Charu Puri, MD, FHM, is a hospitalist and medical informaticist at Sutter East Bay Medical Group in Oakland, Calif. She also serves as medical director for onboarding, mentoring, and physician development.

Dr. Puri has been a member of the Society of Hospital Medicine since 2009, and attended the Society’s Leadership Academy, where she was inspired to create a mentorship program at her own institution. She is a member of the San Francisco Bay chapter of SHM and serves on the Performance Measurement and Reporting Committee.
 

At what point in your education/training did you decide to practice hospital medicine? What about hospital medicine appealed to you?

It was early on in my residency that it became clear to me that I wanted to pursue the hospitalist track. It was a natural fit, and I gravitated toward the hospitalist side of medicine. What appealed to me most was that we had the opportunity and privilege to provide care to patients in their most vulnerable state and experience the effects of that care in real time. I found that very gratifying.

There is also a sense of community and camaraderie that comes with working in a hospital setting. Everyone is working together, trying to help patients. The collegiality and the relationships that develop are very rewarding. I have been fortunate enough to have built strong friendships with the hospitalists in my group as well as colleagues from other disciplines in medicine that work in the hospital.
 

What is your current role at Sutter Health?

Alta Bates Summit Medical Center is part of the larger Sutter Health system. I have an administrative role with my medical group in addition to the clinical work I do at the medical center, although first and foremost I identify myself as a hospitalist. About 5 years ago I took on a role in clinical informatics, when our hospital implemented an EHR. Since then I have been working as an inpatient physician informaticist. Most recently I took on a new role as medical director for onboarding, mentoring, and physician development in my medical group.

How do you balance the different duties of your various roles?

I am full time in my administration role, between my informatics role and my onboarding role. I technically don’t have to do clinical shifts if I don’t want to, but it’s important to me to continue clinical practice and maintain my skills and connection to the hospital and colleagues. I do about four clinical shifts a month, and plan to continue doing that. In our group you must do 14 shifts a month to be considered full time, so what I do could be considered about one-third of that.

What are your favorite areas of clinical practice and/or research?

I haven’t had a lot of research experience. My residency program was a community-based program, and my current setting is a community hospital. I haven’t been involved much in the academic side of hospital medicine. As far as clinical practices goes, I think it’s the diversity of hospital medicine that appeals to me. You really get to be a jack of all trades, and experience all the different disciplines of medicine. I like the variety.

Both my informatics and onboarding roles came out of a need that I identified, and just began doing the work before there was an official role. When we implemented our EHR, it was essential to get our doctors organized to make sure they were ready to take care of patients that first day of go live. By the time our hospital went live on the EHR, I had a good understanding of how it worked, and so I was able to create a miniature curriculum for our physicians – templates, order sets, workflows, etc. – to help ensure everything went smoothly. A few months after we implemented the EHR, I was officially offered a physician informaticist role.

The onboarding role came about in an interesting way. I was participating in the leadership course offered by SHM and was lucky enough to be in the pilot for the Capstone course. That leadership course is focused around mentoring and sponsorship, and one of the faculty members was Nancy Spector, MD, the associate dean of faculty development at Drexel University, Philadelphia. She talked a lot about mentoring, and I was inspired to set up a mentoring program for our hospitalists. Dr. Spector graciously agreed to mentor me as I worked on my Capstone project, which was to create a mentoring program in a community-based hospitalist group. As I continued to work on the project, coincidentally our medical group decided to redesign our new physician onboarding process. Because I was already involved in the onboarding and training related to our EHR, I became very involved with our medical group's onboarding redesign.

My group's CEO decided to create a new directorship role for onboarding and mentoring, which I recently interviewed for and was offered about two months ago.

I think setting up systems to support our doctors is the common threat between the informatics and the onboarding roles. I want to implement systems that support our doctors, help them succeed, and hopefully make their jobs a little easier.
 

What are the most challenging aspects of practicing hospital medicine? What are the most rewarding?

We practice in a very urban environment, with many low-income patients who have limited resources and access to health care. That can be very challenging. You always wonder if these patients have all the support they need after leaving the hospital. Sometimes I feel that I am just putting a band-aid on the medical problem, so to speak, but not solving the underlying issue. But it can be very rewarding during those times when the hospital and the broader community can bring our resources together to create interventions to help at-risk patients. It doesn’t happen as frequently as we would like, but when it does happen it feels good.

Another challenging aspect is related to perception. There are a lot of consultants in the hospital who view hospitalists as "house staff." That can be very frustrating, and it’s important to steer the conversations away from that perspective, and really try to establish ourselves as colleagues and peers.
 

How will hospital medicine change in the next decade or 2?

It’s a relatively young field, and we’re still figuring it out. I really don’t know how hospital medicine is going to change, but I do know that the field will continue to evolve, given the way U.S. health care is rapidly changing.

Do you have any advice for students and residents interested in hospital medicine?

It’s a fun way to practice medicine and I would encourage students to go into hospital medicine. It’s great for work/life balance. The advice I would give is that it is very important to get involved early in your career. Get involved in medical group or hospital committees. Stay away from the “shift mentality” – that I’m going to work my shifts and leave. That can lead to early burnout, which is a real concern in our field now. Early engagement is essential, so you can help lead these conversations at your hospital.

Charu Puri, MD, FHM, is a hospitalist and medical informaticist at Sutter East Bay Medical Group in Oakland, Calif. She also serves as medical director for onboarding, mentoring, and physician development.

Dr. Puri has been a member of the Society of Hospital Medicine since 2009, and attended the Society’s Leadership Academy, where she was inspired to create a mentorship program at her own institution. She is a member of the San Francisco Bay chapter of SHM and serves on the Performance Measurement and Reporting Committee.
 

At what point in your education/training did you decide to practice hospital medicine? What about hospital medicine appealed to you?

It was early on in my residency that it became clear to me that I wanted to pursue the hospitalist track. It was a natural fit, and I gravitated toward the hospitalist side of medicine. What appealed to me most was that we had the opportunity and privilege to provide care to patients in their most vulnerable state and experience the effects of that care in real time. I found that very gratifying.

There is also a sense of community and camaraderie that comes with working in a hospital setting. Everyone is working together, trying to help patients. The collegiality and the relationships that develop are very rewarding. I have been fortunate enough to have built strong friendships with the hospitalists in my group as well as colleagues from other disciplines in medicine that work in the hospital.
 

What is your current role at Sutter Health?

Alta Bates Summit Medical Center is part of the larger Sutter Health system. I have an administrative role with my medical group in addition to the clinical work I do at the medical center, although first and foremost I identify myself as a hospitalist. About 5 years ago I took on a role in clinical informatics, when our hospital implemented an EHR. Since then I have been working as an inpatient physician informaticist. Most recently I took on a new role as medical director for onboarding, mentoring, and physician development in my medical group.

How do you balance the different duties of your various roles?

I am full time in my administration role, between my informatics role and my onboarding role. I technically don’t have to do clinical shifts if I don’t want to, but it’s important to me to continue clinical practice and maintain my skills and connection to the hospital and colleagues. I do about four clinical shifts a month, and plan to continue doing that. In our group you must do 14 shifts a month to be considered full time, so what I do could be considered about one-third of that.

What are your favorite areas of clinical practice and/or research?

I haven’t had a lot of research experience. My residency program was a community-based program, and my current setting is a community hospital. I haven’t been involved much in the academic side of hospital medicine. As far as clinical practices goes, I think it’s the diversity of hospital medicine that appeals to me. You really get to be a jack of all trades, and experience all the different disciplines of medicine. I like the variety.

Both my informatics and onboarding roles came out of a need that I identified, and just began doing the work before there was an official role. When we implemented our EHR, it was essential to get our doctors organized to make sure they were ready to take care of patients that first day of go live. By the time our hospital went live on the EHR, I had a good understanding of how it worked, and so I was able to create a miniature curriculum for our physicians – templates, order sets, workflows, etc. – to help ensure everything went smoothly. A few months after we implemented the EHR, I was officially offered a physician informaticist role.

The onboarding role came about in an interesting way. I was participating in the leadership course offered by SHM and was lucky enough to be in the pilot for the Capstone course. That leadership course is focused around mentoring and sponsorship, and one of the faculty members was Nancy Spector, MD, the associate dean of faculty development at Drexel University, Philadelphia. She talked a lot about mentoring, and I was inspired to set up a mentoring program for our hospitalists. Dr. Spector graciously agreed to mentor me as I worked on my Capstone project, which was to create a mentoring program in a community-based hospitalist group. As I continued to work on the project, coincidentally our medical group decided to redesign our new physician onboarding process. Because I was already involved in the onboarding and training related to our EHR, I became very involved with our medical group's onboarding redesign.

My group's CEO decided to create a new directorship role for onboarding and mentoring, which I recently interviewed for and was offered about two months ago.

I think setting up systems to support our doctors is the common threat between the informatics and the onboarding roles. I want to implement systems that support our doctors, help them succeed, and hopefully make their jobs a little easier.
 

What are the most challenging aspects of practicing hospital medicine? What are the most rewarding?

We practice in a very urban environment, with many low-income patients who have limited resources and access to health care. That can be very challenging. You always wonder if these patients have all the support they need after leaving the hospital. Sometimes I feel that I am just putting a band-aid on the medical problem, so to speak, but not solving the underlying issue. But it can be very rewarding during those times when the hospital and the broader community can bring our resources together to create interventions to help at-risk patients. It doesn’t happen as frequently as we would like, but when it does happen it feels good.

Another challenging aspect is related to perception. There are a lot of consultants in the hospital who view hospitalists as "house staff." That can be very frustrating, and it’s important to steer the conversations away from that perspective, and really try to establish ourselves as colleagues and peers.
 

How will hospital medicine change in the next decade or 2?

It’s a relatively young field, and we’re still figuring it out. I really don’t know how hospital medicine is going to change, but I do know that the field will continue to evolve, given the way U.S. health care is rapidly changing.

Do you have any advice for students and residents interested in hospital medicine?

It’s a fun way to practice medicine and I would encourage students to go into hospital medicine. It’s great for work/life balance. The advice I would give is that it is very important to get involved early in your career. Get involved in medical group or hospital committees. Stay away from the “shift mentality” – that I’m going to work my shifts and leave. That can lead to early burnout, which is a real concern in our field now. Early engagement is essential, so you can help lead these conversations at your hospital.

Charu Puri, MD, FHM, is a hospitalist and medical informaticist at Sutter East Bay Medical Group in Oakland, Calif. She also serves as medical director for onboarding, mentoring, and physician development.

Dr. Puri has been a member of the Society of Hospital Medicine since 2009, and attended the Society’s Leadership Academy, where she was inspired to create a mentorship program at her own institution. She is a member of the San Francisco Bay chapter of SHM and serves on the Performance Measurement and Reporting Committee.
 

At what point in your education/training did you decide to practice hospital medicine? What about hospital medicine appealed to you?

It was early on in my residency that it became clear to me that I wanted to pursue the hospitalist track. It was a natural fit, and I gravitated toward the hospitalist side of medicine. What appealed to me most was that we had the opportunity and privilege to provide care to patients in their most vulnerable state and experience the effects of that care in real time. I found that very gratifying.

There is also a sense of community and camaraderie that comes with working in a hospital setting. Everyone is working together, trying to help patients. The collegiality and the relationships that develop are very rewarding. I have been fortunate enough to have built strong friendships with the hospitalists in my group as well as colleagues from other disciplines in medicine that work in the hospital.
 

What is your current role at Sutter Health?

Alta Bates Summit Medical Center is part of the larger Sutter Health system. I have an administrative role with my medical group in addition to the clinical work I do at the medical center, although first and foremost I identify myself as a hospitalist. About 5 years ago I took on a role in clinical informatics, when our hospital implemented an EHR. Since then I have been working as an inpatient physician informaticist. Most recently I took on a new role as medical director for onboarding, mentoring, and physician development in my medical group.

How do you balance the different duties of your various roles?

I am full time in my administration role, between my informatics role and my onboarding role. I technically don’t have to do clinical shifts if I don’t want to, but it’s important to me to continue clinical practice and maintain my skills and connection to the hospital and colleagues. I do about four clinical shifts a month, and plan to continue doing that. In our group you must do 14 shifts a month to be considered full time, so what I do could be considered about one-third of that.

What are your favorite areas of clinical practice and/or research?

I haven’t had a lot of research experience. My residency program was a community-based program, and my current setting is a community hospital. I haven’t been involved much in the academic side of hospital medicine. As far as clinical practices goes, I think it’s the diversity of hospital medicine that appeals to me. You really get to be a jack of all trades, and experience all the different disciplines of medicine. I like the variety.

Both my informatics and onboarding roles came out of a need that I identified, and just began doing the work before there was an official role. When we implemented our EHR, it was essential to get our doctors organized to make sure they were ready to take care of patients that first day of go live. By the time our hospital went live on the EHR, I had a good understanding of how it worked, and so I was able to create a miniature curriculum for our physicians – templates, order sets, workflows, etc. – to help ensure everything went smoothly. A few months after we implemented the EHR, I was officially offered a physician informaticist role.

The onboarding role came about in an interesting way. I was participating in the leadership course offered by SHM and was lucky enough to be in the pilot for the Capstone course. That leadership course is focused around mentoring and sponsorship, and one of the faculty members was Nancy Spector, MD, the associate dean of faculty development at Drexel University, Philadelphia. She talked a lot about mentoring, and I was inspired to set up a mentoring program for our hospitalists. Dr. Spector graciously agreed to mentor me as I worked on my Capstone project, which was to create a mentoring program in a community-based hospitalist group. As I continued to work on the project, coincidentally our medical group decided to redesign our new physician onboarding process. Because I was already involved in the onboarding and training related to our EHR, I became very involved with our medical group's onboarding redesign.

My group's CEO decided to create a new directorship role for onboarding and mentoring, which I recently interviewed for and was offered about two months ago.

I think setting up systems to support our doctors is the common threat between the informatics and the onboarding roles. I want to implement systems that support our doctors, help them succeed, and hopefully make their jobs a little easier.
 

What are the most challenging aspects of practicing hospital medicine? What are the most rewarding?

We practice in a very urban environment, with many low-income patients who have limited resources and access to health care. That can be very challenging. You always wonder if these patients have all the support they need after leaving the hospital. Sometimes I feel that I am just putting a band-aid on the medical problem, so to speak, but not solving the underlying issue. But it can be very rewarding during those times when the hospital and the broader community can bring our resources together to create interventions to help at-risk patients. It doesn’t happen as frequently as we would like, but when it does happen it feels good.

Another challenging aspect is related to perception. There are a lot of consultants in the hospital who view hospitalists as "house staff." That can be very frustrating, and it’s important to steer the conversations away from that perspective, and really try to establish ourselves as colleagues and peers.
 

How will hospital medicine change in the next decade or 2?

It’s a relatively young field, and we’re still figuring it out. I really don’t know how hospital medicine is going to change, but I do know that the field will continue to evolve, given the way U.S. health care is rapidly changing.

Do you have any advice for students and residents interested in hospital medicine?

It’s a fun way to practice medicine and I would encourage students to go into hospital medicine. It’s great for work/life balance. The advice I would give is that it is very important to get involved early in your career. Get involved in medical group or hospital committees. Stay away from the “shift mentality” – that I’m going to work my shifts and leave. That can lead to early burnout, which is a real concern in our field now. Early engagement is essential, so you can help lead these conversations at your hospital.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

Intensive postoperative chemotherapy and focal radiation may improve event-free survival (EFS) among patients with atypical teratoid/rhabdoid tumors (AT/RT), results of the phase 3 ACNS0333 trial suggest.

Compared with historical therapies, the treatment protocol reduced the risk of EFS events by 57%, reported lead author Alyssa T. Reddy, MD, of the University of California San Francisco Benioff Children’s Hospital, and colleagues, who also noted that this is the first AT/RT-specific cooperative group trial.

“Case series and retrospective data suggested high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue, early radiation therapy, and methotrexate had activity against AT/RT,” the investigators wrote in the Journal of Clinical Oncology.

Based on these findings, the investigators designed the ACNS0333 treatment protocol. Following surgery, all patients received two cycles of induction with methotrexate, vincristine, etoposide, cyclophosphamide, and cisplatin. They then underwent PBSC harvest.

Next, patients were divided into two groups based on age, disease location, and extent. Conformal radiotherapy was given between induction and consolidation to patients who were at least 6 months of age with tumor localized to the infratentorial brain or at least 12 months of age with tumor localized to the supratentorial brain. For younger patients or those with metastatic disease, radiotherapy was administered after consolidation was complete. Consolidation consisted of three cycles of thiotepa and carboplatin with PBSC support.

In addition to efficacy and safety analyses, molecular testing was performed on frozen tumor tissue and blood. This enabled a retrospective exploratory analysis of methylation profiles, which were used to subtype disease into three molecular classes: 2A/TYR, 2B/MYC, or 1/SHH-NOTCH.
 

Patient characteristics and results

The evaluable cohort included 65 patients, most of whom (83%) were younger than 36 months of age at baseline. About half of patients (51%) had infratentorial tumors, slightly fewer (40%) had supratentorial tumors, and 7.5% had a contiguous tumor in both locations. About one-third of patients (37%) had metastatic disease, and almost two-thirds (62%) had residual disease after surgery.

The median follow-up was 4.7 years. At 4 years, patients had an EFS rate of 35%. For patients aged 36 months or older, the 4-year EFS rate was higher still, at 48%.

These EFS rates compared favorably with the 6.4% EFS rate observed in a historical cohort of patients from the CCG-9921 trial (J Clin Oncol. 2005 Oct 20;23[30]:7621-31) and the POG-9233/4 trial (Neuro Oncol. 2014 Mar;16[3]:457-65). Overall, there was a 57% reduction in risk of EFS events in the ACNS0333 cohort compared with the historical controls (hazard ratio, 0.43; P less than .0005).

The 4-year overall survival rate was 43% for the entire ACNS0333 cohort and 57% for patients aged 36 months or older. Looking at molecular subtypes, patients with 1/SHH-NOTCH tumors had the best 4-year overall survival rate, at 56%, compared with 41% for 2A/TYR and 27% for 2B/MYC.

Adverse events were predominantly hematologic or infectious events reported during the induction and consolidation phases. Grade 4 or higher adverse events that occurred in at least 5% of patients were hypokalemia, hypotension, hypoxia, sepsis, ALT increase, and decreases in lymphocyte, neutrophil, platelet, and white blood cell counts.

Eight deaths were reported, four of which were associated with treatment. Causes of treatment-related death were sepsis after prolonged myelosuppression, respiratory failure from pulmonary fibrosis, and central nervous system necrosis (n = 2). One patient with central nervous system necrosis had viral encephalitis and sepsis at the time of death.

“ACNS0333 has shown that intensive multimodal therapy significantly improves survival for patients with AT/RT,” the investigators concluded. “However, further intensification using cytotoxic agents is likely not feasible. There are increasing data suggesting that AT/RT may be a good candidate for pathway-specific targeted therapies.”

The study was funded by the Children’s Oncology Group, the National Institutes of Health, the St. Baldrick’s Foundation, the Canadian Cancer Society, and the Children’s of Alabama Kaul Pediatric Research Institute. The investigators disclosed relationships with Novartis, AstraZeneca, and Merck Sharp & Dohme.

SOURCE: Reddy AT et al. J Clin Oncol. 2020 Feb 27. doi: 10.1200/JCO.19.01776.

LAS VEGAS – More than 10 years ago, Gerard Sanacora, PhD, MD, came across a study in the medical literature that stopped him in his tracks.

For the study, Austrian neurologist Eberhard A. Deisenhammer, MD, and colleagues sought to determine the length of the period between consideration and accomplishment of a suicide attempt (J Clin Psychiatry. 2009;70[1]:19-24). To do so, they interviewed 82 patients who were referred to a psychiatric university hospital after a suicide attempt. Nearly half of the patients (48%) reported that the period between the first current thought of suicide and the actual attempt had lasted 10 minutes or less.

“When you’re talking about treating suicide behavior, there are so many components: the impulsivity component, the resilience component – all these things that can’t be measured with a simple outcome measure,” Dr. Sanacora said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “That’s one of the real challenges. It requires us to take a good look at how we’re treating these patients in general.”

It also underscores the need for new treatments that target suicidal ideation and behavior.

“There is increasing evidence that ketamine and esketamine can produce effects that could be used in the treatment of mood disorder patients with suicidal ideation or behavior,” said Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn. “However, there are many challenges to performing the studies that are required to more definitively demonstrate rapid and sustained improvement in suicide risks.”

The global 12-month prevalence of nonfatal suicide attempts is about 0.3% to 0.4%, and the lifetime prevalence is 3%, “which is pretty shocking,” he said. In the United States, there are more than 30 suicide attempts for each suicide death. At the same time, a World Health Organization community survey conducted in 21 countries found that the 12-month prevalence of suicidal ideation was about 2%, and that the lifetime prevalence was 9%. “These are large numbers that we’re talking about internationally,” said Dr. Sanacora, who also directs the Yale Depression Research Program. In 2013, suicidal ideation constituted nearly 1% of all adult ED visits in the United States, with conservative costs of $2.2 billion. “Every step along the process takes a large toll on the health care system and society, from the top level of completed suicide to suicidal ideation,” he said.

According to 2016 data from the Centers for Disease Control and Prevention, nearly 10 million people in the United States have seriously considered suicide, about 2.5 million made a plan, about 1 million attempted suicide, and about 40,000 completed suicide. “We have to think about what we’re treating,” Dr. Sanacora said. “Are we treating the suicidal ideation, or are we trying to prevent completed suicides?”

A prior history of attempted suicide is the strongest single predictive factor of a completed suicide. “In fact, the risk of dying by suicide is approximately 100 times than that of the general population within 1 year of an index attempt,” he said. Another major risk factor is having a previous psychiatric hospitalization. In fact, up to 41% of those who completed suicide had been psychiatric inpatients within the previous year, and as many as 9% of suicides occurred within 1 day of discharge from psychiatric inpatient care. Other identified risk factors include marital status, belonging to a sexual minority, occupation, military service, general medical comorbidities, diagnosis of personality disorder, chronic pain, traumatic brain injury, childhood abuse, location of residence, access to firearms, and family history of suicide. Protective factors include having a strong social support network, being a parent, and religiosity. “These are things that typically aren’t part of a treatment, but they can be woven into a treatment plan in some way,” he said.

Other identified risk symptoms include feelings of worthlessness and hopelessness, the combination of depression and anxiety, and psychosis, regardless of the specific diagnosis.

Medical stabilization constitutes the first step in the standard treatment approach to suicidal ideation and behavior. “You want to make sure the person is hospitalized and take care of any injuries that may have been sustained in the suicide attempt,” Dr. Sanacora said. The next step is reducing the immediate risks. “For the most part, that’s making sure the individual is in a safe setting commensurate with the level of risk,” he said. “You want to remove any other risks that could be around them. Then, you want to assure that an appropriate level of follow-up is provided on stepdown to lower levels of care. That year after hospitalization puts you at incredible risk, so we want to make sure we’re not just treating something in the acute phase and then not having longer-term follow-up for it.”

Existing treatments that have some evidence to help with the treatment of suicidal ideation and behavior include the use of antidepressants, lithium, and clozapine, but these agents are far from fast-acting for a patient in crisis. “In addition, a lot of docs are hesitant to give lithium because it has the potential of overdose itself,” Dr. Sanacora said. With clozapine, he continued, “there is some level of confounding by indication because, when you’re giving clozapine, it’s usually a more reliable patient, one who is not at risk of self-harm.”

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial demonstrated that, for the patients who do not respond to the first two levels of treatment with citalopram, their chances of having a remission by getting a third or fourth level of treatment is reduced to below 15% (Am J Psychiatry. 2006;163[1]:28-40).

“This suggests that, with our current armamentarium, we are limited,” said Dr. Sanacora, who is also codirector of the Yale New Haven Hospital Interventional Psychiatry Service. In the STAR*D trial, the time to response to citalopram was 6 weeks in 50% of patients. “So, when somebody is going through a crisis and is at imminent risk for suicide, and you tell them, ‘You’ll be 50% better in 6 weeks,’ that’s hard to swallow,” he said.

Recent studies of ketamine and esketamine have demonstrated a rapid onset of effect in patients with major depressive disorder, but whether they alter suicidal ideation and behavior remains unclear. “If you are wanting to improve suicidal ideation and behavior, what outcome measure are you using to do this?” Dr. Sanacora asked. “It may seem simple, but it’s not. To do a clinical trial, you would need large sample sizes to look at behavior as an outcome. In fact, even retrospective studies on this topic don’t have enough events to give you statistical meaning.” This leaves clinicians to consider scales that have been used for examining suicidal ideation and behavior over the years, including the MINI suicidality module, the SAD PERSONS scale, and the Suicide Intent Scale. “However, while they could have some value to be used clinically, these scales really don’t have great value as outcome measures,” Dr. Sanacora said.

There also have been attempts to develop scales that capture changes in suicidal ideation and behavior over time, including the C-SSRS (Columbia-Suicide Severity Rating Scale) and the Sheehan Suicidality Tracking Scale. “The sad thing is, none of these measures have been proven to be very useful clinically,” he said. “They may have some level of sensitivity and specificity, but their actual predictive value is not great. So using these clinically is somewhat difficult.”

In 2018, Dr. Sanacora and his colleagues published results from a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation (Am J Psychiatry. 2018;175[2]:150-8). The analysis included 167 participants with suicidal ideation at baseline. “Within 24 hours there was a very clear decrease in suicidal ideation in terms of clinician-reported scale,” he said. “Over 50% of patients reported having minimal or no ideation after treatment. That was maintained for 7 days.” Effect sizes were moderate to large at all time points post dose.

In the largest meta-analysis of its kind to date, researchers reviewed 15 independent trials of ketamine for suicide ideation in 572 adults with psychiatric disorders, all with a single dose of drug with varying routes and dosages (Aust N Z J Psychiatry. 2020;54[1]:29-45). The researchers in that study concluded that ketamine “may have a role in acute treatment for suicidality. However, there is clearly a need for clinical measures to ensure persistence of any benefits.”

Esketamine, which was approved in March 2019 for major depressive disorder, also shows promise in patients with suicidal ideation and behavior. In a double-blind, multicenter, proof-of-concept study, researchers randomized 68 participants to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment (Am J Psychiatry. 2018;175[7]:620-30). The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the MADRS (Montgomery-Asberg Depression Rating Scale). “There was a nice effect in the antidepressant response, compared with placebo. It hit the primary endpoint at 4 hours. The patients got treated twice a week for 4 weeks. People got better quickly and stayed well moving on.” The researchers also found that the rate of remission at day 25 was 60% in the esketamine group, compared with 42% in the placebo group. “The take-home message is that, even without the esketamine, the remission rate was 42% at day 25. That means if you’re giving people really good care, meaning that you’re seeing them twice a week and they’re inpatient until they’re able to go outpatient, people can do pretty well with that level of care.”

Meanwhile, additional evidence supporting the use of ketamine in acute care settings is starting to emerge. In a proof-of-concept trial, 18 depressed subjects with acute suicidal ideation who presented to the emergency department and required hospitalization were randomized to either IV ketamine 0.2 mg/kg or to saline placebo (Depress Anxiety. 2019 Nov 16. doi: 10.1002/da.22975). Ninety minutes after infusion, 88% of patients in the ketamine group had achieved remission of suicidal ideation, compared with 33% in the placebo group (P less than .05). No serious adverse events were noted.

“There is a clear need for new treatments targeting suicidal ideation and behavior,” Dr. Sanacora concluded. “Any plan to institute a rapid-acting treatment for individuals with imminent risk of suicidal behavior must be placed in the context of a larger comprehensive treatment plan. Getting somebody to feel better in the short run is great, but you really have to think about the whole treatment plan.”

Dr. Sanacora reported having received grants and research support from numerous pharmaceutical companies. He also holds an ownership interest in Biohaven Pharmaceuticals.

dbrunk@mdedge.com

LAS VEGAS – More than 10 years ago, Gerard Sanacora, PhD, MD, came across a study in the medical literature that stopped him in his tracks.

For the study, Austrian neurologist Eberhard A. Deisenhammer, MD, and colleagues sought to determine the length of the period between consideration and accomplishment of a suicide attempt (J Clin Psychiatry. 2009;70[1]:19-24). To do so, they interviewed 82 patients who were referred to a psychiatric university hospital after a suicide attempt. Nearly half of the patients (48%) reported that the period between the first current thought of suicide and the actual attempt had lasted 10 minutes or less.

“When you’re talking about treating suicide behavior, there are so many components: the impulsivity component, the resilience component – all these things that can’t be measured with a simple outcome measure,” Dr. Sanacora said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “That’s one of the real challenges. It requires us to take a good look at how we’re treating these patients in general.”

It also underscores the need for new treatments that target suicidal ideation and behavior.

“There is increasing evidence that ketamine and esketamine can produce effects that could be used in the treatment of mood disorder patients with suicidal ideation or behavior,” said Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn. “However, there are many challenges to performing the studies that are required to more definitively demonstrate rapid and sustained improvement in suicide risks.”

The global 12-month prevalence of nonfatal suicide attempts is about 0.3% to 0.4%, and the lifetime prevalence is 3%, “which is pretty shocking,” he said. In the United States, there are more than 30 suicide attempts for each suicide death. At the same time, a World Health Organization community survey conducted in 21 countries found that the 12-month prevalence of suicidal ideation was about 2%, and that the lifetime prevalence was 9%. “These are large numbers that we’re talking about internationally,” said Dr. Sanacora, who also directs the Yale Depression Research Program. In 2013, suicidal ideation constituted nearly 1% of all adult ED visits in the United States, with conservative costs of $2.2 billion. “Every step along the process takes a large toll on the health care system and society, from the top level of completed suicide to suicidal ideation,” he said.

According to 2016 data from the Centers for Disease Control and Prevention, nearly 10 million people in the United States have seriously considered suicide, about 2.5 million made a plan, about 1 million attempted suicide, and about 40,000 completed suicide. “We have to think about what we’re treating,” Dr. Sanacora said. “Are we treating the suicidal ideation, or are we trying to prevent completed suicides?”

A prior history of attempted suicide is the strongest single predictive factor of a completed suicide. “In fact, the risk of dying by suicide is approximately 100 times than that of the general population within 1 year of an index attempt,” he said. Another major risk factor is having a previous psychiatric hospitalization. In fact, up to 41% of those who completed suicide had been psychiatric inpatients within the previous year, and as many as 9% of suicides occurred within 1 day of discharge from psychiatric inpatient care. Other identified risk factors include marital status, belonging to a sexual minority, occupation, military service, general medical comorbidities, diagnosis of personality disorder, chronic pain, traumatic brain injury, childhood abuse, location of residence, access to firearms, and family history of suicide. Protective factors include having a strong social support network, being a parent, and religiosity. “These are things that typically aren’t part of a treatment, but they can be woven into a treatment plan in some way,” he said.

Other identified risk symptoms include feelings of worthlessness and hopelessness, the combination of depression and anxiety, and psychosis, regardless of the specific diagnosis.

Medical stabilization constitutes the first step in the standard treatment approach to suicidal ideation and behavior. “You want to make sure the person is hospitalized and take care of any injuries that may have been sustained in the suicide attempt,” Dr. Sanacora said. The next step is reducing the immediate risks. “For the most part, that’s making sure the individual is in a safe setting commensurate with the level of risk,” he said. “You want to remove any other risks that could be around them. Then, you want to assure that an appropriate level of follow-up is provided on stepdown to lower levels of care. That year after hospitalization puts you at incredible risk, so we want to make sure we’re not just treating something in the acute phase and then not having longer-term follow-up for it.”

Existing treatments that have some evidence to help with the treatment of suicidal ideation and behavior include the use of antidepressants, lithium, and clozapine, but these agents are far from fast-acting for a patient in crisis. “In addition, a lot of docs are hesitant to give lithium because it has the potential of overdose itself,” Dr. Sanacora said. With clozapine, he continued, “there is some level of confounding by indication because, when you’re giving clozapine, it’s usually a more reliable patient, one who is not at risk of self-harm.”

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial demonstrated that, for the patients who do not respond to the first two levels of treatment with citalopram, their chances of having a remission by getting a third or fourth level of treatment is reduced to below 15% (Am J Psychiatry. 2006;163[1]:28-40).

“This suggests that, with our current armamentarium, we are limited,” said Dr. Sanacora, who is also codirector of the Yale New Haven Hospital Interventional Psychiatry Service. In the STAR*D trial, the time to response to citalopram was 6 weeks in 50% of patients. “So, when somebody is going through a crisis and is at imminent risk for suicide, and you tell them, ‘You’ll be 50% better in 6 weeks,’ that’s hard to swallow,” he said.

Recent studies of ketamine and esketamine have demonstrated a rapid onset of effect in patients with major depressive disorder, but whether they alter suicidal ideation and behavior remains unclear. “If you are wanting to improve suicidal ideation and behavior, what outcome measure are you using to do this?” Dr. Sanacora asked. “It may seem simple, but it’s not. To do a clinical trial, you would need large sample sizes to look at behavior as an outcome. In fact, even retrospective studies on this topic don’t have enough events to give you statistical meaning.” This leaves clinicians to consider scales that have been used for examining suicidal ideation and behavior over the years, including the MINI suicidality module, the SAD PERSONS scale, and the Suicide Intent Scale. “However, while they could have some value to be used clinically, these scales really don’t have great value as outcome measures,” Dr. Sanacora said.

There also have been attempts to develop scales that capture changes in suicidal ideation and behavior over time, including the C-SSRS (Columbia-Suicide Severity Rating Scale) and the Sheehan Suicidality Tracking Scale. “The sad thing is, none of these measures have been proven to be very useful clinically,” he said. “They may have some level of sensitivity and specificity, but their actual predictive value is not great. So using these clinically is somewhat difficult.”

In 2018, Dr. Sanacora and his colleagues published results from a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation (Am J Psychiatry. 2018;175[2]:150-8). The analysis included 167 participants with suicidal ideation at baseline. “Within 24 hours there was a very clear decrease in suicidal ideation in terms of clinician-reported scale,” he said. “Over 50% of patients reported having minimal or no ideation after treatment. That was maintained for 7 days.” Effect sizes were moderate to large at all time points post dose.

In the largest meta-analysis of its kind to date, researchers reviewed 15 independent trials of ketamine for suicide ideation in 572 adults with psychiatric disorders, all with a single dose of drug with varying routes and dosages (Aust N Z J Psychiatry. 2020;54[1]:29-45). The researchers in that study concluded that ketamine “may have a role in acute treatment for suicidality. However, there is clearly a need for clinical measures to ensure persistence of any benefits.”

Esketamine, which was approved in March 2019 for major depressive disorder, also shows promise in patients with suicidal ideation and behavior. In a double-blind, multicenter, proof-of-concept study, researchers randomized 68 participants to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment (Am J Psychiatry. 2018;175[7]:620-30). The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the MADRS (Montgomery-Asberg Depression Rating Scale). “There was a nice effect in the antidepressant response, compared with placebo. It hit the primary endpoint at 4 hours. The patients got treated twice a week for 4 weeks. People got better quickly and stayed well moving on.” The researchers also found that the rate of remission at day 25 was 60% in the esketamine group, compared with 42% in the placebo group. “The take-home message is that, even without the esketamine, the remission rate was 42% at day 25. That means if you’re giving people really good care, meaning that you’re seeing them twice a week and they’re inpatient until they’re able to go outpatient, people can do pretty well with that level of care.”

Meanwhile, additional evidence supporting the use of ketamine in acute care settings is starting to emerge. In a proof-of-concept trial, 18 depressed subjects with acute suicidal ideation who presented to the emergency department and required hospitalization were randomized to either IV ketamine 0.2 mg/kg or to saline placebo (Depress Anxiety. 2019 Nov 16. doi: 10.1002/da.22975). Ninety minutes after infusion, 88% of patients in the ketamine group had achieved remission of suicidal ideation, compared with 33% in the placebo group (P less than .05). No serious adverse events were noted.

“There is a clear need for new treatments targeting suicidal ideation and behavior,” Dr. Sanacora concluded. “Any plan to institute a rapid-acting treatment for individuals with imminent risk of suicidal behavior must be placed in the context of a larger comprehensive treatment plan. Getting somebody to feel better in the short run is great, but you really have to think about the whole treatment plan.”

Dr. Sanacora reported having received grants and research support from numerous pharmaceutical companies. He also holds an ownership interest in Biohaven Pharmaceuticals.

dbrunk@mdedge.com

LAS VEGAS – More than 10 years ago, Gerard Sanacora, PhD, MD, came across a study in the medical literature that stopped him in his tracks.

For the study, Austrian neurologist Eberhard A. Deisenhammer, MD, and colleagues sought to determine the length of the period between consideration and accomplishment of a suicide attempt (J Clin Psychiatry. 2009;70[1]:19-24). To do so, they interviewed 82 patients who were referred to a psychiatric university hospital after a suicide attempt. Nearly half of the patients (48%) reported that the period between the first current thought of suicide and the actual attempt had lasted 10 minutes or less.

“When you’re talking about treating suicide behavior, there are so many components: the impulsivity component, the resilience component – all these things that can’t be measured with a simple outcome measure,” Dr. Sanacora said at an annual psychopharmacology update held by the Nevada Psychiatric Association. “That’s one of the real challenges. It requires us to take a good look at how we’re treating these patients in general.”

It also underscores the need for new treatments that target suicidal ideation and behavior.

“There is increasing evidence that ketamine and esketamine can produce effects that could be used in the treatment of mood disorder patients with suicidal ideation or behavior,” said Dr. Sanacora, professor of psychiatry at Yale University, New Haven, Conn. “However, there are many challenges to performing the studies that are required to more definitively demonstrate rapid and sustained improvement in suicide risks.”

The global 12-month prevalence of nonfatal suicide attempts is about 0.3% to 0.4%, and the lifetime prevalence is 3%, “which is pretty shocking,” he said. In the United States, there are more than 30 suicide attempts for each suicide death. At the same time, a World Health Organization community survey conducted in 21 countries found that the 12-month prevalence of suicidal ideation was about 2%, and that the lifetime prevalence was 9%. “These are large numbers that we’re talking about internationally,” said Dr. Sanacora, who also directs the Yale Depression Research Program. In 2013, suicidal ideation constituted nearly 1% of all adult ED visits in the United States, with conservative costs of $2.2 billion. “Every step along the process takes a large toll on the health care system and society, from the top level of completed suicide to suicidal ideation,” he said.

According to 2016 data from the Centers for Disease Control and Prevention, nearly 10 million people in the United States have seriously considered suicide, about 2.5 million made a plan, about 1 million attempted suicide, and about 40,000 completed suicide. “We have to think about what we’re treating,” Dr. Sanacora said. “Are we treating the suicidal ideation, or are we trying to prevent completed suicides?”

A prior history of attempted suicide is the strongest single predictive factor of a completed suicide. “In fact, the risk of dying by suicide is approximately 100 times than that of the general population within 1 year of an index attempt,” he said. Another major risk factor is having a previous psychiatric hospitalization. In fact, up to 41% of those who completed suicide had been psychiatric inpatients within the previous year, and as many as 9% of suicides occurred within 1 day of discharge from psychiatric inpatient care. Other identified risk factors include marital status, belonging to a sexual minority, occupation, military service, general medical comorbidities, diagnosis of personality disorder, chronic pain, traumatic brain injury, childhood abuse, location of residence, access to firearms, and family history of suicide. Protective factors include having a strong social support network, being a parent, and religiosity. “These are things that typically aren’t part of a treatment, but they can be woven into a treatment plan in some way,” he said.

Other identified risk symptoms include feelings of worthlessness and hopelessness, the combination of depression and anxiety, and psychosis, regardless of the specific diagnosis.

Medical stabilization constitutes the first step in the standard treatment approach to suicidal ideation and behavior. “You want to make sure the person is hospitalized and take care of any injuries that may have been sustained in the suicide attempt,” Dr. Sanacora said. The next step is reducing the immediate risks. “For the most part, that’s making sure the individual is in a safe setting commensurate with the level of risk,” he said. “You want to remove any other risks that could be around them. Then, you want to assure that an appropriate level of follow-up is provided on stepdown to lower levels of care. That year after hospitalization puts you at incredible risk, so we want to make sure we’re not just treating something in the acute phase and then not having longer-term follow-up for it.”

Existing treatments that have some evidence to help with the treatment of suicidal ideation and behavior include the use of antidepressants, lithium, and clozapine, but these agents are far from fast-acting for a patient in crisis. “In addition, a lot of docs are hesitant to give lithium because it has the potential of overdose itself,” Dr. Sanacora said. With clozapine, he continued, “there is some level of confounding by indication because, when you’re giving clozapine, it’s usually a more reliable patient, one who is not at risk of self-harm.”

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) trial demonstrated that, for the patients who do not respond to the first two levels of treatment with citalopram, their chances of having a remission by getting a third or fourth level of treatment is reduced to below 15% (Am J Psychiatry. 2006;163[1]:28-40).

“This suggests that, with our current armamentarium, we are limited,” said Dr. Sanacora, who is also codirector of the Yale New Haven Hospital Interventional Psychiatry Service. In the STAR*D trial, the time to response to citalopram was 6 weeks in 50% of patients. “So, when somebody is going through a crisis and is at imminent risk for suicide, and you tell them, ‘You’ll be 50% better in 6 weeks,’ that’s hard to swallow,” he said.

Recent studies of ketamine and esketamine have demonstrated a rapid onset of effect in patients with major depressive disorder, but whether they alter suicidal ideation and behavior remains unclear. “If you are wanting to improve suicidal ideation and behavior, what outcome measure are you using to do this?” Dr. Sanacora asked. “It may seem simple, but it’s not. To do a clinical trial, you would need large sample sizes to look at behavior as an outcome. In fact, even retrospective studies on this topic don’t have enough events to give you statistical meaning.” This leaves clinicians to consider scales that have been used for examining suicidal ideation and behavior over the years, including the MINI suicidality module, the SAD PERSONS scale, and the Suicide Intent Scale. “However, while they could have some value to be used clinically, these scales really don’t have great value as outcome measures,” Dr. Sanacora said.

There also have been attempts to develop scales that capture changes in suicidal ideation and behavior over time, including the C-SSRS (Columbia-Suicide Severity Rating Scale) and the Sheehan Suicidality Tracking Scale. “The sad thing is, none of these measures have been proven to be very useful clinically,” he said. “They may have some level of sensitivity and specificity, but their actual predictive value is not great. So using these clinically is somewhat difficult.”

In 2018, Dr. Sanacora and his colleagues published results from a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation (Am J Psychiatry. 2018;175[2]:150-8). The analysis included 167 participants with suicidal ideation at baseline. “Within 24 hours there was a very clear decrease in suicidal ideation in terms of clinician-reported scale,” he said. “Over 50% of patients reported having minimal or no ideation after treatment. That was maintained for 7 days.” Effect sizes were moderate to large at all time points post dose.

In the largest meta-analysis of its kind to date, researchers reviewed 15 independent trials of ketamine for suicide ideation in 572 adults with psychiatric disorders, all with a single dose of drug with varying routes and dosages (Aust N Z J Psychiatry. 2020;54[1]:29-45). The researchers in that study concluded that ketamine “may have a role in acute treatment for suicidality. However, there is clearly a need for clinical measures to ensure persistence of any benefits.”

Esketamine, which was approved in March 2019 for major depressive disorder, also shows promise in patients with suicidal ideation and behavior. In a double-blind, multicenter, proof-of-concept study, researchers randomized 68 participants to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment (Am J Psychiatry. 2018;175[7]:620-30). The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the MADRS (Montgomery-Asberg Depression Rating Scale). “There was a nice effect in the antidepressant response, compared with placebo. It hit the primary endpoint at 4 hours. The patients got treated twice a week for 4 weeks. People got better quickly and stayed well moving on.” The researchers also found that the rate of remission at day 25 was 60% in the esketamine group, compared with 42% in the placebo group. “The take-home message is that, even without the esketamine, the remission rate was 42% at day 25. That means if you’re giving people really good care, meaning that you’re seeing them twice a week and they’re inpatient until they’re able to go outpatient, people can do pretty well with that level of care.”

Meanwhile, additional evidence supporting the use of ketamine in acute care settings is starting to emerge. In a proof-of-concept trial, 18 depressed subjects with acute suicidal ideation who presented to the emergency department and required hospitalization were randomized to either IV ketamine 0.2 mg/kg or to saline placebo (Depress Anxiety. 2019 Nov 16. doi: 10.1002/da.22975). Ninety minutes after infusion, 88% of patients in the ketamine group had achieved remission of suicidal ideation, compared with 33% in the placebo group (P less than .05). No serious adverse events were noted.

“There is a clear need for new treatments targeting suicidal ideation and behavior,” Dr. Sanacora concluded. “Any plan to institute a rapid-acting treatment for individuals with imminent risk of suicidal behavior must be placed in the context of a larger comprehensive treatment plan. Getting somebody to feel better in the short run is great, but you really have to think about the whole treatment plan.”

Dr. Sanacora reported having received grants and research support from numerous pharmaceutical companies. He also holds an ownership interest in Biohaven Pharmaceuticals.

dbrunk@mdedge.com

Hospital-related infections have been widely reported during the ongoing coronavirus outbreak, with healthcare professionals bearing a disproportionate risk. However, a proactive response in Hong Kong’s public hospital system appears to have bucked this trend and successfully protected both patients and staff from SARS-CoV-2, according to a study published online today in Infection Control & Hospital Epidemiology.

During the first 42 days of the outbreak, the 43 hospitals in the network tested 1275 suspected cases and treated 42 patients with confirmed COVID-19, the disease caused by SARS-CoV-2 infection. Yet, there were no nosocomial infections or infections among healthcare personnel, report Vincent C.C. Cheng, MD, FRCPath, the hospital’s infection control officer, and colleagues.

Cheng and colleagues note that 11 out of 413 healthcare workers who treat patients with confirmed infections had unprotected exposure and were in quarantine for 14 days, but none became ill.

In comparison, they note, the 2003 SARS outbreak saw almost 60% of nosocomial cases occurring in healthcare workers.

Proactive bundle

The Hong Kong success story may be due to a stepped-up proactive bundle of measures that included enhanced laboratory surveillance, early airborne infection isolation, and rapid-turnaround molecular diagnostics. Other strategies included staff forums and one-on-one discussions about infection control, employee training in protective equipment use, hand-hygiene compliance enforcement, and contact tracing for workers with unprotected exposure.

In addition, surgical masks were provided for all healthcare workers, patients, and visitors to clinical areas, a practice previously associated with reduced in-hospital transmission during influenza outbreaks, the authors note.

Hospitals also mandated use of personal protective equipment (PPE) for aerosol-generating procedures (AGPs), such as endotracheal intubation, open suctioning, and high-flow oxygen use, as AGPs had been linked to nosocomial transmission to healthcare workers during the 2003 SARS outbreak.

The infection control measures, which were part of a preparedness plan developed after the SARS outbreak, were initiated on December 31, when the first reports of a cluster of infections came from Wuhan, China.

As the outbreak evolved, the Hong Kong hospitals quickly widened the epidemiologic criteria for screening, from initially including only those who had been to a wet market in Wuhan within 14 days of symptom onset, to eventually including anyone who had been to Hubei province, been in a medical facility in mainland China, or in contact with a known case.  

All suspected cases were sent to an airborne-infection isolation room (AIIR) or a ward with at least a meter of space between patients.

“Appropriate hospital infection control measures could prevent nosocomial transmission of SARS-CoV-2,” the authors write. “Vigilance in hand hygiene practice, wearing of surgical mask in the hospital, and appropriate use of PPE in patient care, especially [when] performing AGPs, are the key infection control measures to prevent nosocomial transmission of SARS-CoV-2 even before the availability of effective antiviral agents and vaccine.”

Asked for his perspective on the report, Aaron E. Glatt, MD, chairman of the department of medicine and chief of infectious diseases at Mount Sinai South Nassau in Oceanside, New York, said that apart from the widespread issuing of surgical masks to workers, patients, and visitors, the measures taken in Hong Kong are not different from standard infection-control practices in American hospitals. Glatt, who is also a hospital epidemiologist, said it was unclear how much impact the masks would have.

“Although the infection control was impressive, I don’t see any evidence of a difference in care,” he told Medscape Medical News.

Could zero infection transmission be achieved in the more far-flung and variable settings of hospitals across the United States? “The ability to get zero transmission is only possible if people adhere to the strictest infection-control guidelines,” Glatt said. “That is clearly the goal, and it will take time to see if our existing strict guidelines are sufficient to maintain zero or close to zero contamination and transmission rates in our hospitals.”

Rather than looking to change US practices, he stressed adherence to widely established tenets of care. “It’s critically important to keep paying close attention to the basics, to the simple blocking and tackling, and to identify which patients are at risk, and therefore, when workers need protective equipment,” he said.

“Follow the recommended standards,” continued Glatt, who is also a spokesperson for the Infectious Diseases Society of America and did not participate in this study.

In a finding from an ancillary pilot experiment, the Hong Kong researchers found exhaled air from a patient with a moderate coronavirus load showed no evidence of the virus, whether the patient was breathing normally or heavily, speaking, or coughing. And spot tests around the room detected the virus in just one location.

“We may not be able to make a definite conclusion based on the analysis of a single patient,” the authors write. “However, it may help to reassure our staff that the exhaled air may be rapidly diluted inside the AIIR with 12 air changes per hour, or probably the SARS-CoV-2 may not be predominantly transmitted by [the] airborne route.”

However, a recent Singapore study showed widespread environmental contamination by SARS-CoV-2 through respiratory droplets and fecal shedding, underlining the need for strict adherence to environmental and hand hygiene. Post-cleaning samples tested negative, suggesting that standard decontamination practices are effective. 

This work was partly supported by the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases of the Department of Health, Hong Kong Special Administrative Region; and the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Education of China. The authors and Glatt have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Hospital-related infections have been widely reported during the ongoing coronavirus outbreak, with healthcare professionals bearing a disproportionate risk. However, a proactive response in Hong Kong’s public hospital system appears to have bucked this trend and successfully protected both patients and staff from SARS-CoV-2, according to a study published online today in Infection Control & Hospital Epidemiology.

During the first 42 days of the outbreak, the 43 hospitals in the network tested 1275 suspected cases and treated 42 patients with confirmed COVID-19, the disease caused by SARS-CoV-2 infection. Yet, there were no nosocomial infections or infections among healthcare personnel, report Vincent C.C. Cheng, MD, FRCPath, the hospital’s infection control officer, and colleagues.

Cheng and colleagues note that 11 out of 413 healthcare workers who treat patients with confirmed infections had unprotected exposure and were in quarantine for 14 days, but none became ill.

In comparison, they note, the 2003 SARS outbreak saw almost 60% of nosocomial cases occurring in healthcare workers.

Proactive bundle

The Hong Kong success story may be due to a stepped-up proactive bundle of measures that included enhanced laboratory surveillance, early airborne infection isolation, and rapid-turnaround molecular diagnostics. Other strategies included staff forums and one-on-one discussions about infection control, employee training in protective equipment use, hand-hygiene compliance enforcement, and contact tracing for workers with unprotected exposure.

In addition, surgical masks were provided for all healthcare workers, patients, and visitors to clinical areas, a practice previously associated with reduced in-hospital transmission during influenza outbreaks, the authors note.

Hospitals also mandated use of personal protective equipment (PPE) for aerosol-generating procedures (AGPs), such as endotracheal intubation, open suctioning, and high-flow oxygen use, as AGPs had been linked to nosocomial transmission to healthcare workers during the 2003 SARS outbreak.

The infection control measures, which were part of a preparedness plan developed after the SARS outbreak, were initiated on December 31, when the first reports of a cluster of infections came from Wuhan, China.

As the outbreak evolved, the Hong Kong hospitals quickly widened the epidemiologic criteria for screening, from initially including only those who had been to a wet market in Wuhan within 14 days of symptom onset, to eventually including anyone who had been to Hubei province, been in a medical facility in mainland China, or in contact with a known case.  

All suspected cases were sent to an airborne-infection isolation room (AIIR) or a ward with at least a meter of space between patients.

“Appropriate hospital infection control measures could prevent nosocomial transmission of SARS-CoV-2,” the authors write. “Vigilance in hand hygiene practice, wearing of surgical mask in the hospital, and appropriate use of PPE in patient care, especially [when] performing AGPs, are the key infection control measures to prevent nosocomial transmission of SARS-CoV-2 even before the availability of effective antiviral agents and vaccine.”

Asked for his perspective on the report, Aaron E. Glatt, MD, chairman of the department of medicine and chief of infectious diseases at Mount Sinai South Nassau in Oceanside, New York, said that apart from the widespread issuing of surgical masks to workers, patients, and visitors, the measures taken in Hong Kong are not different from standard infection-control practices in American hospitals. Glatt, who is also a hospital epidemiologist, said it was unclear how much impact the masks would have.

“Although the infection control was impressive, I don’t see any evidence of a difference in care,” he told Medscape Medical News.

Could zero infection transmission be achieved in the more far-flung and variable settings of hospitals across the United States? “The ability to get zero transmission is only possible if people adhere to the strictest infection-control guidelines,” Glatt said. “That is clearly the goal, and it will take time to see if our existing strict guidelines are sufficient to maintain zero or close to zero contamination and transmission rates in our hospitals.”

Rather than looking to change US practices, he stressed adherence to widely established tenets of care. “It’s critically important to keep paying close attention to the basics, to the simple blocking and tackling, and to identify which patients are at risk, and therefore, when workers need protective equipment,” he said.

“Follow the recommended standards,” continued Glatt, who is also a spokesperson for the Infectious Diseases Society of America and did not participate in this study.

In a finding from an ancillary pilot experiment, the Hong Kong researchers found exhaled air from a patient with a moderate coronavirus load showed no evidence of the virus, whether the patient was breathing normally or heavily, speaking, or coughing. And spot tests around the room detected the virus in just one location.

“We may not be able to make a definite conclusion based on the analysis of a single patient,” the authors write. “However, it may help to reassure our staff that the exhaled air may be rapidly diluted inside the AIIR with 12 air changes per hour, or probably the SARS-CoV-2 may not be predominantly transmitted by [the] airborne route.”

However, a recent Singapore study showed widespread environmental contamination by SARS-CoV-2 through respiratory droplets and fecal shedding, underlining the need for strict adherence to environmental and hand hygiene. Post-cleaning samples tested negative, suggesting that standard decontamination practices are effective. 

This work was partly supported by the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases of the Department of Health, Hong Kong Special Administrative Region; and the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Education of China. The authors and Glatt have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Hospital-related infections have been widely reported during the ongoing coronavirus outbreak, with healthcare professionals bearing a disproportionate risk. However, a proactive response in Hong Kong’s public hospital system appears to have bucked this trend and successfully protected both patients and staff from SARS-CoV-2, according to a study published online today in Infection Control & Hospital Epidemiology.

During the first 42 days of the outbreak, the 43 hospitals in the network tested 1275 suspected cases and treated 42 patients with confirmed COVID-19, the disease caused by SARS-CoV-2 infection. Yet, there were no nosocomial infections or infections among healthcare personnel, report Vincent C.C. Cheng, MD, FRCPath, the hospital’s infection control officer, and colleagues.

Cheng and colleagues note that 11 out of 413 healthcare workers who treat patients with confirmed infections had unprotected exposure and were in quarantine for 14 days, but none became ill.

In comparison, they note, the 2003 SARS outbreak saw almost 60% of nosocomial cases occurring in healthcare workers.

Proactive bundle

The Hong Kong success story may be due to a stepped-up proactive bundle of measures that included enhanced laboratory surveillance, early airborne infection isolation, and rapid-turnaround molecular diagnostics. Other strategies included staff forums and one-on-one discussions about infection control, employee training in protective equipment use, hand-hygiene compliance enforcement, and contact tracing for workers with unprotected exposure.

In addition, surgical masks were provided for all healthcare workers, patients, and visitors to clinical areas, a practice previously associated with reduced in-hospital transmission during influenza outbreaks, the authors note.

Hospitals also mandated use of personal protective equipment (PPE) for aerosol-generating procedures (AGPs), such as endotracheal intubation, open suctioning, and high-flow oxygen use, as AGPs had been linked to nosocomial transmission to healthcare workers during the 2003 SARS outbreak.

The infection control measures, which were part of a preparedness plan developed after the SARS outbreak, were initiated on December 31, when the first reports of a cluster of infections came from Wuhan, China.

As the outbreak evolved, the Hong Kong hospitals quickly widened the epidemiologic criteria for screening, from initially including only those who had been to a wet market in Wuhan within 14 days of symptom onset, to eventually including anyone who had been to Hubei province, been in a medical facility in mainland China, or in contact with a known case.  

All suspected cases were sent to an airborne-infection isolation room (AIIR) or a ward with at least a meter of space between patients.

“Appropriate hospital infection control measures could prevent nosocomial transmission of SARS-CoV-2,” the authors write. “Vigilance in hand hygiene practice, wearing of surgical mask in the hospital, and appropriate use of PPE in patient care, especially [when] performing AGPs, are the key infection control measures to prevent nosocomial transmission of SARS-CoV-2 even before the availability of effective antiviral agents and vaccine.”

Asked for his perspective on the report, Aaron E. Glatt, MD, chairman of the department of medicine and chief of infectious diseases at Mount Sinai South Nassau in Oceanside, New York, said that apart from the widespread issuing of surgical masks to workers, patients, and visitors, the measures taken in Hong Kong are not different from standard infection-control practices in American hospitals. Glatt, who is also a hospital epidemiologist, said it was unclear how much impact the masks would have.

“Although the infection control was impressive, I don’t see any evidence of a difference in care,” he told Medscape Medical News.

Could zero infection transmission be achieved in the more far-flung and variable settings of hospitals across the United States? “The ability to get zero transmission is only possible if people adhere to the strictest infection-control guidelines,” Glatt said. “That is clearly the goal, and it will take time to see if our existing strict guidelines are sufficient to maintain zero or close to zero contamination and transmission rates in our hospitals.”

Rather than looking to change US practices, he stressed adherence to widely established tenets of care. “It’s critically important to keep paying close attention to the basics, to the simple blocking and tackling, and to identify which patients are at risk, and therefore, when workers need protective equipment,” he said.

“Follow the recommended standards,” continued Glatt, who is also a spokesperson for the Infectious Diseases Society of America and did not participate in this study.

In a finding from an ancillary pilot experiment, the Hong Kong researchers found exhaled air from a patient with a moderate coronavirus load showed no evidence of the virus, whether the patient was breathing normally or heavily, speaking, or coughing. And spot tests around the room detected the virus in just one location.

“We may not be able to make a definite conclusion based on the analysis of a single patient,” the authors write. “However, it may help to reassure our staff that the exhaled air may be rapidly diluted inside the AIIR with 12 air changes per hour, or probably the SARS-CoV-2 may not be predominantly transmitted by [the] airborne route.”

However, a recent Singapore study showed widespread environmental contamination by SARS-CoV-2 through respiratory droplets and fecal shedding, underlining the need for strict adherence to environmental and hand hygiene. Post-cleaning samples tested negative, suggesting that standard decontamination practices are effective. 

This work was partly supported by the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases of the Department of Health, Hong Kong Special Administrative Region; and the Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Ministry of Education of China. The authors and Glatt have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

Empagliflozin and dulaglutide became the most-prescribed drugs in their respective classes for treating type 2 diabetes in the United States from July 2013 to June 2018, new research shows.

The findings, from U.S.-based administrative claims data, were published online in Diabetes Care by Chintan V. Dave, PharmD, PhD, and colleagues.

Among patients initiating oral sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) over the 5-year period, empagliflozin (Jardiance, Boehringer Ingelheim/Lilly) became the most commonly prescribed glucose-lowering drug, primarily driven by an increasing proportion of patients with diabetes who had a diagnosis of myocardial infarction, stroke, or heart failure (collectively called cardiovascular disease-heart failure [CVD-HF]).

And within the subcutaneous injectable glucagonlike peptide–1 receptor (GLP-1) agonist class, initiations of dulaglutide (Trulicity, Lilly) surpassed liraglutide in 2013-2018, although patients starting liraglutide (Victoza, Novo Nordisk) were more likely to have a CVD-HF diagnosis.

“This study shows that by preferring empagliflozin, prescribers have largely reacted in accordance with the available evidence and drug labels, while other factors such as lower price, frequency of administration [dulaglutide is given weekly and liraglutide is given daily], or prior authorizations may have led prescribers to select dulaglutide over liraglutide,” Dr. Dave, of the Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, and colleagues wrote.

Internists and endocrinologists were the most frequent prescribers of both drug classes, but cardiologists rarely prescribed them, even for patients with established CVD-HF. “As patients with co-occurring diabetes and CVD are likely to see their cardiologist, these encounters may provide an additional opportunity to optimize their treatment,” the authors emphasized.

SGLT2 inhibitors and label changes

Over the study period, the proportion of patients who had CVD-HF and who received SGLT2 inhibitors rose by 3.4 percentage points, from 8.8% to 12.2% (P trend < .001).

The proportion of overall prescriptions for SGLT2 inhibitors written by endocrinologists dropped by 12.0%, although the absolute number of SGLT2-inhibitor prescriptions written by endocrinologists increased (P < .001).

The proportion written by internists did not change (P = .58), whereas it increased slightly among cardiologists but still barely exceeded 1% (P < .001). The findings were similar for the subgroup of patients with CVD-HF who initiated SGLT2 inhibitors.

By individual agents, canagliflozin (Invokana, Janssen) prescriptions dropped by 75.1 percentage points over the study period, from 100% in 2013 to just 24.9% by 2018 (P < .001), whereas empagliflozin initiation rose by 51.7 percentage points, from 13.9% to 65.6% of all SGLT2 inhibitor initiations (P < .001).

Among those initiating empagliflozin, the proportion with CVD-HF rose by 5.3 percentage points, from 8.8% to 14.1% (P < .001), mostly after the additional indication for reducing CV events and death was added to the U.S. label in December 2016.

In contrast, there were no significant changes in the proportions of those with CVD-HF who initiated canagliflozin (P = 065), dapagliflozin (P = .87), or other medications (P = .060).

“Changes in the drug label for canagliflozin (boxed warning for amputation) and empagliflozin (for reduction in CV events and death) in 2016 likely contributed to a rapid change in prescribing preference for empagliflozin,” Dr. Dave and colleagues wrote.
 

GLP-1 agonists and frequency

Among the patients starting GLP-1 agonists, the proportion with CVD-HF increased by 3.9 percentage points, from 10.5% to 14.4% (P < .001) during the study period.

Prescriptions by endocrinologists declined as a proportion, but rose in absolute numbers (P < .001), and remained consistent for internists (> 55%; P = .12).

Prescribing of GLP-1 agonists by cardiologists remained low (< 0.5%) and was not higher for individuals with CVD-HF.

By individual GLP-1 agonist, liraglutide initiation declined by 32.1 percentage points, from 72.4% to 40.3% of GLP-1 agonist initiations (P < .001), whereas dulaglutide initiation rose by 43.8 percentage points, from 5.0% to 48.8% (P < .001). Again, these trends were similar in the subgroup of patients with CVD-HF.

The proportion of patients with CVD-HF in liraglutide initiators increased by 5.1 percentage points, from 10.5% to 15.6% (P = .018), and in exenatide initiators by 2.1 percentage points, from 10.3% to 13.8% (P = .77).

“Due to the reduced frequency of administration and possible formulary preferences, dulaglutide initiations surpassed liraglutide, the only GLP-1 agonist with evidence of CV benefit at the time,” Dr. Dave and colleagues noted.

Dulaglutide has just been granted an additional approval by the Food and Drug Administration for reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes with and without established CVD or multiple CV risk factors. That makes it the first and only type 2 diabetes medicine approved to reduce the risk of CV events for both primary and secondary prevention populations.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Dave has reported receiving support from the New Jersey Alliance for Clinical and Translational Science.
 

This article first appeared on Medscape.com.

The Centers for Medicare & Medicaid Services issued two guidance documents related to helping contain the spread of the coronavirus, primarily aimed at ensuring that health care providers are implementing proper infection control procedures.

The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.

“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”

The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.

The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.

Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”

The CMS also announced that it is suspending all nonemergency survey activity.

“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”

In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”

gtwachtman@mdedge.com

The Centers for Medicare & Medicaid Services issued two guidance documents related to helping contain the spread of the coronavirus, primarily aimed at ensuring that health care providers are implementing proper infection control procedures.

The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.

“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”

The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.

The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.

Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”

The CMS also announced that it is suspending all nonemergency survey activity.

“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”

In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”

gtwachtman@mdedge.com

The Centers for Medicare & Medicaid Services issued two guidance documents related to helping contain the spread of the coronavirus, primarily aimed at ensuring that health care providers are implementing proper infection control procedures.

The first guidance document, “Guidance for Infection Control and Prevention Concerning Coronavirus Disease (COVID-19): FAQs and Considerations for Patient Triage, Placement and Hospital Discharge,” issued March 4, provides some basic guidance, including identifying which patients are at risk, how facilities should screen for COVID-19, how facilities should monitor or restrict health care facility staff, and other recommendations for infection prevention and control.

“Hospitals should identify visitors and patients at risk for having COVID-19 infection before or immediately upon arrival to the healthcare facility,” the guidance document notes. “For patients, implement respiratory hygiene and cough etiquette (i.e., placing a face mask over the patient’s nose and mouth if that has not already been done) and isolate the patient in an examination room with the door closed. If the patient cannot be immediately moved to an examination room, ensure they are not allowed to wait among other patients seeking care.”

The document offers further information regarding the care of patients and provides numerous links to existing guidance from the Centers for Disease Control and Prevention.

The second document, “Guidance for Infection Control and Prevention of Coronavirus Disease 2019 (COVID-19) in Nursing Homes,” issued the same day, provides information on how to limit and monitor visitors as well as monitor and restrict health staff. It details when to transfer residents with suspected or confirmed coronavirus infection, and when a nursing home should accept a resident diagnosed with COVID-19.

Facilities “should contact their local health department if they have questions or suspect a resident of a nursing home has COVID-19,” the document states. “Per CDC, prompt detection, triage and isolation of potentially infectious patients are essential to prevent unnecessary exposure among patients, healthcare personnel, and visitors at the facility.”

The CMS also announced that it is suspending all nonemergency survey activity.

“CMS is suspending nonemergency inspections across the country, allowing inspectors to turn their focus on the most serious health and safety threats like infectious diseases and abuse,” the agency stated in a March 4 memo. “This shift in approach will also allow inspectors to focus on addressing the spread of ... COVID-19. CMS is issuing this memorandum to State Survey Agencies to provide important guidelines for the inspection process in situations in which a COVID-19 is suspected.”

In a statement, CMS Administrator Seema Verma said these actions “represent a call to action across the health care system. All health care providers must immediately review their procedures to ensure compliance with CMS’ infection control requirements, as well as the guidelines from the Centers for Disease Control and Prevention.”

gtwachtman@mdedge.com

Vidyard Video

Additional videos from SGS are available here, including these recent offerings:

• Laparoscopic techniques for Essure device removal
• A clitoral cyst of 'epidermal' proportions
• Clean cuts: Tips and tricks for laparoscopic colpotomy

Vidyard Video

Additional videos from SGS are available here, including these recent offerings:

• Laparoscopic techniques for Essure device removal
• A clitoral cyst of 'epidermal' proportions
• Clean cuts: Tips and tricks for laparoscopic colpotomy

Vidyard Video

Additional videos from SGS are available here, including these recent offerings:

• Laparoscopic techniques for Essure device removal
• A clitoral cyst of 'epidermal' proportions
• Clean cuts: Tips and tricks for laparoscopic colpotomy

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

aotto@mdedge.com

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

aotto@mdedge.com

Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.

Several of the batches tested from a total of 22 companies contained more than 10 times the accepted 96-ng daily limit for NDMA set by the agency.

“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”

The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.

The FDA declined to comment on the petition, pending a formal written response, a spokesman said.

Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.

“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.

The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.

In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.

David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”

He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.

Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.

Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.

Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.

Valisure launched its investigation after it found NDMA in metformin a client asked it to check.

aotto@mdedge.com

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

PHOENIX – Oral estrogen therapy taken within 6 years after the onset of menopause significantly reduced progression of lipid deposition in the carotid arterial wall, compared with placebo. However, starting oral estrogen 10 years after menopause did not confer a similar benefit.

“The clinical practice of estradiol therapy has been nothing short of a roller coaster ride,” lead study author Roksana Karim, PhD, MBBS, said in an interview at the Epidemiology and Prevention/Lifestyle and Cardiometabolic Health meeting sponsored by the American Heart Association. “Clinicians have been sort of conservative in terms of prescribing estradiol therapy. But over the last 2 decades things have changed, and eventually the timing hypothesis evolved based on the final analysis of the Women’s Health Initiative results as well.”

The findings come from a secondary analysis of the Early Versus Late Intervention Trial With Estradiol (ELITE), which examined the effects of oral 17-beta-estradiol (estrogen) on the progression of early atherosclerosis and cognitive decline in healthy postmenopausal women.

In the original trial, 643 healthy postmenopausal women were randomized to receive 1 mg/day of estradiol or a placebo pill either within 6 years after the onset of menopause or more than a decade after menopause (N Engl J Med 2016;374[13]:1221-31). All study participants took estradiol or placebo daily for an average of 5 years. The study’s initial findings showed that the mean carotid intima-media thickness progression rate was decreased by 0.0034 mm per year with estradiol, compared with placebo, but only in women who initiated hormone therapy within 6 years of menopause onset.

For the current analysis, researchers led by Dr. Karim looked further into estradiol’s impact on heart health by using echogenicity to analyze lipids in the arterial wall among the ELITE participants. The main outcome of interest was gray-scale median (GSM, unitless), a qualitative measure of atherosclerosis based on echogenicity obtained by high-resolution ultrasonography of the common carotid arterial wall. Whereas higher GSM values result with plaques rich in calcium and fibrous tissue, lower GSM values indicate more lipid deposition.

Dr. Karim, an associate professor of clinical preventive medicine at the University of Southern California, Los Angeles, and colleagues assessed GSM and serum concentrations of estradiol every 6 months over a median 5-year trial period, and used linear mixed effects regression models to compare the rate of GSM progression between the randomized groups within time-since-menopause strata.

The researchers found that effect of estradiol on the annual rate of GSM progression significantly differed between women in the early and late postmenopause groups (P for interaction = .006). Specifically, the annual GSM progression rate among women in early postmenopause fell by 0.30 per year in women taking estradiol, compared with 1.41 per year in those in the placebo group (P less than .0001), indicating significantly more atherosclerosis in the placebo group. On the other hand, the annual GSM progression rate was not significantly different between the estradiol and placebo groups among the late postmenopausal women (P = .37).

“I think this should comfort clinicians in terms of prescribing estradiol therapy to women who don’t have any contraindications and who are within 6 years of menopause,” Dr. Karim said. “Accumulation of lipids is the key event for atherosclerosis progression.” She and her colleagues also observed that the positive association between mean on-trial serum estradiol levels and GSM progression rate was stronger and significant among early postmenopausal women (P = .008), compared with women in the late postmenopausal group (P = .003). However, this differential association between estradiol level and GSM progression rate was not statistically significant (P for interaction = .33).

“This study is important and raises a critical question: Is there a time period where getting hormone therapy would be most beneficial for the heart?” Nieca Goldberg, MD, medical director of the New York University women’s heart program and senior advisor for women’s health strategy at NYU Langone Health, said in an interview. “I think more studies and more analyses are needed, but we haven’t changed the indications for estradiol. We’re not giving estradiol to prevent progression of heart disease. We use estradiol hormone therapy as indicated for women who are having menopausal symptoms.”

Dr. Karim and colleagues plan to conduct a follow-up analysis from the same cohort of ELITE study participants to validate the findings by assessing lipid particles and markers of inflammation.

She reported having no financial disclosures. The study was funded by the National Institute on Aging.

dbrunk@mdedge.com

SOURCE: Karim R et al. Epi/Lifestyle 2020, Abstract MP09.

Two international phase 3 randomized trials of injections of long-acting suspensions of cabotegravir and rilpivirine show promise for the control of HIV, according to reports published in the New England Journal of Medicine.

© Dr. A. Harrison; Dr. P. Feorino / CDC

The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.

The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.

At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.

Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.

An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.

The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.

At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.

HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.

Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.

Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.

The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.

mlesney@mdedge.com

SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.

Two international phase 3 randomized trials of injections of long-acting suspensions of cabotegravir and rilpivirine show promise for the control of HIV, according to reports published in the New England Journal of Medicine.

© Dr. A. Harrison; Dr. P. Feorino / CDC

The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.

The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.

At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.

Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.

An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.

The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.

At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.

HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.

Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.

Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.

The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.

mlesney@mdedge.com

SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.

Two international phase 3 randomized trials of injections of long-acting suspensions of cabotegravir and rilpivirine show promise for the control of HIV, according to reports published in the New England Journal of Medicine.

© Dr. A. Harrison; Dr. P. Feorino / CDC

The Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection (FLAIR) study and the Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression (ATLAS) study looked at a separate facet of the use of a monthly therapeutic injection as a replacement for daily oral HIV therapy.

The FLAIR trial (ClinicalTrials.gov number, NCT02938520) was a phase 3, randomized, open-label study in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir–abacavir–lamivudine. Those patients with an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were then randomly assigned (1:1) to continue their current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and rilpivirine, a nonnucleoside reverse-transcriptase inhibitor.

At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 patients (2.1%) who received the long-acting therapy and in 7 of 283 (2.5%) who received oral therapy, which met the criterion for noninferiority for the primary endpoint. An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% of patients who received long-acting therapy and in 93.3% who received oral therapy, which also met the criterion for noninferiority, according to the study published in the New England Journal of Medicine.

Injection site reactions were reported in 86% of the long-acting therapy patients, 4 of whom withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, of those who received long-acting therapy and in 4% and 1% of those who received oral therapy.

An assessment of treatment satisfaction at 48 weeks showed that 91% of the patients who switched to long-acting therapy preferred it to their daily oral therapy.

The ATLAS trial (ClinicalTrials.gov number, NCT02951052) was a phase 3, open-label, multicenter, noninferiority trial involving patients who had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy. These patients were randomized (308 in each group) to the long-acting cabotegravir plus rilpivirine injection therapy or daily oral therapy.

At 48 weeks, HIV-1 RNA levels of 50 copies per milliliter or higher were found in five participants (1.6%) receiving long-acting therapy and in three (1.0%) receiving oral therapy, which met the criterion for noninferiority for the primary endpoint, according to a study reported in the New England Journal of Medicine.

HIV-1 RNA levels of less than 50 copies per milliliter at week 48 occurred in 92.5% of patients on long-acting therapy and in 95.5% of those receiving oral therapy, which also met the criterion for noninferiority for this endpoint. Three patients in the long-acting therapy group had virologic failure, compared with four participants who received oral therapy.

Adverse events were more common in the long-acting–therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy. This was mild or moderate in most cases, according to the authors. However, 1% of the participants in this group withdrew because of it. Overall, serious adverse events were reported in no more than 5% of participants in each group.

Together, the ATLAS and the FLAIR trials show that long-acting intramuscular injection therapy is noninferior to oral therapy as both an early regimen for HIV treatment, as well as for later, maintenance dosing. The use of long-acting therapy may improve patient adherence to treatment, according to both sets of study authors.

The ATLAS and FLAIR trials were funded by ViiV Healthcare and Janssen. The authors of both studies reported ties to pharmaceutical associations, and some authors are employees of the two funding sources.

mlesney@mdedge.com

SOURCE: Orkin C et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1909512 and Swindells S et al. N Engl J Med. 2020 Mar 4. doi: 10.1056/NEJMoa1904398.