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Lower glucose target linked to improved mortality in critically ill
compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.
With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST®.
However, it does raise the possibility that earlier investigations finding an association between intensive insulin therapy and excess mortality “may have been accurate only in the setting of technologies which led to high rates of severe hypoglycemia,” they wrote.
The retrospective cohort analysis by Dr. Hersh and his colleagues included 1,809 adult patients treated at three different ICUs in two hospitals between January 2010 and December 2015. Treatment was delivered with a computerized ICU insulin infusion protocol that allows clinicians to choose between two blood glucose targets: 80-110 mg/dL or 90-140 mg/dL. The lower target was chosen for 951 patients, and the moderate target for 858 patients.
The most common primary admission diagnoses in the cohort included chest pain or acute coronary syndrome in 43.3%, cardiothoracic surgery in 31.9%, heart failure (including cardiogenic shock) in 6.8%, and vascular surgery in 6.0%.
While patients in the low blood glucose target group had a higher rate of moderate hypoglycemia, both groups had a low rate of severe hypoglycemia, at 1.16% in the low target group and 0.35% in the moderate target group (P = .051).
Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.
Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).
These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.
Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.
“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.
Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.
SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.
compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.
With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST®.
However, it does raise the possibility that earlier investigations finding an association between intensive insulin therapy and excess mortality “may have been accurate only in the setting of technologies which led to high rates of severe hypoglycemia,” they wrote.
The retrospective cohort analysis by Dr. Hersh and his colleagues included 1,809 adult patients treated at three different ICUs in two hospitals between January 2010 and December 2015. Treatment was delivered with a computerized ICU insulin infusion protocol that allows clinicians to choose between two blood glucose targets: 80-110 mg/dL or 90-140 mg/dL. The lower target was chosen for 951 patients, and the moderate target for 858 patients.
The most common primary admission diagnoses in the cohort included chest pain or acute coronary syndrome in 43.3%, cardiothoracic surgery in 31.9%, heart failure (including cardiogenic shock) in 6.8%, and vascular surgery in 6.0%.
While patients in the low blood glucose target group had a higher rate of moderate hypoglycemia, both groups had a low rate of severe hypoglycemia, at 1.16% in the low target group and 0.35% in the moderate target group (P = .051).
Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.
Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).
These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.
Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.
“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.
Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.
SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.
compared with patients with a target of 90-140 mg/dL, according to results of a retrospective cohort analysis.
With the computerized intravenous insulin protocol used in the study, the strict target could be achieved with a low rate of hypoglycemia, the authors wrote. The analysis was published in the journal CHEST®.
However, it does raise the possibility that earlier investigations finding an association between intensive insulin therapy and excess mortality “may have been accurate only in the setting of technologies which led to high rates of severe hypoglycemia,” they wrote.
The retrospective cohort analysis by Dr. Hersh and his colleagues included 1,809 adult patients treated at three different ICUs in two hospitals between January 2010 and December 2015. Treatment was delivered with a computerized ICU insulin infusion protocol that allows clinicians to choose between two blood glucose targets: 80-110 mg/dL or 90-140 mg/dL. The lower target was chosen for 951 patients, and the moderate target for 858 patients.
The most common primary admission diagnoses in the cohort included chest pain or acute coronary syndrome in 43.3%, cardiothoracic surgery in 31.9%, heart failure (including cardiogenic shock) in 6.8%, and vascular surgery in 6.0%.
While patients in the low blood glucose target group had a higher rate of moderate hypoglycemia, both groups had a low rate of severe hypoglycemia, at 1.16% in the low target group and 0.35% in the moderate target group (P = .051).
Unadjusted 30-day mortality was significantly lower in the 80-110–mg/dL group compared with the 90-140–mg/dL group (4.3% vs. 9.2%, respectively; P less than .001), according to the investigators.
Furthermore, logistic regression analysis showed that patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).
These results advance the debate over appropriate blood glucose targets in critically ill patients, as they suggest that the effects of targeting blood glucose and the effects of severe hypoglycemia “can be separated,” the investigators wrote.
Current guidelines on intensive insulin therapy are based in part on findings of the NICE-SUGAR trial, which found that among adults treated in the ICU, intensive glucose control increased mortality. However, a post hoc analysis suggested the mortality increase in NICE-SUGAR was “largely driven by a significant incidence of moderate hypoglycemia, and to a greater degree severe hypoglycemia,” Dr. Hersh and his coauthors noted in their report.
“Given improvements in insulin delivery and glucose monitoring, a reassessment of potential benefits of [intensive insulin therapy] should once again be evaluated in a prospective randomized trial,” they wrote.
Dr. Hersh and his coauthors declared no financial or nonfinancial disclosures related to the study.
SOURCE: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.
FROM THE JOURNAL CHEST®
Key clinical point: Among critically ill cardiac and cardiothoracic patients, a lower glucose target was associated with improved 30-day mortality.
Major finding: Patients treated with a target of 80-110 mg/dL had a lower risk of 30-day mortality compared with patients with a target of 90-140 mg/dL (odds ratio 0.65; 95% confidence interval, 0.43-0.98; P = .04).
Study details: A retrospective cohort analysis of 1,809 adult patients treated at three ICUs from two hospitals between January 2010 and December 2015.
Disclosures: The authors declared no disclosures.
Source: Hersh AM et al. CHEST 2018. doi: 10.1016/j.chest.2018.04.025.
Colorectal surgeons see barriers to optimal palliative care
While to its optimal implementation at the patient, family, and clinician level, results of a recent survey suggest.
“We found that surgeons reported the most important barriers to be their own,” said Pasithorn A. Suwanabol, MD, division of colorectal surgery, University of Michigan, Ann Arbor, and coauthors of a report on the survey.
More than three-quarters of surgeons said they had no formal education in palliative care, and a substantial number specifically noted inadequate training in both communication and techniques to forgo life-sustaining measures, according to the report, published in the Journal of Palliative Medicine.
Dr. Suwanabol and her colleagues sought surgeon perspectives on palliative care for stage IV colorectal cancer in part because palliative care is often not integrated with cancer treatment in these potentially incurable patients.
“Compared with patients treated by primary providers, surgical patients with terminal diseases are significantly less likely to receive palliative or end-of-life care,” they said in the report.
They conducted a mixed methods study including members of a surgical society (American Society of Colon and Rectal Surgeons) who were asked to submit Internet responses to a validated survey. This mixed methods study is believed to be the first to characterize surgeons’ perceived barriers to optimal palliative and end-of life care for patients with advanced colorectal cancer, Dr. Suwanabol and her colleagues noted.
A total of 131 surgeons responded to the survey, for a response rate of 16.5%. The majority of surgeons responding (76.1%) said they did not have any formal palliative care training, while 42.7% said they lacked specific education in communication and 37.9% lacked training in techniques to forgo life-sustaining measures.
Many patients with stage IV colorectal cancer are candidates for palliative care. “Specialty palliative care should be offered to patients who have more complex issues such as refractory pain, depression and anxiety, and existential distress. In addition, specialty palliative care may be helpful in those with challenging family dynamics and/or conflict between family members and/or members of the care team. Patients with stage IV colon cancer may not be candidates for curative therapies and a palliative approach allows the surgeon and patient to carefully weigh the risk and benefits of each therapy in the context of the overall goals of the patient,” Dr. Suwanabol said in an interview.
Among the survey responders, 61.8% said discussion of palliation was limited because of patients and families who had unrealistic expectations and demanded aggressive interventions.
One such recollection in the report reads as follows: ‘‘Patient with poorly responding stage IV colon cancer in multisystem organ failure getting same chemo that already failed ... family wanted everything done…’’
The report includes a number of other reflections from surgeons that suggest a level of anxiety, frustration, disappointment, or uncertainty regarding palliative care.
“I once operated on a young man with carcinomatosis, implants everywhere in the abdominal cavity,” one surgeon said in his survey response. “(He) went to another major center where they reoperated … I still have doubts about whether or not (a) I didn’t do enough for the patient or (b) the other center did too much.’’
Another surgeon reflected on the uncertainty of prognostication in some cases of advanced colon cancer. “I had a patient in the ICU with florid sepsis and multisystem organ failure. The entire care team began to wonder how long we should continue to press on with a patient who clearly could not survive. Days later he is awake and alert, off pressors, on trach collar, and fully communicative. Sometimes even experienced clinicians cannot predict when a patient will die or recover.”
Communication barriers remain. “A number of surgeons reported not knowing how to discuss this with families knowing that there is a stigma associated with palliative care – how to convey that they may pursue continued treatment in conjunction with palliative care,” said Dr. Suwanabol.
Surgeons adept at incorporating palliative care into their treatment plans continue to see the patients. “Even if a patient is not pursuing curative treatment, we do not want the patient to lose hope or feel abandoned by us, and I continue seeing my patients in follow-up until they feel overburdened by their clinic visits and choose not to come,” said Dr. Suwanabol.
In the absence of required palliative care training in medical schools or residencies, alternative approaches to achieving competency could include the American College of Surgeons Palliative Surgical Care Course, mentorships or collaborations with local palliative care specialists, or structured curricula implemented by experienced faculty, they added.
Dr. Suwanabol and her coauthors reported that they had no competing financial interests related to their study.
SOURCE: Suwanabol PA, et al. J Palliat Med. 2018 Mar 13. doi: 10.1089/jpm.2017.0470.
While to its optimal implementation at the patient, family, and clinician level, results of a recent survey suggest.
“We found that surgeons reported the most important barriers to be their own,” said Pasithorn A. Suwanabol, MD, division of colorectal surgery, University of Michigan, Ann Arbor, and coauthors of a report on the survey.
More than three-quarters of surgeons said they had no formal education in palliative care, and a substantial number specifically noted inadequate training in both communication and techniques to forgo life-sustaining measures, according to the report, published in the Journal of Palliative Medicine.
Dr. Suwanabol and her colleagues sought surgeon perspectives on palliative care for stage IV colorectal cancer in part because palliative care is often not integrated with cancer treatment in these potentially incurable patients.
“Compared with patients treated by primary providers, surgical patients with terminal diseases are significantly less likely to receive palliative or end-of-life care,” they said in the report.
They conducted a mixed methods study including members of a surgical society (American Society of Colon and Rectal Surgeons) who were asked to submit Internet responses to a validated survey. This mixed methods study is believed to be the first to characterize surgeons’ perceived barriers to optimal palliative and end-of life care for patients with advanced colorectal cancer, Dr. Suwanabol and her colleagues noted.
A total of 131 surgeons responded to the survey, for a response rate of 16.5%. The majority of surgeons responding (76.1%) said they did not have any formal palliative care training, while 42.7% said they lacked specific education in communication and 37.9% lacked training in techniques to forgo life-sustaining measures.
Many patients with stage IV colorectal cancer are candidates for palliative care. “Specialty palliative care should be offered to patients who have more complex issues such as refractory pain, depression and anxiety, and existential distress. In addition, specialty palliative care may be helpful in those with challenging family dynamics and/or conflict between family members and/or members of the care team. Patients with stage IV colon cancer may not be candidates for curative therapies and a palliative approach allows the surgeon and patient to carefully weigh the risk and benefits of each therapy in the context of the overall goals of the patient,” Dr. Suwanabol said in an interview.
Among the survey responders, 61.8% said discussion of palliation was limited because of patients and families who had unrealistic expectations and demanded aggressive interventions.
One such recollection in the report reads as follows: ‘‘Patient with poorly responding stage IV colon cancer in multisystem organ failure getting same chemo that already failed ... family wanted everything done…’’
The report includes a number of other reflections from surgeons that suggest a level of anxiety, frustration, disappointment, or uncertainty regarding palliative care.
“I once operated on a young man with carcinomatosis, implants everywhere in the abdominal cavity,” one surgeon said in his survey response. “(He) went to another major center where they reoperated … I still have doubts about whether or not (a) I didn’t do enough for the patient or (b) the other center did too much.’’
Another surgeon reflected on the uncertainty of prognostication in some cases of advanced colon cancer. “I had a patient in the ICU with florid sepsis and multisystem organ failure. The entire care team began to wonder how long we should continue to press on with a patient who clearly could not survive. Days later he is awake and alert, off pressors, on trach collar, and fully communicative. Sometimes even experienced clinicians cannot predict when a patient will die or recover.”
Communication barriers remain. “A number of surgeons reported not knowing how to discuss this with families knowing that there is a stigma associated with palliative care – how to convey that they may pursue continued treatment in conjunction with palliative care,” said Dr. Suwanabol.
Surgeons adept at incorporating palliative care into their treatment plans continue to see the patients. “Even if a patient is not pursuing curative treatment, we do not want the patient to lose hope or feel abandoned by us, and I continue seeing my patients in follow-up until they feel overburdened by their clinic visits and choose not to come,” said Dr. Suwanabol.
In the absence of required palliative care training in medical schools or residencies, alternative approaches to achieving competency could include the American College of Surgeons Palliative Surgical Care Course, mentorships or collaborations with local palliative care specialists, or structured curricula implemented by experienced faculty, they added.
Dr. Suwanabol and her coauthors reported that they had no competing financial interests related to their study.
SOURCE: Suwanabol PA, et al. J Palliat Med. 2018 Mar 13. doi: 10.1089/jpm.2017.0470.
While to its optimal implementation at the patient, family, and clinician level, results of a recent survey suggest.
“We found that surgeons reported the most important barriers to be their own,” said Pasithorn A. Suwanabol, MD, division of colorectal surgery, University of Michigan, Ann Arbor, and coauthors of a report on the survey.
More than three-quarters of surgeons said they had no formal education in palliative care, and a substantial number specifically noted inadequate training in both communication and techniques to forgo life-sustaining measures, according to the report, published in the Journal of Palliative Medicine.
Dr. Suwanabol and her colleagues sought surgeon perspectives on palliative care for stage IV colorectal cancer in part because palliative care is often not integrated with cancer treatment in these potentially incurable patients.
“Compared with patients treated by primary providers, surgical patients with terminal diseases are significantly less likely to receive palliative or end-of-life care,” they said in the report.
They conducted a mixed methods study including members of a surgical society (American Society of Colon and Rectal Surgeons) who were asked to submit Internet responses to a validated survey. This mixed methods study is believed to be the first to characterize surgeons’ perceived barriers to optimal palliative and end-of life care for patients with advanced colorectal cancer, Dr. Suwanabol and her colleagues noted.
A total of 131 surgeons responded to the survey, for a response rate of 16.5%. The majority of surgeons responding (76.1%) said they did not have any formal palliative care training, while 42.7% said they lacked specific education in communication and 37.9% lacked training in techniques to forgo life-sustaining measures.
Many patients with stage IV colorectal cancer are candidates for palliative care. “Specialty palliative care should be offered to patients who have more complex issues such as refractory pain, depression and anxiety, and existential distress. In addition, specialty palliative care may be helpful in those with challenging family dynamics and/or conflict between family members and/or members of the care team. Patients with stage IV colon cancer may not be candidates for curative therapies and a palliative approach allows the surgeon and patient to carefully weigh the risk and benefits of each therapy in the context of the overall goals of the patient,” Dr. Suwanabol said in an interview.
Among the survey responders, 61.8% said discussion of palliation was limited because of patients and families who had unrealistic expectations and demanded aggressive interventions.
One such recollection in the report reads as follows: ‘‘Patient with poorly responding stage IV colon cancer in multisystem organ failure getting same chemo that already failed ... family wanted everything done…’’
The report includes a number of other reflections from surgeons that suggest a level of anxiety, frustration, disappointment, or uncertainty regarding palliative care.
“I once operated on a young man with carcinomatosis, implants everywhere in the abdominal cavity,” one surgeon said in his survey response. “(He) went to another major center where they reoperated … I still have doubts about whether or not (a) I didn’t do enough for the patient or (b) the other center did too much.’’
Another surgeon reflected on the uncertainty of prognostication in some cases of advanced colon cancer. “I had a patient in the ICU with florid sepsis and multisystem organ failure. The entire care team began to wonder how long we should continue to press on with a patient who clearly could not survive. Days later he is awake and alert, off pressors, on trach collar, and fully communicative. Sometimes even experienced clinicians cannot predict when a patient will die or recover.”
Communication barriers remain. “A number of surgeons reported not knowing how to discuss this with families knowing that there is a stigma associated with palliative care – how to convey that they may pursue continued treatment in conjunction with palliative care,” said Dr. Suwanabol.
Surgeons adept at incorporating palliative care into their treatment plans continue to see the patients. “Even if a patient is not pursuing curative treatment, we do not want the patient to lose hope or feel abandoned by us, and I continue seeing my patients in follow-up until they feel overburdened by their clinic visits and choose not to come,” said Dr. Suwanabol.
In the absence of required palliative care training in medical schools or residencies, alternative approaches to achieving competency could include the American College of Surgeons Palliative Surgical Care Course, mentorships or collaborations with local palliative care specialists, or structured curricula implemented by experienced faculty, they added.
Dr. Suwanabol and her coauthors reported that they had no competing financial interests related to their study.
SOURCE: Suwanabol PA, et al. J Palliat Med. 2018 Mar 13. doi: 10.1089/jpm.2017.0470.
FROM THE JOURNAL OF PALLIATIVE MEDICINE
Key clinical point: Surgeons valued palliative and end-of-life care for patients with stage IV colorectal cancer, but reported multiple barriers to implementation.
Major finding: More than three-quarters of surgeons (76.1%) reported no formal education in palliative care, and 61.8% said patients and families had unrealistic expectations.
Study details: A mixed methods study including 131 members of a surgical society (American Society of Colon and Rectal Surgeons) who submitted Internet responses to a validated survey.
Disclosures: The authors declared that no competing interests relative to this report exist.
Source: Suwanabol PA et al. J Palliat Med. 2018 Mar 13. doi: 10.1089/jpm.2017.0470.
Constipation on opioids? Follow these three steps to ID the true cause
LAS VEGAS – To appropriately manage patients on opioids who develop constipation, one of the most important distinctions to make is whether the condition was caused by the pain treatment or was just exacerbated by it, according to Darren M. Brenner, MD.
Because of the rampant use of opioids, the answer to that question is increasingly relevant to clinical practice, said Dr. Brenner, associate professor of medicine (gastroenterology and hepatology) and surgery at Northwestern University, Chicago.
Dr. Brenner described a concise algorithm (Curr Gastroenterol Rep. 2017 Mar;19[3]:12) for discerning these patient groups; he codeveloped the algorithm with meeting cochair Brooks D. Cash, MD, chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston.
Step 1 in the algorithm is simply to ask patients whether they are constipated. “You should ask all of your patients who are on opioids if they have this problem,” Dr. Brenner said. “A significant percentage of individuals using opioids will develop constipation.”
According to the results of studies that Dr. Brenner summarized, up to 80% of patients taking opioids for chronic, noncancer pain will develop opioid-induced constipation, and more than 90% of opioid-taking patients with advanced illness will need laxatives.
Given this prevalence, clinicians might want to be skeptical when patients on opioids reply “no” when asked whether they are constipated.
“From my own clinical experience, you will miss a third of your population that has constipation,” Dr. Brenner said, noting that some patients will instead think of their condition in terms of incomplete evacuation or decreased stool frequency.
Step 2 of the algorithm, therefore, is to assess for signs and symptoms of functional constipation in all patients, regardless of whether they report the condition.
The recently published Rome IV diagnostic criteria included a new category for opioid-induced constipation. According to the new definition, opioid-induced constipation must include new or worsening symptoms, such as fewer than three solid bowel movements per week, and straining, blockage sensation, or manual maneuvers on at least 25% of bowel movements, among other symptoms listed in the report.
If patients do have constipation meeting these criteria, then step 3 of the algorithm is to determine whether the symptoms were present prior to taking opioids.
If onset of constipation is related to the start of opioid treatment, options may include prescribing peripherally acting mu-opioid receptor antagonists (PAMORAs). By contrast, onset unrelated to the start of opioids, also known as opioid-exacerbated constipation, may require treatment according to the underlying cause. For example, slow-transit constipation may respond to laxatives, while evacuation disorders may be treated with surgery, biofeedback, or physical therapy.
The hardest group to identify, according to Dr. Brenner, is individuals whose symptoms were so minor that they didn’t even realize they had constipation symptoms prior to opioids.
Because treatment protocols for opioid-induced and opioid-exacerbated constipation are so different, “we must tease these people out,” Dr. Brenner said.
Global Academy and this news organization are owned by the same parent company.
Dr. Brenner reported disclosures related to Allergan, Daiichi Sankyo, Ironwood Pharmaceuticals, Prius Medical, Salix Pharmaceuticals, Synergy Pharmaceuticals, Shionogi, and others.
LAS VEGAS – To appropriately manage patients on opioids who develop constipation, one of the most important distinctions to make is whether the condition was caused by the pain treatment or was just exacerbated by it, according to Darren M. Brenner, MD.
Because of the rampant use of opioids, the answer to that question is increasingly relevant to clinical practice, said Dr. Brenner, associate professor of medicine (gastroenterology and hepatology) and surgery at Northwestern University, Chicago.
Dr. Brenner described a concise algorithm (Curr Gastroenterol Rep. 2017 Mar;19[3]:12) for discerning these patient groups; he codeveloped the algorithm with meeting cochair Brooks D. Cash, MD, chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston.
Step 1 in the algorithm is simply to ask patients whether they are constipated. “You should ask all of your patients who are on opioids if they have this problem,” Dr. Brenner said. “A significant percentage of individuals using opioids will develop constipation.”
According to the results of studies that Dr. Brenner summarized, up to 80% of patients taking opioids for chronic, noncancer pain will develop opioid-induced constipation, and more than 90% of opioid-taking patients with advanced illness will need laxatives.
Given this prevalence, clinicians might want to be skeptical when patients on opioids reply “no” when asked whether they are constipated.
“From my own clinical experience, you will miss a third of your population that has constipation,” Dr. Brenner said, noting that some patients will instead think of their condition in terms of incomplete evacuation or decreased stool frequency.
Step 2 of the algorithm, therefore, is to assess for signs and symptoms of functional constipation in all patients, regardless of whether they report the condition.
The recently published Rome IV diagnostic criteria included a new category for opioid-induced constipation. According to the new definition, opioid-induced constipation must include new or worsening symptoms, such as fewer than three solid bowel movements per week, and straining, blockage sensation, or manual maneuvers on at least 25% of bowel movements, among other symptoms listed in the report.
If patients do have constipation meeting these criteria, then step 3 of the algorithm is to determine whether the symptoms were present prior to taking opioids.
If onset of constipation is related to the start of opioid treatment, options may include prescribing peripherally acting mu-opioid receptor antagonists (PAMORAs). By contrast, onset unrelated to the start of opioids, also known as opioid-exacerbated constipation, may require treatment according to the underlying cause. For example, slow-transit constipation may respond to laxatives, while evacuation disorders may be treated with surgery, biofeedback, or physical therapy.
The hardest group to identify, according to Dr. Brenner, is individuals whose symptoms were so minor that they didn’t even realize they had constipation symptoms prior to opioids.
Because treatment protocols for opioid-induced and opioid-exacerbated constipation are so different, “we must tease these people out,” Dr. Brenner said.
Global Academy and this news organization are owned by the same parent company.
Dr. Brenner reported disclosures related to Allergan, Daiichi Sankyo, Ironwood Pharmaceuticals, Prius Medical, Salix Pharmaceuticals, Synergy Pharmaceuticals, Shionogi, and others.
LAS VEGAS – To appropriately manage patients on opioids who develop constipation, one of the most important distinctions to make is whether the condition was caused by the pain treatment or was just exacerbated by it, according to Darren M. Brenner, MD.
Because of the rampant use of opioids, the answer to that question is increasingly relevant to clinical practice, said Dr. Brenner, associate professor of medicine (gastroenterology and hepatology) and surgery at Northwestern University, Chicago.
Dr. Brenner described a concise algorithm (Curr Gastroenterol Rep. 2017 Mar;19[3]:12) for discerning these patient groups; he codeveloped the algorithm with meeting cochair Brooks D. Cash, MD, chief of the division of gastroenterology, hepatology, and nutrition at the University of Texas, Houston.
Step 1 in the algorithm is simply to ask patients whether they are constipated. “You should ask all of your patients who are on opioids if they have this problem,” Dr. Brenner said. “A significant percentage of individuals using opioids will develop constipation.”
According to the results of studies that Dr. Brenner summarized, up to 80% of patients taking opioids for chronic, noncancer pain will develop opioid-induced constipation, and more than 90% of opioid-taking patients with advanced illness will need laxatives.
Given this prevalence, clinicians might want to be skeptical when patients on opioids reply “no” when asked whether they are constipated.
“From my own clinical experience, you will miss a third of your population that has constipation,” Dr. Brenner said, noting that some patients will instead think of their condition in terms of incomplete evacuation or decreased stool frequency.
Step 2 of the algorithm, therefore, is to assess for signs and symptoms of functional constipation in all patients, regardless of whether they report the condition.
The recently published Rome IV diagnostic criteria included a new category for opioid-induced constipation. According to the new definition, opioid-induced constipation must include new or worsening symptoms, such as fewer than three solid bowel movements per week, and straining, blockage sensation, or manual maneuvers on at least 25% of bowel movements, among other symptoms listed in the report.
If patients do have constipation meeting these criteria, then step 3 of the algorithm is to determine whether the symptoms were present prior to taking opioids.
If onset of constipation is related to the start of opioid treatment, options may include prescribing peripherally acting mu-opioid receptor antagonists (PAMORAs). By contrast, onset unrelated to the start of opioids, also known as opioid-exacerbated constipation, may require treatment according to the underlying cause. For example, slow-transit constipation may respond to laxatives, while evacuation disorders may be treated with surgery, biofeedback, or physical therapy.
The hardest group to identify, according to Dr. Brenner, is individuals whose symptoms were so minor that they didn’t even realize they had constipation symptoms prior to opioids.
Because treatment protocols for opioid-induced and opioid-exacerbated constipation are so different, “we must tease these people out,” Dr. Brenner said.
Global Academy and this news organization are owned by the same parent company.
Dr. Brenner reported disclosures related to Allergan, Daiichi Sankyo, Ironwood Pharmaceuticals, Prius Medical, Salix Pharmaceuticals, Synergy Pharmaceuticals, Shionogi, and others.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
Celiac disease: Can biopsy be avoided?
LAS VEGAS – It may be only a matter of time before the “gold standard” small biopsy is no longer considered mandatory to make a diagnosis of celiac disease in adults, according to Joseph A. Murray, MD, consultant in the division of gastroenterology and hepatology and department of immunology, Mayo Clinic, Rochester, Minn.
“Right now, none of the adult societies support biopsy avoidance, but I predict that it will come to be,” Dr. Murray said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
In one recently reported study, investigators at Royal Derby Hospital, England, suggested that clinicians could make a reliable diagnosis of celiac disease by looking at serum IgA-tissue transglutaminase antibody levels.
Those investigators retrospectively analyzed an unselected series of 270 adult patients and found that an IgA-tissue transglutaminase antibody cut-off of 45 U/mL, or 8 times the upper limit of normal, had a positive predictive value of 100%.
Biopsy avoidance remains controversial, however. In a published letter to the editor commenting on the Derby study, authors took issue with some of the statistical analysis and remarked that the study included some patients with Marsh 1 histology.
“Studies suggest that the majority of seropositive patients with Marsh 1 histology do not progress to develop villous atrophy while on a gluten-containing diet, raising the question whether all of them are truly celiac,” they wrote.
The first society to endorse skipping the biopsy was the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
In guidelines for the diagnosis of celiac disease, that group said a celiac diagnosis could be made based on symptoms, antibodies, and HLA in children with symptoms suggestive of the disease and high antibody levels (IgA anti-tissue transglutaminase type 2 antibody titers greater than 10 times the upper limit of normal).
“The data [are] now pretty good to support that approach in symptomatic children,” Dr. Murray said. “If we apply these to adult patients, it’s not bad, actually, partly because our biopsies aren’t perfect.”
However, not all adult gastroenterology specialists agreed with the recommendations of the pediatric society. Guidelines from the British Society of Gastroenterology have stated that serology cannot replace biopsy, which “remains essential” for celiac disease diagnosis.
Global Academy and this news organization are owned by the same parent company.
Dr. Murray reported disclosures related to Ardent Mills, DBV Technologies, Evelo, GlaxoSmithKline, Johnson & Johnson, Immunogenix, Innovate, National Center for Complementary and Integrative Health, Takeda, Torax Medical, and UCB.
LAS VEGAS – It may be only a matter of time before the “gold standard” small biopsy is no longer considered mandatory to make a diagnosis of celiac disease in adults, according to Joseph A. Murray, MD, consultant in the division of gastroenterology and hepatology and department of immunology, Mayo Clinic, Rochester, Minn.
“Right now, none of the adult societies support biopsy avoidance, but I predict that it will come to be,” Dr. Murray said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
In one recently reported study, investigators at Royal Derby Hospital, England, suggested that clinicians could make a reliable diagnosis of celiac disease by looking at serum IgA-tissue transglutaminase antibody levels.
Those investigators retrospectively analyzed an unselected series of 270 adult patients and found that an IgA-tissue transglutaminase antibody cut-off of 45 U/mL, or 8 times the upper limit of normal, had a positive predictive value of 100%.
Biopsy avoidance remains controversial, however. In a published letter to the editor commenting on the Derby study, authors took issue with some of the statistical analysis and remarked that the study included some patients with Marsh 1 histology.
“Studies suggest that the majority of seropositive patients with Marsh 1 histology do not progress to develop villous atrophy while on a gluten-containing diet, raising the question whether all of them are truly celiac,” they wrote.
The first society to endorse skipping the biopsy was the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
In guidelines for the diagnosis of celiac disease, that group said a celiac diagnosis could be made based on symptoms, antibodies, and HLA in children with symptoms suggestive of the disease and high antibody levels (IgA anti-tissue transglutaminase type 2 antibody titers greater than 10 times the upper limit of normal).
“The data [are] now pretty good to support that approach in symptomatic children,” Dr. Murray said. “If we apply these to adult patients, it’s not bad, actually, partly because our biopsies aren’t perfect.”
However, not all adult gastroenterology specialists agreed with the recommendations of the pediatric society. Guidelines from the British Society of Gastroenterology have stated that serology cannot replace biopsy, which “remains essential” for celiac disease diagnosis.
Global Academy and this news organization are owned by the same parent company.
Dr. Murray reported disclosures related to Ardent Mills, DBV Technologies, Evelo, GlaxoSmithKline, Johnson & Johnson, Immunogenix, Innovate, National Center for Complementary and Integrative Health, Takeda, Torax Medical, and UCB.
LAS VEGAS – It may be only a matter of time before the “gold standard” small biopsy is no longer considered mandatory to make a diagnosis of celiac disease in adults, according to Joseph A. Murray, MD, consultant in the division of gastroenterology and hepatology and department of immunology, Mayo Clinic, Rochester, Minn.
“Right now, none of the adult societies support biopsy avoidance, but I predict that it will come to be,” Dr. Murray said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
In one recently reported study, investigators at Royal Derby Hospital, England, suggested that clinicians could make a reliable diagnosis of celiac disease by looking at serum IgA-tissue transglutaminase antibody levels.
Those investigators retrospectively analyzed an unselected series of 270 adult patients and found that an IgA-tissue transglutaminase antibody cut-off of 45 U/mL, or 8 times the upper limit of normal, had a positive predictive value of 100%.
Biopsy avoidance remains controversial, however. In a published letter to the editor commenting on the Derby study, authors took issue with some of the statistical analysis and remarked that the study included some patients with Marsh 1 histology.
“Studies suggest that the majority of seropositive patients with Marsh 1 histology do not progress to develop villous atrophy while on a gluten-containing diet, raising the question whether all of them are truly celiac,” they wrote.
The first society to endorse skipping the biopsy was the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition.
In guidelines for the diagnosis of celiac disease, that group said a celiac diagnosis could be made based on symptoms, antibodies, and HLA in children with symptoms suggestive of the disease and high antibody levels (IgA anti-tissue transglutaminase type 2 antibody titers greater than 10 times the upper limit of normal).
“The data [are] now pretty good to support that approach in symptomatic children,” Dr. Murray said. “If we apply these to adult patients, it’s not bad, actually, partly because our biopsies aren’t perfect.”
However, not all adult gastroenterology specialists agreed with the recommendations of the pediatric society. Guidelines from the British Society of Gastroenterology have stated that serology cannot replace biopsy, which “remains essential” for celiac disease diagnosis.
Global Academy and this news organization are owned by the same parent company.
Dr. Murray reported disclosures related to Ardent Mills, DBV Technologies, Evelo, GlaxoSmithKline, Johnson & Johnson, Immunogenix, Innovate, National Center for Complementary and Integrative Health, Takeda, Torax Medical, and UCB.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
Endoscopic therapy for Barrett’s: highly effective, but not perfect
LAS VEGAS – While endoscopic therapy of Barrett’s esophagus is often successful, the risk of recurrence after complete ablation remains considerable, according to Prateek Sharma, MD, of the department of medicine in the division of gastroenterology and hepatology at the University of Kansas, Kansas City.
“This is not perfect therapy,” Dr. Sharma said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
The risk of recurrence for intestinal metaplasia was 7.1% per patient-year, authors of that study found. The risk of dysplastic Barrett’s esophagus was 1.3% per patient-year in the meta-analysis, while the risk of high-grade dysplasia or esophageal adenocarcinoma was 0.8%.
Because of these risks, patients should be followed up regularly with careful examination and biopsies to ensure there is no recurrent intestinal metaplasia, dysplasia, or adenocarcinoma, Dr. Sharma told attendees at the meeting.
“If it comes back, you can still treat it endoscopically,” he continued, “but you have to be aware of the situation, and inform the patient that it can be curative, but at the same time it’s not a 100% success story in all situations.”
When patients do develop early cancers or high-grade lesions, the latest evidence suggests endoscopic therapy is effective and helps avoid esophagectomy in the majority of patients.
“It used to be esophagectomy for all,” Dr. Sharma said. “Now the paradigm has switched, and it is endoscopic therapy for all.”
That paradigm shift is supported in part by a German study showing excellent long-term results in 1,000 consecutive patients receiving endoscopic treatment of mucosal adenocarcinoma of the esophagus.
In that study, nearly all of the patients (963, or 96.3%) had a complete response, with 12 patients undergoing surgery because of failure of endoscopic therapy. Fifteen patients (1.5%) had major complications that were nonetheless managed conservatively, according to investigators. Although new lesions or recurrences were seen in 140 patients (14.5%) over 5 years of follow-up, 115 patients had successful endoscopic retreatment. Based on these data, the investigators calculated a 10-year survival rate of 75%.
On the basis of these findings, investigators said endoscopic therapy should be considered the standard of care for patients with mucosal adenocarcinoma of the esophagus.
“That’s the paradigm shift that I was talking about – now, we are sending less than 4% of our patients for surgery for this condition,” Dr. Sharma said at the meeting.
Global Academy and this news organization are owned by the same parent company.
Dr. Sharma reported disclosures related to Medtronics, National Institutes of Health, and US Endoscopy.
LAS VEGAS – While endoscopic therapy of Barrett’s esophagus is often successful, the risk of recurrence after complete ablation remains considerable, according to Prateek Sharma, MD, of the department of medicine in the division of gastroenterology and hepatology at the University of Kansas, Kansas City.
“This is not perfect therapy,” Dr. Sharma said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
The risk of recurrence for intestinal metaplasia was 7.1% per patient-year, authors of that study found. The risk of dysplastic Barrett’s esophagus was 1.3% per patient-year in the meta-analysis, while the risk of high-grade dysplasia or esophageal adenocarcinoma was 0.8%.
Because of these risks, patients should be followed up regularly with careful examination and biopsies to ensure there is no recurrent intestinal metaplasia, dysplasia, or adenocarcinoma, Dr. Sharma told attendees at the meeting.
“If it comes back, you can still treat it endoscopically,” he continued, “but you have to be aware of the situation, and inform the patient that it can be curative, but at the same time it’s not a 100% success story in all situations.”
When patients do develop early cancers or high-grade lesions, the latest evidence suggests endoscopic therapy is effective and helps avoid esophagectomy in the majority of patients.
“It used to be esophagectomy for all,” Dr. Sharma said. “Now the paradigm has switched, and it is endoscopic therapy for all.”
That paradigm shift is supported in part by a German study showing excellent long-term results in 1,000 consecutive patients receiving endoscopic treatment of mucosal adenocarcinoma of the esophagus.
In that study, nearly all of the patients (963, or 96.3%) had a complete response, with 12 patients undergoing surgery because of failure of endoscopic therapy. Fifteen patients (1.5%) had major complications that were nonetheless managed conservatively, according to investigators. Although new lesions or recurrences were seen in 140 patients (14.5%) over 5 years of follow-up, 115 patients had successful endoscopic retreatment. Based on these data, the investigators calculated a 10-year survival rate of 75%.
On the basis of these findings, investigators said endoscopic therapy should be considered the standard of care for patients with mucosal adenocarcinoma of the esophagus.
“That’s the paradigm shift that I was talking about – now, we are sending less than 4% of our patients for surgery for this condition,” Dr. Sharma said at the meeting.
Global Academy and this news organization are owned by the same parent company.
Dr. Sharma reported disclosures related to Medtronics, National Institutes of Health, and US Endoscopy.
LAS VEGAS – While endoscopic therapy of Barrett’s esophagus is often successful, the risk of recurrence after complete ablation remains considerable, according to Prateek Sharma, MD, of the department of medicine in the division of gastroenterology and hepatology at the University of Kansas, Kansas City.
“This is not perfect therapy,” Dr. Sharma said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
The risk of recurrence for intestinal metaplasia was 7.1% per patient-year, authors of that study found. The risk of dysplastic Barrett’s esophagus was 1.3% per patient-year in the meta-analysis, while the risk of high-grade dysplasia or esophageal adenocarcinoma was 0.8%.
Because of these risks, patients should be followed up regularly with careful examination and biopsies to ensure there is no recurrent intestinal metaplasia, dysplasia, or adenocarcinoma, Dr. Sharma told attendees at the meeting.
“If it comes back, you can still treat it endoscopically,” he continued, “but you have to be aware of the situation, and inform the patient that it can be curative, but at the same time it’s not a 100% success story in all situations.”
When patients do develop early cancers or high-grade lesions, the latest evidence suggests endoscopic therapy is effective and helps avoid esophagectomy in the majority of patients.
“It used to be esophagectomy for all,” Dr. Sharma said. “Now the paradigm has switched, and it is endoscopic therapy for all.”
That paradigm shift is supported in part by a German study showing excellent long-term results in 1,000 consecutive patients receiving endoscopic treatment of mucosal adenocarcinoma of the esophagus.
In that study, nearly all of the patients (963, or 96.3%) had a complete response, with 12 patients undergoing surgery because of failure of endoscopic therapy. Fifteen patients (1.5%) had major complications that were nonetheless managed conservatively, according to investigators. Although new lesions or recurrences were seen in 140 patients (14.5%) over 5 years of follow-up, 115 patients had successful endoscopic retreatment. Based on these data, the investigators calculated a 10-year survival rate of 75%.
On the basis of these findings, investigators said endoscopic therapy should be considered the standard of care for patients with mucosal adenocarcinoma of the esophagus.
“That’s the paradigm shift that I was talking about – now, we are sending less than 4% of our patients for surgery for this condition,” Dr. Sharma said at the meeting.
Global Academy and this news organization are owned by the same parent company.
Dr. Sharma reported disclosures related to Medtronics, National Institutes of Health, and US Endoscopy.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
New options emerge for primary biliary cholangitis
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
LAS VEGAS – Evidence is mounting for several adjuvant treatments that may be appropriate for patients with primary biliary cholangitis who are not responding to first-line ursodeoxycholic acid (UDCA), according to Cynthia Levy, MD.
Given these new potential treatment options, it’s important for clinicians to assess biochemical response to first-line UDCA, said Dr. Levy, assistant director for the Schiff Center for Liver Diseases at the University of Miami.
“Up until recently, we didn’t have anything to offer to nonresponders,” Dr. Levy said at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education. “Now we know at 1 year, we need to restratify to evaluate the need for adjuvant therapy.”
Many UDCA-treated patients will not respond to that first-line treatment, putting them at risk for progression to hepatocellular carcinoma and end-stage liver disease, according to Dr. Levy.
Obeticholic acid, a farnesoid X receptor agonist, is now a Food and Drug Administration–approved option for these patients, while fibrates and budesonide have recent data supporting their use and are available off-label, she added.
The conditional FDA approval for obeticholic acid, granted in May 2016, is for treatment as monotherapy in patients who do not tolerate UDCA or in combination with UDCA for patients who had had incomplete responses to that treatment for at least a year. Improvement in survival without liver transplantation has not yet been demonstrated for this agent, though studies are ongoing, Dr. Levy noted.
In the meantime, research is progressing with the peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists fenofibrate and bezafibrate.
In the BEZURSO study, presented at the 2017 EASL Congress, 100 patients with incomplete response to UDCA were randomized to bezafibrate plus UDCA or placebo plus UDCA for 2 years. The primary endpoint, normalization of liver function tests at 2 years, was achieved in 30% of the bezafibrate group and 0% of the placebo group. In addition, 67% of the bezafibrate-treated patients had alkaline phosphatase normalization, compared with 0% in the placebo group.
Bezafibrate was also associated with significant reductions in fatigue and itching, as well as surrogate liver fibrosis markers, according to investigators. The serious adverse event rate was similar between groups, as was the rate of end-stage liver complications, which was 4% for each arm.
Fenofibrate was studied in a small 20-patient, open-label, phase 2 study by Dr. Levy and her colleagues. “Alkaline phosphatase significantly improved fairly early when the drug was started,” she said. Treatment was for 48 weeks, and once the drug was discontinued, there was a rebound in alkaline phosphatase levels.
Seladelpar is another PPAR agonist far along in the pipeline, according to Dr. Levy. This selective PPAR-delta agonist demonstrated significant improvements in alkaline phosphatase and other measures in a 12-week trial that included 75 patients with primary biliary cholangitis and incomplete response to UDCA.
While fenofibrate and bezafibrate can be used off-label for primary biliary cholangitis, Dr. Levy said, fenofibrate labeling indicates that it is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cholangitis.
According to Dr. Levy, that contraindication is based on experience with clofibrate, a first-generation fibrate that was associated with increased risk of gallstone formation. “If you choose to use fenofibrate, this is off-label use, and you need to warn your patients,” she told attendees at the meeting.
Two other agents under investigation in primary biliary cholangitis that have shown some promising results recently, according to Dr. Levy, include budesonide and an engineered variant of the human hormone FGF19 known as NGM282.
Global Academy and this news organization are owned by the same parent company.
Dr. Levy reported disclosures related to CymaBay Therapeutics, Enanta Pharmaceuticals, Genfit, GenKyoTex, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, NGM Biopharmaceuticals, and Novartis.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
Spine fracture risk may be increased in IBD patients
Moreover, fracture risk appears to be higher among IBD patients using steroids, according to a report published in the Journal of Clinical Gastroenterology by Yuga Komaki, MD, of the Inflammatory Bowel Disease Center, University of Chicago, and coauthors.
“Further studies addressing the differential risk among Crohn’s disease and ulcerative colitis are needed, but strict surveillance and prevention of spine fractures are indicated in IBD,” wrote Dr. Komaki and associates.
The systematic review and meta-analysis by Dr. Komaki and colleagues was based on 10 studies comprising 470,541 patients with IBD for whom the risk of fracture was reported.
“It is of importance to identify the risk of fractures, as it will increase patient morbidity, disability, and mortality,” the authors wrote. “However, it is often overlooked in the management of IBD.”
Results of the analysis by this group of researchers showed that there was no significant difference in fracture risk overall between IBD patients and controls (odds ratio, 1.08; 95% confidence interval, 0.72-1.62; P = .70).
By contrast, the OR for spine fractures was significantly elevated (OR, 2.21; 95% CI, 1.39-3.50; P less than .0001), while risk of hip, rib, and wrist fractures were not, Dr. Komaki and coauthors said in their report.
Steroids were more often being used in the treatment of IBD patients who had fractures than in patients with no fractures, though the finding did not quite reach statistical significance (OR, 1.47; 95% CI, 0.99-2.20; P = .057).
Prior studies of fracture risk in IBD have shown “controversial results,” according to Dr. Komaki and colleagues. Some of those studies suggest an increased risk of fractures, whereas others suggest the risk is not different from what is seen in the general population.
“Individual studies may be underpowered to detect any risk,” they said in the report.
Steroids have been shown to increase risk of spine and rib fracture, but whether those earlier studies apply in IBD is unclear, they noted.
While the present meta-analysis sheds light on fracture risk in IBD patients, further meta-analyses may be needed to specifically look at cohorts of patients with Crohn’s disease and ulcerative colitis.
In this study, the investigators did find that spine fracture risk was significantly elevated in patients with Crohn’s disease, and was trending toward significance for ulcerative colitis patients. They cautioned that those results were based on a limited amount of patient data.
Dr. Komaki reported that he had no disclosures related to the reported study. One study coauthor reported disclosures related to AbbVie and Celltrion.
SOURCE: Komaki Y et al. J Clin Gastroenterol. 2018 Apr 18. 2018 Apr 18. doi: 10.1097/MCG.0000000000001031.
Moreover, fracture risk appears to be higher among IBD patients using steroids, according to a report published in the Journal of Clinical Gastroenterology by Yuga Komaki, MD, of the Inflammatory Bowel Disease Center, University of Chicago, and coauthors.
“Further studies addressing the differential risk among Crohn’s disease and ulcerative colitis are needed, but strict surveillance and prevention of spine fractures are indicated in IBD,” wrote Dr. Komaki and associates.
The systematic review and meta-analysis by Dr. Komaki and colleagues was based on 10 studies comprising 470,541 patients with IBD for whom the risk of fracture was reported.
“It is of importance to identify the risk of fractures, as it will increase patient morbidity, disability, and mortality,” the authors wrote. “However, it is often overlooked in the management of IBD.”
Results of the analysis by this group of researchers showed that there was no significant difference in fracture risk overall between IBD patients and controls (odds ratio, 1.08; 95% confidence interval, 0.72-1.62; P = .70).
By contrast, the OR for spine fractures was significantly elevated (OR, 2.21; 95% CI, 1.39-3.50; P less than .0001), while risk of hip, rib, and wrist fractures were not, Dr. Komaki and coauthors said in their report.
Steroids were more often being used in the treatment of IBD patients who had fractures than in patients with no fractures, though the finding did not quite reach statistical significance (OR, 1.47; 95% CI, 0.99-2.20; P = .057).
Prior studies of fracture risk in IBD have shown “controversial results,” according to Dr. Komaki and colleagues. Some of those studies suggest an increased risk of fractures, whereas others suggest the risk is not different from what is seen in the general population.
“Individual studies may be underpowered to detect any risk,” they said in the report.
Steroids have been shown to increase risk of spine and rib fracture, but whether those earlier studies apply in IBD is unclear, they noted.
While the present meta-analysis sheds light on fracture risk in IBD patients, further meta-analyses may be needed to specifically look at cohorts of patients with Crohn’s disease and ulcerative colitis.
In this study, the investigators did find that spine fracture risk was significantly elevated in patients with Crohn’s disease, and was trending toward significance for ulcerative colitis patients. They cautioned that those results were based on a limited amount of patient data.
Dr. Komaki reported that he had no disclosures related to the reported study. One study coauthor reported disclosures related to AbbVie and Celltrion.
SOURCE: Komaki Y et al. J Clin Gastroenterol. 2018 Apr 18. 2018 Apr 18. doi: 10.1097/MCG.0000000000001031.
Moreover, fracture risk appears to be higher among IBD patients using steroids, according to a report published in the Journal of Clinical Gastroenterology by Yuga Komaki, MD, of the Inflammatory Bowel Disease Center, University of Chicago, and coauthors.
“Further studies addressing the differential risk among Crohn’s disease and ulcerative colitis are needed, but strict surveillance and prevention of spine fractures are indicated in IBD,” wrote Dr. Komaki and associates.
The systematic review and meta-analysis by Dr. Komaki and colleagues was based on 10 studies comprising 470,541 patients with IBD for whom the risk of fracture was reported.
“It is of importance to identify the risk of fractures, as it will increase patient morbidity, disability, and mortality,” the authors wrote. “However, it is often overlooked in the management of IBD.”
Results of the analysis by this group of researchers showed that there was no significant difference in fracture risk overall between IBD patients and controls (odds ratio, 1.08; 95% confidence interval, 0.72-1.62; P = .70).
By contrast, the OR for spine fractures was significantly elevated (OR, 2.21; 95% CI, 1.39-3.50; P less than .0001), while risk of hip, rib, and wrist fractures were not, Dr. Komaki and coauthors said in their report.
Steroids were more often being used in the treatment of IBD patients who had fractures than in patients with no fractures, though the finding did not quite reach statistical significance (OR, 1.47; 95% CI, 0.99-2.20; P = .057).
Prior studies of fracture risk in IBD have shown “controversial results,” according to Dr. Komaki and colleagues. Some of those studies suggest an increased risk of fractures, whereas others suggest the risk is not different from what is seen in the general population.
“Individual studies may be underpowered to detect any risk,” they said in the report.
Steroids have been shown to increase risk of spine and rib fracture, but whether those earlier studies apply in IBD is unclear, they noted.
While the present meta-analysis sheds light on fracture risk in IBD patients, further meta-analyses may be needed to specifically look at cohorts of patients with Crohn’s disease and ulcerative colitis.
In this study, the investigators did find that spine fracture risk was significantly elevated in patients with Crohn’s disease, and was trending toward significance for ulcerative colitis patients. They cautioned that those results were based on a limited amount of patient data.
Dr. Komaki reported that he had no disclosures related to the reported study. One study coauthor reported disclosures related to AbbVie and Celltrion.
SOURCE: Komaki Y et al. J Clin Gastroenterol. 2018 Apr 18. 2018 Apr 18. doi: 10.1097/MCG.0000000000001031.
FROM THE JOURNAL OF CLINICAL GASTROENTEROLOGY
Key clinical point: Patients with inflammatory bowel disease may be at increased risk of fractures in the spine.
Major finding: The odds ratio for spine fractures was 2.21 (95% CI, 1.39-3.50; P less than .0001).
Study details: A systematic review and meta-analysis of 10 studies including 470,541 patients.
Disclosures: One study author reported disclosures related to AbbVie and Celltrion.
Source: Komaki Y et al. J Clin Gastroenterol. 2018 Apr 18. doi: 10.1097/MCG.0000000000001031.
Use these two questions to simplify H. pylori treatment choice
Recent clinical guidelines have expanded not only the pool of patients who should be tested for Helicobacter pylori infection, but also the number of first-line treatment strategies clinicians should consider.
The American College of Gastroenterology guidelines from 2007 recommended just two treatments: clarithromycin-based triple therapy or bismuth-based quadruple therapy.
The 2017 update to ACG guidelines adds five additional recommended treatment possibilities, not all of which have been well studied in U.S. clinical practice, Colin W. Howden, MD, AGAF, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are a variety of options, and unfortunately for us as practitioners, antibiotic sensitivity testing is not routinely or easily available in contemporary U.S. practice,” said Dr. Howden, professor of medicine–gastroenterology at the University of Tennessee Health Sciences Center, Memphis.
Dr. Howden, a coauthor of the latest ACG guidelines, said asking two pointed questions outlined in the document can help simplify the treatment decision:
- Is there a penicillin allergy?
- Has there been previous macrolide exposure?
“The ideal situation is that the patient is not penicillin allergic, and they’ve never had a macrolide before,” Dr. Howden said. In that case, bismuth-based quadruple therapy would be an appropriate choice.
“Bismuth quadruple therapy is never the wrong answer,” he added.
Clarithromycin-based triple therapy might be considered, according to Dr. Howden, if the local rate of resistance to H. pylori is known to be low.
Bismuth-based quadruple therapy consists of a proton pump inhibitor (PPI) or H2 blocker, bismuth, tetracycline, and metronidazole for 10-14 days, while clarithromycin triple therapy consists of a PPI, clarithromycin, and amoxicillin or metronidazole for 10-14 days.
Several other options recently added to the guidelines have been tried in this scenario, he noted, including concomitant therapy, which consists of a PPI, clarithromycin, amoxicillin, and metronidazole for 10-14 days.
If there has been previous macrolide use but the patient is not penicillin allergic, bismuth quadruple therapy is again recommended, Dr. Howden said, and an additional approach might be the introduction of a levofloxacin-based regimen, as outlined in the guidelines.
Conversely, if there has been no previous macrolide use but the patient is confirmed to be penicillin allergic, the current guideline-recommended options are limited to bismuth quadruple therapy, or clarithromycin triple therapy with metronidazole instead of amoxicillin, Dr. Howden said at the meeting.
Finally, for penicillin-allergic patients with previous macrolide use, recommended options are whittled down to just bismuth-based quadruple therapy. “Again, it’s never the wrong answer,” Dr. Howden said.
Global Academy and this news organization are owned by the same parent company.
Dr. Howden reported disclosures related to Horizon, Otsuka, Allergan, Aralaez, EndoStim, Ironwood, Pfizer, and SynteractHCR.
Recent clinical guidelines have expanded not only the pool of patients who should be tested for Helicobacter pylori infection, but also the number of first-line treatment strategies clinicians should consider.
The American College of Gastroenterology guidelines from 2007 recommended just two treatments: clarithromycin-based triple therapy or bismuth-based quadruple therapy.
The 2017 update to ACG guidelines adds five additional recommended treatment possibilities, not all of which have been well studied in U.S. clinical practice, Colin W. Howden, MD, AGAF, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are a variety of options, and unfortunately for us as practitioners, antibiotic sensitivity testing is not routinely or easily available in contemporary U.S. practice,” said Dr. Howden, professor of medicine–gastroenterology at the University of Tennessee Health Sciences Center, Memphis.
Dr. Howden, a coauthor of the latest ACG guidelines, said asking two pointed questions outlined in the document can help simplify the treatment decision:
- Is there a penicillin allergy?
- Has there been previous macrolide exposure?
“The ideal situation is that the patient is not penicillin allergic, and they’ve never had a macrolide before,” Dr. Howden said. In that case, bismuth-based quadruple therapy would be an appropriate choice.
“Bismuth quadruple therapy is never the wrong answer,” he added.
Clarithromycin-based triple therapy might be considered, according to Dr. Howden, if the local rate of resistance to H. pylori is known to be low.
Bismuth-based quadruple therapy consists of a proton pump inhibitor (PPI) or H2 blocker, bismuth, tetracycline, and metronidazole for 10-14 days, while clarithromycin triple therapy consists of a PPI, clarithromycin, and amoxicillin or metronidazole for 10-14 days.
Several other options recently added to the guidelines have been tried in this scenario, he noted, including concomitant therapy, which consists of a PPI, clarithromycin, amoxicillin, and metronidazole for 10-14 days.
If there has been previous macrolide use but the patient is not penicillin allergic, bismuth quadruple therapy is again recommended, Dr. Howden said, and an additional approach might be the introduction of a levofloxacin-based regimen, as outlined in the guidelines.
Conversely, if there has been no previous macrolide use but the patient is confirmed to be penicillin allergic, the current guideline-recommended options are limited to bismuth quadruple therapy, or clarithromycin triple therapy with metronidazole instead of amoxicillin, Dr. Howden said at the meeting.
Finally, for penicillin-allergic patients with previous macrolide use, recommended options are whittled down to just bismuth-based quadruple therapy. “Again, it’s never the wrong answer,” Dr. Howden said.
Global Academy and this news organization are owned by the same parent company.
Dr. Howden reported disclosures related to Horizon, Otsuka, Allergan, Aralaez, EndoStim, Ironwood, Pfizer, and SynteractHCR.
Recent clinical guidelines have expanded not only the pool of patients who should be tested for Helicobacter pylori infection, but also the number of first-line treatment strategies clinicians should consider.
The American College of Gastroenterology guidelines from 2007 recommended just two treatments: clarithromycin-based triple therapy or bismuth-based quadruple therapy.
The 2017 update to ACG guidelines adds five additional recommended treatment possibilities, not all of which have been well studied in U.S. clinical practice, Colin W. Howden, MD, AGAF, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are a variety of options, and unfortunately for us as practitioners, antibiotic sensitivity testing is not routinely or easily available in contemporary U.S. practice,” said Dr. Howden, professor of medicine–gastroenterology at the University of Tennessee Health Sciences Center, Memphis.
Dr. Howden, a coauthor of the latest ACG guidelines, said asking two pointed questions outlined in the document can help simplify the treatment decision:
- Is there a penicillin allergy?
- Has there been previous macrolide exposure?
“The ideal situation is that the patient is not penicillin allergic, and they’ve never had a macrolide before,” Dr. Howden said. In that case, bismuth-based quadruple therapy would be an appropriate choice.
“Bismuth quadruple therapy is never the wrong answer,” he added.
Clarithromycin-based triple therapy might be considered, according to Dr. Howden, if the local rate of resistance to H. pylori is known to be low.
Bismuth-based quadruple therapy consists of a proton pump inhibitor (PPI) or H2 blocker, bismuth, tetracycline, and metronidazole for 10-14 days, while clarithromycin triple therapy consists of a PPI, clarithromycin, and amoxicillin or metronidazole for 10-14 days.
Several other options recently added to the guidelines have been tried in this scenario, he noted, including concomitant therapy, which consists of a PPI, clarithromycin, amoxicillin, and metronidazole for 10-14 days.
If there has been previous macrolide use but the patient is not penicillin allergic, bismuth quadruple therapy is again recommended, Dr. Howden said, and an additional approach might be the introduction of a levofloxacin-based regimen, as outlined in the guidelines.
Conversely, if there has been no previous macrolide use but the patient is confirmed to be penicillin allergic, the current guideline-recommended options are limited to bismuth quadruple therapy, or clarithromycin triple therapy with metronidazole instead of amoxicillin, Dr. Howden said at the meeting.
Finally, for penicillin-allergic patients with previous macrolide use, recommended options are whittled down to just bismuth-based quadruple therapy. “Again, it’s never the wrong answer,” Dr. Howden said.
Global Academy and this news organization are owned by the same parent company.
Dr. Howden reported disclosures related to Horizon, Otsuka, Allergan, Aralaez, EndoStim, Ironwood, Pfizer, and SynteractHCR.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES
Women’s representation in CV drug trials still lagging
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Any optimism for results of this study by FDA authors are dampened significantly by the continued under-representation of women in heart failure and ischemic heart disease.
Even though progress has been made toward a higher participation of women in pivotal clinical trials, it still is not time to rest on our laurels.
One key contributor to the persistently low representation of women is the eligibility criteria of clinical trials. Those criteria often describe a male pattern of disease, particularly in drug trials for ischemic heart disease and heart failure.
As an example, heart failure trials have included eligibility criteria that consistently exclude women, such as a glomerular filtration rate less than 30 mL/min per 1.73 m2, and an ejection fraction of 40% or less.
The inclusion criteria in randomized, controlled trials impose homogeneous clinical characteristics for men and women and may be responsible for the lack of sex differences in efficacy outcomes.
Thus, the current analysis exposes not only successes but also failings of clinical trial design for FDA approval. We are still far from providing equitable cardiovascular health care for women.
Louise Pilote, MD, MPH, PhD, and Valeria Raparelli, MD, PhD, are both affiliated with McGill University Health Centre, Montreal. These comments are derived from their editorial in the Journal of the American College of Cardiology . Both reported that they had no relationships relevant to the contents of their editorial.
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
Although women have been well represented recently in certain types of cardiovascular drug trials, they remain underrepresented in studies of heart failure, coronary artery disease, and acute coronary syndrome, a recent study authored by Food and Drug Administration researchers has revealed.
However, representation of women fell below an acceptable participation-to-prevalence ratio in those other trial types that were evaluated, according to researchers, including lead author Pamela E. Scott, PhD, of the FDA’s Office of Women’s Health.
“As we move into the era of precision medicine – that is, assessing the impact of a wide range of patient and disease characteristics on drug effects – it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed,” Dr. Scott and her colleagues said in the report.
To quantify the participation of women in clinical trials, Dr. Scott and coinvestigators reviewed publicly available FDA reviews from 2005 to 2015 supporting the approval of 36 drugs.
They used a metric called the participation-to-prevalence ratio (PPR) to compare representation of women in a study relative to the representation of women in the disease population being studied. The range of PPR of 0.8-1.2 represented similar representation of women in the study and disease population.
Participation of women in drug trials varied widely – from a low of 22% to a high of 81% – with a mean of 46%, they found.
The PPR was within the desirable range for hypertension, at 0.9, and atrial fibrillation trials, at 0.8-1.1, while participation for pulmonary arterial hypertension trials was above the desirable range, at 1.4, according to the report.
However, a PPR of less than 0.8 was found for coronary artery disease trials, at 0.6; acute coronary syndrome/myocardial infarction trials, also at 0.6; and heart failure trials, at 0.5 to 0.6.
Few clinically meaningful gender differences were found in efficacy or safety, they added, noting that such differences were discussed in the prescribing information for four different drugs.
To ensure that representative patient populations are enrolled in drug trials, clinical researchers, patient advocacy groups, federal agencies, and the industry as a whole should work together, Dr. Scott and her colleagues said.
“These steps will move us closer toward the goal of providing the best information possible about the use of drugs for every patient,” they wrote.
Dr. Scott and coauthors reported that they had no relationships relevant to their study.
SOURCE: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
FROM THE JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
Key clinical point: Although women are well represented in clinical trials for hypertension, atrial fibrillation, and pulmonary arterial hypertension, they are not well represented in other trial types.
Major finding: The participation-to-prevalence ratio fell below 0.8 (that is, the bottom end of the range reflecting a similar representation of women) for coronary artery disease, acute coronary syndrome, and heart failure.
Study details: An assessment of publicly available FDA data from 2005 to 2015 on enrollment of women in clinical trials representing 36 drug approvals.
Disclosures: Authors reported that they had no relationships relevant to their report.
Source: Scott PE et al. J Am Coll Cardiol. 2018 May 18;71:1960-9.
Hep B therapy: Indefinite or FINITE for e-negative patients?
LAS VEGAS – Current guidelines recommend indefinite continuation of antiviral therapy in chronic hepatitis B patients who are hepatitis B e-antigen (HBeAg)-negative. But emerging data suggest that this may not always be the case.
“It’s very provocative data, though not at the guideline level,” W. Ray Kim, MD, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are patients who really have begged to go off treatment because they are sick of taking the medication for year after year after year,” said Dr. Kim, professor of medicine, gastroenterology and hepatology, Stanford (Calif.) University.
In light of new data, taking them off medication might be “something to consider” in noncirrhotic patients if they are completely suppressed, have normal ALT, and have a low level of quantitative hepatitis B surface antigen (HBsAg), Dr. Kim told attendees.
The most current Association for the Advancement of the Study of Liver Diseases guidelines state that unless there is a competing rationale, antiviral therapy should be continued indefinitely for noncirrhotic adults with HBeAg‐negative immune‐active chronic hepatitis B.
They do also say that treatment discontinuation “may be considered” for individuals with proven loss of HBsAg. “However, there is currently insufficient evidence to definitively guide treatment decisions for such persons,” the guidelines say.
Evidence has emerged since those guideline statements were written. Most recently, German investigators published results of the FINITE study showing some long-term responses after stopping tenofovir disoproxil fumarate (TDF) in noncirrhotic, HBeAg-negative patients.
In that prospective, controlled study, 62% of patients who stopped TDF therapy (n = 13) stayed off therapy to week 144 of treatment follow-up. Four of the patients achieved HBsAg loss, and median HBsAg change was –0.59log10IU/mL vs. 0.21log10IU/mL in patients who stayed on TDF therapy.
Investigators said that result demonstrated the potential of stopping long-term TDF treatment and seeing either HBsAg loss or sustained virologic response.
Before that, a retrospective study from investigators in Taiwan showed that age plus level of HBsAg were associated with HBV relapse after entecavir treatment in HBeAg-negative patients. According to investigators, those results suggested HBsAg levels could be used to guide timing of entecavir cessation.
If antiviral therapy is stopped in an HBeAg-negative patient, that patient should be monitored every 3 month for a year for recurrent viremia, ALT flares, and hepatic decompensation, Dr. Kim said at the meeting.
Even before stopping, “there are a number of factors to consider, including biological relapse, flare, hepatic decompensation,” he said.
On the other hand, there is the burden of continued therapy, financial concerns of continuing treatment due not only to medication costs but also long-term monitoring, as well as patient and provider preference, he noted in his presentation.
Global Academy and this news organization are owned by the same parent company.
Dr. Kim reported serving as a consultant to Gilead.
LAS VEGAS – Current guidelines recommend indefinite continuation of antiviral therapy in chronic hepatitis B patients who are hepatitis B e-antigen (HBeAg)-negative. But emerging data suggest that this may not always be the case.
“It’s very provocative data, though not at the guideline level,” W. Ray Kim, MD, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are patients who really have begged to go off treatment because they are sick of taking the medication for year after year after year,” said Dr. Kim, professor of medicine, gastroenterology and hepatology, Stanford (Calif.) University.
In light of new data, taking them off medication might be “something to consider” in noncirrhotic patients if they are completely suppressed, have normal ALT, and have a low level of quantitative hepatitis B surface antigen (HBsAg), Dr. Kim told attendees.
The most current Association for the Advancement of the Study of Liver Diseases guidelines state that unless there is a competing rationale, antiviral therapy should be continued indefinitely for noncirrhotic adults with HBeAg‐negative immune‐active chronic hepatitis B.
They do also say that treatment discontinuation “may be considered” for individuals with proven loss of HBsAg. “However, there is currently insufficient evidence to definitively guide treatment decisions for such persons,” the guidelines say.
Evidence has emerged since those guideline statements were written. Most recently, German investigators published results of the FINITE study showing some long-term responses after stopping tenofovir disoproxil fumarate (TDF) in noncirrhotic, HBeAg-negative patients.
In that prospective, controlled study, 62% of patients who stopped TDF therapy (n = 13) stayed off therapy to week 144 of treatment follow-up. Four of the patients achieved HBsAg loss, and median HBsAg change was –0.59log10IU/mL vs. 0.21log10IU/mL in patients who stayed on TDF therapy.
Investigators said that result demonstrated the potential of stopping long-term TDF treatment and seeing either HBsAg loss or sustained virologic response.
Before that, a retrospective study from investigators in Taiwan showed that age plus level of HBsAg were associated with HBV relapse after entecavir treatment in HBeAg-negative patients. According to investigators, those results suggested HBsAg levels could be used to guide timing of entecavir cessation.
If antiviral therapy is stopped in an HBeAg-negative patient, that patient should be monitored every 3 month for a year for recurrent viremia, ALT flares, and hepatic decompensation, Dr. Kim said at the meeting.
Even before stopping, “there are a number of factors to consider, including biological relapse, flare, hepatic decompensation,” he said.
On the other hand, there is the burden of continued therapy, financial concerns of continuing treatment due not only to medication costs but also long-term monitoring, as well as patient and provider preference, he noted in his presentation.
Global Academy and this news organization are owned by the same parent company.
Dr. Kim reported serving as a consultant to Gilead.
LAS VEGAS – Current guidelines recommend indefinite continuation of antiviral therapy in chronic hepatitis B patients who are hepatitis B e-antigen (HBeAg)-negative. But emerging data suggest that this may not always be the case.
“It’s very provocative data, though not at the guideline level,” W. Ray Kim, MD, said in a presentation at the inaugural Perspectives in Digestive Diseases meeting held by Global Academy for Medical Education.
“There are patients who really have begged to go off treatment because they are sick of taking the medication for year after year after year,” said Dr. Kim, professor of medicine, gastroenterology and hepatology, Stanford (Calif.) University.
In light of new data, taking them off medication might be “something to consider” in noncirrhotic patients if they are completely suppressed, have normal ALT, and have a low level of quantitative hepatitis B surface antigen (HBsAg), Dr. Kim told attendees.
The most current Association for the Advancement of the Study of Liver Diseases guidelines state that unless there is a competing rationale, antiviral therapy should be continued indefinitely for noncirrhotic adults with HBeAg‐negative immune‐active chronic hepatitis B.
They do also say that treatment discontinuation “may be considered” for individuals with proven loss of HBsAg. “However, there is currently insufficient evidence to definitively guide treatment decisions for such persons,” the guidelines say.
Evidence has emerged since those guideline statements were written. Most recently, German investigators published results of the FINITE study showing some long-term responses after stopping tenofovir disoproxil fumarate (TDF) in noncirrhotic, HBeAg-negative patients.
In that prospective, controlled study, 62% of patients who stopped TDF therapy (n = 13) stayed off therapy to week 144 of treatment follow-up. Four of the patients achieved HBsAg loss, and median HBsAg change was –0.59log10IU/mL vs. 0.21log10IU/mL in patients who stayed on TDF therapy.
Investigators said that result demonstrated the potential of stopping long-term TDF treatment and seeing either HBsAg loss or sustained virologic response.
Before that, a retrospective study from investigators in Taiwan showed that age plus level of HBsAg were associated with HBV relapse after entecavir treatment in HBeAg-negative patients. According to investigators, those results suggested HBsAg levels could be used to guide timing of entecavir cessation.
If antiviral therapy is stopped in an HBeAg-negative patient, that patient should be monitored every 3 month for a year for recurrent viremia, ALT flares, and hepatic decompensation, Dr. Kim said at the meeting.
Even before stopping, “there are a number of factors to consider, including biological relapse, flare, hepatic decompensation,” he said.
On the other hand, there is the burden of continued therapy, financial concerns of continuing treatment due not only to medication costs but also long-term monitoring, as well as patient and provider preference, he noted in his presentation.
Global Academy and this news organization are owned by the same parent company.
Dr. Kim reported serving as a consultant to Gilead.
EXPERT ANALYSIS FROM PERSPECTIVES IN DIGESTIVE DISEASES