Conference Coverage

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

PHILADELPHIA – The new American College of Rheumatology Guideline for Vaccinations in Patients with Rheumatic and Musculoskeletal Diseases (RMDs) emphasizes that both adult and pediatric patients should receive recommended vaccinations whenever possible.

But the guideline, currently in press, also offers recommendations about whether and when to withhold vaccines from patients with RMDs, such as avoiding the use of live attenuated virus vaccines in patients who are on immunosuppressive drug regimens, such as conventional synthetic disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs, or targeted synthetic DMARDs.

The new consensus guideline was formulated with the understanding that patients with RMDs are at increased risk for vaccine-preventable infections and more serious complications from infections, compared with the general population.

However, the guideline also acknowledges that the immunogenicity and safety of vaccines may differ among patients with RMDs, and that, depending on the patient age and disease state, individuals may benefit from modified vaccine indications, schedules, or modified medication schedules, said guideline panel member Anne Bass, MD, a rheumatologist at Hospital for Special Surgery and a professor of clinical medicine at Weill Cornell Medicine in New York, who presented the guideline with other panel members in a session outlining the recommendations at the annual meeting of the ACR.

“In addition, vaccination recommendations – since much of it relates to medications – really applies across diseases, and so the ACR felt that, rather than having vaccine recommendations tacked onto the end of treatment guidelines for each individual disease, that the topic should be discussed or tackled as a whole,” she said.

The guideline does not cover vaccinations in patients taking nonsteroidal anti-inflammatory drugs because this class of agents has minimal or no impact on antibody responses to vaccines. The guideline also does not address vaccinations against COVID-19 infections since the rapidly changing formulations would make the recommendations obsolete before they were even published, and because the U.S. Centers for Disease Control and Prevention provides up-to-date guidance on COVID-19 vaccinations in patients with compromised immunity, she said.
 

Guiding principles

The overarching principles of the guideline are to give indicated vaccines to patients with RMD whenever possible and that any decision to hold medications before or after vaccination consider the dosage used, RMD disease activity, and the patient’s risk for vaccine-preventable infection.

The guideline also states that “shared decision-making with patients is a key component of any vaccination strategy.”

Panel member Clifton O. Bingham III, MD, professor of medicine at Johns Hopkins University in Baltimore, outlined expanded indications for vaccinations against influenza, pneumococcal infections, varicella zoster virus (VZV) and human papillomavirus (HPV).
 

Influenza

The guideline conditionally recommends that patients with RMD aged 65 years and older and adults older than age 18 years who are on immunosuppressive medications should receive either high-dose or adjuvanted influenza vaccination rather than regular-dose vaccines.

“It’s recognized that the high-dose or adjuvanted vaccinations may be unavailable for patients when they’re seen in your practice,” Dr. Bingham said,” and we came out with two additional statements within the guidelines that said that any flu vaccine is recommended over no flu vaccinations, because we do know that responses are elicited, and a flu vaccination today is preferred over a flu vaccination delay.”
 

Pneumococcal vaccination

The panelists strongly recommended that patients with RMD younger than age 65 years who are on immunosuppressive medication receive pneumococcal vaccinations.

The ACR guideline is in sync with those issued by the CDC’s Advisory Committee on Immunization Practices, Dr. Bingham said. He urged audience members to visit a CDC-ACIP web page for more information on who should receive pneumococcal vaccination and when.
 

Recombinant varicella zoster

The recommendations strongly support that patients aged 18 years and over who are on immunosuppressive therapies should receive the recombinant VZV vaccine (Shingrix).

HPV

A less robust, conditional recommendation is for patients with RMDs who are between the ages of 26 and 45 years and on immunosuppressive medications to receive the HPV vaccine (if they have not already received the vaccine).

Non-live attenuated vaccines

Kevin Winthrop, MD, MPH, professor of infectious diseases and public health at Oregon Health & Science University, Portland, summarized the recommendations for managing immunosuppressive therapies in patients scheduled to receive vaccinations using killed or nonactive antigens.

“In influenza season, don’t pass up the opportunity to vaccinate,” he said, adding, “if you can wait on rituximab dosing, do it, and if you can’t, go ahead and vaccinate.”

The guidelines also recommend a 2-week methotrexate hold at the time of influenza vaccination; other DMARD dosing changes are likely not necessary at the time of vaccination, “but this is an area of fervent study, and I think in a year or two we’ll have more experimental hold data with regard to other DMARDs,” Dr. Winthrop said.

For other nonlive attenuated vaccinations, recommendations are similar to those for influenza, except with more flexible timing because these vaccinations are not seasonal. When and how to hold methotrexate is still up in the air, he said.

Additionally, it’s recommended that vaccinations be delayed in patients on high-dose prednisone until the drug is tapered to below 20 mg per day, and ideally to less than 10 mg per day, he said.
 

Live-attenuated vaccines

The guideline conditionally recommends deferring live-attenuated vaccines in patients on immunosuppressive drugs. It also recommends holding these medications “for an appropriate period before” vaccination and for 4 weeks afterward.

“Although the evidence around conventional synthetic DMARDs and TNF inhibitors is reassuring in terms of their safety at the time of live attenuated vaccines, as you can see the number of studies is quite small, and so the voting panel conditionally recommend against administering live-attenuated virus vaccines to patients who are on conventional synthetics, biologic, or targeted DMARDs,” Dr. Bass said.
 

In utero exposures

Most women with RMD who have recently given birth will consult their general pediatricians rather than rheumatologists for infant vaccinations, but pediatricians may not be aware of the affect that in utero exposures to biologic DMARDs can have on vaccine safety and immunogenicity in infants, Dr, Bass said.

“It’s important that you, as a provider, give your recommendations regarding infant rotavirus vaccination after in utero exposure to the pregnant rheumatic disease patient prior to delivery, and let that patient know that this is something that they should share with their pediatrician to be,” she advised audience members.
 

Getting the message out

In an interview, session moderator and guidelines panelist Lisa F. Imundo, MD, director of the center for adolescent rheumatology at Columbia University in New York, noted that rheumatologists don’t usually have the full schedule of pediatric vaccinations in stock and often leave the decisions about what to give – and when – to general practitioners.

“Pediatric rheumatologists sometimes will give patients flu vaccinations because they’re a high-risk population of patients, and we want to make sure that they’re getting it in a timely manner,” she said.

In addition, because pneumococcal polysaccharide vaccines are not indicated in the general pediatric population, children on biologic DMARDs who have completed their standard series of pneumococcal conjugate vaccines (PCV13 or PVC15) are recommended to get a 23-valent pneumococcal polysaccharide vaccine, Dr. Imundo said.

She also noted that communication between pediatric rheumatologists and general practitioners about vaccine recommendations can be challenging.

“It’s a huge issue, figuring out how we’re going to communicate all of this information to our pediatric colleagues,” she said. “With individual patients, we may sometimes remind doctors, especially with our younger patients who haven’t gotten their live vaccines, that they really shouldn’t get live vaccines until they’re off medication or until we arrange holding medication for some period of time.”

She said that ACR vaccine committee members are working with infectious disease specialists and guideline developers for the American Academy of Pediatrics to ensure guidelines include the most important vaccination recommendations for pediatric patients with RMDs.

The development process for the guidelines was supported by the ACR. Dr. Bass reported no relevant disclosures, Dr. Bingham disclosed consulting activities, grant/research support, and royalties from various corporate entities. Dr. Winthrop disclosed consulting activities for and research funding from various companies. Dr. Imundo reported no relevant financial relationships.

A new model for predicting breast cancer risk that is based on standard clinical measures could be used to develop personalized breast screening strategies that are more effective than the current “one size fits all” approach, say researchers.

“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.

“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.

Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.

“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”

However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”

Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
 

Details of the new prediction model

To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.

The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.

All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.

Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.

Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.

The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.

Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.

The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.

Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”

“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.

This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

A new model for predicting breast cancer risk that is based on standard clinical measures could be used to develop personalized breast screening strategies that are more effective than the current “one size fits all” approach, say researchers.

“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.

“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.

Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.

“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”

However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”

Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
 

Details of the new prediction model

To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.

The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.

All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.

Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.

Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.

The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.

Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.

The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.

Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”

“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.

This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

A new model for predicting breast cancer risk that is based on standard clinical measures could be used to develop personalized breast screening strategies that are more effective than the current “one size fits all” approach, say researchers.

“Several breast cancer risk prediction models have been created, but we believe this is one of the first models designed to guide breast screening strategies over a person’s lifetime using real data from a screening program,” said study author Javier Louro, PhD, Hospital del Mar Medical Research Institute, Barcelona, Spain.

“Our model might be considered a key for designing personalized screening aimed at reducing the harms and increasing the benefits of mammographic screening,” he said in a statement.

Someone with a low risk “might be offered screening with standard mammography every 3 or 4 years instead of 2 years,” Dr. Louro explained.

“Someone with medium risk might be offered screening with advanced 3D mammography every 3 years, while those at a high risk might be offered a new screening test with mammography or MRI every year.”

However, he cautioned that “all of these strategies are still theoretical and should be studied with regard to their effectiveness.”

Dr. Louro was talking about the new model at the 13th European Breast Cancer Conference.
 

Details of the new prediction model

To develop the new model, Louro and colleagues conducted a retrospective study of 57,411 women who underwent mammography in four counties in Norway between 2007 and 2019 as part of the BreastScreen Norway program, and followed them up to 2022.

The team gathered data on age, breast density, family history of breast cancer, body mass index, age at menarche, alcohol habit, exercise, pregnancy, hormone replacement therapy, and benign breast disease, and compared women with and those without a breast cancer diagnosis.

All of these 10 variables used were found to significantly explain part of the variability in the breast cancer risk.

Overall, the 4-year breast cancer risk predicted by the resulting model varied across the participants, from 0.22% to 7.43%, at a median of 1.10%.

Bootstrap resampling analysis revealed that the model overestimated the risk for breast cancer, at an expected-to-observed ratio of 1.10.

The largest effect on risk was from breast density on mammography. Women with dense breasts were at much higher risk: the adjusted hazard ratio was 1.71 for women with Volpara Density Grade 4 vs Grade 2 and was 1.37 when compared with Grade 3.

Exercise had a large impact on breast cancer risk, the researchers found. Women who exercised for 4 or more hours per week had an adjusted hazard ratio of 0.65 for breast cancer risk compared with women who never exercised. Although this effect of exercise reducing the risk for breast cancer is now widely known, it is not usually included in models that predict breast cancer risk, the team pointed out.

The team concluded that their prediction model could be used to personalize breast screening for women according to their risk assessment, although they acknowledge that more work is needed. This work is based on one screening program in one country, and similar studies in different settings are needed.

Reacting to the findings, Laura Biganzoli, MD, co-chair of the European Breast Cancer Conference and director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, commented, “We know that breast screening programs are beneficial, but we also know that some people will experience potential harms caused by false-positives or overdiagnosis.”

“This research shows how we might be able to identify people with a high risk of breast cancer, but equally how we could identify those with a low risk. So it’s an important step toward personalized screening,” Dr. Biganzoli said.

This study was supported by a grant from Instituto de Salud Carlos III FEDER (grant PI/00047). No relevant financial relationships declared.

A version of this article first appeared on Medscape.com.

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

A woman who had breast cancer for 23 years, and who had gone through 12 different lines of therapy, has shown a dramatic response to a novel cancer vaccine in a clinical trial.

A recent 6-month follow-up showed no evidence of new or recurrent disease, and scans showed regression of a distant bulky left adrenal metastasis, as well as at other sites.

A small site of residual hypermetabolism remains in the sternum, but this is thought to be related to scar tissue.

The patient, Stephanie Gangi, told Medscape Medical News that, before she entered into the trial for the novel cancer vaccine, she was “mentally and physically exhausted.” She had benefited from being diagnosed with hormone-positive breast cancer just as its treatment was evolving and progressing, which meant that, every time a treatment failed, “there was the next thing to try, which was great and kept me going.”

“But I will admit that, by age 66, and more than 20 years of cancer treatments, I was exhausted.”

Ms. Gangi, a New York City-based poet, essayist, and fiction writer, said she was “cautiously optimistic” about the cancer vaccine, but the “overriding thought was I wanted to avoid chemotherapy.”

“I was not really signing on for great outcomes, I was signing on for something that might keep chemo at bay. The biggest impact so far for me has been that, for the first time in more than a decade, I am not on any medication. That’s really amazing…and that means no side effects,” she said.

Ms. Gangi stopped the vaccine treatment this past July, and just over 3 months later, she is still “wrapping her head around” the fact that her cancer has regressed. “I’ve had breast cancer a long time,” she said, “and you can’t just snap your fingers and be fine.”

Although the two scans that she has had since the trial ended have been “astonishing,” she underlined that this is not about a ‘cure,’ but rather “clearing tumors for the first time in many years.”

“Cancer is sneaky and sinister, and it figures out how to circumvent all kinds of treatments,” she said, adding nevertheless that she is “happy and hopeful, and my family is thrilled, of course.”

Ms. Gangi was classed as having had a partial response to the cancer vaccine, one of a few in a small phase 1/2 trial at the Icahn School of Medicine at Mount Sinai in New York. One other patient also had a partial response, and one patient had a complete response.

However, six patients have progressive disease, and one has stable disease.  

These results come from an interim analysis of 10 patients from the trial, and show a 30% response rate. They were presented at the recent annual meeting of the Society for Immunotherapy of Cancer.

The vaccine that was being tested combines local low-dose radiation, intramural Flt3L, which stimulates dendritic cells, and intravenous poly-ICLC, an immune stimulating factor, with the PD-1 inhibitor pembrolizumab (Keytruda).

The result is that, instead of making a vaccine in a laboratory and administering it, “we’re actually formulating it within the body,” lead author Thomas Marron, MD, PhD, professor of medicine (hematology and medical oncology) at Mount Sinai, said in an interview.

“What people don’t realize,” he said, is that bulky tumor sites contain “a lot of dead tumor, because they grow so fast and in a haphazard way.” This means that the immune system can be recruited to recognize the dead tumor and “gobble up the dead stuff that’s already there,” he added.

The hope is that the immune system will then kill not only “the tumor you are injecting into, but also tumors elsewhere in the body,” Dr. Marron said. “So you’re basically using your body’s own immune system and on and off switches to vaccinate the patient against their cancer.”

Another patient in the trial who had a complete response to the vaccine was William Morrison, with non-Hodgkin lymphoma (NHL).

Mr. Morrison was diagnosed in 2017, at which time he was enrolled onto a phase 1 trial of an earlier version of this novel vaccine treatment regimen. “Basically, they didn’t get the results they were hoping for, and I still had the lymphoma,” he said. In 2018, his indolent follicular lymphoma transformed into an aggressive diffuse large B-cell lymphoma, for which Mr. Morrison was given six cycles of chemotherapy. This put him into remission and cleared his lymphoma.

“But the remission lasted for maybe a little over a year,” he said.

The cancer came back, and at that point he was given the opportunity to enroll in the Mount Sinai trial. At the end of the treatment, “everything was clear.”

“I’ve been for PET scans every 6 months, and I just had a scan done the other week, and everything has been fine…I’ve been pretty excited. I was pretty lucky.”

“This recent one really has worked wonders,” he said, “When they gave me the good news the other day. I felt like a big weight had been lifted.”

Mr. Morrison also said that he did not experience any serious adverse events while being treated with the vaccine. “Other than a few minor things, I tolerated it pretty well,” he said.

In contrast, Ms. Gangi said she experienced “intense” flu-like symptoms that started in the first few days after the treatment and lasted for a couple of days.
 

Need to improve response rate

The current trial achieved responses in 30% of patients, which “is great, [but] we want to be at 100%,” said Dr. Marron.

“What we’re doing in the laboratory right now is using this as an opportunity to study what it is that’s special about those three people who responded and what’s not happening in the other seven people, and we have some initial data that we’re analyzing,” he said.

“We are seeing that the patients who responded have a much more robust response to the Ft3L in particular…and that could suggest that maybe we need a better Ft3L, or we could think about other ways to potentially manipulate this vaccine.

“Most of the patients who are referred to me are people who have run out of options…and that usually means they’ve had many different types of chemotherapy,” Dr. Marron commented. For example, Ms. Gangi had already been through 12 different chemotherapy regimens.

Chemotherapy suppresses the immune system, but it’s not only that — also having an effect are all the other treatments aimed at reducing nausea and allergic reactions to the anti-cancer therapy, Dr. Marron explained.

“By the time that I see a patient,” Dr. Marron said, “oftentimes their immune system is not optimal. So another way in which we would hope to see better responses is by moving this vaccine earlier in the treatment paradigm, and administering it to patients as their first or second treatment.”

Senior author Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Mount Sinai’s Tisch Cancer Institute, added that it “might be easy” to incorporate the vaccine into earlier lines of therapy.

He said in an interview that both immunotherapy and radiation therapy are “standard” treatments, and the key is “adding multiple ingredients together that don’t have cumulative toxicity.”

“You can’t just chemo one plus chemo two, because they have some of the same toxicities, but the delightful thing here is this therapy had been quite safe.

“So in theory it would be fairly easy to incorporate this into earlier lines of therapy, once we can get a bit more proof of principle,” Dr. Brody said.

Approached for comment, Ann W. Silk, MD, said that the results are “particularly impressive because we know anti-PD-1 plus radiation therapy does not work in hormone-positive breast cancer or lymphoma.”

Dr. Silk, an oncologist at the Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, said in an interview that one advantage of this vaccine is that it “is not restricted to a certain number of antigens and does not rely on an algorithm.”

“I would love to see more data in hormone-positive metastatic breast cancer patients,” she added. “I would use this approach after the hormonal treatments stop working, but before chemotherapy.”

Dr. Silk also said that the safety profile “looks quite good, and I imagine this approach would result in a much better quality of life for patients as compared to chemotherapy.”
 

Details of the trial and results

The Mount Sinai researchers had previously developed a personalized genomic cancer vaccine, PGV-001, which showed promise in a phase 1 trial in 13 patients with solid tumors or multiple myeloma and a high risk of recurrence after surgery or autologous stem cell transplant.

Next, they worked to develop the concept further to turn the tumor into its own vaccine, which involved inducing anti-tumor responses in indolent NHL, which typically responds poorly to checkpoint blockade, by combining Ft3L, low-dose irradiation, and poly-ICLC.

The next phase 1 trial showed that this approach was feasible, but preclinical modeling suggested that the addition of PD-1 blockade could improve the cure rates. The researchers therefore conducted the current trial, recruiting 10 patients with indolent NHL, metastatic breast cancer, or head and neck squamous cell carcinoma (HNSCC).

Patients were given local radiation therapy on days 1 and 2, and intramural Ft3L to the same tumor on day 9, followed by eight intravenous injections of poly-ICLC over 6 weeks. On day 23, they received their first of eight doses of pembrolizumab.

Dr. Marron explained that the radiotherapy increases the amount of dead material for the immune system to work on by “killing some of the tumor cells,” adding: “We’re not trying to kill the whole tumor with the radiation…it just starts the process of releasing some more of that dead stuff.”

He explained that Ft3L is a human growth factor that simulates dendritic cells, “which I always say are the professor cells of the immune system,” as they tell the body “what’s good and what’s bad.”

The poly-ICLC is “basically like a fake virus,” Dr. Marron said, as it “turns on those immune cells that have taken up the tumor antigen in the neighborhood” of the tumor, so they “teach the immune system that there is something bad”.

Finally, the pembrolizumab is there to “take the foot off the brake of the immune system” and “grease the wheels a bit more,” he added, even though it does not work in all patients, or in all tumor types, including indolent NHL.

The trial was planned in two phases. In the first part, six patients were enrolled to assess the safety of the approach; the phase 2 stage of the trial followed a Simon’s Two-Stage design, with the aim of recruiting seven patients of each tumor type, followed by a further 12 patients if they showed a response.

The current interim analysis that was presented at the SITC meeting focused on the first 10 patients in the phase 2 part, who were enrolled between April 2019 and July 2022. This included six patients with metastatic breast cancer, three with indolent NHL, and one with HNSCC, all of whom completed their first disease response assessment.

All patients experienced treatment-related adverse events, largely comprising low-grade injection site reactions and flu-like symptoms linked to the poly-ICLC injections.

One patient experienced grade 3 pembrolizumab-related colitis, while another had self-resolving grade 3 fever following poly-ICLC injection.

The study was sponsored by Icahn School of Medicine at Mount Sinai and conducted in collaboration with Merck Sharp & Dohme LLC and Celldex Therapeutics. No relevant financial relationships were reported.

A version of this article first appeared on Medscape.com.

WASHINGTON – For patients with acute-on-chronic liver failure (ACLF) undergoing modest-volume paracentesis for ascites, oral midodrine may be an alternative to intravenous albumin for preventing paracentesis-induced circulatory dysfunction (PICD), according to the results of a randomized controlled trial.

Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.

Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.

But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
 

PICD common in ACLF

PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.

The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.

Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.

In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).

In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.

Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
 

Study details

Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.

They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.

They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.

The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.

Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.

The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.

The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.

Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
 

Complications and costs

PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.

No cases of hypertension or urinary retention arose in either group.

Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.

Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.

At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.

Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.

A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
 

More data needed

Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.

Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.

The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

WASHINGTON – For patients with acute-on-chronic liver failure (ACLF) undergoing modest-volume paracentesis for ascites, oral midodrine may be an alternative to intravenous albumin for preventing paracentesis-induced circulatory dysfunction (PICD), according to the results of a randomized controlled trial.

Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.

Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.

But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
 

PICD common in ACLF

PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.

The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.

Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.

In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).

In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.

Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
 

Study details

Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.

They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.

They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.

The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.

Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.

The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.

The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.

Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
 

Complications and costs

PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.

No cases of hypertension or urinary retention arose in either group.

Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.

Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.

At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.

Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.

A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
 

More data needed

Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.

Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.

The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

WASHINGTON – For patients with acute-on-chronic liver failure (ACLF) undergoing modest-volume paracentesis for ascites, oral midodrine may be an alternative to intravenous albumin for preventing paracentesis-induced circulatory dysfunction (PICD), according to the results of a randomized controlled trial.

Albumin protected 80% of patients from PICD 6 days after paracentesis, whereas midodrine protected 84%, a difference that was not statistically significant. However, albumin was associated with a slightly higher incidence of adverse events and higher costs, said Mithun Sharma, MD, during his presentation at the annual meeting of the American Association for the Study of Liver Diseases.

Midodrine may be a safer and cost-effective option for these patients, said Dr. Sharma, of the department of hepatology and liver transplantation, AIG Hospitals, Hyderabad, India.

But he cautioned that given the small size of the open-label study, with only 25 patients in each arm, the results should be considered as proof of concept and need to be validated in larger studies.
 

PICD common in ACLF

PICD is caused by fluid shift during paracentesis, leading to a decrease in effective circulating blood volume.

The incidence of PICD after large-volume paracentesis in patients receiving albumin ranges from 12% to 20%, Dr. Sharma noted.

Albumin has been shown in several trials to be effective at reducing the incidence of PICD in patients undergoing paracentesis, but this agent requires IV infusion and is comparatively costly, he said.

In contrast, midodrine, a selective alpha-adrenergic agonist usually prescribed for orthostatic hypotension, may help to prevent PICD through its mechanism of action, maintaining mean arterial pressure (MAP).

In two small studies comparing albumin infusion in patients undergoing paracentesis with 8 liters of fluid removal, midodrine was either inferior to albumin or had no beneficial effect, Dr. Sharma said.

Patients with ACLF, however, have paracentesis with much lower fluid volumes, typically with less than 5 liters removed, and may be good candidates for midodrine.
 

Study details

Dr. Sharma and colleagues tested their hypothesis that in patients with ACLF undergoing modest-volume paracentesis, with fluid removal below 5 liters, midodrine could prevent PICD by increasing MAP, with an efficacy similar to that of intravenous 20% human albumin infusions.

They enrolled 50 patients with ACLF defined by Asian Pacific Association for the Study of the Liver criteria who were undergoing paracentesis with 3- to 4-liter fluid volumes.

They defined PICD as at least a 50% increase in plasma renin activity (PRA) over baseline on the 6th day following paracentesis.

The patients were randomly assigned to receive either intravenous 20% human albumin infusions toward the end of paracentesis or midodrine-hydrochloride 7.5 mg three times daily starting 2 hours before paracentesis. Because of the difference in drug delivery methods, the study could not be blinded to treatment type.

Patients’ mean arterial pressures were recorded daily, renal parameters and serum electrolytes were monitored on days 3 and 6, and blood samples were tested for PRA on day 1 and day 6.

The most common acute and chronic hepatic insults and baseline characteristics of the patients were similar between the groups, with alcohol-related liver disease the most common underlying etiology of cirrhosis.

The incidence of PICD at day 6, the primary endpoint, did not differ significantly between the groups, although mean PRA levels on day 6 were numerically higher in the midodrine group. There was a significant rise in the absolute PRA volume from baseline (P = .006), but this rise did not meet the PICD definition.

Researchers found no significant differences between the two groups in absolute change in PRA, and no significant changes in either group in MAP, creatinine, or sodium levels.
 

Complications and costs

PICD developed in four patients assigned to the albumin group and five patients assigned to the midodrine group; however, this difference was not significant. Fluid overload occurred in only one patient, in the albumin group.

No cases of hypertension or urinary retention arose in either group.

Grade I/II hepatic encephalopathy occurred 2-3 days after paracentesis in three patients on albumin and in two patients on midodrine.

Acute kidney injury was seen in three patients on albumin and in one patient on midodrine.

At 28 days after paracentesis, three patients in the albumin group had died, all from sepsis and multiorgan failure, while four patients in the midodrine group had died, three from sepsis and multiorgan failure and one from an upper gastrointestinal bleed.

Two patients in the albumin group and one patient in the midodrine group underwent liver transplant 1 month after paracentesis.

A cost-effectiveness analysis showed that the mean cost of albumin infusions was about sixfold higher than that of oral midodrine.
 

More data needed

Session moderator Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences in New Delhi, India, who was not involved in the study, commented that while midodrine is a good drug and generally safe, he would wait to use it in patients who needed modest-volume paracentesis until more data are published.

Dr. Sarin also emphasized that albumin is “mandatory” for protecting patients who require large-volume paracentesis, and that it would be “unethical” not to use it in that clinical situation.

The study was internally supported. Dr. Sharma and Dr. Sarin have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.

“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.

Mitchel L. Zoler/MDedge News

Treating 10 patients prevents one delayed graft function

The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.

This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.

Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.

A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.

Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
 

Chloride is the culprit

“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.

“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Success attributed to early treatment

But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.

Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.   

The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.

Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.

During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.

The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.

BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.

A version of this article first appeared on Medscape.com.

ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.

“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.

Mitchel L. Zoler/MDedge News

Treating 10 patients prevents one delayed graft function

The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.

This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.

Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.

A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.

Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
 

Chloride is the culprit

“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.

“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Success attributed to early treatment

But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.

Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.   

The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.

Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.

During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.

The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.

BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.

A version of this article first appeared on Medscape.com.

ORLANDO – Using a low-chloride, balanced crystalloid solution for all intravenous fluids received by patients who received a deceased donor kidney transplant resulted in significantly fewer episodes of delayed graft function, compared with patients who received saline as their IV fluids, in a new multicenter trial with 807 randomized and evaluable patients called BEST-Fluids.

“The findings suggest that balanced crystalloids should be the standard-of-care IV fluid in deceased donor kidney transplantations,” Michael G. Collins, MBChB, PhD, said at the annual meeting of the American Society of Nephrology.

Mitchel L. Zoler/MDedge News

Treating 10 patients prevents one delayed graft function

The incidence of delayed graft function, defined as the need for dialysis during the 7 days following transplantation, occurred in 30.0% of 404 patients who received balanced crystalloid fluids (Plasma-Lyte 148) and in 39.7% of 403 patients who received saline starting at the time of randomization (prior to surgery) until 48 hours post-surgery, Dr. Collins reported.

This translated into a significant, adjusted relative risk reduction of 26% and a number needed to treat of 10 to result in one avoided episode of delayed graft function.

Preventing delayed graft function is important because it is a “major complication” of deceased donor kidney transplantation that usually occurs in about 30%-50% of people who receive these organs, Dr. Collins explained. Incident delayed graft function leads to higher hospitalization costs because of a prolonged need for dialysis and extended hospital days, as well as increased risk for long-term graft failure and death.

A secondary outcome – the number of dialysis sessions required during the 28 days following transplantation – was 406 sessions among those who received balanced crystalloid fluids and 596 sessions among the controls who received saline, a significant adjusted relative decrease of 30%.

Freedom from need for dialysis by 12 weeks after surgery increased by a significant 10% among those treated with balanced crystalloid fluids, compared with controls. The balanced crystalloid fluids were also significantly linked with an average 1-L increase in urine output during the first 2 days after transplantation, compared with controls.
 

Chloride is the culprit

“I think this is driven by the harmful effects of saline,” which is currently the standard fluid that kidney transplant patients receive worldwide, said Dr. Collins. Specifically, he cited the chloride content of saline – which contains 0.9% sodium chloride – as the culprit by causing reduced kidney perfusion.

“Some data suggest that saline may be harmful because of chloride acidosis producing vasoconstriction and increasing ischemia,” commented Karen A. Griffin, MD, chief of the renal section at the Edward Hines, Jr. VA Medical Center, Hines, Illinois. But Dr. Griffin said she’d like to see further study of balanced crystalloid fluids in this setting before she’d be comfortable using it routinely as a replacement for saline.

Mitchel L. Zoler/MDedge News

Mitchel L. Zoler/MDedge News

Success attributed to early treatment

But Dr. Lafayette also wondered, “Why should this work for transplant patients when it did not work for patients who develop acute kidney injury in the ICU?” And he found it hard to understand how the impact of the balanced crystalloid fluid could manifest so quickly, with a change in urine output during the first day following surgery.

Dr. Collins attributed the rapid effects and overall success to the early initiation of balanced crystalloid fluids before the transplant occurred.   

The BEST-Fluids trial ran at 16 centers in Australia and New Zealand and enrolled patients from January 2018 to August 2020. It enrolled adults and children scheduled to receive a deceased donor kidney, excluding those who weighed less than 20 kg and those who received multiple organs.

Enrolled patients averaged about 55 years old, about 63% were men, and their average duration on dialysis prior to surgery was about 30 months. The study randomized 808 patients who received their transplanted kidney, with 807 included in the efficacy analysis. Patients in each of the two groups showed very close balance for all reported parameters of patient and donor characteristics. During the period of randomized fluid treatment, patients in the balanced crystalloid group received an average of just over 8 L of fluid, while those in the control group received an average of just over 7 L.

During follow-up, serious adverse events were rare and balanced, with three in the balanced crystalloid group and four among controls.

The only significant difference in adverse events was the rate of ICU admissions that required ventilation, which occurred in one patient in the balanced crystalloid group and 12 controls.

BEST-Fluids received balanced crystalloid and saline solutions at no charge from Baxter Healthcare, which markets Plasma-Lyte 148. The study received no other commercial funding. Dr. Collins, Dr. Griffin, and Dr. Lane have reported no relevant financial relationships. Dr. Lafayette has received personal fees and grants from Alexion, Aurinia, Calliditas, Omeros, Pfizer, Roche, Travere, and Vera and has been an advisor to Akahest and Equillium.

A version of this article first appeared on Medscape.com.

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

A version of this article first appeared on Medscape.com.

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

A version of this article first appeared on Medscape.com.

CHICAGO – An investigational aldosterone synthase inhibitor could be an effective new treatment to reduce blood pressure in patients with treatment-resistant hypertension, reslts of a phase 2 study suggest.

The BrigHTN trial showed systolic blood pressure fell by an average of 20.3 mm Hg, 17.5 mm Hg, and 12.1 mm Hg with baxdrostat 2 mg, 1 mg, and 0.5 mg after 12 weeks follow-up in 248 patients unable to achieve target blood pressure on stable doses of at least three antihypertensive agents, including a diuretic.

After adjustment for the –9.4 mm Hg change observed in the placebo group, there was a statistically significant difference of 11.0 mm Hg in the 2-mg baxdrostat group (P = .0001) and of 8.1 mm Hg in the 1-mg baxdrostat group (P = .003).

The adjusted change in diastolic blood pressure was significant only for the 2-mg dose (–5.2 mm Hg; P = .004).

Once-daily oral baxdrostat had an acceptable side-effect profile and no patients died.

The study, which was stopped early after meeting criteria for overwhelming efficacy, was presented in the final late-breaking science session at the American Heart Association scientific sessions and published simultaneously in the New England Journal of Medicine.
 

Threading the needle

For at least 20 years, researchers have tried to create a drug that would lower aldosterone levels directly by inhibiting hormone synthesis rather than blocking the mineralocorticoid receptor.

What’s made this extraordinarily difficult is that the enzyme that makes aldosterone synthase and the enzyme required for cortisol synthase, 11-beta-hydroxylase, are 93% sequence similar. Baxdrostat, however, is able to selectively block aldosterone synthase, and thus the production of aldosterone, without also blocking the production of cortisol, explained Mason W. Freeman, MD, lead author of the study and executive vice president of clinical development at CinCor Pharma, which is developing the agent.

“We have beautiful biomarker evidence of not only blood pressure lowering but the mechanism by which that blood pressure reduction is occurring,” he said.

Over 12 weeks of follow-up in the new study, the use of baxdrostat led to decreases in serum aldosterone levels ranging from 3.0 ng/dL with the 0.5-mg dose to 4.9 ng/dL with the 2-mg dose. The 24-hour urinary aldosterone levels decreased with all three doses tested.

Baxdrostat increased plasma renin activity by 3.6, 5.0, and 13.8 mg/mL per hr with the 0.5, 1.0, and 2.0 mg doses, respectively, an indicator of its effect on lowering salt and fluid retention, Dr. Freeman said. Serum cortisol levels were not reduced in any of the baxdrostat groups throughout the study.
 

‘A bright future’

“It seems to have a bright future in the area of resistant hypertension, particularly in patients who are producing too much aldosterone,” said Suzanne Oparil, MD, invited discussant for the study and director of the Vascular Biology and Hypertension program at the University of Alabama at Birmingham.

She noted that aldosterone is a major contributor to the pathogenesis of resistant hypertension, which afflicts about 20% of the hypertensive population. Aldosterone antagonists are considered by many to be the best add-on treatment for resistant hypertension and do lower blood pressure.

“But they have major problems,” Dr. Oparil added. “Spironolactone, for example, causes hyperkalemia in many patients and adverse effects such as gynecomastia, erectile dysfunction, and feminization.”

Baxdrostat was well tolerated with no serious adverse events deemed related to treatment, Dr. Freeman reported. A total of 18 serious adverse events occurred in 10 patients, 6 of which were in a patient with urosepsis.

Ten adverse events of special interest occurred in eight patients, including one case of hypotension, three cases of hyponatremia, and six cases of hyperkalemia.

Potassium levels ranged from 6.0 to 6.3 mmol/L (6.0-6.3 mEq/L) in three patients and between 5.5 and 5.9 mmol/L (5.5-5.9 mEq/L) on at least two consecutive occasions in three others. Four of the patients were able to resume baxdrostat and complete the trial, whereas two patients discontinued treatment, one of whom was the patient with urosepsis.

Dr. Freeman pointed out that the study population was relatively diverse, with 33%-48% of participants of Hispanic or Latinx ethnicity and 23%-32% being Black.

At baseline, all patients had a seated blood pressure of at least 130/80 mm Hg (average 147.8/87.9 mm Hg) on a background therapy that included a diuretic in 100%, an agent targeting the renin-angiotensin-aldosterone system in 91%-96%, a beta-blocker in 52%-68%, and a calcium channel blocker in 64%-70%.

The study was not designed to test the benefits and risks of aldosterone synthase inhibition beyond 12 weeks and baxdrostat was not compared to alternative antihypertensives, he said. Additional limitations are that medication adherence was based on pill counts rather than drug analysis and enrolling only patients with an estimated glomerular filtration rate over 45 mL/min per 1.73m² reduced the likelihood of hyperkalemia and other adverse events.

Nevertheless, “we think that these data suggest that baxdrostat has the potential to treat disorders associated with aldosterone excess, including hypertension and primary hyperaldosteronism,” Dr. Freeman said.

The intention is to carry the drug forward into additional phase 2 studies in chronic kidney disease and to begin a phase 3 study in hypertension in 2023, he noted.

The study was funded by CinCor Pharma. Dr. Freeman and three coauthors are employees of CinCor and receive stock-based compensation. The remaining authors have a financial relationship with CinRx Pharma, which has an equity stake in CinCor. Dr. Oparil reports grant/research support from Bayer, Higi, and Novartis; and serving on the scientific advisory board/expert committee for CinCor Pharma and Preventric Diagnostics.

A version of this article first appeared on Medscape.com.

Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.

The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.

Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.

However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.

Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.

The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.

Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).

The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.

Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.

For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.

Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.

Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.

Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.

On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.

Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.

Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.

It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.

Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.

“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.

The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.

The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.

Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.

However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.

Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.

The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.

Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).

The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.

Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.

For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.

Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.

Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.

Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.

On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.

Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.

Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.

It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.

Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.

“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.

The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Treatment with bepirovirsen led to sustained clearance of hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA for 24 weeks after the end of treatment for adults with chronic HBV in the phase 2b B-Clear study.

The study results were presented at the annual meeting of the American Association for the Study of Liver Diseases and were simultaneously published in The New England Journal of Medicine.

Currently, nucleoside/nucleotide analogue (NA) therapy is the recommended first-line therapy for patients with chronic HBV because it can inhibit viral replication.

However, fewer than 5% of patients have HBsAg loss after 12 months of NA therapy, which underscores the need for therapies that can achieve a “functional” cure, largely defined as sustained, undetectable levels of HBV DNA and HBsAg in the blood, with or without generation of protective antibodies against HBsAg, the researchers noted.

Bepirovirsen is a potential first-in-class antisense oligonucleotide that targets all HBV messenger RNA and acts to decrease levels of viral proteins.

The phase 2b B-Clear study enrolled 457 patients with chronic HBV; 227 were receiving NA therapy, and 230 were not.

Participants were randomly assigned to receive weekly subcutaneous injections of bepirovirsen 300 mg for 24 weeks; bepirovirsen 300 mg for 12 weeks, then 150 mg for 12 weeks; bepirovirsen 300 mg for 12 weeks, then placebo for 12 weeks; or placebo for 12 weeks, then bepirovirsen 300 mg for 12 weeks (groups 1, 2, 3, and 4, respectively).

The composite primary outcome was HBsAg level below the limit of detection and HBV DNA level below the limit of quantification maintained for 24 weeks after the end of bepirovirsen treatment, without newly initiated antiviral medication.

Bepirovirsen 300 mg weekly for 24 weeks (group 1) led to HBsAg and HBV DNA loss in 9% of patients receiving NA therapy and 10% of patients not receiving NA treatment, which was sustained for 24 weeks after the last dose.

For groups 2, 3, and 4, HBsAg and HBV DNA loss occurred in 9%, 3%, and 0%, respectively, of patients receiving NA therapy and 6%, 1%, and 0%, respectively, of patients not receiving NA treatment.

Patients with low baseline HBsAg levels (< 1,000 IU/mL) responded best to treatment with bepirovirsen. Among patients who received bepirovirsen 300 mg weekly for 24 weeks, the primary outcome was achieved by 16% of patients taking NA therapy and by 25% of patients not taking NA therapy.

Although a “relatively low percentage” of patients overall achieved the primary outcome, the study “indicates the possibility of enhanced efficacy with the selection of patients according to baseline characteristics (low HBsAg level at baseline), with combination therapies, or both,” the researchers wrote.

Adverse events with bepirovirsen included injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase (ALT) levels. Increases in ALT levels, which were more common in those not receiving NA therapy than in those receiving NA therapy (41% vs. 17%), led to two serious adverse events.

On the basis of phase 2b data, GlaxoSmithKline (GSK) plans to advance bepirovirsen into phase 3 development, according to a news release.

Further pursuit of bepirovirsen therapy is “certainly warranted, with the use of a dose of 300 mg per week for at least 24 weeks; indeed, the duration of therapy might be dictated best by HBsAg levels at baseline,” Jay H. Hoofnagle, MD, director of the liver disease research branch at the National Institute of Diabetes and Digestive and Kidney Diseases, wrote in an editorial in the New England Journal of Medicine.

Several critical questions remain, including whether HBsAg negativity will persist beyond 24 weeks, wrote Dr. Hoofnagle, who was not involved in the study.

It’s a question GSK is addressing in the B-Sure trial, which will follow participants for an additional 33 months, the study noted.

Other questions include when NA therapy can be safely stopped, what other factors predict response, and whether RNA therapy–induced loss of HBsAg materially improves long-term outcomes, Dr. Hoofnagle wrote.

“Bepirovirsen is just one RNA-based HBV therapy now being pursued. Several other antisense RNAs as well as the more malleable small interfering RNA molecules (‘-sirans’) are currently in early-phase clinical trials. A new era in the control of hepatitis B may be at hand with these most modern of therapies for this most ancient disease,” Dr. Hoofnagle noted.

The B-Clear study was supported by GSK. Several authors have disclosed relationships with the company. A complete list of author disclosures is available with the original article. Dr. Hoofnagle has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

ORLANDO – Automated alerts sent to clinicians via patients’ electronic health records identified patients with diagnosable acute kidney injury (AKI) who were taking one or more medications that could potentially further worsen their renal function. This led to a significant increase in discontinuations of the problematic drugs and better clinical outcomes in a subgroup of patients in a new multicenter, randomized study with more than 5,000 participants.

“Automated alerts for AKI can increase the rate of cessation of potentially nephrotoxic medications without endangering patients,” said F. Perry Wilson, MD, at Kidney Week 2022, organized by the American Society of Nephrology.

Mitchel L Zoler, Medscape Medical News © 2022 WebMD, LLC

In addition, the study provides “limited evidence that these alerts change clinical practice,” said Dr. Wilson, a nephrologist and director of the clinical and translational research accelerator at Yale School of Medicine in New Haven, Conn.

“It was encouraging to get providers to change their behavior” by quickly stopping treatment with potentially nephrotoxic medications in patients with incident AKI. But the results also confirmed that “patient decision-support systems tend to not be panaceas,” Dr. Wilson explained in an interview. Instead, “they tend to marginally improve” patients’ clinical status.

“Our hope is that widespread use may make some difference on a population scale, but rarely are these game changers,” he admitted.

“This was a very nice study showing how we can leverage the EHR to look not only at drugs but also contrast agents to direct educational efforts aimed at clinicians about when to discontinue” these treatments, commented Karen A. Griffin, MD, who was not involved with the study.
 

A danger for alert fatigue

But the results also showed that more research is needed to better refine this approach, added Dr. Griffin, a professor at Loyola University Chicago, Maywood, Ill., and chief of the renal section at the Edward Hines Jr. VA Medical Center in Hines, Ill. And she expressed caution about expanding the alerts that clinicians receive “because of the potential for alert fatigue.”

Dr. Wilson also acknowledged the danger for alert fatigue. “We’re doing these studies to try to reduce the number of alerts,” he said. “Most clinicians say that if we could show an alert improves patient outcomes, they would embrace it.”

Dr. Wilson and associates designed their current study to evaluate an enhanced type of alert that not only warned clinicians that a patient had developed AKI but also gave them an option to potentially intervene by stopping treatment with a medication that could possibly exacerbate worsening renal function. This enhancement followed their experience in a 2021 study that tested a purely informational alert that gave physicians no guidance about what actions to take to more quickly resolve the AKI.

These findings plus results from other studies suggested that “purely informational alerts may not be enough. They need to be linked” to suggested changes in patient management, Dr. Wilson explained.
 

Targeting NSAIDS, RAAS inhibitors, and PPIs

The new study used automated EHR analysis to not only identify patients with incident AKI, but also to flag medications these patients were receiving from any of three classes suspected of worsening renal function: nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system (RAAS) inhibitors (which include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), and proton-pump inhibitors (PPIs).

“Our hypothesis was that giving clinicians actionable advice could significantly improve patient outcomes,” Dr. Wilson said. “NSAIDs are frequently discontinued” in patients who develop AKI. “RAAS inhibitors are sometimes discontinued,” although the benefit from doing this remains unproven and controversial. “PPIs are rarely discontinued,” and may be an underappreciated contributor to AKI by causing interstitial nephritis in some patients.

The prospective study included 5,060 adults admitted with a diagnosis of stage 1 AKI at any of four Yale-affiliated teaching hospitals who were also taking agents from at least one of the three targeted drug classes at the time of admission. Clinicians caring for 2,532 of these patients received an alert about the AKI diagnosis and use of the questionable medications, while those caring for the 2,528 control patients received no alert and delivered usual care.

The study excluded patients with higher-risk profiles, including those with extremely elevated serum creatinine levels at admission (4.0 mg/dL or higher), those recently treated with dialysis, and patients with end-stage kidney disease.

The study had two primary outcomes. One measured the impact of the intervention on stopping the targeted drugs. The second assessed the clinical effect of the intervention on progression of AKI to a higher stage, need for dialysis, or death during either the duration of hospitalization or during the first 14 days following randomization.
 

Overall, a 9% relative increase in discontinuations

In general, the intervention had a modest but significant effect on cessation of the targeted drug classes within 24 hours of sending the alert.

Overall, there was about a 58% discontinuation rate among controls and about a 62% discontinuation rate among patients managed using the alerts, a significant 9% relative increase in any drug discontinuation, Dr. Wilson reported.

Discontinuations of NSAIDs occurred at the highest rate, in about 80% of patients in both groups, and the intervention showed no significant effect on stopping agents from this class. Discontinuations of RAAS inhibitors showed the largest absolute difference in between-group effect, about a 10–percentage point increase that represented a significant 14% relative increase in stopping agents from this class. Discontinuations of PPIs occurred at the lowest rate, in roughly 20% of patients, but the alert intervention had the greatest impact by raising the relative rate of stopping by a significant 26% compared with controls.

Analysis of the effect of the intervention on the combined clinical outcome showed a less robust impact. The alerts produced no significant change in the clinical outcome overall, or in the use of NSAIDs or RAAS inhibitors. However, the change in use of PPIs following the alerts significantly linked with a 12% relative drop in the incidence of the combined clinical endpoint of progression of AKI to a higher stage, need for dialysis, or death.

The results were consistent across several prespecified subgroups based on parameters such as age, sex, and race, but these analyses showed a signal that the alerts were most helpful for patients who had serum creatinine levels at admission of less than 0.5 mg/dL.

Dr. Wilson speculated that the alerts might have been especially effective for these patients because their low creatinine levels might otherwise mask AKI onset.

A safety analysis showed no evidence that the alert interventions and drug cessations increased the incidence of any complications.
 

PPIs may distinguish ‘sicker’ patients

Dr. Wilson cited two potential explanations for why the tested alerts appeared most effective for patients taking a PPI at the time of admission. One is that PPIs are underappreciated as a contributor to AKI, a possibility supported by the low rates of discontinuation in both the control and intervention groups.

In addition, treatment with a PPI may be a marker of “sicker” patients who may have more to gain from quicker identification of their AKI. For example, 28% of the patients who were taking a PPI at admission were in the ICU when they entered the study compared with a 14% rate of ICU care among everyone else.

PPIs were also the most-used targeted drug class among enrolled patients, used by 65% at baseline, compared with 53% who were taking a RAAS inhibitor and about 31% who were taking an NSAID. About 6% of enrolled patients were taking agents from all three classes at baseline, and 36% were on treatment with agents from two of the classes.

The next step is to assess adding more refinement to the alert process, Dr. Wilson said. He and his associates are now running a study in which an AKI alert goes to a “kidney action team” that includes a trained clinician and a pharmacist. The team would review the patient who triggered the alert and quickly make an individualized assessment of the best intervention for resolving the AKI.

The study received no commercial funding. Dr. Wilson has received research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop. Dr. Griffin has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – A double dose of the antiosteoporosis biologic denosumab (Prolia) slowed progression and repaired joints in erosive hand osteoarthritis (OA) but showed no impact on pain levels until 2 years after patients received the first dose, the lead investigator of a Belgium-based randomized clinical trial reported at the annual meeting of the American College of Rheumatology.

“This is the first placebo-controlled, randomized clinical trial showing the efficacy of denosumab double-dosing regimen in structural modification of erosive hand osteoarthritis,” Ruth Wittoek, MD, PhD, a rheumatologist at Ghent (Belgium) University, said in presenting the results.

“Our primary endpoint was confirmed by a more robust secondary endpoint, both showing that denosumab stopped erosive progression and induced remodeling in patients with erosive hand OA,” she added. “Moreover, the double-dosing regimen was well-tolerated.”

However, during the question-and-answer period after her presentation, Dr. Wittoek acknowledged the study didn’t evaluate the impact denosumab had on cartilage and didn’t detect a signal for pain resolution until 96 weeks during the open-label extension phase. “I’m not quite sure if denosumab is sufficient to treat symptoms in osteoarthritis,” she said. “There were positive signals but, of course, having to wait 2 years for an effect is kind of hard for our patients.”

The trial randomized 100 adult patients 1:1 to denosumab 60 mg every 12 weeks – double the normal dose for osteoporosis – or placebo. The primary endpoint was changes in erosive progression and signs of repair based on x-ray at 48 weeks, after which all patients were switched to denosumab for the open-label study. To quantify changes, the investigators used the Ghent University Scoring System (GUSS), which uses a scale of 0-300 to quantify radiographic changes in erosive hand OA.

Dr. Wittoek said that the average change in GUSS at week 24 was +6 vs. –2.8 (P = .024) in the treatment and placebo groups, respectively, widening at week 48 to +10.1 and –7.9 (P = .003). By week 96, the variation was +18.8 for denosumab and +17 for placebo with switch to denosumab (P = .03).

“During the open-label extension the denosumab treatment group continued to increase to show remodeling while the former placebo treatment group, now also receiving denosumab, also  showed signs of remodeling,” she said. “So, there was no more erosive progression.”

The secondary endpoint was the percentage of new erosive joint development at week 48: 1.8% in the denosumab group and 7% in placebo group (odds ratio, 0.23; 95% confidence interval, 0.10-0.50; P < .001). “Meaning the odds of erosive progression is 77% lower in the denosumab treatment group,” Dr. Wittoek said.

By week 96, those percentages were 0% and 0.7% in the respective treatment groups. “During the open-label extension, it was clear that denosumab blocked all new development of erosive joints,” she said.

Pain was one of the study’s exploratory endpoints, and the mean numeric rating scale showed no difference between treatment arms until the 96-week results, with a reduction by almost half in the denosumab group (from 4.2 at week 48 to 2.4) and a lesser reduction in the placebo-switched-to-denosumab arm (from 4.2 to 3.5; P = .028) between arms.

The placebo group was more susceptible to adverse events, namely musculoskeletal complaints and nervous system disorders, Dr. Wittoek noted. Infection rates, the most common adverse event, were similar between the two groups: 41 and 39 in the respective arms. Despite the double dose of denosumab, safety and tolerability in this trial was comparable to other trials, she said.

In comments submitted by e-mail, Dr. Wittoek noted that the extension study results will go out to 144 weeks. She also addressed the issues surrounding pain as an outcome.

“Besides disability, pain is also important from the patient’s perspective,” Dr. Wittoek said in the e-mailed comments. “However, pain and radiographic progression are undeniably coupled, but it’s unclear how.”

In erosive hand OA, structural progression and pain may not be related on a molecular level, she said. “Therefore, we don’t deny that pain levels should also be covered by treatment, but they should not be confused with structural modification; it is just another domain, not more nor less important.

The second year of the open-label extension study should clarify the pain outcomes, she said.

Richard Mark Kirkner/MDedge News

In an interview, David T. Felson, MD, MPH, professor and director of clinical epidemiology research at Boston University, questioned the delayed pain effect the study suggested. “It didn’t make any sense to me that there would be because both groups at that point got denosumab, so if there was going to be a pain effect that would’ve happened,” he said.

The pain effect is “really important,” he said. “We don’t use denosumab in rheumatoid arthritis to treat erosions because it doesn’t necessarily affect the pain and dysfunction of rheumatoid arthritis, and I’m not sure that isn’t going to be true in erosive hand osteoarthritis, but it’s possible.”

To clarify the pain outcomes, he said, “They’re going to have to work on the data.”

Amgen sponsored the trial but had no role in the design. Dr. Wittoek and Dr. Felson reported no relevant disclosures.
 

PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.

The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.

That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.

With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.

“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
 

Real-world setting

The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”

Ariel Skelley/Getty Images

A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.

The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.

The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.

Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
 

Endpoints met

The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).

In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).

In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).

Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).

Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.

He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
 

‘Tour de force’

In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”

Richard Mark Kirkner/MDedge News

Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.

Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”

In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.

“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.

She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.

“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.

The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.

PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.

The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.

That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.

With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.

“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
 

Real-world setting

The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”

Ariel Skelley/Getty Images

A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.

The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.

The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.

Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
 

Endpoints met

The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).

In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).

In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).

Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).

Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.

He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
 

‘Tour de force’

In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”

Richard Mark Kirkner/MDedge News

Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.

Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”

In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.

“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.

She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.

“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.

The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.

PHILADELPHIA – What works in the clinic can also work in community settings: Patients who are overweight or obese with knee osteoarthritis can find relief from pain through diet and exercise programs conducted in recreation centers, local gyms, fitness centers, and other places close to home, according to investigators in a pragmatic randomized trial.

The Weight Loss and Exercise for Communities With Arthritis in North Carolina (WE-CAN) study was modeled after the successful Intensive Diet and Exercise for Arthritis trial, which showed that adults randomized to 18 months of either a diet and exercise program or diet alone had more weight loss and larger reductions in levels of the inflammatory cytokine interleukin-6 than patients randomized to exercise alone, and that diet alone was associated with greater reductions in knee compressive force than exercise alone.

That study was conducted by Stephen P. Messier, PhD, and colleagues at Wake Forest University, Winston-Salem, N.C.. As previously reported, the investigators also saw continued benefits for participants years after the original trial.

With the WE-CAN trial, results of which were reported at the annual meeting of the American College of Rheumatology, Dr. Messier and colleagues took the intervention one step further, randomizing 823 community-dwelling adults who were overweight or obese (body mass index [BMI], ≥ 27 kg/m2) with knee OA to either an 18-month diet and exercise intervention or attention control group consisting of five 1-hour face-to-face meetings over 18 months, plus information packets and phone sessions during alternate months.

“Compared to the control group, diet plus exercise had a statistically significant but modest reduction in pain. Diet plus exercise was 20% more likely to attain a clinically important 2-point improvement in pain,” Dr. Messier said in an oral abstract session at ACR.
 

Real-world setting

The primary goal of WE-CAN was to “determine whether adaptation of a diet and exercise academic center–based efficacy trial to community settings results in a statistically significant reduction in pain relative to an attention control.”

Ariel Skelley/Getty Images

A total of 3,751 potential candidates were screened, and 823 were randomized and assigned to either a diet and exercise arm (414) or attention control arm (409). Of the patients randomized, 336 in the diet/exercise arm and 322 in the control arm attended the final 18-month follow-up visit.

The exercise component consisted of a 15-minute walking period, followed by a 20-minute weight-training period, and ending with a second 15-minute walking period. The diet goal was 10% or greater weight loss, aided by a distribution of low-calorie recipes to produce a reduced-calorie diet of the patient’s choice, with the option to include nutritional powder to make low-calories shakes as meal replacements, one or two per day for the first 6 months, with the option of one per day for the remaining months.

The pragmatic components included the use of established community facilities in both urban and rural counties in North Carolina, broad inclusion criteria, patient-centered outcomes, use of community-based staff to deliver the treatment, nonphysicians trained by study physicians to perform knee exams, and various means of communication, Dr. Messier said.

Participants in each arm were closely matched by demographic and clinical characteristics, with a mean age of 64.5 years in the diet/exercise group and 64.7 years in the attention control group, respective mean weight of 100.7 kg and 101.1 kg, and respective BMI of 36.7 and 36.9. Women comprised about 77% of participants in each group.
 

Endpoints met

The trial met its primary endpoint of a significantly greater reduction in pain at 18 months in the diet and exercise group as measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and scored on a scale of 0 (no pain) to 20 (worst pain).

In an analysis adjusted for sex, BMI, and baseline values, there was a 32% reduction in pain scores from baseline in the active intervention arm versus 24% in the control arm (P = .02).

In all, 60.2% of participants assigned to diet and exercise had a minimum reduction in pain scores of at least 2 points at 18 months, compared with 49.7% of participants assigned to the attention control group. This translated into a relative risk for achieving at least a 2-point improvement with diet and exercise was 1.20 (P = .01).

Among participants who remained in the study for the entire 18 months, there were significant improvements in the diet and exercise group compared with controls in the prespecified secondary endpoints of weight change (–8 kg vs. –2 kg), waist circumference, WOMAC function, 6-minute walk distance, and mean Short Form–36 health-related quality of life subscale (P < .001 for all comparisons).

Dr. Messier acknowledged that the diagnosis of knee OA was based only on ACR clinical criteria and was not confirmed with imaging. In addition, offering patients the option of free meal replacement limited the pragmatic nature of the intervention.

He also noted that the 24% reduction in pain seen in the control group suggests that interacting with patients can improve clinical outcomes.
 

‘Tour de force’

In the question-and-answer session following Dr. Messier’s presentation, David T. Felson, MD, a rheumatologist at Boston Medical Center, called in and said the study was “a tour de force” and congratulated Dr. Messier and colleagues on “a lovely study.”

Richard Mark Kirkner/MDedge News

Dr. Felson asked whether the investigators had conducted a mediation analysis to determine what proportion of the improvement was attributable to weight loss, and whether patients assigned to exercise were sticking with it throughout the study.

Dr. Messier replied that they had not yet done a mediation analysis but were continuing to examine the data. Regarding the exercise question, he noted that “the adherence was over 80% for 6 months and over 70% for the whole 18 months, so they did a really nice job.”

In an interview, session moderator Anne Davidson, MBBS, director of the rheumatology program at Northwell Health in Manhasset, N.Y., commented that the investigators managed to accomplish a very challenging task.

“In terms of recruitment of patients with engagement of community facilities and quality of data, I would say that, as far as an osteoarthritis study goes, this was really a tremendous effort on the part of all people involved,” she said.

She noted that, while the WE-CAN program may work in North Carolina, there may be barriers to implementing it elsewhere, such as large suburban areas where some patients experience food insecurity and others have difficulty with transportation and access to treatment facilities.

“The question here that remains is, as Dr. Felson asked, what is the contribution of weight loss and what is the contribution of exercise? Because if it’s just weight loss, we have a whole lot of new things coming to help with that,” she said.

The WE-CAN study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Messier disclosed that GNC, a health food and nutrition chain, donated the meal replacements used by patients. Dr. Davidson reported no relevant conflicts of interest.