and chronic side effects such as mood and irreversible movement disorders, and a black box warning imposed on it by the FDA in 2009 for tardive dyskinesia. One drug approved in India, though not by the FDA, is domperidone, which has no side effects to the central nervous system but does raise cardiovascular concerns in patients with “mild hERG affinity.”
Currently, the APRON trial is investigating the efficacy of aprepitant to relieve chronic nausea and vomiting in gastroparesis patients. Those enrolled in the study are all at least 18 years old, have undergone gastric-emptying scintigraphy, and either a normal upper endoscopy or an upper GI series within the 2 years prior to enrollment, have symptoms of chronic nausea or vomiting consistent with a functional gastric disorder for at least 6 months before enrollment, and nausea defined as “significant” by a visual analog scale score of at least 25 mm.
“Continuing to focus solely on accelerating gastric emptying is a failed strategy,” said Dr. Pasricha, adding that research needs to focus on the unique aspects of the disease’s biology, including pathogenic similarities with functional dyspepsia.
To that end, the final disease covered was functional dyspepsia. In terms of ongoing or planned clinical studies, Jan Tack, MD, from the University of Leuven (Belgium), mentioned three. Two of them are multicenter controlled trials investigating acotiamide, one in Europe and the other in India, for the management of functional dyspepsia and postprandial distress syndrome, while the other is a multicenter study examining rikkunshito, a traditional Japanese medicine. Additionally, ongoing or planned mechanistic studies include single-center controlled trials in Belgium on the efficacy of acotiamide and rikkunshito for intragastric pressure, as well as another Belgian study analyzing the impact of monoacylglycerol lipase inhibitors on intragastric pressure in patients that have functional dyspepsia with “impaired accommodation.”
Meal-related symptoms, nutrient challenge tests, and intragastric pressure measurements should all become short-term pathophysiology and efficacy markers, said Dr. Tack, adding that it’s also important for new therapeutic targets to include gastric emptying, hypersensitivity, and duodenal alterations, if necessary.
Hurdles persist in getting drugs through the approval process, however. Juli Tomaino, MD, of the FDA’s Center for Drug Evaluation and Research, explained where many proposed drugs run into issues in the regulatory process.
“We really have to know what we’re diagnosing, so the regulatory pathway to any of these approvals will really depend on the independent patient population, it will depend on the mechanism of action of the drug, what the drug is able to do and not do, and how you’re going to design that trial to target whatever that drug can do,” Dr. Tomaino said.
The issue of labeling also factors in, according to her. “We know that patients with acid-mediated heartburn do well on PPIs, but if they’re having different symptoms due to different mechanisms of action, then you have to design that drug with that patient population in mind, and that’s what the labeling would look like,” she explained. “So I’m not saying that it would necessarily have to list all the enrollment criteria, all the enrichment techniques that we use in that trial, but it would be a description of the intended patient population and what the drug would do.”
Mrs. Carson also chimed in on the topic of trial difficulties, saying that “[Irritable bowel syndrome] and [chronic idiopathic constipation] became quite an impediment to recruitment, and I think as we get farther away from the complete overlapping conditions, I think that’s where in discussions with the [Qualification Review Team] at FDA, they recognize that [we should] track that and let this evidence drive the next step,” adding that “we’ll have data on that shortly.”
The AGA Center for Diagnostics and Therapeutics will be issuing white papers on each of the four upper GI disorders discussed at the meeting.
Dr. Howden disclosed that he is a consultant for Aralez, Ironwood, Allergan, Otsuka, and SynteractHCR; an expert witness for Allergan; and coeditor of Alimentary Pharmacology & Therapeutics. Dr. Spechler disclosed that he is a consultant for Interpace Diagnostics, Takeda Pharmaceuticals, and Ironwood Pharmaceuticals. Dr. Pasricha disclosed that he is the cofounder of Neurogastrx, OrphoMed, and ETX Pharma, and is a consultant for Vanda and Allergan. Dr. Tack disclosed that he is a consultant for Abide, Allergan, AstraZeneca, Danone, El Pharma, Menarini, Novartis, Ono, Shire, Takeda, Theravance, Tsumura, and Zeria, as well as being on several of their advisory boards and speakers bureaus. Dr. Vela is a consultant for Medtronic and Torax.*
*Additions were made to the story on 11/8/2016 and 11/18/2016.
AT THE AGA DRUG DEVELOPMENT CONFERENCE
POEM procedure effective over the long term in achalasia
The therapeutic endoscopic procedure per-oral endoscopic myotomy (POEM) is safe and has a high clinical success rate at 2 years in patients with the rare esophageal motility disorder achalasia, according to results of the longest follow-up study to date.
The research team said that achalasia is characterized by the loss of enteric neurons, which results in impaired relaxation of the lower esophageal sphincter and absence of esophageal peristalsis.
The newer procedure, called POEM, is based on a technique of submucosal endoscopy and endoscopic myotomy. However, while short-term studies have shown it to be safe and effective for achalasia, long-term data have been limited.
“As achalasia is a chronic disease with a risk of recurrence of symptoms after treatment, long-term efficacy, rather than short-term data, is important for decision making surrounding the optimal therapeutic modalities,” wrote the investigators, led by Saowanee Ngamruengphong, MD, of Johns Hopkins Hospital, Baltimore (Gastrointest Endosc. 2016. doi: 10.1016/j.gie.2016.09.017).
The study involved 205 patients with achalasia from 10 centers in the United States, Europe, and Asia. Patients were included in the study if they had at least 2 years of follow-up data available.
Results showed that the overall clinical success – defined by a decrease in Eckardt score to 3 or lower – for the procedure was 91% at 2 years. The Eckardt score (maximum 12) is a composite measure of frequency of symptoms and severity of weight loss.
Overall, 18 patients (8.8%) were considered to have clinical failure (Eckardt score greater than 3) after POEM.
A history of prior pneumatic dilation was associated with long-term treatment failure (odds ratio, 3.41; 95% confidence interval, 1.25-9.23).
The researchers noted that the therapeutic success of POEM decreased over time as the clinical success rate of the procedure at 6 months’ follow-up had been 98%.
This is consistent with findings from other studies and also with other procedures such as Heller myotomy and pneumatic dilation.
“After POEM or other standard therapies, patients with achalasia require ongoing follow-up to assess recurrent symptoms with additional evaluation and treatment when indicated,” they wrote.
In terms of safety, the researchers reported procedure-related adverse events in 8.2% of patients, with one patient requiring surgical intervention.
Abnormal esophageal acid exposure and reflux esophagitis were also documented in 37.5% and 18% of patients, respectively.
Multivariate analysis revealed that full-thickness myotomy was independently associated with postoperative reflux esophagitis (adjusted OR, 3.99; 95% CI, 1.16-13.68; P = .002).
The authors noted that while reflux was common after POEM, almost all patients could be successfully treated with proton pump inhibitors.
“Prospective randomized studies comparing POEM and current standard therapy are awaited, but in the meantime, it can be considered an effective alternative option for patients with achalasia where expertise is available,” they concluded.
The therapeutic endoscopic procedure per-oral endoscopic myotomy (POEM) is safe and has a high clinical success rate at 2 years in patients with the rare esophageal motility disorder achalasia, according to results of the longest follow-up study to date.
The research team said that achalasia is characterized by the loss of enteric neurons, which results in impaired relaxation of the lower esophageal sphincter and absence of esophageal peristalsis.
The newer procedure, called POEM, is based on a technique of submucosal endoscopy and endoscopic myotomy. However, while short-term studies have shown it to be safe and effective for achalasia, long-term data have been limited.
“As achalasia is a chronic disease with a risk of recurrence of symptoms after treatment, long-term efficacy, rather than short-term data, is important for decision making surrounding the optimal therapeutic modalities,” wrote the investigators, led by Saowanee Ngamruengphong, MD, of Johns Hopkins Hospital, Baltimore (Gastrointest Endosc. 2016. doi: 10.1016/j.gie.2016.09.017).
The study involved 205 patients with achalasia from 10 centers in the United States, Europe, and Asia. Patients were included in the study if they had at least 2 years of follow-up data available.
Results showed that the overall clinical success – defined by a decrease in Eckardt score to 3 or lower – for the procedure was 91% at 2 years. The Eckardt score (maximum 12) is a composite measure of frequency of symptoms and severity of weight loss.
Overall, 18 patients (8.8%) were considered to have clinical failure (Eckardt score greater than 3) after POEM.
A history of prior pneumatic dilation was associated with long-term treatment failure (odds ratio, 3.41; 95% confidence interval, 1.25-9.23).
The researchers noted that the therapeutic success of POEM decreased over time as the clinical success rate of the procedure at 6 months’ follow-up had been 98%.
This is consistent with findings from other studies and also with other procedures such as Heller myotomy and pneumatic dilation.
“After POEM or other standard therapies, patients with achalasia require ongoing follow-up to assess recurrent symptoms with additional evaluation and treatment when indicated,” they wrote.
In terms of safety, the researchers reported procedure-related adverse events in 8.2% of patients, with one patient requiring surgical intervention.
Abnormal esophageal acid exposure and reflux esophagitis were also documented in 37.5% and 18% of patients, respectively.
Multivariate analysis revealed that full-thickness myotomy was independently associated with postoperative reflux esophagitis (adjusted OR, 3.99; 95% CI, 1.16-13.68; P = .002).
The authors noted that while reflux was common after POEM, almost all patients could be successfully treated with proton pump inhibitors.
“Prospective randomized studies comparing POEM and current standard therapy are awaited, but in the meantime, it can be considered an effective alternative option for patients with achalasia where expertise is available,” they concluded.
The therapeutic endoscopic procedure per-oral endoscopic myotomy (POEM) is safe and has a high clinical success rate at 2 years in patients with the rare esophageal motility disorder achalasia, according to results of the longest follow-up study to date.
The research team said that achalasia is characterized by the loss of enteric neurons, which results in impaired relaxation of the lower esophageal sphincter and absence of esophageal peristalsis.
The newer procedure, called POEM, is based on a technique of submucosal endoscopy and endoscopic myotomy. However, while short-term studies have shown it to be safe and effective for achalasia, long-term data have been limited.
“As achalasia is a chronic disease with a risk of recurrence of symptoms after treatment, long-term efficacy, rather than short-term data, is important for decision making surrounding the optimal therapeutic modalities,” wrote the investigators, led by Saowanee Ngamruengphong, MD, of Johns Hopkins Hospital, Baltimore (Gastrointest Endosc. 2016. doi: 10.1016/j.gie.2016.09.017).
The study involved 205 patients with achalasia from 10 centers in the United States, Europe, and Asia. Patients were included in the study if they had at least 2 years of follow-up data available.
Results showed that the overall clinical success – defined by a decrease in Eckardt score to 3 or lower – for the procedure was 91% at 2 years. The Eckardt score (maximum 12) is a composite measure of frequency of symptoms and severity of weight loss.
Overall, 18 patients (8.8%) were considered to have clinical failure (Eckardt score greater than 3) after POEM.
A history of prior pneumatic dilation was associated with long-term treatment failure (odds ratio, 3.41; 95% confidence interval, 1.25-9.23).
The researchers noted that the therapeutic success of POEM decreased over time as the clinical success rate of the procedure at 6 months’ follow-up had been 98%.
This is consistent with findings from other studies and also with other procedures such as Heller myotomy and pneumatic dilation.
“After POEM or other standard therapies, patients with achalasia require ongoing follow-up to assess recurrent symptoms with additional evaluation and treatment when indicated,” they wrote.
In terms of safety, the researchers reported procedure-related adverse events in 8.2% of patients, with one patient requiring surgical intervention.
Abnormal esophageal acid exposure and reflux esophagitis were also documented in 37.5% and 18% of patients, respectively.
Multivariate analysis revealed that full-thickness myotomy was independently associated with postoperative reflux esophagitis (adjusted OR, 3.99; 95% CI, 1.16-13.68; P = .002).
The authors noted that while reflux was common after POEM, almost all patients could be successfully treated with proton pump inhibitors.
“Prospective randomized studies comparing POEM and current standard therapy are awaited, but in the meantime, it can be considered an effective alternative option for patients with achalasia where expertise is available,” they concluded.
FROM GASTROINTESTINAL ENDOSCOPY
Key clinical point: The therapeutic endoscopic procedure per-oral endoscopic myotomy (POEM) has a high clinical success rate at 2 years in patients with achalasia.
Main finding: Overall clinical success for the procedure – defined by a decrease in Eckardt score to 3 or lower – was 91% at 2 years’ follow-up.
Data source: Retrospective study of 205 patients with achalasia from 10 centers across the United States, Europe, and Asia.
Disclosures: Several of the authors are consultants for Medtronic, Boston Scientific, and Sandhill Scientific, but no conflicts of interest were declared in relation to the current paper.
AGA Clinical Practice Update: Refer early Barrett’s dysplasia to a specialist
Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).
In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.
In the absence of reliable biomarkers, AGA turned to expertise to combat mistreatment. Although it’s clear that high-grade disease and esophageal adenocarcinoma need intervention, LGD sometimes seems to regress on its own, but it’s unclear if it’s due to natural history or diagnosis in patients who don’t really have it.
For now, expertise is the best solution. “Unfortunately, there is no database that clearly identifies experts in the field of Barrett’s esophagus,” but most practitioners can identify people to “refer these patients to within their state or region.” Meanwhile, “we are working tirelessly” to establish a referral and outcome database. “We owe it to” patients to let them know “how good the” people we are referring them to are, Dr. Wani said.
Given the diagnosis uncertainty, AGA side-stepped the biggest controversy in LGD: whether patients should be treated or watched. Among “patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a [second] endoscopy despite intensification of acid-suppressive therapy” at 8-12 weeks with proton pump inhibitors twice a day, “risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation) and ongoing surveillance should be discussed and documented,” the group said.
When patients opt for treatment, endoscopic eradication should proceed “with the goal of achieving complete eradication of intestinal metaplasia ... radiofrequency ablation should be used,” AGA said.
Meanwhile, “patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times two, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1-2 cm and of any visible lesions.”
AGA funded the work. Dr. Wani is a Medtronic and Boston Scientific consultant.
Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).
In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.
In the absence of reliable biomarkers, AGA turned to expertise to combat mistreatment. Although it’s clear that high-grade disease and esophageal adenocarcinoma need intervention, LGD sometimes seems to regress on its own, but it’s unclear if it’s due to natural history or diagnosis in patients who don’t really have it.
For now, expertise is the best solution. “Unfortunately, there is no database that clearly identifies experts in the field of Barrett’s esophagus,” but most practitioners can identify people to “refer these patients to within their state or region.” Meanwhile, “we are working tirelessly” to establish a referral and outcome database. “We owe it to” patients to let them know “how good the” people we are referring them to are, Dr. Wani said.
Given the diagnosis uncertainty, AGA side-stepped the biggest controversy in LGD: whether patients should be treated or watched. Among “patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a [second] endoscopy despite intensification of acid-suppressive therapy” at 8-12 weeks with proton pump inhibitors twice a day, “risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation) and ongoing surveillance should be discussed and documented,” the group said.
When patients opt for treatment, endoscopic eradication should proceed “with the goal of achieving complete eradication of intestinal metaplasia ... radiofrequency ablation should be used,” AGA said.
Meanwhile, “patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times two, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1-2 cm and of any visible lesions.”
AGA funded the work. Dr. Wani is a Medtronic and Boston Scientific consultant.
Low-grade esophageal dysplasia must be confirmed by a GI pathologist with a special interest in Barrett’s esophagus, one who deals with the problem on a daily basis and whom peers recognize as an expert in the field, according to a new expert review from the American Gastroenterological Association (Gastroenterology. doi: http://dx.doi.org/10.1053/j.gastro.2016.09.040).
In the absence of reliable biomarkers, it’s the best guarantee that low-grade dysplasia (LGD) is truly present. Overdiagnosis of early dysplasia is common, and it leads to mistreatment and uncertainty about study results, the AGA said.
In the absence of reliable biomarkers, AGA turned to expertise to combat mistreatment. Although it’s clear that high-grade disease and esophageal adenocarcinoma need intervention, LGD sometimes seems to regress on its own, but it’s unclear if it’s due to natural history or diagnosis in patients who don’t really have it.
For now, expertise is the best solution. “Unfortunately, there is no database that clearly identifies experts in the field of Barrett’s esophagus,” but most practitioners can identify people to “refer these patients to within their state or region.” Meanwhile, “we are working tirelessly” to establish a referral and outcome database. “We owe it to” patients to let them know “how good the” people we are referring them to are, Dr. Wani said.
Given the diagnosis uncertainty, AGA side-stepped the biggest controversy in LGD: whether patients should be treated or watched. Among “patients with confirmed Barrett’s esophagus with LGD by expert GI pathology review that persists on a [second] endoscopy despite intensification of acid-suppressive therapy” at 8-12 weeks with proton pump inhibitors twice a day, “risks and benefits of management options of endoscopic eradication therapy (specifically adverse events associated with endoscopic resection and ablation) and ongoing surveillance should be discussed and documented,” the group said.
When patients opt for treatment, endoscopic eradication should proceed “with the goal of achieving complete eradication of intestinal metaplasia ... radiofrequency ablation should be used,” AGA said.
Meanwhile, “patients with LGD undergoing surveillance rather than endoscopic eradication therapy should undergo surveillance every 6 months times two, then annually unless there is reversion to nondysplastic Barrett’s esophagus. Biopsies should be obtained in 4-quadrants every 1-2 cm and of any visible lesions.”
AGA funded the work. Dr. Wani is a Medtronic and Boston Scientific consultant.
Oral bacterium linked to poor esophageal cancer survival
Fusobacterium nucleatum, a component of the human microbiome, appears to be associated with shorter survival in esophageal cancer, according to new findings.
F. nucleatum, generally found in the oral cavity and associated with periodontal disease, may have a potential role as a prognostic biomarker, and it might also contribute to aggressive tumor behavior via activation of chemokines, the study authors suggest (Clin Cancer Res. 2016 Oct. doi: 10.1158/1078-0432.CCR-16-1786).
They add that this is “the first study to provide the evidence for the relationship between F. nucleatum and poor prognosis in esophageal cancer.”
An assessment of F. nucleatum DNA in esophageal cancer tissues by qPCR assay showed that levels were higher in malignant tissue than in paired adjacent nontumor tissues (P = .021). The relative F. nucleatum DNA levels were also measured in samples from 325 esophageal cancer cases.
Within those samples, F. nucleatum was detected in 74 (23%) of 325 cases. F. nucleatum positivity was not associated with most clinicopathologic features including patient sex, year of surgery, preoperative performance status, smoking history, alcohol history, comorbidity, tumor location, histology, tumor size, or preoperative therapy (all P greater than .05). However, it was associated with tumor stage (P = .016), T stage (P less than .01), and N stage (P = .039).
There were a total of 112 deaths among the 325 esophageal cancer patients, with 75 specific to the disease. The median follow-up time for censored patients was 2.6 years.
Patients positive for F. nucleatum had significantly shorter cancer-specific survival (logrank P = .0039) and overall survival (logrank P = .046) as compared with those who were F. nucleatum negative. In an analysis of F. nucleatum DNA status by Cox regression analysis, patients who were positive had significantly higher cancer-specific mortality as compared with those who were negative (hazard ratio, 2.01; P = .0068). After the analysis was adjusted for clinical, pathologic, and epidemiologic features, F. nucleatum positivity was associated with significantly higher cancer-specific mortality (multivariate HR, 1.78; P = .032), and similar findings were observed for overall mortality.
Dr. Yamamura and his team had also hypothesized that F. nucleatum might contribute to aggressive tumor behavior by activation of chemokines, and they were able to confirm that the presence or absence of F. nucleatum was significantly associated with CCL20 expression status, which was identified as the most upregulated chemokine.
*This article was updated 10/26/2016.
Fusobacterium nucleatum, a component of the human microbiome, appears to be associated with shorter survival in esophageal cancer, according to new findings.
F. nucleatum, generally found in the oral cavity and associated with periodontal disease, may have a potential role as a prognostic biomarker, and it might also contribute to aggressive tumor behavior via activation of chemokines, the study authors suggest (Clin Cancer Res. 2016 Oct. doi: 10.1158/1078-0432.CCR-16-1786).
They add that this is “the first study to provide the evidence for the relationship between F. nucleatum and poor prognosis in esophageal cancer.”
An assessment of F. nucleatum DNA in esophageal cancer tissues by qPCR assay showed that levels were higher in malignant tissue than in paired adjacent nontumor tissues (P = .021). The relative F. nucleatum DNA levels were also measured in samples from 325 esophageal cancer cases.
Within those samples, F. nucleatum was detected in 74 (23%) of 325 cases. F. nucleatum positivity was not associated with most clinicopathologic features including patient sex, year of surgery, preoperative performance status, smoking history, alcohol history, comorbidity, tumor location, histology, tumor size, or preoperative therapy (all P greater than .05). However, it was associated with tumor stage (P = .016), T stage (P less than .01), and N stage (P = .039).
There were a total of 112 deaths among the 325 esophageal cancer patients, with 75 specific to the disease. The median follow-up time for censored patients was 2.6 years.
Patients positive for F. nucleatum had significantly shorter cancer-specific survival (logrank P = .0039) and overall survival (logrank P = .046) as compared with those who were F. nucleatum negative. In an analysis of F. nucleatum DNA status by Cox regression analysis, patients who were positive had significantly higher cancer-specific mortality as compared with those who were negative (hazard ratio, 2.01; P = .0068). After the analysis was adjusted for clinical, pathologic, and epidemiologic features, F. nucleatum positivity was associated with significantly higher cancer-specific mortality (multivariate HR, 1.78; P = .032), and similar findings were observed for overall mortality.
Dr. Yamamura and his team had also hypothesized that F. nucleatum might contribute to aggressive tumor behavior by activation of chemokines, and they were able to confirm that the presence or absence of F. nucleatum was significantly associated with CCL20 expression status, which was identified as the most upregulated chemokine.
*This article was updated 10/26/2016.
Fusobacterium nucleatum, a component of the human microbiome, appears to be associated with shorter survival in esophageal cancer, according to new findings.
F. nucleatum, generally found in the oral cavity and associated with periodontal disease, may have a potential role as a prognostic biomarker, and it might also contribute to aggressive tumor behavior via activation of chemokines, the study authors suggest (Clin Cancer Res. 2016 Oct. doi: 10.1158/1078-0432.CCR-16-1786).
They add that this is “the first study to provide the evidence for the relationship between F. nucleatum and poor prognosis in esophageal cancer.”
An assessment of F. nucleatum DNA in esophageal cancer tissues by qPCR assay showed that levels were higher in malignant tissue than in paired adjacent nontumor tissues (P = .021). The relative F. nucleatum DNA levels were also measured in samples from 325 esophageal cancer cases.
Within those samples, F. nucleatum was detected in 74 (23%) of 325 cases. F. nucleatum positivity was not associated with most clinicopathologic features including patient sex, year of surgery, preoperative performance status, smoking history, alcohol history, comorbidity, tumor location, histology, tumor size, or preoperative therapy (all P greater than .05). However, it was associated with tumor stage (P = .016), T stage (P less than .01), and N stage (P = .039).
There were a total of 112 deaths among the 325 esophageal cancer patients, with 75 specific to the disease. The median follow-up time for censored patients was 2.6 years.
Patients positive for F. nucleatum had significantly shorter cancer-specific survival (logrank P = .0039) and overall survival (logrank P = .046) as compared with those who were F. nucleatum negative. In an analysis of F. nucleatum DNA status by Cox regression analysis, patients who were positive had significantly higher cancer-specific mortality as compared with those who were negative (hazard ratio, 2.01; P = .0068). After the analysis was adjusted for clinical, pathologic, and epidemiologic features, F. nucleatum positivity was associated with significantly higher cancer-specific mortality (multivariate HR, 1.78; P = .032), and similar findings were observed for overall mortality.
Dr. Yamamura and his team had also hypothesized that F. nucleatum might contribute to aggressive tumor behavior by activation of chemokines, and they were able to confirm that the presence or absence of F. nucleatum was significantly associated with CCL20 expression status, which was identified as the most upregulated chemokine.
*This article was updated 10/26/2016.
FROM CLINICAL CANCER RESEARCH
Key clinical point: F. nucleatum present in esophageal cancer tissue is associated with poorer prognosis.
Major finding: Patients positive for F. nucleatum had significantly shorter cancer-specific survival (logrank P = .0039) and OS (logrank P = .046).
Data source: Tissue samples from 325 patients with esophageal cancer.
Disclosures: This study was supported in part by the SGH Foundation. The authors have no disclosures.
Tryptase gene variant linked to GI, joint, and skin symptoms
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.
FROM NATURE GENETICS
Key clinical point:
Major finding: Increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene is associated with elevated basal serum tryptase and a collection of symptoms including irritable bowel syndrome, joint hypermobility, and autonomic dysfunction.
Data source: Study of 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms.
Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.