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AGA releases clinical practice update for pancreatic necrosis
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
Review the Gastroenterology clinical guidelines collection for AGA Institute statements detailing preferred approaches to specific medical problems or issues based on the most current available data at https://www.gastrojournal.
FROM GASTROENTEROLOGY
Bile acid diarrhea guideline highlights data shortage
The Canadian Association of Gastroenterology (CAG) recently published a clinical practice guideline for the management of bile acid diarrhea (BAD).
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
The Canadian Association of Gastroenterology (CAG) recently published a clinical practice guideline for the management of bile acid diarrhea (BAD).
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
The Canadian Association of Gastroenterology (CAG) recently published a clinical practice guideline for the management of bile acid diarrhea (BAD).
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The Canadian Association of Gastroenterology recently published a clinical practice guideline for the management of bile acid diarrhea (BAD).
Major finding: BAD occurs in up to 35% of patients with chronic diarrhea or diarrhea-predominant irritable bowel syndrome.
Study details: A clinical practice guideline for the management of BAD.
Disclosures: The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
Source: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
Bile acid diarrhea guideline highlights data shortage
The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
The Canadian Association of Gastroenterology (CAG) recently co-published a clinical practice guideline for the management of bile acid diarrhea (BAD) in Clinical Gastroenterology and Hepatology and the Journal of the Canadian Association of Gastroenterology.
Given a minimal evidence base, 16 out of the 17 guideline recommendations are conditional, according to lead author Daniel C. Sadowski, MD, of Royal Alexandra Hospital, Edmonton, Alta., and colleagues. Considering the shortage of high-quality evidence, the panel called for more randomized clinical trials to address current knowledge gaps.
“BAD is an understudied, often underappreciated condition, and questions remain regarding its diagnosis and treatment,” the panelists wrote in Clinical Gastroenterology and Hepatology. “There have been guidelines on the management of chronic diarrhea from the American Gastroenterological Association, and the British Society of Gastroenterology, but diagnosis and management of BAD was not assessed extensively in these publications. The British Society of Gastroenterology updated guidelines on the investigation of chronic diarrhea in adults, published after the consensus meeting, addressed some issues related to BAD.”
For the current guideline, using available evidence and clinical experience, expert panelists from Canada, the United States, and the United Kingdom aimed to “provide a reasonable and practical approach to care for specialists.” The guideline was further reviewed by the CAG Practice Affairs and Clinical Affairs Committees and the CAG Board of Directors.
The guideline first puts BAD in clinical context, noting a chronic diarrhea prevalence rate of approximately 5%. According to the guideline, approximately 1 out of 4 of these patients with chronic diarrhea may have BAD and prevalence of BAD is likely higher among those with other conditions, such as terminal ileal disease.
While BAD may be relatively common, it isn’t necessarily easy to diagnose, the panelists noted.
“The diagnosis of BAD continues to be a challenge, although this may be improved in the future with the general availability of screening serologic tests and other diagnostic tests,” the panelists wrote. “Although a treatment trial with bile acid sequestrants therapy (BAST) often is used, this approach has not been studied adequately, and likely is imprecise, and may lead to both undertreatment and overtreatment.”
Instead, the panelists recommended testing for BAD with 75-selenium homocholic acid taurine (SeHCAT) or 7-alpha-hydroxy-4-cholesten-3-one.
After addressing treatable causes of BAD, the guideline recommends initial therapy with cholestyramine or, if this is poorly tolerated, switching to BAST. However, the panelists advised against BAST for patients with resection or ileal Crohn’s disease, for whom other antidiarrheal agents are more suitable. When appropriate, BAST should be given at the lowest effective dose, with periodic trials of on-demand, intermittent administration, the panelists recommended. When BAST is ineffective, the guideline recommends that clinicians review concurrent medications as a possible cause of BAD or reinvestigate.
Concluding the guideline, the panelists emphasized the need for more high-quality research.
“The group recognized that specific, high-certainty evidence was lacking in many areas and recommended further studies that would improve the data available in future methodologic evaluations,” the panelists wrote.
While improving diagnostic accuracy of BAD should be a major goal of such research, progress is currently limited by an integral shortcoming of diagnostic test accuracy (DTA) studies, the panelists wrote.
“The main challenge in conducting DTA studies for BAD is the lack of a widely accepted or universally agreed-upon reference standard because the condition is defined and classified based on pathophysiologic mechanisms and its response to treatment (BAST),” the panelists wrote. “In addition, the index tests (SeHCAT, C4, FGF19, fecal bile acid assay) provide a continuous measure of metabolic function. Hence, DTA studies are not the most appropriate study design.”
“Therefore, one of the research priorities in BAD is for the scientific and clinical communities to agree on a reference standard that best represents BAD (e.g., response to BAST), with full understanding that the reference standard is and likely will be imperfect.”
The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
Review the AGA clinical practice guideline on the laboratory evaluation of functional diarrhea and diarrhea-predominan irritable bowel syndrome in adults at https:/www.gastrojournal.org/article/S0016-5085(19)41083-4/fulltext.
SOURCE: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The Canadian Association of Gastroenterology recently published a clinical practice guideline for the management of bile acid diarrhea (BAD).
Major finding: BAD occurs in up to 35% of patients with chronic diarrhea or diarrhea-predominant irritable bowel syndrome.
Study details: A clinical practice guideline for the management of BAD.
Disclosures: The guideline was funded by unrestricted grants from Pendopharm and GE Healthcare Canada. The panelists disclosed relationships with AstraZeneca, AbbVie, Merck, Pfizer, and others.
Source: Sadowski DC et al. Clin Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.cgh.2019.08.062.
AGA releases clinical practice update for pancreatic necrosis
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
The American Gastroenterological Association recently issued a clinical practice update for the management of pancreatic necrosis, including 15 recommendations based on a comprehensive literature review and the experiences of leading experts.
Recommendations range from the general, such as the need for a multidisciplinary approach, to the specific, such as the superiority of metal over plastic stents for endoscopic transmural drainage.
The expert review, which was conducted by lead author Todd H. Baron, MD, of the University of North Carolina in Chapel Hill and three other colleagues, was vetted by the AGA Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board. In addition, the update underwent external peer review prior to publication in Gastroenterology.
In the update, the authors outlined the clinical landscape for pancreatic necrosis, including challenges posed by complex cases and a mortality rate as high as 30%.
“Successful management of these patients requires expert multidisciplinary care by gastroenterologists, surgeons, interventional radiologists, and specialists in critical care medicine, infectious disease, and nutrition,” the investigators wrote.
They went on to explain how management has evolved over the past 10 years.
“Whereby major surgical intervention and debridement was once the mainstay of therapy for patients with symptomatic necrotic collections, a minimally invasive approach focusing on percutaneous drainage and/or endoscopic drainage or debridement is now favored,” they wrote. They added that debridement is still generally agreed to be the best choice for cases of infected necrosis or patients with sterile necrosis “marked by abdominal pain, nausea, vomiting, and nutritional failure or with associated complications including gastrointestinal luminal obstruction, biliary obstruction, recurrent acute pancreatitis, fistulas, or persistent systemic inflammatory response syndrome (SIRS).”
Other elements of care, however, remain debated, the investigators noted, which has led to variations in multiple aspects of care, such as interventional timing, intravenous fluids, antibiotics, and nutrition. Within this framework, the present practice update is aimed at offering “concise best practice advice for the optimal management of patients with this highly morbid condition.”
Among these pieces of advice, the authors emphasized that routine prophylactic antibiotics and/or antifungals to prevent infected necrosis are unsupported by multiple clinical trials. When infection is suspected, the update recommends broad spectrum intravenous antibiotics, noting that, in most cases, it is unnecessary to perform CT-guided fine-needle aspiration for cultures and gram stain.
Regarding nutrition, the update recommends against “pancreatic rest”; instead, it calls for early oral intake and, if this is not possible, then initiation of total enteral nutrition. Although the authors deemed multiple routes of enteral feeding acceptable, they favored nasogastric or nasoduodenal tubes, when appropriate, because of ease of placement and maintenance. For prolonged total enteral nutrition or patients unable to tolerate nasoenteric feeding, the authors recommended endoscopic feeding tube placement with a percutaneous endoscopic gastrostomy tube for those who can tolerate gastric feeding or a percutaneous endoscopic jejunostomy tube for those who cannot or have a high risk of aspiration.
As described above, the update recommends debridement for cases of infected pancreatic necrosis. Ideally, this should be performed at least 4 weeks after onset, and avoided altogether within the first 2 weeks, because of associated risks of morbidity and mortality; instead, during this acute phase, percutaneous drainage may be considered.
For walled-off pancreatic necrosis, the authors recommended transmural drainage via endoscopic therapy because this mitigates risk of pancreatocutaneous fistula. Percutaneous drainage may be considered in addition to, or in absence of, endoscopic drainage, depending on clinical status.
The remainder of the update covers decisions related to stents, other minimally invasive techniques, open operative debridement, and disconnected left pancreatic remnants, along with discussions of key supporting clinical trials.
The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
SOURCE: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
FROM GASTROENTEROLOGY
Key clinical point: The American Gastroenterological Association has issued a clinical practice update for the management of pancreatic necrosis.
Major finding: N/A
Study details: A clinical practice update for the management of pancreatic necrosis.
Disclosures: The investigators disclosed relationships with Cook Endoscopy, Boston Scientific, Olympus, and others.
Source: Baron TH et al. Gastroenterology. 2019 Aug 31. doi: 10.1053/j.gastro.2019.07.064.
Inner demons
Julia Brennan sings about inner demons. They just won’t go away and they don’t play fair with angels. We have marveled at the miracles of fecal microbiome transplants (FMT), but this month we read about an inner demon. Two patients developed bacteremia from extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli transmitted during FMT from stool derived from a single donor. One patient, with cirrhosis, who received FMT as part of a trial to treat hepatic encephalopathy, recovered. A second patient with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation and received FMT as part of a phase 2 trial. This severely immunocompromised patient succumbed to sepsis related to the E. coli bacteremia. Both organisms were genetically traced to the donor stool. The AGA has NIH funding to develop and maintain an FMT registry (see https://www.gastrojournal.org/article/S0016-5085(17)30088-4/pdf) so we can understand long-term risks and benefits.
These rare experiences will lead to increased scrutiny and likely further FDA regulations. Gastroenterologists should be careful about choosing patients for FMT.
This month, we again feature an article about incorporating telehealth into your practice – this month’s article highlights the potential for private practices to incorporate this emerging technology. There are interesting articles about treatment of eosinophilic esophagitis, acute liver failure, and postcolonoscopy interval cancers. Finally, we are cautioned about the vulnerability of our biosimilar market. This market may wither despite the great potential to reduce therapeutic costs.
Last week, I taught an undergraduate course about health care economics. After recounting current challenges, one student said, “I am a first-year medical student, what should I do?” I was caught off guard. The future is too overwhelming. As we enter the 12-month countdown to a national election, I would suggest that we continue to advocate for our patients and educate our political leaders about verifiable root causes of our major problems. Despite current antipathy to science and data, we are scientists and eventually truth will prevail. “The arc of the moral universe is long, but it bends towards justice” (Dr. Martin Luther King, Jr.).
John I. Allen, MD, MBA, AGAF
Editor in Chief
Julia Brennan sings about inner demons. They just won’t go away and they don’t play fair with angels. We have marveled at the miracles of fecal microbiome transplants (FMT), but this month we read about an inner demon. Two patients developed bacteremia from extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli transmitted during FMT from stool derived from a single donor. One patient, with cirrhosis, who received FMT as part of a trial to treat hepatic encephalopathy, recovered. A second patient with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation and received FMT as part of a phase 2 trial. This severely immunocompromised patient succumbed to sepsis related to the E. coli bacteremia. Both organisms were genetically traced to the donor stool. The AGA has NIH funding to develop and maintain an FMT registry (see https://www.gastrojournal.org/article/S0016-5085(17)30088-4/pdf) so we can understand long-term risks and benefits.
These rare experiences will lead to increased scrutiny and likely further FDA regulations. Gastroenterologists should be careful about choosing patients for FMT.
This month, we again feature an article about incorporating telehealth into your practice – this month’s article highlights the potential for private practices to incorporate this emerging technology. There are interesting articles about treatment of eosinophilic esophagitis, acute liver failure, and postcolonoscopy interval cancers. Finally, we are cautioned about the vulnerability of our biosimilar market. This market may wither despite the great potential to reduce therapeutic costs.
Last week, I taught an undergraduate course about health care economics. After recounting current challenges, one student said, “I am a first-year medical student, what should I do?” I was caught off guard. The future is too overwhelming. As we enter the 12-month countdown to a national election, I would suggest that we continue to advocate for our patients and educate our political leaders about verifiable root causes of our major problems. Despite current antipathy to science and data, we are scientists and eventually truth will prevail. “The arc of the moral universe is long, but it bends towards justice” (Dr. Martin Luther King, Jr.).
John I. Allen, MD, MBA, AGAF
Editor in Chief
Julia Brennan sings about inner demons. They just won’t go away and they don’t play fair with angels. We have marveled at the miracles of fecal microbiome transplants (FMT), but this month we read about an inner demon. Two patients developed bacteremia from extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli transmitted during FMT from stool derived from a single donor. One patient, with cirrhosis, who received FMT as part of a trial to treat hepatic encephalopathy, recovered. A second patient with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation and received FMT as part of a phase 2 trial. This severely immunocompromised patient succumbed to sepsis related to the E. coli bacteremia. Both organisms were genetically traced to the donor stool. The AGA has NIH funding to develop and maintain an FMT registry (see https://www.gastrojournal.org/article/S0016-5085(17)30088-4/pdf) so we can understand long-term risks and benefits.
These rare experiences will lead to increased scrutiny and likely further FDA regulations. Gastroenterologists should be careful about choosing patients for FMT.
This month, we again feature an article about incorporating telehealth into your practice – this month’s article highlights the potential for private practices to incorporate this emerging technology. There are interesting articles about treatment of eosinophilic esophagitis, acute liver failure, and postcolonoscopy interval cancers. Finally, we are cautioned about the vulnerability of our biosimilar market. This market may wither despite the great potential to reduce therapeutic costs.
Last week, I taught an undergraduate course about health care economics. After recounting current challenges, one student said, “I am a first-year medical student, what should I do?” I was caught off guard. The future is too overwhelming. As we enter the 12-month countdown to a national election, I would suggest that we continue to advocate for our patients and educate our political leaders about verifiable root causes of our major problems. Despite current antipathy to science and data, we are scientists and eventually truth will prevail. “The arc of the moral universe is long, but it bends towards justice” (Dr. Martin Luther King, Jr.).
John I. Allen, MD, MBA, AGAF
Editor in Chief
Leadership & Professional Development: Get to the “Both/And”
“For every complex problem there is a simple solution. And it’s wrong.”
—Anonymous as quoted in Barry Johnson’s Polarity Management1
Hospital medicine leaders often face what seem like unsolvable problems involving two opposing sides or viewpoints. Examples include individual versus team, margin versus mission, learner autonomy versus supervision, and customization versus standardization. Dr. Barry Johnson describes these dyads as polarities, which are two different values or points of view that are interdependent.1,2 Leaders who fail to realize this concept create a problem by artificially inserting the word ‘versus’ between the poles.
Polarities are not problems to be solved. How does one solve individual? Or team? How can a hospital have one without the other? When leaders treat polarities like problems to be solved, they typically crusade for one side over the other, until the losing side rises up for its own cause, causing a perpetual back and forth cycle described as an infinity loop where nobody is happy for long.1
How then can leaders avoid getting caught in this fruitless cycle?
Instead of trying to solve the unsolvable, learn to manage polarities. Polarity management seeks to maximize the best of both poles while minimizing the worst. Both sides of a polarity carry upsides and downsides. When leaders want change, or want to resist change, it is the fear of being caught in the downsides of the opposite pole that motivates behavior, and dominates conversation. The first step to changing this conversation is to introduce the concept to your team so they recognize polarities when they arise and model approaching issues in this manner.
Some issues truly are problems to be solved (for example, the ultrasound machine is broken and needs to be repaired), but many conflicts are polarities masquerading as problems. To identify polarities, ask two questions. (1) Is the situation ongoing? (2) Are there two interdependent poles? If yes, then the issue is a polarity. Ideal polarity management involves maximizing the upside values of both poles before potential conflict even begins. People often force themselves into unnecessary “either/or” mindsets rather than striving for “both/and”.
Here is a classic example in Hospital Medicine: Pole 1: customization Pole 2: standardization -- The Chief Medical Information Officer (CMIO) wants everyone to use the same electronic health record (EHR) template, while the hospitalist group wants to innovate templates using rapid cycles of change. Typical patterns of conflict: the CMIO releases a template and the hospitalists resent it, or the hospitalists each create their own notes but the CMIO bemoans the variability.
Once polarities are recognized, teams can draw a ‘polarity map’ to see the whole picture, identifying the upside values and downside fears of each pole.1,2 For example, standardization reduces unnecessary variation, but stifles innovation, while customization does the opposite. In fact, the upside values of one pole are usually the opposite of the downside fears of the other.
Leaders can actively engage people in both poles to make opposing views productive rather than destructive. The CMIO in our standardization/customization example could insist that everyone begins with the same template, but allow hospitalists to innovate to find a better way. Now the most resistant hospitalists become improvement agents. If a better way is found, then this becomes the new template that all hospitalists use, until the next better way is found. If an innovation is not an improvement, then hospitalists agree to return to the most recent successful template until a better way is found. This method of action and compromise produces both standardization and customization.
Using polarity management strategies does not guarantee success, but it can help engage all stakeholders, and break the frustrating cycle of repeatedly trying to solve the unsolvable.
Disclosures
The authors report no conflicts of interest or sources of funding.
1. Johnson B. Polarity management: Identifying and managing unsolvable problems. Human Resource Development; 1992.
2. Wesorick BL. Polarity thinking: An essential skill for those leading interprofessional integration. J Interprofessional Healthcare. 2014;1(1):12.
“For every complex problem there is a simple solution. And it’s wrong.”
—Anonymous as quoted in Barry Johnson’s Polarity Management1
Hospital medicine leaders often face what seem like unsolvable problems involving two opposing sides or viewpoints. Examples include individual versus team, margin versus mission, learner autonomy versus supervision, and customization versus standardization. Dr. Barry Johnson describes these dyads as polarities, which are two different values or points of view that are interdependent.1,2 Leaders who fail to realize this concept create a problem by artificially inserting the word ‘versus’ between the poles.
Polarities are not problems to be solved. How does one solve individual? Or team? How can a hospital have one without the other? When leaders treat polarities like problems to be solved, they typically crusade for one side over the other, until the losing side rises up for its own cause, causing a perpetual back and forth cycle described as an infinity loop where nobody is happy for long.1
How then can leaders avoid getting caught in this fruitless cycle?
Instead of trying to solve the unsolvable, learn to manage polarities. Polarity management seeks to maximize the best of both poles while minimizing the worst. Both sides of a polarity carry upsides and downsides. When leaders want change, or want to resist change, it is the fear of being caught in the downsides of the opposite pole that motivates behavior, and dominates conversation. The first step to changing this conversation is to introduce the concept to your team so they recognize polarities when they arise and model approaching issues in this manner.
Some issues truly are problems to be solved (for example, the ultrasound machine is broken and needs to be repaired), but many conflicts are polarities masquerading as problems. To identify polarities, ask two questions. (1) Is the situation ongoing? (2) Are there two interdependent poles? If yes, then the issue is a polarity. Ideal polarity management involves maximizing the upside values of both poles before potential conflict even begins. People often force themselves into unnecessary “either/or” mindsets rather than striving for “both/and”.
Here is a classic example in Hospital Medicine: Pole 1: customization Pole 2: standardization -- The Chief Medical Information Officer (CMIO) wants everyone to use the same electronic health record (EHR) template, while the hospitalist group wants to innovate templates using rapid cycles of change. Typical patterns of conflict: the CMIO releases a template and the hospitalists resent it, or the hospitalists each create their own notes but the CMIO bemoans the variability.
Once polarities are recognized, teams can draw a ‘polarity map’ to see the whole picture, identifying the upside values and downside fears of each pole.1,2 For example, standardization reduces unnecessary variation, but stifles innovation, while customization does the opposite. In fact, the upside values of one pole are usually the opposite of the downside fears of the other.
Leaders can actively engage people in both poles to make opposing views productive rather than destructive. The CMIO in our standardization/customization example could insist that everyone begins with the same template, but allow hospitalists to innovate to find a better way. Now the most resistant hospitalists become improvement agents. If a better way is found, then this becomes the new template that all hospitalists use, until the next better way is found. If an innovation is not an improvement, then hospitalists agree to return to the most recent successful template until a better way is found. This method of action and compromise produces both standardization and customization.
Using polarity management strategies does not guarantee success, but it can help engage all stakeholders, and break the frustrating cycle of repeatedly trying to solve the unsolvable.
Disclosures
The authors report no conflicts of interest or sources of funding.
“For every complex problem there is a simple solution. And it’s wrong.”
—Anonymous as quoted in Barry Johnson’s Polarity Management1
Hospital medicine leaders often face what seem like unsolvable problems involving two opposing sides or viewpoints. Examples include individual versus team, margin versus mission, learner autonomy versus supervision, and customization versus standardization. Dr. Barry Johnson describes these dyads as polarities, which are two different values or points of view that are interdependent.1,2 Leaders who fail to realize this concept create a problem by artificially inserting the word ‘versus’ between the poles.
Polarities are not problems to be solved. How does one solve individual? Or team? How can a hospital have one without the other? When leaders treat polarities like problems to be solved, they typically crusade for one side over the other, until the losing side rises up for its own cause, causing a perpetual back and forth cycle described as an infinity loop where nobody is happy for long.1
How then can leaders avoid getting caught in this fruitless cycle?
Instead of trying to solve the unsolvable, learn to manage polarities. Polarity management seeks to maximize the best of both poles while minimizing the worst. Both sides of a polarity carry upsides and downsides. When leaders want change, or want to resist change, it is the fear of being caught in the downsides of the opposite pole that motivates behavior, and dominates conversation. The first step to changing this conversation is to introduce the concept to your team so they recognize polarities when they arise and model approaching issues in this manner.
Some issues truly are problems to be solved (for example, the ultrasound machine is broken and needs to be repaired), but many conflicts are polarities masquerading as problems. To identify polarities, ask two questions. (1) Is the situation ongoing? (2) Are there two interdependent poles? If yes, then the issue is a polarity. Ideal polarity management involves maximizing the upside values of both poles before potential conflict even begins. People often force themselves into unnecessary “either/or” mindsets rather than striving for “both/and”.
Here is a classic example in Hospital Medicine: Pole 1: customization Pole 2: standardization -- The Chief Medical Information Officer (CMIO) wants everyone to use the same electronic health record (EHR) template, while the hospitalist group wants to innovate templates using rapid cycles of change. Typical patterns of conflict: the CMIO releases a template and the hospitalists resent it, or the hospitalists each create their own notes but the CMIO bemoans the variability.
Once polarities are recognized, teams can draw a ‘polarity map’ to see the whole picture, identifying the upside values and downside fears of each pole.1,2 For example, standardization reduces unnecessary variation, but stifles innovation, while customization does the opposite. In fact, the upside values of one pole are usually the opposite of the downside fears of the other.
Leaders can actively engage people in both poles to make opposing views productive rather than destructive. The CMIO in our standardization/customization example could insist that everyone begins with the same template, but allow hospitalists to innovate to find a better way. Now the most resistant hospitalists become improvement agents. If a better way is found, then this becomes the new template that all hospitalists use, until the next better way is found. If an innovation is not an improvement, then hospitalists agree to return to the most recent successful template until a better way is found. This method of action and compromise produces both standardization and customization.
Using polarity management strategies does not guarantee success, but it can help engage all stakeholders, and break the frustrating cycle of repeatedly trying to solve the unsolvable.
Disclosures
The authors report no conflicts of interest or sources of funding.
1. Johnson B. Polarity management: Identifying and managing unsolvable problems. Human Resource Development; 1992.
2. Wesorick BL. Polarity thinking: An essential skill for those leading interprofessional integration. J Interprofessional Healthcare. 2014;1(1):12.
1. Johnson B. Polarity management: Identifying and managing unsolvable problems. Human Resource Development; 1992.
2. Wesorick BL. Polarity thinking: An essential skill for those leading interprofessional integration. J Interprofessional Healthcare. 2014;1(1):12.
© 2019 Society of Hospital Medicine
Click for Credit: PPI use & dementia; Weight loss after gastroplasty; more
Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty
To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020
2. PT beats steroid injections for knee OA
To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020
3. Better screening needed to reduce pregnancy-related overdose, death
To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020
4. Meta-analysis finds no link between PPI use and risk of dementia
To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020
5. Study: Cardiac biomarkers predicted CV events in CAP
To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020
Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty
To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020
2. PT beats steroid injections for knee OA
To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020
3. Better screening needed to reduce pregnancy-related overdose, death
To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020
4. Meta-analysis finds no link between PPI use and risk of dementia
To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020
5. Study: Cardiac biomarkers predicted CV events in CAP
To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020
Here are 5 articles from the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. Sustainable weight loss seen 5 years after endoscopic sleeve gastroplasty
To take the posttest, go to: https://bit.ly/37lteRX
Expires May 16, 2020
2. PT beats steroid injections for knee OA
To take the posttest, go to: https://bit.ly/2KIWKY6
Expires May 17, 2020
3. Better screening needed to reduce pregnancy-related overdose, death
To take the posttest, go to: https://bit.ly/2XEZyuG
Expires May 17, 2020
4. Meta-analysis finds no link between PPI use and risk of dementia
To take the posttest, go to: https://bit.ly/2Xzs7JM
Expires June 3, 2020
5. Study: Cardiac biomarkers predicted CV events in CAP
To take the posttest, go to: https://bit.ly/33bAH2u
Expires August 13, 2020
Ketamine for Depression: Adverse Effects Are Mild and Brief
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
A single subanesthetic dose of ketamine infusion can often relieve depressive symptoms within hours when conventional antidepressants have not worked. But off-label use of IV ketamine—especially given its history of abuse—has raised concerns about adverse effects (AEs).
However, a single low-dose infusion was “relatively free of side effects” for patients with treatment-resistant depression, according to researchers from the National Institute of Mental Health. They compiled data on AEs from 163 patients with major depressive disorder or bipolar disorder and 25 healthy controls from 5 placebo-controlled crossover clinical trials and 1 open-label study conducted at the National Institutes of Health (NIH) Clinical Center over 13 years.
The assessments included active and structured surveillance of emerging AEs in an inpatient setting and used both a rating scale and clinician interviews.
The most common effect was feeling “strange or loopy,” the researchers say. Most AEs peaked within an hour of administration and were gone within 2 hours. The researchers did not see any serious, drug-related AEs or increased ketamine cravings.
The researchers evaluated 120 possible AEs. Of the 44 that occurred in at least 5% of participants over all trials, 33 were significantly associated with treatment. At least half the participants reported the “spacey” feeling, visual distortions, difficulty speaking, and numbness. No AEs lasted beyond 4 hours.
The study did not address AEs associated with repeated infusions or long-term use, but during the approximately 3-month follow-up period, the researchers found no drug-related serious AEs, propensity for recreational use, or significant cognitive or memory deficits.
Trial finds three drugs equally effective for established status epilepticus
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
according to a study published Nov. 27 in the New England Journal of Medicine. The effectiveness and safety of the intravenous medications do not differ significantly, the researchers wrote.
“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations,” wrote Phil E.M. Smith, MD, in an accompanying editorial (doi: 10.1056/NEJMe1913775). Clinicians may consider “factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” said Dr. Smith, who is affiliated with University Hospital of Wales in Cardiff.
A gap in guidance
Evidence supports benzodiazepines as the initial treatment for status epilepticus, but these drugs do not work in up to a third of patients, said first study author Jaideep Kapur, MBBS, PhD, and colleagues. “Clinical guidelines emphasize the need for rapid control of benzodiazepine-refractory status epilepticus but do not provide guidance regarding the choice of medication on the basis of either efficacy or safety,” they wrote. Dr. Kapur is a professor of neurology and the director of UVA Brain Institute at University of Virginia in Charlottesville.
Levetiracetam, fosphenytoin, and valproate are the three most commonly used medications for benzodiazepine-refractory status epilepticus. The Food and Drug Administration has labeled fosphenytoin for this indication in adults, and none of the drugs is approved for children. To determine the superiority or inferiority of these medications, the researchers conducted the Established Status Epilepticus Treatment Trial (ESETT). The blinded, comparative-effectiveness trial enrolled 384 patients at 57 hospital EDs in the United States. Patients were aged 2 years or older, had received a generally accepted cumulative dose of benzodiazepines for generalized convulsive seizures lasting more than 5 minutes and continued to have persistent or recurrent convulsions between 5-30 minutes after the last dose of benzodiazepine.
Patients randomly received one of the three trial drugs, which “were identical in appearance, formulation, packaging, and administration,” the authors said. The primary outcome was absence of clinically apparent seizures and improving responsiveness at 60 minutes after the start of the infusion without administration of additional anticonvulsant medication. ED physicians determined the presence of seizure and improvement in responsiveness.
Trial was stopped for futility
The trial included 400 enrollments of 384 unique patients during 2015-2017. Sixteen patients were enrolled twice, and their second enrollments were not included in the intention-to-treat analysis. A planned interim analysis after 400 enrollments to assess the likelihood of success or futility found that the trial had met the futility criterion. “There was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size” of 795 patients, Dr. Kapur and coauthors wrote. The researchers continued enrollment in a pediatric subcohort for a planned subgroup analysis by age.
In all, 55% of the patients were male, 43% were black, and 16% were Hispanic. The population was 39% children and adolescents, 48% adults aged 18-65 years, and 13% older than 65 years. Most patients had a final diagnosis of status epilepticus (87%). Other final diagnoses included psychogenic nonepileptic seizures (10%).
At 60 minutes after treatment administration, absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
In 39 patients for whom the researchers had reliable information about time to seizure cessation, median time to seizure cessation numerically favored valproate (7 minutes for valproate vs. 10.5 minutes for levetiracetam vs. 11.7 minutes for fosphenytoin), but the number of patients was limited, the authors noted.
“Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant,” wrote Dr. Kapur and colleagues. Seven patients who received levetiracetam died, compared with three who received fosphenytoin and two who received valproate. Life-threatening hypotension occurred in 3.2% of patients who received fosphenytoin, compared with 1.6% who received valproate and 0.7% who received levetiracetam. Endotracheal intubation occurred in 26.4% or patients who received fosphenytoin, compared with 20% of patients in the levetiracetam group and 16.8% in the valproate group.
The trial’s limitations include the enrollment of patients with psychogenic nonepileptic seizures and the use of clinical instead of electroencephalographic criteria for the primary outcome measure, the investigators wrote.
Dr. Smith noted that third- and fourth-line management of status epilepticus is not supported by high-quality evidence, and further studies are needed. Given the evidence from ESETT, “the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he said.
The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Dr. Smith is coeditor of Practical Neurology and a member of the U.K. National Institute for Health and Clinical Excellence (NICE) guidelines committee for epilepsy.
SOURCE: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
FROM NEJM
Key clinical point: Among children and adults with benzodiazepine-refractory status epilepticus, fosphenytoin, valproate, and levetiracetam each stop seizures by 60 minutes in approximately half of patients.
Major finding: Absence of seizures and improved responsiveness occurred in 47% of patients who received levetiracetam, 45% who received fosphenytoin, and 46% who received valproate.
Study details: The Established Status Epilepticus Treatment Trial (ESETT) was a blinded, comparative-effectiveness trial that enrolled 384 patients at 57 hospital EDs in the United States.
Disclosures: The trial was funded by the National Institute of Neurological Disorders and Stroke. Dr. Kapur had no financial disclosures. A coauthor holds a patent on intravenous carbamazepine and intellectual property on intravenous topiramate. Other coauthors have ties to pharmaceutical and medical device companies.
Source: Kapur J et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1905795.
Supplemental MRI found to benefit women with dense breast tissue
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
The use of supplemental MRI screening in women with extremely dense breast tissue and normal results on mammography led to the diagnosis of significantly fewer interval cancers, compared with mammography alone during a 2-year screening period, results from a randomized trial show.
“Women with extremely dense breast tissue have an increased risk of breast cancer, and their cancers are also less likely to be detected on mammography,” Dutch researchers led by Marije F. Bakker, PhD, of Utrecht (The Netherlands) University and colleagues wrote for the Dense Tissue and Early Breast Neoplasm Screening (DENSE) Trial Study Group in an article published in the New England Journal of Medicine.
“Such patients may benefit from a tailored breast-screening strategy, supplemented with more sensitive imaging methods. The benefit of supplemental imaging is the subject of a worldwide debate. In the United States, a federal law directs breast-density reporting, but supplemental screening is not recommended in American guidelines. Although supplemental imaging increases the rate of cancer detection in women with dense breasts, the question remains whether it improves health outcomes,” they said.
In the DENSE trial, researchers assigned 40,373 women with extremely dense breast tissue and negative results on screening mammography to a group that was invited to undergo supplemental MRI or to a group that received mammography screening only. The women were between the ages of 50 and 75 years and were enrolled between December 2011 and November 2015 as part of the Dutch population-based digital mammography screening program. The primary outcome was the between-group difference in the incidence of interval cancers during a 2-year screening period.
Dr. Bakker and associates found that the interval cancer rate was 2.5 per 1,000 screenings among 4,783 women in the MRI invitation group, compared with 5 per 1,000 among the 32,312 women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001). Among the women who were invited to undergo MRI, 59% actually underwent the procedure. Of the 20 interval cancers diagnosed in the MRI-invitation group, 4 were diagnosed in the women who had undergone MRI, which translated to 0.8 per 1,000 screenings. The remaining 16 were diagnosed in those who had not undergone MRI, which translated into 4.9 per 1,000 screenings.
“Undergoing supplemental MRI was associated with a cancer-detection rate of 16.5 per 1,000 screenings and resulted in a false positive rate of 8.0% (79.8 per 1,000 screenings),” the researchers wrote. “Of the women who underwent a breast biopsy on the basis of an MRI indication, 26.3% had breast cancer and 73.7% did not.”
Dr. Bakker and coauthors acknowledged certain limitations of the trial, including the fact that it was not large enough to examine the effect of MRI screening on breast cancer–specific or overall mortality. “This outcome would require a much larger sample size and longer follow-up,” they wrote. “The lower rate of interval cancers that we found among participants who underwent MRI is indicative of and prerequisite for an effect on mortality. After that, a reduction in the number of advanced cancers would also be required to show a mortality benefit, which would require several years of follow-up.”
In an accompanying editorial, Dan L. Longo, MD, noted that the study provides high-quality data from a randomized trial where none existed (N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMe1912943). “It appears to show that among women with dense breasts, the risk of interval cancers is halved by following a negative mammogram with MRI screening,” wrote Dr. Longo, who is deputy editor of the New England Journal of Medicine, as well as professor of medicine at Harvard Medical School, Boston. “But is a reduction in interval cancers an appropriate surrogate for improved overall survival? It appears that most of the cancers that were detected on supplemental MRI screening were found at an early stage. Ductal carcinoma in situ was 10 times more frequent among patients undergoing MRI, and these diagnoses were likely to lead to treatments. What remains unclear is whether the tumors would never otherwise have been detected or threatened the patient’s survival.”
The trial was supported by the University Medical Center Utrecht (the Netherlands), the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
The researchers reported having no relevant financial disclosures other than the trial funding. Dr. Longo is employed by the New England Journal of Medicine as deputy editor.
SOURCE: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The interval cancer rate was 2.5 per 1,000 screenings among women in the MRI invitation group, compared with 5 per 1,000 among women in the mammography-only group, a difference of 2.5 per 1,000 screenings (P less than 0.001).
Study details: A multicenter, randomized study of 40,373 women between the ages of 50 and 75 years. One-quarter were offered supplemental MRI to the mammography all received.
Disclosures: The trial was supported by the University Medical Center Utrecht, the Netherlands Organization for Health Research and Development, the Dutch Cancer Society, the Dutch Pink Ribbon–A Sister’s Hope organization, Stichting Kankerpreventie Midden-West, and Bayer Pharmaceuticals, with an in-kind contribution from Volpara Health Technologies.
Source: Bakker MF et al. N Engl J Med. 2019 Nov 27. doi: 10.1056/NEJMoa1903986.