On Sept. 20, I had the opportunity to participate in AGA’s Advocacy Day for the second time, joining 40 of our gastroenterology colleagues from across the United States on Capitol Hill to advocate for our profession and our patients.

AGA Institute

The evening before Advocacy Day, we discussed strategies for having a successful meeting on Capitol Hill with AGA staff (including Kathleen Teixeira, AGA vice president of government affairs, and Jonathan Sollish, AGA senior coordinator, public policy). We discussed having our “asks” supported with evidence, and “getting personal” about how these policy issues directly affect us and our patients. We also had the chance to hear from Rep. Jim McGovern (D-Mass.) and Sen. Roy Blunt (R-Mo.) , both of whom invited our questions. Both congressmen are friends of AGA, with McGovern serving as chair of the House Rules Committee, and Blunt serving as chair of the Senate Labor-HHS Subcommittee on Appropriations.

Advocacy Day began with a group breakfast during which we reviewed some of the policy issues of central importance to gastroenterology:

• Removing Barriers to the Colorectal Cancer Screening Act (HR1570/S668), which enjoys strong bipartisan support, would correct the “cost-sharing” problem of screening colonoscopies turning therapeutic (with polypectomy) for our Medicare patients, by waiving the coinsurance for screening colonoscopies – regardless of whether we remove polyps during these colonoscopies.

• Safe Step Act, HR2279, legislation introduced in the House, facilitates a common-sense and timely (72 hours or 24 hours if life-threatening) appeals process when our patients are subjected to step therapy (“fail first”) by insurers.

• Improving Seniors’ Timely Access to Care Act of 2019, HR3107, legislation in the House, eases onerous prior authorization burdens by promoting an electronic prior authorization process, ensuring requests are approved by qualified medical professionals who have specialty-specific experience, and mandating that plans report their rates of delays and denials.

• NIH research funding facilitates innovative research and supports young investigators in our field.

Full of enthusiasm, our six-strong North Carolina contingent (pictured, L-R, Ziad Gellad, MD, MPH, AGAF; David Leiman, MD, MSPH; Animesh Jain, MD; Anne Finefrock Peery, MD; Lisa Gangarosa, MD, AGAF, chair of the AGA Government Affairs Committee; and Amit Patel, MD) met with the offices of Rep. David Price (D-N.C.), and both North Carolina Senators, Richard Burr (R) and Thom Tillis (R) on Capitol Hill to convey our “asks.”

AGA Institute

Dr. Patel is assistant professor, division of gastroenterology, Duke University, Cary, N.C.; member, AGA Clinical Guidelines Committee.

On Sept. 20, I had the opportunity to participate in AGA’s Advocacy Day for the second time, joining 40 of our gastroenterology colleagues from across the United States on Capitol Hill to advocate for our profession and our patients.

AGA Institute

The evening before Advocacy Day, we discussed strategies for having a successful meeting on Capitol Hill with AGA staff (including Kathleen Teixeira, AGA vice president of government affairs, and Jonathan Sollish, AGA senior coordinator, public policy). We discussed having our “asks” supported with evidence, and “getting personal” about how these policy issues directly affect us and our patients. We also had the chance to hear from Rep. Jim McGovern (D-Mass.) and Sen. Roy Blunt (R-Mo.) , both of whom invited our questions. Both congressmen are friends of AGA, with McGovern serving as chair of the House Rules Committee, and Blunt serving as chair of the Senate Labor-HHS Subcommittee on Appropriations.

Advocacy Day began with a group breakfast during which we reviewed some of the policy issues of central importance to gastroenterology:

• Removing Barriers to the Colorectal Cancer Screening Act (HR1570/S668), which enjoys strong bipartisan support, would correct the “cost-sharing” problem of screening colonoscopies turning therapeutic (with polypectomy) for our Medicare patients, by waiving the coinsurance for screening colonoscopies – regardless of whether we remove polyps during these colonoscopies.

• Safe Step Act, HR2279, legislation introduced in the House, facilitates a common-sense and timely (72 hours or 24 hours if life-threatening) appeals process when our patients are subjected to step therapy (“fail first”) by insurers.

• Improving Seniors’ Timely Access to Care Act of 2019, HR3107, legislation in the House, eases onerous prior authorization burdens by promoting an electronic prior authorization process, ensuring requests are approved by qualified medical professionals who have specialty-specific experience, and mandating that plans report their rates of delays and denials.

• NIH research funding facilitates innovative research and supports young investigators in our field.

Full of enthusiasm, our six-strong North Carolina contingent (pictured, L-R, Ziad Gellad, MD, MPH, AGAF; David Leiman, MD, MSPH; Animesh Jain, MD; Anne Finefrock Peery, MD; Lisa Gangarosa, MD, AGAF, chair of the AGA Government Affairs Committee; and Amit Patel, MD) met with the offices of Rep. David Price (D-N.C.), and both North Carolina Senators, Richard Burr (R) and Thom Tillis (R) on Capitol Hill to convey our “asks.”

AGA Institute

Dr. Patel is assistant professor, division of gastroenterology, Duke University, Cary, N.C.; member, AGA Clinical Guidelines Committee.

On Sept. 20, I had the opportunity to participate in AGA’s Advocacy Day for the second time, joining 40 of our gastroenterology colleagues from across the United States on Capitol Hill to advocate for our profession and our patients.

AGA Institute

The evening before Advocacy Day, we discussed strategies for having a successful meeting on Capitol Hill with AGA staff (including Kathleen Teixeira, AGA vice president of government affairs, and Jonathan Sollish, AGA senior coordinator, public policy). We discussed having our “asks” supported with evidence, and “getting personal” about how these policy issues directly affect us and our patients. We also had the chance to hear from Rep. Jim McGovern (D-Mass.) and Sen. Roy Blunt (R-Mo.) , both of whom invited our questions. Both congressmen are friends of AGA, with McGovern serving as chair of the House Rules Committee, and Blunt serving as chair of the Senate Labor-HHS Subcommittee on Appropriations.

Advocacy Day began with a group breakfast during which we reviewed some of the policy issues of central importance to gastroenterology:

• Removing Barriers to the Colorectal Cancer Screening Act (HR1570/S668), which enjoys strong bipartisan support, would correct the “cost-sharing” problem of screening colonoscopies turning therapeutic (with polypectomy) for our Medicare patients, by waiving the coinsurance for screening colonoscopies – regardless of whether we remove polyps during these colonoscopies.

• Safe Step Act, HR2279, legislation introduced in the House, facilitates a common-sense and timely (72 hours or 24 hours if life-threatening) appeals process when our patients are subjected to step therapy (“fail first”) by insurers.

• Improving Seniors’ Timely Access to Care Act of 2019, HR3107, legislation in the House, eases onerous prior authorization burdens by promoting an electronic prior authorization process, ensuring requests are approved by qualified medical professionals who have specialty-specific experience, and mandating that plans report their rates of delays and denials.

• NIH research funding facilitates innovative research and supports young investigators in our field.

Full of enthusiasm, our six-strong North Carolina contingent (pictured, L-R, Ziad Gellad, MD, MPH, AGAF; David Leiman, MD, MSPH; Animesh Jain, MD; Anne Finefrock Peery, MD; Lisa Gangarosa, MD, AGAF, chair of the AGA Government Affairs Committee; and Amit Patel, MD) met with the offices of Rep. David Price (D-N.C.), and both North Carolina Senators, Richard Burr (R) and Thom Tillis (R) on Capitol Hill to convey our “asks.”

AGA Institute

Dr. Patel is assistant professor, division of gastroenterology, Duke University, Cary, N.C.; member, AGA Clinical Guidelines Committee.

Dear Colleagues,

Join me in supporting talented investigators through a personal gift to the AGA Research Foundation.

As a member of the GI community, you understand the physical, emotional and financial costs of digestive diseases. And you understand the value of research to advance patient care. The gap in federal funding for research continues to grow. Many well-qualified young investigators cannot get government funding. Gifts to the AGA Research Foundation this year directly supported 52 talented investigators. Despite this success, over 200 other innovative and promising research ideas went unfunded.

That’s why I’m asking for your help.

Securing the future of the field is no small task. Every dollar is a step forward in helping to spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow.

Everyone benefits from GI research developed by dedicated investigators.

I invite you to help the AGA Research Foundation continue our efforts to fund and retain talented GI scientists whose research will impact the future care of patients. Donate today at www.gastro.org/donate.

Thank you for your generosity. Best wishes for a happy, healthy holiday season and successful New Year.

[email protected]

Dear Colleagues,

Join me in supporting talented investigators through a personal gift to the AGA Research Foundation.

As a member of the GI community, you understand the physical, emotional and financial costs of digestive diseases. And you understand the value of research to advance patient care. The gap in federal funding for research continues to grow. Many well-qualified young investigators cannot get government funding. Gifts to the AGA Research Foundation this year directly supported 52 talented investigators. Despite this success, over 200 other innovative and promising research ideas went unfunded.

That’s why I’m asking for your help.

Securing the future of the field is no small task. Every dollar is a step forward in helping to spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow.

Everyone benefits from GI research developed by dedicated investigators.

I invite you to help the AGA Research Foundation continue our efforts to fund and retain talented GI scientists whose research will impact the future care of patients. Donate today at www.gastro.org/donate.

Thank you for your generosity. Best wishes for a happy, healthy holiday season and successful New Year.

[email protected]

Dear Colleagues,

Join me in supporting talented investigators through a personal gift to the AGA Research Foundation.

As a member of the GI community, you understand the physical, emotional and financial costs of digestive diseases. And you understand the value of research to advance patient care. The gap in federal funding for research continues to grow. Many well-qualified young investigators cannot get government funding. Gifts to the AGA Research Foundation this year directly supported 52 talented investigators. Despite this success, over 200 other innovative and promising research ideas went unfunded.

That’s why I’m asking for your help.

Securing the future of the field is no small task. Every dollar is a step forward in helping to spark the scientific breakthroughs of today so clinicians will have the tools to improve care tomorrow.

Everyone benefits from GI research developed by dedicated investigators.

I invite you to help the AGA Research Foundation continue our efforts to fund and retain talented GI scientists whose research will impact the future care of patients. Donate today at www.gastro.org/donate.

Thank you for your generosity. Best wishes for a happy, healthy holiday season and successful New Year.

[email protected]

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. In case you missed it, here are the most popular clinical discussions shared in the forum recently:

1. Severe ulcerative colitis # IBD – A 41-year-old female patient with ulcerative colitis had a flare that didn’t improve with adalimumab and prednisone, and was admitted to the hospital with bloody stools and abdominal pain. The GI community discussed considerations for next steps and other tests to consider.

2. Unexplained diarrhea – Following the eQ&A with an AGA guideline coauthor on chronic diarrhea, this popular case follows a celiac disease patient on a gluten-free diet who continues to have significant diarrhea and fatigue.

3. Difficult ERCP – How would you handle an ERCP where the papilla is small and in a tricky location? View photos from your colleague’s scope and share your advice with the GI community.

Access these clinical cases and more discussions at https://community.gastro.org/discussions.
 

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. In case you missed it, here are the most popular clinical discussions shared in the forum recently:

1. Severe ulcerative colitis # IBD – A 41-year-old female patient with ulcerative colitis had a flare that didn’t improve with adalimumab and prednisone, and was admitted to the hospital with bloody stools and abdominal pain. The GI community discussed considerations for next steps and other tests to consider.

2. Unexplained diarrhea – Following the eQ&A with an AGA guideline coauthor on chronic diarrhea, this popular case follows a celiac disease patient on a gluten-free diet who continues to have significant diarrhea and fatigue.

3. Difficult ERCP – How would you handle an ERCP where the papilla is small and in a tricky location? View photos from your colleague’s scope and share your advice with the GI community.

Access these clinical cases and more discussions at https://community.gastro.org/discussions.
 

Physicians with difficult patient scenarios regularly bring their questions to the AGA Community to seek advice from colleagues about therapy and disease management options, best practices, and diagnoses. In case you missed it, here are the most popular clinical discussions shared in the forum recently:

1. Severe ulcerative colitis # IBD – A 41-year-old female patient with ulcerative colitis had a flare that didn’t improve with adalimumab and prednisone, and was admitted to the hospital with bloody stools and abdominal pain. The GI community discussed considerations for next steps and other tests to consider.

2. Unexplained diarrhea – Following the eQ&A with an AGA guideline coauthor on chronic diarrhea, this popular case follows a celiac disease patient on a gluten-free diet who continues to have significant diarrhea and fatigue.

3. Difficult ERCP – How would you handle an ERCP where the papilla is small and in a tricky location? View photos from your colleague’s scope and share your advice with the GI community.

Access these clinical cases and more discussions at https://community.gastro.org/discussions.
 

NEW ORLEANS – While further data are awaited on the role of vitamin C, thiamine, and steroids in sepsis, there is at least biologic plausibility for using the combination, and clinical equipoise that supports continued enrollment of patients in the ongoing randomized, controlled VICTAS trial, according to that study’s principal investigator.

“There is tremendous biologic plausibility for giving vitamin C in sepsis,” said Jon Sevransky, MD, professor of medicine at Emory University in Atlanta. But until more data are available on vitamin C–based regimens, those who choose to use vitamin C with thiamine and steroids in this setting need to ensure that glucose is being measured appropriately, he warned.

“If you decide that vitamin C is right for your patient, prior to having enough data – so if you’re doing a Hail Mary, or a ‘this patient is sick, and it’s probably not going to hurt them’ – please make sure that you measure your glucose with something that uses whole blood, which is either a blood gas or sending it down to the core lab, because otherwise, you might get an inaccurate result,” Dr. Sevransky said at the annual meeting of the American College of Chest Physicians.

Results from the randomized, placebo-controlled Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial may be available within the next few months, according to Dr. Sevransky, who noted that the trial was funded for 500 patients, which provides an 80% probability of showing an absolute risk reduction of 10% in mortality.

The primary endpoint of the phase 3 trial is vasopressor and ventilator-free days at 30 days after randomization, while 30-day mortality has been described as “the key secondary outcome” by Dr. Sevransky and colleagues in a recent report on the trial design.

Clinicians have been “captivated” by the potential benefit of vitamin C, thiamine, and hydrocortisone in patients with severe sepsis and septic shock, as published in CHEST in June 2017, Dr. Sevransky said. In that study, reported by Paul E. Marik, MD, and colleagues, hospital mortality was 8.5% for the treatment group, versus 40.4% in the control group, a significant difference.

That retrospective, single-center study had a number of limitations, however, including its before-and-after design and the use of steroids in the comparator arm. In addition, little information was available on antibiotics or fluids given at the time of the intervention, according to Dr. Sevransky.

In results of the CITRIS-ALI randomized clinical trial, just published in JAMA, intravenous administration of high-dose vitamin C in patients with sepsis and acute respiratory distress syndrome (ARDS) failed to significantly reduce organ failure scores or biomarkers of inflammation and vascular injury.

In an exploratory analysis of CITRIS-ALI, mortality at day 28 was 29.8% for the treatment group and 46.3% for placebo, with a statistically significant difference between Kaplan-Meier survival curves for the two arms, according to the investigators.

That exploratory result from CITRIS-ALI, however, is indicative of “something that needs further study,” Dr. Sevransky cautioned. “In summary, I hope I told you that biologic plausibility is present for vitamin C, thiamine, and steroids. I think that, and this is my own personal opinion, that evidence to date allows for randomization of patients, that there’s current equipoise.”

Dr. Sevransky disclosed current grant support from the Biomedical Advanced Research and Development Authority (BARDA) and the Marcus Foundation, as well as a stipend from Critical Care Medicine related to work as an associate editor. He is also a medical advisor to Project Hope and ARDS Foundation and a member of the Surviving Sepsis guideline committees.

SOURCE: Sevransky J et al. Chest 2019.

NEW ORLEANS – While further data are awaited on the role of vitamin C, thiamine, and steroids in sepsis, there is at least biologic plausibility for using the combination, and clinical equipoise that supports continued enrollment of patients in the ongoing randomized, controlled VICTAS trial, according to that study’s principal investigator.

“There is tremendous biologic plausibility for giving vitamin C in sepsis,” said Jon Sevransky, MD, professor of medicine at Emory University in Atlanta. But until more data are available on vitamin C–based regimens, those who choose to use vitamin C with thiamine and steroids in this setting need to ensure that glucose is being measured appropriately, he warned.

“If you decide that vitamin C is right for your patient, prior to having enough data – so if you’re doing a Hail Mary, or a ‘this patient is sick, and it’s probably not going to hurt them’ – please make sure that you measure your glucose with something that uses whole blood, which is either a blood gas or sending it down to the core lab, because otherwise, you might get an inaccurate result,” Dr. Sevransky said at the annual meeting of the American College of Chest Physicians.

Results from the randomized, placebo-controlled Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial may be available within the next few months, according to Dr. Sevransky, who noted that the trial was funded for 500 patients, which provides an 80% probability of showing an absolute risk reduction of 10% in mortality.

The primary endpoint of the phase 3 trial is vasopressor and ventilator-free days at 30 days after randomization, while 30-day mortality has been described as “the key secondary outcome” by Dr. Sevransky and colleagues in a recent report on the trial design.

Clinicians have been “captivated” by the potential benefit of vitamin C, thiamine, and hydrocortisone in patients with severe sepsis and septic shock, as published in CHEST in June 2017, Dr. Sevransky said. In that study, reported by Paul E. Marik, MD, and colleagues, hospital mortality was 8.5% for the treatment group, versus 40.4% in the control group, a significant difference.

That retrospective, single-center study had a number of limitations, however, including its before-and-after design and the use of steroids in the comparator arm. In addition, little information was available on antibiotics or fluids given at the time of the intervention, according to Dr. Sevransky.

In results of the CITRIS-ALI randomized clinical trial, just published in JAMA, intravenous administration of high-dose vitamin C in patients with sepsis and acute respiratory distress syndrome (ARDS) failed to significantly reduce organ failure scores or biomarkers of inflammation and vascular injury.

In an exploratory analysis of CITRIS-ALI, mortality at day 28 was 29.8% for the treatment group and 46.3% for placebo, with a statistically significant difference between Kaplan-Meier survival curves for the two arms, according to the investigators.

That exploratory result from CITRIS-ALI, however, is indicative of “something that needs further study,” Dr. Sevransky cautioned. “In summary, I hope I told you that biologic plausibility is present for vitamin C, thiamine, and steroids. I think that, and this is my own personal opinion, that evidence to date allows for randomization of patients, that there’s current equipoise.”

Dr. Sevransky disclosed current grant support from the Biomedical Advanced Research and Development Authority (BARDA) and the Marcus Foundation, as well as a stipend from Critical Care Medicine related to work as an associate editor. He is also a medical advisor to Project Hope and ARDS Foundation and a member of the Surviving Sepsis guideline committees.

SOURCE: Sevransky J et al. Chest 2019.

NEW ORLEANS – While further data are awaited on the role of vitamin C, thiamine, and steroids in sepsis, there is at least biologic plausibility for using the combination, and clinical equipoise that supports continued enrollment of patients in the ongoing randomized, controlled VICTAS trial, according to that study’s principal investigator.

“There is tremendous biologic plausibility for giving vitamin C in sepsis,” said Jon Sevransky, MD, professor of medicine at Emory University in Atlanta. But until more data are available on vitamin C–based regimens, those who choose to use vitamin C with thiamine and steroids in this setting need to ensure that glucose is being measured appropriately, he warned.

“If you decide that vitamin C is right for your patient, prior to having enough data – so if you’re doing a Hail Mary, or a ‘this patient is sick, and it’s probably not going to hurt them’ – please make sure that you measure your glucose with something that uses whole blood, which is either a blood gas or sending it down to the core lab, because otherwise, you might get an inaccurate result,” Dr. Sevransky said at the annual meeting of the American College of Chest Physicians.

Results from the randomized, placebo-controlled Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) trial may be available within the next few months, according to Dr. Sevransky, who noted that the trial was funded for 500 patients, which provides an 80% probability of showing an absolute risk reduction of 10% in mortality.

The primary endpoint of the phase 3 trial is vasopressor and ventilator-free days at 30 days after randomization, while 30-day mortality has been described as “the key secondary outcome” by Dr. Sevransky and colleagues in a recent report on the trial design.

Clinicians have been “captivated” by the potential benefit of vitamin C, thiamine, and hydrocortisone in patients with severe sepsis and septic shock, as published in CHEST in June 2017, Dr. Sevransky said. In that study, reported by Paul E. Marik, MD, and colleagues, hospital mortality was 8.5% for the treatment group, versus 40.4% in the control group, a significant difference.

That retrospective, single-center study had a number of limitations, however, including its before-and-after design and the use of steroids in the comparator arm. In addition, little information was available on antibiotics or fluids given at the time of the intervention, according to Dr. Sevransky.

In results of the CITRIS-ALI randomized clinical trial, just published in JAMA, intravenous administration of high-dose vitamin C in patients with sepsis and acute respiratory distress syndrome (ARDS) failed to significantly reduce organ failure scores or biomarkers of inflammation and vascular injury.

In an exploratory analysis of CITRIS-ALI, mortality at day 28 was 29.8% for the treatment group and 46.3% for placebo, with a statistically significant difference between Kaplan-Meier survival curves for the two arms, according to the investigators.

That exploratory result from CITRIS-ALI, however, is indicative of “something that needs further study,” Dr. Sevransky cautioned. “In summary, I hope I told you that biologic plausibility is present for vitamin C, thiamine, and steroids. I think that, and this is my own personal opinion, that evidence to date allows for randomization of patients, that there’s current equipoise.”

Dr. Sevransky disclosed current grant support from the Biomedical Advanced Research and Development Authority (BARDA) and the Marcus Foundation, as well as a stipend from Critical Care Medicine related to work as an associate editor. He is also a medical advisor to Project Hope and ARDS Foundation and a member of the Surviving Sepsis guideline committees.

SOURCE: Sevransky J et al. Chest 2019.

The U.S. Food and Drug Administration (FDA) recently released a safety communication recommending duodenoscope manufacturers and health care facilities move away from using duodenoscopes with fixed endcaps to those with disposable components that include disposable endcaps – or to fully disposable duodenoscopes when they become available. This announcement may have already produced some questions among your patients when it comes to their procedures that use a duodenoscope, such as endoscopic retrograde cholangiopancreatography (ERCP).

AGA has developed frequently asked questions and talking points below that can help you explain ERCP and infection risk when your patients come to you with questions.
 

Talking points:

• Duodenoscopes are an important tool used during an ERCP to help localize and treat abnormal issues in your bile duct system and pancreas, and possibly help you avoid surgery.

• The complex design of duodenoscopes can sometimes result in bacteria remaining in a small portion of the duodenoscope (the “elevator channel”) even after careful cleaning according to approved instructions. However, the chance of getting an identified “superbug infection” with a duodenoscope is very low, currently estimated at 1 per 20,000 ERCPs performed in more than 650,000 ERCP procedures each year in the U.S. FDA continues to work with duodenoscope manufacturers to provide strict guidelines for cleaning and disinfection of these tools.

• The switch to new duodenoscopes with disposable components will be slow and orderly to make sure that there are enough duodenoscopes to perform ERCPs so that patients who need this often life-saving procedure will still have access.

• Do not cancel or delay any planned procedure without first discussing the benefits and risks with me or another health care provider, as delaying the procedure and alternatives like surgery or radiologic intervention may be riskier than a timely ERCP.

• The esophagogastroduodenoscopy (EGD) procedure does not use the same tool that is used for ERCP. EGD uses a different endoscope than ERCP and has not been shown to have the same risk of infection because there is no “elevator channel.”
 

[email protected]

The U.S. Food and Drug Administration (FDA) recently released a safety communication recommending duodenoscope manufacturers and health care facilities move away from using duodenoscopes with fixed endcaps to those with disposable components that include disposable endcaps – or to fully disposable duodenoscopes when they become available. This announcement may have already produced some questions among your patients when it comes to their procedures that use a duodenoscope, such as endoscopic retrograde cholangiopancreatography (ERCP).

AGA has developed frequently asked questions and talking points below that can help you explain ERCP and infection risk when your patients come to you with questions.
 

Talking points:

• Duodenoscopes are an important tool used during an ERCP to help localize and treat abnormal issues in your bile duct system and pancreas, and possibly help you avoid surgery.

• The complex design of duodenoscopes can sometimes result in bacteria remaining in a small portion of the duodenoscope (the “elevator channel”) even after careful cleaning according to approved instructions. However, the chance of getting an identified “superbug infection” with a duodenoscope is very low, currently estimated at 1 per 20,000 ERCPs performed in more than 650,000 ERCP procedures each year in the U.S. FDA continues to work with duodenoscope manufacturers to provide strict guidelines for cleaning and disinfection of these tools.

• The switch to new duodenoscopes with disposable components will be slow and orderly to make sure that there are enough duodenoscopes to perform ERCPs so that patients who need this often life-saving procedure will still have access.

• Do not cancel or delay any planned procedure without first discussing the benefits and risks with me or another health care provider, as delaying the procedure and alternatives like surgery or radiologic intervention may be riskier than a timely ERCP.

• The esophagogastroduodenoscopy (EGD) procedure does not use the same tool that is used for ERCP. EGD uses a different endoscope than ERCP and has not been shown to have the same risk of infection because there is no “elevator channel.”
 

[email protected]

The U.S. Food and Drug Administration (FDA) recently released a safety communication recommending duodenoscope manufacturers and health care facilities move away from using duodenoscopes with fixed endcaps to those with disposable components that include disposable endcaps – or to fully disposable duodenoscopes when they become available. This announcement may have already produced some questions among your patients when it comes to their procedures that use a duodenoscope, such as endoscopic retrograde cholangiopancreatography (ERCP).

AGA has developed frequently asked questions and talking points below that can help you explain ERCP and infection risk when your patients come to you with questions.
 

Talking points:

• Duodenoscopes are an important tool used during an ERCP to help localize and treat abnormal issues in your bile duct system and pancreas, and possibly help you avoid surgery.

• The complex design of duodenoscopes can sometimes result in bacteria remaining in a small portion of the duodenoscope (the “elevator channel”) even after careful cleaning according to approved instructions. However, the chance of getting an identified “superbug infection” with a duodenoscope is very low, currently estimated at 1 per 20,000 ERCPs performed in more than 650,000 ERCP procedures each year in the U.S. FDA continues to work with duodenoscope manufacturers to provide strict guidelines for cleaning and disinfection of these tools.

• The switch to new duodenoscopes with disposable components will be slow and orderly to make sure that there are enough duodenoscopes to perform ERCPs so that patients who need this often life-saving procedure will still have access.

• Do not cancel or delay any planned procedure without first discussing the benefits and risks with me or another health care provider, as delaying the procedure and alternatives like surgery or radiologic intervention may be riskier than a timely ERCP.

• The esophagogastroduodenoscopy (EGD) procedure does not use the same tool that is used for ERCP. EGD uses a different endoscope than ERCP and has not been shown to have the same risk of infection because there is no “elevator channel.”
 

[email protected]

The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, which were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to what was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.

The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential effect on patients who have been taking ranitidine.

With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available.
 

Talking to your patients

The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that:

• Ranitidine is an H₂ blocker (antihistamine) – available OTC and in prescription strength – used to prevent and relieve heartburn associated with acid indigestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.

• Not all ranitidine medicines marketed in the United States are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.

• It might be prudent to hold off taking Zantac until a final FDA conclusion is released.

• Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.

• Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco, or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.
 

[email protected]

The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, which were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to what was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.

The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential effect on patients who have been taking ranitidine.

With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available.
 

Talking to your patients

The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that:

• Ranitidine is an H₂ blocker (antihistamine) – available OTC and in prescription strength – used to prevent and relieve heartburn associated with acid indigestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.

• Not all ranitidine medicines marketed in the United States are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.

• It might be prudent to hold off taking Zantac until a final FDA conclusion is released.

• Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.

• Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco, or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.
 

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The FDA recently released several safety alerts on ranitidine formulations, including the brand-name drug Zantac, which were found to contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests and animal studies. NDMA is a known environmental contaminant and found in water and foods, including meats, dairy products, and vegetables. This contaminant is similar to what was recently found in losartan, an angiotensin II receptor blocker used to treat hypertension, that was recalled by the FDA.

The FDA is continuing to test ranitidine products from multiple manufacturers and is assessing the potential effect on patients who have been taking ranitidine.

With the voluntary recall of 14 lots of prescription ranitidine capsules distributed by Sandoz Inc., as well as the voluntary recall of over-the-counter (OTC) ranitidine tablets (75 mg and 150 mg), labeled by Walgreens, Walmart, and Rite-Aid and manufactured by Apotex Corp, your patients might be asking a lot of questions about whether to continue to using their medicines and what alternatives are available.
 

Talking to your patients

The FDA safety alerts have been covered by various media outlets since early September. This may cause your patients to question whether they should stay on or start using ranitidine products. When discussing the recall with your patients, let them know that:

• Ranitidine is an H₂ blocker (antihistamine) – available OTC and in prescription strength – used to prevent and relieve heartburn associated with acid indigestion and sour stomach. It reduces stomach acid and works longer but not as quickly as antacids.

• Not all ranitidine medicines marketed in the United States are being recalled and the FDA is not recommending individuals stop taking all ranitidine medicines at this time.

• It might be prudent to hold off taking Zantac until a final FDA conclusion is released.

• Multiple drugs are approved for the same or similar uses as ranitidine. Other treatment options are available, both prescription and OTC, for patients who are concerned about ranitidine.

• Life-style modifications may reduce or eliminate the need for heartburn drugs for long-term use. These may include weight loss, avoiding tobacco, or a change in eating patterns. Share AGA’s patient education content on gastroesophageal reflux disease (GERD) for more tips for your patients.
 

[email protected]

ANSWER

There is evidence of significant widening of the pubic symphysis. This injury results in a disruption of the normal pelvic ring. Such fractures are typically referred to as open-book pelvic fractures. Usually the result of high-energy trauma, they can also be associated with bladder and/or vascular injuries.

Orthopedics was consulted for management of this injury. Prompt stabilization with an external binder may help reduce complications. The patient will ultimately require some form of external or internal fixation.

ANSWER

There is evidence of significant widening of the pubic symphysis. This injury results in a disruption of the normal pelvic ring. Such fractures are typically referred to as open-book pelvic fractures. Usually the result of high-energy trauma, they can also be associated with bladder and/or vascular injuries.

Orthopedics was consulted for management of this injury. Prompt stabilization with an external binder may help reduce complications. The patient will ultimately require some form of external or internal fixation.

ANSWER

There is evidence of significant widening of the pubic symphysis. This injury results in a disruption of the normal pelvic ring. Such fractures are typically referred to as open-book pelvic fractures. Usually the result of high-energy trauma, they can also be associated with bladder and/or vascular injuries.

Orthopedics was consulted for management of this injury. Prompt stabilization with an external binder may help reduce complications. The patient will ultimately require some form of external or internal fixation.

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Biogen aims to file with the Food and Drug Administration for regulatory approval of aducanumab, an antibody under investigation for Alzheimer’s disease, in 2020 following largely positive results of a secondary analysis of two failed phase 3 trials, ENGAGE and EMERGE, the company announced Oct. 22.

Biogen’s plans reverse its March 21, 2019, decision with codeveloper Eisai to discontinue work on the drug after a futility analysis of the trials determined aducanumab was unlikely to yield significant benefit. Biogen announced the plan to file a biologic drug application following a new analysis of additional data that became available after the data lock on the futility analysis. But while primary and secondary endpoints were nearly all positive for EMERGE in the secondary analysis of the larger dataset, the same could not be said for the twin trial, ENGAGE, which had negative results for most of its endpoints. However, Biogen said that “results from a subset of patients in the phase 3 ENGAGE study who received sufficient exposure to high-dose aducanumab support the findings from EMERGE.”

Both the Alzheimer’s Association and researchers interpreted the announcement with a measured tone, saying it offered a hopeful sign for a field continually stymied in its quest for an effective treatment. More than 100 clinical trials have failed over the last 20 years.

“This really is very encouraging news,” Rebecca M. Edelmayer, PhD, director of scientific engagement at the Alzheimer’s Association, said in an interview. The secondary combined analyses showed “the largest reductions in clinical and functional decline we have seen. It’s an important moment for the patients with AD and their families, and for researchers all around the world. This deserves to be discussed and considered by the research community, but we really need to dig deep into the data. We expect to see more of them at the Clinical Trials on Alzheimer’s Disease conference,” which is set for early December.

Paul Aisen, MD, a consultant for Biogen and director of the Alzheimer’s Therapeutic Research Institute at the University of Southern California, Los Angeles, was similarly measured.

“There is an enormous amount of data here and they will be very challenging to interpret, especially since both trials were stopped in a futility analysis,” he said in an interview. “We’re now interpreting data that continue to be collected after the initial data lock. But I do believe there is evidence that supports the amyloid hypothesis and the development of aducanumab.”

A deep data dive is in order before the field completely embraces aducanumab’s advancement, agreed Michael Wolfe, PhD, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence.

“We would have to see exactly how they came up with this new data set and analysis. I have felt for many years now that these companies would try to parse and shuffle the data around until they got a statistically significant result, just to get approval. They would make billions per year but not really make a difference in people’s lives. That being said, if aducanumab truly slows the decline in activities of daily living, keeping people independent longer, that would be a worthwhile clinical result.”

Still to be considered is whether aducanumab could confer enough benefits to be worth monthly, potentially lifelong, infusions of a pricey medication that still won’t stop disease progression.

“Whether the clinical impact will be worth the anticipated cost remains to be seen,” Richard J. Caselli, MD, said in an interview. “This is likely to be a very expensive treatment for a subgroup of individuals with the hope of slowing decline, but – unless there is a huge upside surprise in data yet to be released – it is not going to halt progression and will certainly increase the cost of care dramatically.”

Dr. Caselli, clinical core director of the Alzheimer’s Disease Center at the Mayo Clinic in Phoenix, continued: “I imagine if approved, there will be a number of insurance obstacles to overcome regarding who qualifies, for how long, etc. Scientifically, this certainly supports the long-held view that beta amyloid is important in the pathophysiology of Alzheimer’s disease. But, again, unless the impact is unexpectedly huge, I don’t think this quiets those who feel there is more to the story than only a gain of beta amyloid toxicity, though this does support the idea that it plays a role, which should not surprise anyone.”

Dr. Edelmayer said the Alzheimer’s Association has raised the issue of access and cost with Biogen.

“We have had many discussions about their capacity to roll this out,” if aducanumab is approved, she said. “Those who were in the studies will be the first recipients. But Biogen is making plans to move this into the general population if approved, to all patients who meet the diagnostic criteria.”

“There is precedent out there when it comes to doing infusion medicines, and those centers are part of the planning process. In terms of pricing, this is a problem we would be happy to see, because it would mean that we have a treatment. But we’ll cross that bridge when we come to it.”
 

Secondary analysis results

The new analysis comprised 2,066 patients who had the opportunity to complete the full 18-month trials by March 20, 2019. The full intent-to-treat population of the trials comprised 3,285 patients with mild cognitive impairment caused by Alzheimer’s disease or mild Alzheimer’s disease dementia.

In the secondary analysis of EMERGE’s intent-to-treat population, patients who took the highest dose of aducanumab (10 mg/kg every month) showed 23% lower functional and cognitive decline on the trial’s primary endpoint of Clinical Dementia Rating–Sum of Boxes (CDR-SB) at 18 months when compared with placebo. The rate of decline was slowed by a nonsignificant 14% among users of the lower dose (6 mg/kg monthly).Secondary endpoints for the high-dose group in EMERGE showed 27% slower cognitive decline on the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13) and 40% lower decline in function among patients with mild cognitive impairment based on the MCI version of the AD Cooperative Study–Activities of Daily Living Inventory (ADCS-ADL-MCI).

However, data from the ENGAGE trial, which had the same primary endpoint, were not positive. CDR-SB scores worsened 2% more among high-dose aducanumab users but low-dose users slowed decline by a nonsignificant 12% when compared with placebo.“Exposure to high-dose aducanumab was important for efficacy,” the company noted in a slide set presented at an Oct. 22 investors webcast. “Differences in exposure to high-dose aducanumab largely explain the different results between the futility analysis and the new analysis of this larger dataset, as well as the different results between the two studies.”

In EMERGE, changes in secondary endpoints among patients who had the opportunity to complete the full 18-month trials included:

• Mini Mental State Exam (MMSE): Significant 23% decrease in rate of decline in the high-dose group and nonsignificant 3% increase in decline in the low-dose group.
• ADAS-Cog13: Significant 25% decrease for high-dose users and nonsignificant 10% decrease for low dose.
• ADCS-ADL-MCI: Significant decreases of 46% for high-dose and 20% for low-dose users.

The ENGAGE secondary endpoints of high- vs. low-dose patients who completed the full trials were:

• MMSE: Significant 13% increase, nonsignificant 3% decrease.
• ADAS-Cog13: Nonsignificant 2% decrease, nonsignificant 1% decrease.
• ADCS-ADL-MCI: Significant 12% declines in both dosage groups.

All of the positive cognitive and functional results tracked along with results of amyloid PET imaging and CSF biomarkers. In EMERGE, amyloid plaque binding declined about 27% in the high-dose group and about 16% in the low-dose group, reflecting plaque clearance. Phosphorylated tau in CSF decreased by about 17 pg/mL and 10 pg/mL, respectively, and total tau decreased by 160 pg/mL and 120 pg/mL. Tau decreases indicate a slowing of neuronal damage.

In ENGAGE, amyloid plaque binding decreased by about 24% in the high-dose group and by about 16% in the low-dose group. Phosphorylated tau dropped by about 10 pg/mL and 11 pg/mL, respectively. But total tau dropped more in the low-dose group than in the high-dose group (about –100 pg/mL vs. –20 pg/mL).

Biogen said the amyloid PET imaging biomarker results and CDR-SB scores in both studies were consistent with each other in a subset of patients with “sufficient exposure to 10 mg/kg,” which was defined as “10 or more uninterrupted 10-mg/kg dosing intervals at steady-state.”

The most common adverse events were amyloid related imaging abnormalities–edema (ARIA-E), which occurred in 35%, and headache in 20%. The majority of patients who experienced ARIA-E (74%) were asymptomatic; episodes generally resolved within 4-16 weeks, typically without long-term sequelae.

Dr. Aisen is a consultant for Biogen and on the aducanumab steering committee. None of the other sources in this article have any financial relationship with Biogen or Eisai.

This article was updated 10/23/19.

[email protected]

Federal health officials once again are warning individuals to refrain from using all e-cigarette and vaping products, especially those containing tetrahydrocannabinol (THC).

The restated warning, issued by the Centers for Disease Control and Prevention, is based on a study of 83 patients with e-cigarette, or vaping, product use–associated lung injury (EVALI) in Utah, where researchers found several common characteristics, most strikingly the use of THC-containing products.

Fifty-three patients were interviewed by researchers. Of them, 49 (92%) reported use of THC-containing e-cigarette or vaping products during the 3 months preceding illness; 35 (66%) reported using nicotine-containing products; and 32 (60%) reported using both THC- and nicotine-containing products.

In addition, 17 (32%) patients reported exclusive use of THC-containing products, whereas only 3 (6%) reported exclusive use of nicotine-containing products. Non-medical THC use is illegal in Utah.

The median age of patients was 26 years, 3 years older than the national median; more than one-third were aged 30 years or older, according to the researchers.

Utah is seeing a higher-than-average rate of EVALI cases, with 26/million cases, compared with 4/million nationally.

Vitamin E acetate has been considered to have a suspect role in EVALI and was identified in the majority of THC cartridge samples tested in this study; however, those samples represented only six patients, according to the researchers. They added that testing of different THC cartridge samples by the Food and Drug Administration and other laboratories has shown vitamin E acetate concentrations of 31%-88% and lower-than-expected THC concentrations (14%-76% versus the typically advertised 75%-95%).

“The potential role of vitamin E acetate in lung injury remains unknown; however, the identification of vitamin E acetate among products collected from patients in Utah and elsewhere indicates that the outbreak might be associated with cutting agents or adulterants. Ascertaining the potential contribution of diluents to the current outbreak will require data from multiple states and analysis at the national level,” the researchers concluded.

The authors reported that they had no conflicts.
 

[email protected]

SOURCE: Lewis N et al. MMWR Morb Mortal Wkly Rep. Early Release. Oct. 22, 2019. 68:1-5.

Federal health officials once again are warning individuals to refrain from using all e-cigarette and vaping products, especially those containing tetrahydrocannabinol (THC).

The restated warning, issued by the Centers for Disease Control and Prevention, is based on a study of 83 patients with e-cigarette, or vaping, product use–associated lung injury (EVALI) in Utah, where researchers found several common characteristics, most strikingly the use of THC-containing products.

Fifty-three patients were interviewed by researchers. Of them, 49 (92%) reported use of THC-containing e-cigarette or vaping products during the 3 months preceding illness; 35 (66%) reported using nicotine-containing products; and 32 (60%) reported using both THC- and nicotine-containing products.

In addition, 17 (32%) patients reported exclusive use of THC-containing products, whereas only 3 (6%) reported exclusive use of nicotine-containing products. Non-medical THC use is illegal in Utah.

The median age of patients was 26 years, 3 years older than the national median; more than one-third were aged 30 years or older, according to the researchers.

Utah is seeing a higher-than-average rate of EVALI cases, with 26/million cases, compared with 4/million nationally.

Vitamin E acetate has been considered to have a suspect role in EVALI and was identified in the majority of THC cartridge samples tested in this study; however, those samples represented only six patients, according to the researchers. They added that testing of different THC cartridge samples by the Food and Drug Administration and other laboratories has shown vitamin E acetate concentrations of 31%-88% and lower-than-expected THC concentrations (14%-76% versus the typically advertised 75%-95%).

“The potential role of vitamin E acetate in lung injury remains unknown; however, the identification of vitamin E acetate among products collected from patients in Utah and elsewhere indicates that the outbreak might be associated with cutting agents or adulterants. Ascertaining the potential contribution of diluents to the current outbreak will require data from multiple states and analysis at the national level,” the researchers concluded.

The authors reported that they had no conflicts.
 

[email protected]

SOURCE: Lewis N et al. MMWR Morb Mortal Wkly Rep. Early Release. Oct. 22, 2019. 68:1-5.

Federal health officials once again are warning individuals to refrain from using all e-cigarette and vaping products, especially those containing tetrahydrocannabinol (THC).

The restated warning, issued by the Centers for Disease Control and Prevention, is based on a study of 83 patients with e-cigarette, or vaping, product use–associated lung injury (EVALI) in Utah, where researchers found several common characteristics, most strikingly the use of THC-containing products.

Fifty-three patients were interviewed by researchers. Of them, 49 (92%) reported use of THC-containing e-cigarette or vaping products during the 3 months preceding illness; 35 (66%) reported using nicotine-containing products; and 32 (60%) reported using both THC- and nicotine-containing products.

In addition, 17 (32%) patients reported exclusive use of THC-containing products, whereas only 3 (6%) reported exclusive use of nicotine-containing products. Non-medical THC use is illegal in Utah.

The median age of patients was 26 years, 3 years older than the national median; more than one-third were aged 30 years or older, according to the researchers.

Utah is seeing a higher-than-average rate of EVALI cases, with 26/million cases, compared with 4/million nationally.

Vitamin E acetate has been considered to have a suspect role in EVALI and was identified in the majority of THC cartridge samples tested in this study; however, those samples represented only six patients, according to the researchers. They added that testing of different THC cartridge samples by the Food and Drug Administration and other laboratories has shown vitamin E acetate concentrations of 31%-88% and lower-than-expected THC concentrations (14%-76% versus the typically advertised 75%-95%).

“The potential role of vitamin E acetate in lung injury remains unknown; however, the identification of vitamin E acetate among products collected from patients in Utah and elsewhere indicates that the outbreak might be associated with cutting agents or adulterants. Ascertaining the potential contribution of diluents to the current outbreak will require data from multiple states and analysis at the national level,” the researchers concluded.

The authors reported that they had no conflicts.
 

[email protected]

SOURCE: Lewis N et al. MMWR Morb Mortal Wkly Rep. Early Release. Oct. 22, 2019. 68:1-5.

NEW ORLEANS – A history of recent exacerbations did not significantly affect the safety or efficacy of aclidinium bromide (Tudorza) in patients with moderate to severe chronic obstructive pulmonary disease and high cardiovascular risk, analysis of a postmarketing surveillance trial suggests.

Andrew D. Bowser/MDedge News

Regardless of exacerbation history, the long-acting muscarinic antagonist reduced the rate of moderate or severe COPD exacerbations versus placebo in this subgroup analysis of the phase IV ASCENT-COPD trial, presented here at the annual meeting of the American College of Chest Physicians.

At the same time, there were no significant increases in the risk of mortality or major cardiac adverse events (MACE) for those patients who had an exacerbation in the past year versus those who did not, according to investigator Robert A. Wise, MD.

Those findings may be reassuring, given that COPD patients commonly have comorbidities and cardiovascular risk factors, according to Dr. Wise, professor of medicine at the Johns Hopkins University, Baltimore.

“There’s a concern and some evidence that patients who have a propensity to COPD exacerbations may also have an increased risk for cardiovascular events,” Dr. Wise said in a podium presentation.

Accordingly, he and coinvestigators sought to tease out the impact of COPD exacerbations on safety as well as efficacy in the randomized, placebo-controlled ASCENT-COPD trial, which included 3,630 patients with moderate to severe COPD plus a cardiovascular disease history or multiple atherothrombotic risk factors.

Of the patients who were analyzed in the study, 1,433 patients had at least one treated COPD exacerbation in the year before screening for the study, while 2,156 had no exacerbations in the prior year, Dr. Wise said.

Top-line results of that study, published several months ago, showed that aclidinium did not increase MACE risk over 3 years, and reduced the rate of moderate to severe COPD exacerbations over the first year (JAMA. 2019 7 May 7;321[17]:1693-701).

In this latest analysis, presented at the meeting, risk of MACE with aclidinium treatment was not increased versus placebo, irrespective of whether they had exacerbations in the prior year (interaction P = .233); likewise, the risk of all-cause mortality was similar between groups (P = .154).

In terms of reduction in moderate or severe COPD exacerbations in the first year, aclidinium was superior to placebo both for the patients who had at least one or exacerbation in the prior year (rate ratio, 0.80) and those who had no exacerbations in the prior year (RR, 0.69).

“This translates into a number-needed-to-treat to prevent one exacerbation of about 11 patients for those without an exacerbation, compared to about 6 patients for those with a prior exacerbation,” Dr. Wise said in his presentation.

The ASCENT-COPD study was funded initially by Forest Laboratories and later by AstraZeneca and Circassia. Dr. Wise provided disclosures related to AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sunovion, Mylan/Theravance, Contrafect, Pearl, Merck, Verona, Novartis, AbbVie, Syneos, Regeneron, and Kiniksa.

SOURCE: Wise R et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.231.

NEW ORLEANS – A history of recent exacerbations did not significantly affect the safety or efficacy of aclidinium bromide (Tudorza) in patients with moderate to severe chronic obstructive pulmonary disease and high cardiovascular risk, analysis of a postmarketing surveillance trial suggests.

Andrew D. Bowser/MDedge News

Regardless of exacerbation history, the long-acting muscarinic antagonist reduced the rate of moderate or severe COPD exacerbations versus placebo in this subgroup analysis of the phase IV ASCENT-COPD trial, presented here at the annual meeting of the American College of Chest Physicians.

At the same time, there were no significant increases in the risk of mortality or major cardiac adverse events (MACE) for those patients who had an exacerbation in the past year versus those who did not, according to investigator Robert A. Wise, MD.

Those findings may be reassuring, given that COPD patients commonly have comorbidities and cardiovascular risk factors, according to Dr. Wise, professor of medicine at the Johns Hopkins University, Baltimore.

“There’s a concern and some evidence that patients who have a propensity to COPD exacerbations may also have an increased risk for cardiovascular events,” Dr. Wise said in a podium presentation.

Accordingly, he and coinvestigators sought to tease out the impact of COPD exacerbations on safety as well as efficacy in the randomized, placebo-controlled ASCENT-COPD trial, which included 3,630 patients with moderate to severe COPD plus a cardiovascular disease history or multiple atherothrombotic risk factors.

Of the patients who were analyzed in the study, 1,433 patients had at least one treated COPD exacerbation in the year before screening for the study, while 2,156 had no exacerbations in the prior year, Dr. Wise said.

Top-line results of that study, published several months ago, showed that aclidinium did not increase MACE risk over 3 years, and reduced the rate of moderate to severe COPD exacerbations over the first year (JAMA. 2019 7 May 7;321[17]:1693-701).

In this latest analysis, presented at the meeting, risk of MACE with aclidinium treatment was not increased versus placebo, irrespective of whether they had exacerbations in the prior year (interaction P = .233); likewise, the risk of all-cause mortality was similar between groups (P = .154).

In terms of reduction in moderate or severe COPD exacerbations in the first year, aclidinium was superior to placebo both for the patients who had at least one or exacerbation in the prior year (rate ratio, 0.80) and those who had no exacerbations in the prior year (RR, 0.69).

“This translates into a number-needed-to-treat to prevent one exacerbation of about 11 patients for those without an exacerbation, compared to about 6 patients for those with a prior exacerbation,” Dr. Wise said in his presentation.

The ASCENT-COPD study was funded initially by Forest Laboratories and later by AstraZeneca and Circassia. Dr. Wise provided disclosures related to AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sunovion, Mylan/Theravance, Contrafect, Pearl, Merck, Verona, Novartis, AbbVie, Syneos, Regeneron, and Kiniksa.

SOURCE: Wise R et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.231.

NEW ORLEANS – A history of recent exacerbations did not significantly affect the safety or efficacy of aclidinium bromide (Tudorza) in patients with moderate to severe chronic obstructive pulmonary disease and high cardiovascular risk, analysis of a postmarketing surveillance trial suggests.

Andrew D. Bowser/MDedge News

Regardless of exacerbation history, the long-acting muscarinic antagonist reduced the rate of moderate or severe COPD exacerbations versus placebo in this subgroup analysis of the phase IV ASCENT-COPD trial, presented here at the annual meeting of the American College of Chest Physicians.

At the same time, there were no significant increases in the risk of mortality or major cardiac adverse events (MACE) for those patients who had an exacerbation in the past year versus those who did not, according to investigator Robert A. Wise, MD.

Those findings may be reassuring, given that COPD patients commonly have comorbidities and cardiovascular risk factors, according to Dr. Wise, professor of medicine at the Johns Hopkins University, Baltimore.

“There’s a concern and some evidence that patients who have a propensity to COPD exacerbations may also have an increased risk for cardiovascular events,” Dr. Wise said in a podium presentation.

Accordingly, he and coinvestigators sought to tease out the impact of COPD exacerbations on safety as well as efficacy in the randomized, placebo-controlled ASCENT-COPD trial, which included 3,630 patients with moderate to severe COPD plus a cardiovascular disease history or multiple atherothrombotic risk factors.

Of the patients who were analyzed in the study, 1,433 patients had at least one treated COPD exacerbation in the year before screening for the study, while 2,156 had no exacerbations in the prior year, Dr. Wise said.

Top-line results of that study, published several months ago, showed that aclidinium did not increase MACE risk over 3 years, and reduced the rate of moderate to severe COPD exacerbations over the first year (JAMA. 2019 7 May 7;321[17]:1693-701).

In this latest analysis, presented at the meeting, risk of MACE with aclidinium treatment was not increased versus placebo, irrespective of whether they had exacerbations in the prior year (interaction P = .233); likewise, the risk of all-cause mortality was similar between groups (P = .154).

In terms of reduction in moderate or severe COPD exacerbations in the first year, aclidinium was superior to placebo both for the patients who had at least one or exacerbation in the prior year (rate ratio, 0.80) and those who had no exacerbations in the prior year (RR, 0.69).

“This translates into a number-needed-to-treat to prevent one exacerbation of about 11 patients for those without an exacerbation, compared to about 6 patients for those with a prior exacerbation,” Dr. Wise said in his presentation.

The ASCENT-COPD study was funded initially by Forest Laboratories and later by AstraZeneca and Circassia. Dr. Wise provided disclosures related to AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Sunovion, Mylan/Theravance, Contrafect, Pearl, Merck, Verona, Novartis, AbbVie, Syneos, Regeneron, and Kiniksa.

SOURCE: Wise R et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.231.