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Antibiotics of Little Benefit in Lower Respiratory Tract Infection
Antibiotics had no measurable effect on the severity or duration of coughs due to acute lower respiratory tract infection (LRTI, or acute bronchitis), a large prospective study found.
In fact, those receiving an antibiotic in the primary- and urgent-care setting had a small but significant increase in overall length of illness (17.5 vs 15.9 days; P = .05) — largely because patients with longer illness before the index visit were more likely to receive these drugs. The study adds further support for reducing the prescription of antibiotics for LRTIs.
“Importantly, the pathogen data demonstrated that the length of time until illness resolution for those with bacterial infection was the same as for those not receiving an antibiotic versus those receiving one (17.3 vs 17.4 days),” researchers led by Daniel J. Merenstein, MD, a professor and director of research programs, family medicine, at Georgetown University Medical Center in Washington, wrote in the Journal of General Internal Medicine (doi: 10.1007/s11606-024-08758-y).
Patients believed an antibiotic would shorten their illness by an average of about 4 days, from 13.4 days to 9.7 days, whereas the average duration of all coughs was more than 2 weeks regardless of pathogen type or receipt of an antibiotic.
“Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics, which should be the target of antibiotic stewardship efforts,” the group wrote.
LRTIs can, however, be dangerous, with 3%-5% progressing to pneumonia, “but not everyone has easy access at an initial visit to an x-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection,” Dr. Merenstein said in a news release. “Patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time bring a resolution to most people’s infections.”
The authors noted that cough is the most common reason for an ambulatory care visit, accounting for 2.7 million outpatient visits and more than 4 million emergency department visits annually.
Risks
Overuse of antibiotics can result in dizziness, nausea, diarrhea, and rash, along with a roughly 4% chance of serious adverse effects including anaphylaxis; Stevens-Johnson syndrome, a serious skin and mucous membrane disorder; and Clostridioides difficile-associated diarrhea.
An estimated half of all antibiotic prescriptions for acute respiratory conditions are unnecessary. Before the COVID-19 pandemic, antibiotics were prescribed about 70% of the time for a diagnosis of uncomplicated cough and LRTI. The viral pandemic did not change this practice according to a meta-analysis of 130 studies showing that 78% of COVID-19 patients were prescribed an antibiotic.
The study
The study looked at a cohort of 718 patients, with a mean age of 38.9 years, 65.3% female, of whom 207 received an antibiotic and 511 did not. Of those with baseline data, 29% had an antibiotic prescribed at baseline, the most common (in 85%) being amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin. Antibiotics had no effect on the duration or overall severity of cough in viral, bacterial, or mixed infections. Receipt of an antibiotic did, however, reduce the likelihood of a follow-up visit: 14.1% vs 8.2% (adjusted odds ratio, 0.47; 95% confidence interval, 0.26-0.84) — perhaps because it removed the motivation for seeking another consultation. Antibiotic recipients were more likely to receive a systemic corticosteroid (31.9% vs 4.5%, P <.001) and were also more likely to receive an albuterol inhaler (22.7% vs 7.6%, P <.001).
Jeffrey A. Linder, MD, MPH, a primary care physician and chief of internal medicine and geriatrics at Northwestern University Feinberg School of Medicine in Chicago, agrees that in the vast majority of LRTIs — usually acute bronchitis — antibiotics do not speed the healing process. “Forty years of research show that antibiotics do not make acute bronchitis go away any faster,” Dr. Linder, who was not involved in the current study, said in an interview. “There’s even growing evidence that a lot of pneumonia is viral as well, and 10 or 20 years from now we may often not be giving antibiotics for pneumonia because we’ll be able to see better if it’s caused by a virus.”
A large 2018 review by Dr. Linder and associates reported that 46% of antibiotics were prescribed without any infection-related diagnosis code and 20% without an office visit.
Dr. Linder routinely informs patients requesting an antibiotic about the risks of putting an ineffective chemical into their body. “I stress that it can cause rash and other allergic reactions, and even promote C diff infection,” he said. “And I also say it messes with the good bacteria in the microbiome, and they usually come around.”
Patients need to know, Dr. Linder added, that the normal course of healing the respiratory tract after acute bronchitis takes weeks. While a wet cough with sputum or phlegm will last a few days, it’s replaced with a dry annoying cough that persists for up to 3 weeks. “As long as they’re feeling generally better, that cough is normal,” he said. “A virus has run roughshod over their airways and they need a long time to heal and the cough is part of the healing process. Think how long it takes to heal a cut on a finger.”
In an era of escalating antimicrobial resistance fueled by antibiotic overuse, it’s become increasingly important to reserve antibiotics for necessary cases. According to a recent World Health Organization call to action, “Uncontrolled antimicrobial resistance is expected to lower life expectancy and lead to unprecedented health expenditure and economic losses.”
That said, there is important clinical work to be done to determine if there is a limited role for antibiotics in patients with cough, perhaps based on age and baseline severity. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012,” Dr. Merenstein said.
This research was funded by the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to declare. Dr. Linder reported stock ownership in pharmaceutical companies but none that make antibiotics or other infectious disease drugs.
Antibiotics had no measurable effect on the severity or duration of coughs due to acute lower respiratory tract infection (LRTI, or acute bronchitis), a large prospective study found.
In fact, those receiving an antibiotic in the primary- and urgent-care setting had a small but significant increase in overall length of illness (17.5 vs 15.9 days; P = .05) — largely because patients with longer illness before the index visit were more likely to receive these drugs. The study adds further support for reducing the prescription of antibiotics for LRTIs.
“Importantly, the pathogen data demonstrated that the length of time until illness resolution for those with bacterial infection was the same as for those not receiving an antibiotic versus those receiving one (17.3 vs 17.4 days),” researchers led by Daniel J. Merenstein, MD, a professor and director of research programs, family medicine, at Georgetown University Medical Center in Washington, wrote in the Journal of General Internal Medicine (doi: 10.1007/s11606-024-08758-y).
Patients believed an antibiotic would shorten their illness by an average of about 4 days, from 13.4 days to 9.7 days, whereas the average duration of all coughs was more than 2 weeks regardless of pathogen type or receipt of an antibiotic.
“Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics, which should be the target of antibiotic stewardship efforts,” the group wrote.
LRTIs can, however, be dangerous, with 3%-5% progressing to pneumonia, “but not everyone has easy access at an initial visit to an x-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection,” Dr. Merenstein said in a news release. “Patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time bring a resolution to most people’s infections.”
The authors noted that cough is the most common reason for an ambulatory care visit, accounting for 2.7 million outpatient visits and more than 4 million emergency department visits annually.
Risks
Overuse of antibiotics can result in dizziness, nausea, diarrhea, and rash, along with a roughly 4% chance of serious adverse effects including anaphylaxis; Stevens-Johnson syndrome, a serious skin and mucous membrane disorder; and Clostridioides difficile-associated diarrhea.
An estimated half of all antibiotic prescriptions for acute respiratory conditions are unnecessary. Before the COVID-19 pandemic, antibiotics were prescribed about 70% of the time for a diagnosis of uncomplicated cough and LRTI. The viral pandemic did not change this practice according to a meta-analysis of 130 studies showing that 78% of COVID-19 patients were prescribed an antibiotic.
The study
The study looked at a cohort of 718 patients, with a mean age of 38.9 years, 65.3% female, of whom 207 received an antibiotic and 511 did not. Of those with baseline data, 29% had an antibiotic prescribed at baseline, the most common (in 85%) being amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin. Antibiotics had no effect on the duration or overall severity of cough in viral, bacterial, or mixed infections. Receipt of an antibiotic did, however, reduce the likelihood of a follow-up visit: 14.1% vs 8.2% (adjusted odds ratio, 0.47; 95% confidence interval, 0.26-0.84) — perhaps because it removed the motivation for seeking another consultation. Antibiotic recipients were more likely to receive a systemic corticosteroid (31.9% vs 4.5%, P <.001) and were also more likely to receive an albuterol inhaler (22.7% vs 7.6%, P <.001).
Jeffrey A. Linder, MD, MPH, a primary care physician and chief of internal medicine and geriatrics at Northwestern University Feinberg School of Medicine in Chicago, agrees that in the vast majority of LRTIs — usually acute bronchitis — antibiotics do not speed the healing process. “Forty years of research show that antibiotics do not make acute bronchitis go away any faster,” Dr. Linder, who was not involved in the current study, said in an interview. “There’s even growing evidence that a lot of pneumonia is viral as well, and 10 or 20 years from now we may often not be giving antibiotics for pneumonia because we’ll be able to see better if it’s caused by a virus.”
A large 2018 review by Dr. Linder and associates reported that 46% of antibiotics were prescribed without any infection-related diagnosis code and 20% without an office visit.
Dr. Linder routinely informs patients requesting an antibiotic about the risks of putting an ineffective chemical into their body. “I stress that it can cause rash and other allergic reactions, and even promote C diff infection,” he said. “And I also say it messes with the good bacteria in the microbiome, and they usually come around.”
Patients need to know, Dr. Linder added, that the normal course of healing the respiratory tract after acute bronchitis takes weeks. While a wet cough with sputum or phlegm will last a few days, it’s replaced with a dry annoying cough that persists for up to 3 weeks. “As long as they’re feeling generally better, that cough is normal,” he said. “A virus has run roughshod over their airways and they need a long time to heal and the cough is part of the healing process. Think how long it takes to heal a cut on a finger.”
In an era of escalating antimicrobial resistance fueled by antibiotic overuse, it’s become increasingly important to reserve antibiotics for necessary cases. According to a recent World Health Organization call to action, “Uncontrolled antimicrobial resistance is expected to lower life expectancy and lead to unprecedented health expenditure and economic losses.”
That said, there is important clinical work to be done to determine if there is a limited role for antibiotics in patients with cough, perhaps based on age and baseline severity. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012,” Dr. Merenstein said.
This research was funded by the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to declare. Dr. Linder reported stock ownership in pharmaceutical companies but none that make antibiotics or other infectious disease drugs.
Antibiotics had no measurable effect on the severity or duration of coughs due to acute lower respiratory tract infection (LRTI, or acute bronchitis), a large prospective study found.
In fact, those receiving an antibiotic in the primary- and urgent-care setting had a small but significant increase in overall length of illness (17.5 vs 15.9 days; P = .05) — largely because patients with longer illness before the index visit were more likely to receive these drugs. The study adds further support for reducing the prescription of antibiotics for LRTIs.
“Importantly, the pathogen data demonstrated that the length of time until illness resolution for those with bacterial infection was the same as for those not receiving an antibiotic versus those receiving one (17.3 vs 17.4 days),” researchers led by Daniel J. Merenstein, MD, a professor and director of research programs, family medicine, at Georgetown University Medical Center in Washington, wrote in the Journal of General Internal Medicine (doi: 10.1007/s11606-024-08758-y).
Patients believed an antibiotic would shorten their illness by an average of about 4 days, from 13.4 days to 9.7 days, whereas the average duration of all coughs was more than 2 weeks regardless of pathogen type or receipt of an antibiotic.
“Patients had unrealistic expectations regarding the duration of LRTI and the effect of antibiotics, which should be the target of antibiotic stewardship efforts,” the group wrote.
LRTIs can, however, be dangerous, with 3%-5% progressing to pneumonia, “but not everyone has easy access at an initial visit to an x-ray, which may be the reason clinicians still give antibiotics without any other evidence of a bacterial infection,” Dr. Merenstein said in a news release. “Patients have come to expect antibiotics for a cough, even if it doesn’t help. Basic symptom-relieving medications plus time bring a resolution to most people’s infections.”
The authors noted that cough is the most common reason for an ambulatory care visit, accounting for 2.7 million outpatient visits and more than 4 million emergency department visits annually.
Risks
Overuse of antibiotics can result in dizziness, nausea, diarrhea, and rash, along with a roughly 4% chance of serious adverse effects including anaphylaxis; Stevens-Johnson syndrome, a serious skin and mucous membrane disorder; and Clostridioides difficile-associated diarrhea.
An estimated half of all antibiotic prescriptions for acute respiratory conditions are unnecessary. Before the COVID-19 pandemic, antibiotics were prescribed about 70% of the time for a diagnosis of uncomplicated cough and LRTI. The viral pandemic did not change this practice according to a meta-analysis of 130 studies showing that 78% of COVID-19 patients were prescribed an antibiotic.
The study
The study looked at a cohort of 718 patients, with a mean age of 38.9 years, 65.3% female, of whom 207 received an antibiotic and 511 did not. Of those with baseline data, 29% had an antibiotic prescribed at baseline, the most common (in 85%) being amoxicillin-clavulanate, azithromycin, doxycycline, and amoxicillin. Antibiotics had no effect on the duration or overall severity of cough in viral, bacterial, or mixed infections. Receipt of an antibiotic did, however, reduce the likelihood of a follow-up visit: 14.1% vs 8.2% (adjusted odds ratio, 0.47; 95% confidence interval, 0.26-0.84) — perhaps because it removed the motivation for seeking another consultation. Antibiotic recipients were more likely to receive a systemic corticosteroid (31.9% vs 4.5%, P <.001) and were also more likely to receive an albuterol inhaler (22.7% vs 7.6%, P <.001).
Jeffrey A. Linder, MD, MPH, a primary care physician and chief of internal medicine and geriatrics at Northwestern University Feinberg School of Medicine in Chicago, agrees that in the vast majority of LRTIs — usually acute bronchitis — antibiotics do not speed the healing process. “Forty years of research show that antibiotics do not make acute bronchitis go away any faster,” Dr. Linder, who was not involved in the current study, said in an interview. “There’s even growing evidence that a lot of pneumonia is viral as well, and 10 or 20 years from now we may often not be giving antibiotics for pneumonia because we’ll be able to see better if it’s caused by a virus.”
A large 2018 review by Dr. Linder and associates reported that 46% of antibiotics were prescribed without any infection-related diagnosis code and 20% without an office visit.
Dr. Linder routinely informs patients requesting an antibiotic about the risks of putting an ineffective chemical into their body. “I stress that it can cause rash and other allergic reactions, and even promote C diff infection,” he said. “And I also say it messes with the good bacteria in the microbiome, and they usually come around.”
Patients need to know, Dr. Linder added, that the normal course of healing the respiratory tract after acute bronchitis takes weeks. While a wet cough with sputum or phlegm will last a few days, it’s replaced with a dry annoying cough that persists for up to 3 weeks. “As long as they’re feeling generally better, that cough is normal,” he said. “A virus has run roughshod over their airways and they need a long time to heal and the cough is part of the healing process. Think how long it takes to heal a cut on a finger.”
In an era of escalating antimicrobial resistance fueled by antibiotic overuse, it’s become increasingly important to reserve antibiotics for necessary cases. According to a recent World Health Organization call to action, “Uncontrolled antimicrobial resistance is expected to lower life expectancy and lead to unprecedented health expenditure and economic losses.”
That said, there is important clinical work to be done to determine if there is a limited role for antibiotics in patients with cough, perhaps based on age and baseline severity. “Serious cough symptoms and how to treat them properly needs to be studied more, perhaps in a randomized clinical trial as this study was observational and there haven’t been any randomized trials looking at this issue since about 2012,” Dr. Merenstein said.
This research was funded by the Agency for Healthcare Research and Quality. The authors have no conflicts of interest to declare. Dr. Linder reported stock ownership in pharmaceutical companies but none that make antibiotics or other infectious disease drugs.
FROM JOURNAL OF GENERAL INTERNAL MEDICINE
How New ICI Combos Change Bladder Cancer Management
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
according to Thomas W. Flaig, MD, vice chancellor for research at the University of Colorado Anschutz Medical Campus, Aurora.
Combination therapies involving enfortumab and nivolumab are demonstrating success in recent studies and have been incorporated into the latest guidelines, Dr. Flaig said in a presentation at the National Comprehensive Cancer Network (NCCN) annual conference.
What's New in The Updated Guidelines?
Advances in the treatment options for metastatic urothelial carcinoma in the last decade have been dramatic, with ongoing developments and new emerging treatment options, Dr. Flaig told the audience of his session.
This has led to the identification of new and effective immune checkpoint inhibitor combinations. Consequently, immune checkpoint inhibitors are currently included in all preferred/other recommended first-line treatment regimens, he said.
“Enfortumab vedotin plus pembrolizumab is now the sole preferred first-line regimen for locally advanced or metastatic disease.” Based on the recent research, the mindset regarding cisplatin-eligible patient selection may be changing, he added.
“We have used cisplatin eligibility as a key factor in determining first-line therapy for years, and that paradigm is now shifting with the emergence of enfortumab plus pembrolizumab, a new non–cisplatin containing regimen” Dr. Flaig noted.
Although the optimal choice for second- or third-line therapy after immune checkpoint inhibitors is not well-defined, options include platinum regimens, antibody-drug conjugate, and erdafitinib in eligible patients, he said.
Other Current Strategies for Localized Bladder Cancer Management
The incidence of bladder cancer has been stable for decades, with minimal therapeutic developments until the approval of immune checkpoint inhibitors in the last decade, Dr. Flaig said.
Bladder cancer is more common in older adults, with an average onset age of 73 years, and most patients (75%) are male, he said. Comorbid disease is common in these patients, and many have a history of smoking, Dr. Flaig added.
The traditional medical approach to treating bladder cancer has been based on combination therapies including cisplatin. This has also reflected the approach used in the treatment of lung cancer, historically, Dr. Flaig said.
Cisplatin, while effective, is a challenging therapy to administer and is not an option for all bladder cancer patients because of potential adverse effects, he noted. Antibody drug conjugates and immune checkpoint inhibitors are new alternatives for some who are not able to receive cisplatin.
What are the New Options for Treating Metastatic Urothelial Bladder Cancer?
The approval of antibody drug conjugates offers new treatment with a “specific target and therapeutic payload,” said Dr. Flaig in his presentation. Two antibody drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been approved by the US Food and Drug Administration (FDA), he said. Enforumab vedotin was approved by the FDA in 2021 for adults with locally advanced or metastatic urothelial cancer for subsequent line therapy in select patients. In a 2021 study published in The New England Journal of Medicine, the primary outcome of overall response rate was significantly greater in patients with advanced urothelial carcinoma who were treated with enfortumab vedotin than in those treated with standard chemotherapy (overall response rate [ORR] 40.6% vs 17.9%, respectively).
Side effects associated with enfortumab vedotin “are intrinsic to the payload toxicity and the target distribution. Ideally, the target would be present on all of the cancer cells and none of the normal tissue,” said Dr. Flaig. With enfortumab, specific toxicities included neuropathy, skin reactions, and blood glucose elevation/diabetic ketoacidosis, he said.
A second agent, sacituzumab govitecan, was approved by the FDA for metastatic urothelial cancer patients in 2021, based on data from the TROPHY-U-O1 phase 2 open-label study of 113 individuals. In that study, the ORR was 27% at a median follow-up of 9.1 months. Adverse events included neutropenia, leukopenia, and diarrhea.
What Do the Latest Studies of Combination Therapy Show?
Immune checkpoint inhibitor combinations are significantly changing the landscape of bladder cancer treatment, Dr. Flaig explained.
A recent phase 3 study published in 2024 in The New England Journal of Medicine comparing enfortumab vedotin plus pembrolizumab to platinum-based combination chemotherapy showed an overall response rate of 67.7% vs 44.4% in favor of enfortumab/pembrolizumab, said Dr. Flaig. In addition, the risk of disease progression or death was approximately 55% lower in the enfortumab vedotin-pembrolizumab group vs the chemotherapy group (hazard ratio [HR], 0.45; P less than .001) and the median progression-free survival was approximately doubled (12.5 months vs 6.3 months).
Dr. Flaig described this study as “very notable”because “the enfortumab plus pembrolizumab arm was clearly more effective than the long-standing chemotherapy arm, now becoming the preferred, first-line treatment in the NCCN guidelines. Based on preliminary results of the study, this combination was approved by the FDA in 2023 for locally advanced or metastatic urothelial cancer patients regardless of their eligibility for cisplatin.
Another promising combination, nivolumab plus gemcitabine-cisplatin, was associated with significantly longer overall and progression-free survival in patients with previously untreated unresectable or metastatic urothelial carcinoma, Dr. Flaig said. The therapy was approved by the FDA in March 2024 for first-line therapy.
In a study of 608 patients published in The New England Journal of Medicine, median overall survival was 21.7 months for the nivolumab group vs 18.9 months for the gemcitabine-cisplatin alone group. The overall response rates were 57.6% in the nivolumab group vs 43.1% in the gemcitabine-cisplatin–alone group, and complete response rates were 21.7% and 11.8%, respectively. Serious adverse events (grade 3 or higher) were similar between the groups (61.8% and 51.7%, respectively).
What About Targeted Therapy?
Erdafitinib, a tyrosine kinase inhibitor of FGFR1–4, was approved by the FDA in January 2024 for adults with locally advanced or metastatic urothelial carcinoma who had susceptible FGFR3 genetic alterations, said Dr. Flaig, during his presentation. The limitation of this treatment to only those patients with an FGFR3 mutation is a recent update in its use, he noted.
“Up to 20% of patients with advanced urothelial carcinoma have FGFR alterations,” he said. In an open-label phase 2 study of 99 individuals with unresectable or metastatic urothelial carcinoma, past chemotherapy, and FGFR alterations, confirmed response to erdafitinib was 40% with a median overall survival of 13.8 months.
Dr. Flaig disclosed grant/research support from Agensys; Astellas Pharma US; AstraZeneca Pharmaceuticals LP; Bristol Myers Squibb; Genentech, Inc.; Janssen Pharmaceutica Products, LP; Merck & Co.; Sanofi-Aventis U.S.; and SeaGen. He also disclosed equity interest/stock options and intellectual property rights in Aurora Oncology, and serving as a consultant or scientific advisor for Janssen Pharmaceutica Product, LP, and Criterium, Inc.
FROM NCCN 2024
Panel: MRD Tests May Speed Myeloma Tx Approvals
The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”
The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”
The Oncologic Drugs Advisory Committee (ODAC) of the US Food and Drug Administration (FDA) voted 12-0 on April 12 on the following question: Does the evidence support the use of MRD as an accelerated approval endpoint in multiple myeloma clinical trials?
The FDA is not bound to accept the recommendations of its panels, but often does so.
ODAC panelists said they felt comfortable in this recommendation because they expected the FDA to mandate confirmatory studies of any drugs to be given accelerated approval based on MRD data.
There’s a risk that MRD results might mislead regulators into clearing a drug later found to lack benefit, said Christopher Hourigan, DM, DPhil, an ODAC panelist and a physician-scientist at Virginia Tech, Blacksburg, Virginia, who treats people with blood cancer. Further tests would ultimately show if drugs cleared based on MRD data actually delivered benefits such as extending progression-free survival (PFS).
“That’s why we’re talking about accelerated approval,” Dr. Hourigan said. “There is harm to inaction. We’re not currently curing people in multiple myeloma. I’m not willing to make patients wait on principle for a theoretical perfect that may never come.”
“Our responsibility is to accept the world as messy and be agile enough to adapt and iterate that the evidence develops rather than create barriers to the work of discovering effective new therapies for these patients,” he added.
Advances in testing now allow for detection of the presence of malignant cells at orders of magnitude below previous assessments. MRD assays used in tracking what’s happening with myeloma generally have a sensitivity level of 10-5, or a detection capacity of one cell of 100,000, said Ola Landgren, MD, PhD, of the University of Miami, Miami, Florida, during a presentation at the meeting.
The April 12 meeting was somewhat unusual for ODAC.
Instead of reviewing the benefits and risks of a specific drug, the panel reviewed results from two separate major research efforts done to see how MRD could be used in development of drugs.
These were Dr. Landgren’s EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis, and the similar work of the i2TEAMM group, affiliated with the International Myeloma Foundation.
In its review, the FDA staff noted differences in the approaches of the two groups. In its analysis, the i2TEAMM removed information about patients with missing MRD data, while the University of Miami team retained information about these kinds of patients in the analyses and assigned their status to be MRD positive.
The FDA staff also noted in their review and presentations weaknesses in the case for MRD. For example, the FDA staff noted that the treatment effect on MRD negativity was not statistically significant in 4 of the 8 treatment comparisons in the work from Dr. Landgren and colleagues.
The FDA staff looked at what these analyses suggested at both an individual level and trial level. The data from these two research projects taken as a whole showed “strong individual-level” associations between negative MRD findings and later positive outcomes for patients, although trial-level associations were “weak to moderate” in some cases, the staff wrote.
The FDA staff concluded that the research appeared to support arguments in favor of the “prognostic value,” even with outstanding questions about how best to use this test.
In the briefing document for the meeting, the FDA also emphasized the need for new treatments.
Multiple myeloma remains an incurable disease with a 5-year relative survival rate of 59.8%, even after significant recent progress in treatment, the agency said. In the past decade, the FDA has approved 15 new drugs and greater than 20 new indications have been approved for the treatment of patients with multiple myeloma.
The FDA has been working with drugmakers and academic researchers for several years to address the potential of MRD in development of blood cancers. The agency in 2020 issued a guidance document on this issue.
Several ODAC members praised the i2TEAMM and Dr. Landgren’s EVIDENCE teams for their work, which took place across several nations and extended over many years.
“This was a herculean effort. It really changes the playbook for how we think about biomarkers across all cancer types,” said ODAC panelist Neil Vasan, MD, PhD, of Columbia University, New York, NY. “To me, the important word was reasonable. Is this a reasonable surrogate endpoint? Is this a reasonable intermediate endpoint? I think it is more than reasonable.”
Still, ODAC panelist Jorge Nieva, MD, raised a point of concern about how use of MRD as an endpoint could change the design of studies. He urged caution among researchers about potential ramping up of collection of MRD tests in search of more robust data, which could lead to more testing for patients.
“I have this tremendous fear that this is going to mean every myeloma protocol has a marrow biopsy every six weeks on the patients forever,” said Dr. Nieva of the Keck School of Medicine, University of Southern California, Los Angeles. “I just don’t want to see that happen. So I think we need to balance these two things.”
Antidiabetic Drugs That Lower Stroke Risk Do So By Unclear Mechanisms
DENVER —
In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”
In the past, several large randomized studies, such as the ACCORD trial, provided compelling evidence that tighter glycemic control does not translate into meaningful protection across stroke. Performed before many of the modern therapies were available, this lack of protection was observed with essentially “no heterogeneity across specific drugs,” according to Dr. Goldstein.
In long-term results from ACCORD, published in 2011, the odds ratio for a fatal or nonfatal stroke was a nonsignificant 0.97 in favor of tight glycemic control relative to standard control. The wide confidence intervals ruled out any hint of statistical significance (95% CI, 0.77-1.33; P = .85). Dr. Goldstein provided data from numerous other studies and meta-analyses that drew the same conclusion.
Stroke Prevention With Antidiabetic Drugs
“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.
“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.
The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.
Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).
In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
Weight Loss Is Potential Mechanism
Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.
“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.
Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.
The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
Newer Antidiabetic Agents Guideline Recommended
In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.
For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.
“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.
Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.
DENVER —
In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”
In the past, several large randomized studies, such as the ACCORD trial, provided compelling evidence that tighter glycemic control does not translate into meaningful protection across stroke. Performed before many of the modern therapies were available, this lack of protection was observed with essentially “no heterogeneity across specific drugs,” according to Dr. Goldstein.
In long-term results from ACCORD, published in 2011, the odds ratio for a fatal or nonfatal stroke was a nonsignificant 0.97 in favor of tight glycemic control relative to standard control. The wide confidence intervals ruled out any hint of statistical significance (95% CI, 0.77-1.33; P = .85). Dr. Goldstein provided data from numerous other studies and meta-analyses that drew the same conclusion.
Stroke Prevention With Antidiabetic Drugs
“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.
“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.
The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.
Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).
In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
Weight Loss Is Potential Mechanism
Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.
“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.
Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.
The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
Newer Antidiabetic Agents Guideline Recommended
In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.
For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.
“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.
Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.
DENVER —
In patients with type 2 diabetes mellitus (T2DM), the evidence is strong that “they are not working through glycemic control per se,” according to Larry B. Goldstein, MD, chair of neurology, University of Kentucky School of Medicine, Louisville. “But it is not yet clear what the mechanism of benefit is.”
In the past, several large randomized studies, such as the ACCORD trial, provided compelling evidence that tighter glycemic control does not translate into meaningful protection across stroke. Performed before many of the modern therapies were available, this lack of protection was observed with essentially “no heterogeneity across specific drugs,” according to Dr. Goldstein.
In long-term results from ACCORD, published in 2011, the odds ratio for a fatal or nonfatal stroke was a nonsignificant 0.97 in favor of tight glycemic control relative to standard control. The wide confidence intervals ruled out any hint of statistical significance (95% CI, 0.77-1.33; P = .85). Dr. Goldstein provided data from numerous other studies and meta-analyses that drew the same conclusion.
Stroke Prevention With Antidiabetic Drugs
“What has changed is that we have new ways of glycemic control, and some of these do show protection against stroke,” Dr. Goldstein said. Yet, the newer drugs do not do a better job at sustained reductions of HbA1c or other measures of reaching lower blood glucose reductions when adherence is similar.
“The level of glucose control with the newer agents is really about the same,” Dr. Goldstein said at the annual meeting of the American Academy of Neurology, where he led a symposium called Controversies in Stroke Treatment and Prevention.
The newer agents, such as sodium glucose co-transport-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA), have been associated with significant and clinically meaningful reductions in cardiovascular events. However, it is not clear that even these two medications perform similarly for stroke prevention specifically.
Of these two drug classes, Dr. Goldstein said the evidence most strongly supports GLP-1 receptor agonists. He cited one meta-analysis of eight randomized studies that calculated a risk reduction of about 15% whether calculated for fatal or nonfatal strokes. For each the protection was highly statistically significant (P = .0002 and P < .001, respectively).
In contrast, the effect of SGLT-2 inhibitors is weaker. In a study that distilled data from large cardiovascular trials with GLP-1RA, SGLT2i, dipeptidyl peptidase-4 inhibitors (DPP4i), and pioglitazone, a thiazolidinedione, only GLP-1RA drugs were associated with a highly significant (P < .001) reduction in risk of stroke. The risk reduction for pioglitazone reached significance (P = .025), but there was no signal of risk reduction for SGLT2i (P = .88) or for DPP4i (P = .5).
Weight Loss Is Potential Mechanism
Looking to explain the protection from stroke associated with some of the newer antidiabetic therapies, Gordon Kelley, MD, who leads the stroke program for AdventHealth Medical Group, Shawnee Mission, Kansas, suggested that weight loss is probably important.
“In our group, we work as a team to manage stroke risk in patients with diabetes, so I am not much involved in the choice of antidiabetic therapies, but it does seem that SGLT2 inhibitors and the GLP-1 receptor agonists share weight loss as an effect beyond glucose control,” he said.
Dr. Goldstein agreed that weight loss is a potential contributor to the cardiovascular benefits of GLP-1RA and SGLT2i, but he indicated that it might not help explain the reduction in stroke, an effect demonstrated repeatedly with GLP-1RA but inconsistently with SGLT2i.
The argument against weight loss as the critical mechanism of stroke prevention from newer antidiabetic drugs is strengthened by studies that suggest weight loss with SGLT2i appears to be even better than on GLP-1RA. In a study published in a pharmacy journal, weight loss was about twice as great among T2DM patients after 6 months of treatment managed with SGLT2i relative to those on a GLP-1RA (-2.8 vs 1.15 kg; P = .014).
Newer Antidiabetic Agents Guideline Recommended
In the 2019 American College of Cardiology/American Heart Association guidelines on the Primary Prevention of Cardiovascular Disease, stroke reduction is not discussed as an isolated risk, but these guidelines do recommend GLP-1RA or SGLT2i after metformin for glycemic control in T2DM patients with atherosclerotic cardiovascular disease (ASCVD) risk factors. This is based on evidence that drugs of both classes reduce risk for ASCVD events. The risk reduction has been particularly strong for heart failure.
For the risk of stroke specifically in patients with T2DM, Dr. Goldstein recommended calculating the ASCVD risk with the simple but well validated ACC risk calculator that is available online and is quickly completed when values for patient risk factors are readily available. For those with greater than 10% risk of an event in the next 10 years, he thinks GLP-1RA are a reasonable choice for prevention of stroke and other ASCVD events.
“GLP-1RA is mentioned in the guidelines, so this is supported,” said Dr. Goldstein, although adding that his choice of this class over SGLT2i is a personal if informed recommendation. He believes that the data favor GLP-1RA even if the exact mechanism of this protection is yet to be identified.
Dr. Goldstein and Dr. Kelley report no potential conflicts of interest.
FROM AAN 2024
Barcelona’s Best: Vasculitis Treatment Studies on Stopping Steroids, Abatacept, Plasma Exchange, Vaccination
Some of the best clinical trials of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) that were presented at the 21st International Vasculitis Workshop in Barcelona, Spain, included studies addressing relapse after stopping steroids, preventing relapse with abatacept, improving kidney function with plasma exchange, and vaccinating rituximab-treated patients.
Stopping Steroids After Remission in GPA
In the randomized, open-label TAPIR (The Assessment of Prednisone In Remission Trial) study of 159 adults with GPA in remission who had tapered to a prednisone dose of 5 mg/day, those who remained at that dosage had a significantly lower rate of relapse after 6 months than those who tapered to 0 mg/day (4.2% vs 15.5%; P = .227), according to results reported at the meeting.
However, use of a higher dose of prednisone for disease relapse by 6 months was similar for patients who used rituximab at baseline (8.8% with 0 mg/day vs 6.1% with 5 mg/day; P = .667), and the difference in this primary outcome was more pronounced among patients who did not take rituximab at baseline (20.0% with 0 mg/day vs 2.6% with 5 mg/day; P = .023).
A higher percentage of patients taking prednisone 0 mg/day had disease relapses that were considered minor (14.1% and 4.2%; P = .0391). Major relapses occurred in none of the patients taking 5 mg/day and in 1.4% receiving 0 mg/day. About 90% of patients in either treatment arm completed the trial.
The study, funded by the National Institute of Arthritis and Musculoskelatal and Skin Diseases and the National Heart Lung and Blood Institute, was unique in that half of patients randomized in the study were enrolled at community clinics and half were enrolled at Vasculitis Clinical Research Consortium clinical centers.
Abatacept Falls Short for Preventing Relapse in GPA
Adding abatacept to glucocorticoids failed to reduce risk of relapse, worsening disease, or failure to reach remission in adults with relapsing, nonsevere GPA, based on data from a randomized trial of 65 individuals.
In the 20-site, randomized, double-blind ABROGATE (Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis) study, 34 patients received 125 mg subcutaneous abatacept once a week or a placebo in addition to 30 mg/day of prednisone that was tapered and discontinued after 12 weeks. Patients who were receiving methotrexate, azathioprine, mycophenolate, or leflunomide at baseline continued the medication at a stable dose.
The primary outcome of disease worsening or relapse occurred in 62% of the abatacept group and 68% of the placebo group, and no significant difference in treatment failure rate appeared between the groups. In addition, key secondary endpoints of time to full remission, duration of glucocorticoid-free remission, relapse severity, prevention of damage, and patient-reported quality of life outcomes were not significantly different between the groups.
A total of 112 adverse events occurred, with similar type and severity between the groups, including incidence of infections.
The findings were limited by the relatively small sample size, but the results suggest a need for further research to determine mechanisms of disease and explore additional novel treatments for this rare patient population, the researchers wrote in their abstract.
The study was funded by the National Institutes of Health and Bristol-Myers Squibb.
Plasma Exchange Improves Kidney Function in AAV
Use of therapeutic plasma exchange (PLEX) as an adjunct treatment improved early kidney function in adults with AAV and glomerulonephritis but did not extend beyond 8 weeks, and recovery of kidney function was no different between patients receiving a regular glucocorticoid regimen versus a reduced course, based on a post-hoc analysis of 691 individuals in the international randomized controlled trial called PEXIVAS.
The primary outcomes of change in kidney function based on estimated glomerular filtration rate (eGFR) from baseline over 1 year and the percentage of patients with improvement in eGFR of at least 15 mL/min/1.73 m2 at weeks 12, 26, and 52.
The rate of improved eGFR was significantly greater in the PLEX group, compared with controls, at 2, 4, and 8 weeks. At 4 weeks, significantly more patients in the PLEX group had an increase in eGFR by at least 15 mL/min/1.73 m2, compared with the control group (relative risk [RR], 1.41; P = .008). In addition, improved kidney function within 4 weeks was significantly associated with lower risk of kidney failure within 1 year, regardless of treatment group.
The original PEXIVAS trial was supported by various government institutes and agencies from multiple countries.
Reinforced Vaccine Strategy with Rituximab Improved Antibody Response in AAV
A vaccine strategy consisting of a double dose of 13-valent antipneumococcal conjugate vaccine (PCV13) at day 0 and day 7 followed by a single dose of 23-valent unconjugated pneumococcal polysaccharide vaccine (PPV23) at 5 months significantly improved antibody responses against Streptococcus pneumoniae in patients with AAV, compared with standard treatment, based on data from 95 individuals in the multicenter, open-label study called PNEUMOVAS.
Adults with newly diagnosed AAV were randomly assigned to one of three treatment arms: a standard regimen of one dose of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 1); a double dose of PCV13 at day 0 and day 7 with a dose of PPV23 at month 5 (arm 2); or four doses of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 3). These patients received PCV13 within 2 days before or after their first infusion of rituximab.
The primary endpoint was positive antibody response against 12 pneumococcal subtypes common to the PCV13 and PCV23 vaccines at 6 months. At 6 months, the immune response to 0-3, 4-6, 7-9, or 10-12 serotypes was 83.3%, 13.3%, 3.3%, and 0%, respectively, in arm 1; 56.3%, 28.1%, 15.6%, and 0% in arm 2; and 60.6%, 33.3%, 6.1%, and 0% in arm 3.
No severe adverse events related to vaccination were observed in any of the groups; a total of eight AAV flares occurred in six patients (one in arm 1, two in arm 2, and three in arm 3). Local and systemic reactions occurred more frequently with the reinforced dose regimens, but these were mostly grade 1 or 2 local reactions.
The study was supported by the French Ministry of Health.
Some of the best clinical trials of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) that were presented at the 21st International Vasculitis Workshop in Barcelona, Spain, included studies addressing relapse after stopping steroids, preventing relapse with abatacept, improving kidney function with plasma exchange, and vaccinating rituximab-treated patients.
Stopping Steroids After Remission in GPA
In the randomized, open-label TAPIR (The Assessment of Prednisone In Remission Trial) study of 159 adults with GPA in remission who had tapered to a prednisone dose of 5 mg/day, those who remained at that dosage had a significantly lower rate of relapse after 6 months than those who tapered to 0 mg/day (4.2% vs 15.5%; P = .227), according to results reported at the meeting.
However, use of a higher dose of prednisone for disease relapse by 6 months was similar for patients who used rituximab at baseline (8.8% with 0 mg/day vs 6.1% with 5 mg/day; P = .667), and the difference in this primary outcome was more pronounced among patients who did not take rituximab at baseline (20.0% with 0 mg/day vs 2.6% with 5 mg/day; P = .023).
A higher percentage of patients taking prednisone 0 mg/day had disease relapses that were considered minor (14.1% and 4.2%; P = .0391). Major relapses occurred in none of the patients taking 5 mg/day and in 1.4% receiving 0 mg/day. About 90% of patients in either treatment arm completed the trial.
The study, funded by the National Institute of Arthritis and Musculoskelatal and Skin Diseases and the National Heart Lung and Blood Institute, was unique in that half of patients randomized in the study were enrolled at community clinics and half were enrolled at Vasculitis Clinical Research Consortium clinical centers.
Abatacept Falls Short for Preventing Relapse in GPA
Adding abatacept to glucocorticoids failed to reduce risk of relapse, worsening disease, or failure to reach remission in adults with relapsing, nonsevere GPA, based on data from a randomized trial of 65 individuals.
In the 20-site, randomized, double-blind ABROGATE (Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis) study, 34 patients received 125 mg subcutaneous abatacept once a week or a placebo in addition to 30 mg/day of prednisone that was tapered and discontinued after 12 weeks. Patients who were receiving methotrexate, azathioprine, mycophenolate, or leflunomide at baseline continued the medication at a stable dose.
The primary outcome of disease worsening or relapse occurred in 62% of the abatacept group and 68% of the placebo group, and no significant difference in treatment failure rate appeared between the groups. In addition, key secondary endpoints of time to full remission, duration of glucocorticoid-free remission, relapse severity, prevention of damage, and patient-reported quality of life outcomes were not significantly different between the groups.
A total of 112 adverse events occurred, with similar type and severity between the groups, including incidence of infections.
The findings were limited by the relatively small sample size, but the results suggest a need for further research to determine mechanisms of disease and explore additional novel treatments for this rare patient population, the researchers wrote in their abstract.
The study was funded by the National Institutes of Health and Bristol-Myers Squibb.
Plasma Exchange Improves Kidney Function in AAV
Use of therapeutic plasma exchange (PLEX) as an adjunct treatment improved early kidney function in adults with AAV and glomerulonephritis but did not extend beyond 8 weeks, and recovery of kidney function was no different between patients receiving a regular glucocorticoid regimen versus a reduced course, based on a post-hoc analysis of 691 individuals in the international randomized controlled trial called PEXIVAS.
The primary outcomes of change in kidney function based on estimated glomerular filtration rate (eGFR) from baseline over 1 year and the percentage of patients with improvement in eGFR of at least 15 mL/min/1.73 m2 at weeks 12, 26, and 52.
The rate of improved eGFR was significantly greater in the PLEX group, compared with controls, at 2, 4, and 8 weeks. At 4 weeks, significantly more patients in the PLEX group had an increase in eGFR by at least 15 mL/min/1.73 m2, compared with the control group (relative risk [RR], 1.41; P = .008). In addition, improved kidney function within 4 weeks was significantly associated with lower risk of kidney failure within 1 year, regardless of treatment group.
The original PEXIVAS trial was supported by various government institutes and agencies from multiple countries.
Reinforced Vaccine Strategy with Rituximab Improved Antibody Response in AAV
A vaccine strategy consisting of a double dose of 13-valent antipneumococcal conjugate vaccine (PCV13) at day 0 and day 7 followed by a single dose of 23-valent unconjugated pneumococcal polysaccharide vaccine (PPV23) at 5 months significantly improved antibody responses against Streptococcus pneumoniae in patients with AAV, compared with standard treatment, based on data from 95 individuals in the multicenter, open-label study called PNEUMOVAS.
Adults with newly diagnosed AAV were randomly assigned to one of three treatment arms: a standard regimen of one dose of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 1); a double dose of PCV13 at day 0 and day 7 with a dose of PPV23 at month 5 (arm 2); or four doses of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 3). These patients received PCV13 within 2 days before or after their first infusion of rituximab.
The primary endpoint was positive antibody response against 12 pneumococcal subtypes common to the PCV13 and PCV23 vaccines at 6 months. At 6 months, the immune response to 0-3, 4-6, 7-9, or 10-12 serotypes was 83.3%, 13.3%, 3.3%, and 0%, respectively, in arm 1; 56.3%, 28.1%, 15.6%, and 0% in arm 2; and 60.6%, 33.3%, 6.1%, and 0% in arm 3.
No severe adverse events related to vaccination were observed in any of the groups; a total of eight AAV flares occurred in six patients (one in arm 1, two in arm 2, and three in arm 3). Local and systemic reactions occurred more frequently with the reinforced dose regimens, but these were mostly grade 1 or 2 local reactions.
The study was supported by the French Ministry of Health.
Some of the best clinical trials of patients with antineutrophil cytoplasmic antibody–associated vasculitis (AAV) that were presented at the 21st International Vasculitis Workshop in Barcelona, Spain, included studies addressing relapse after stopping steroids, preventing relapse with abatacept, improving kidney function with plasma exchange, and vaccinating rituximab-treated patients.
Stopping Steroids After Remission in GPA
In the randomized, open-label TAPIR (The Assessment of Prednisone In Remission Trial) study of 159 adults with GPA in remission who had tapered to a prednisone dose of 5 mg/day, those who remained at that dosage had a significantly lower rate of relapse after 6 months than those who tapered to 0 mg/day (4.2% vs 15.5%; P = .227), according to results reported at the meeting.
However, use of a higher dose of prednisone for disease relapse by 6 months was similar for patients who used rituximab at baseline (8.8% with 0 mg/day vs 6.1% with 5 mg/day; P = .667), and the difference in this primary outcome was more pronounced among patients who did not take rituximab at baseline (20.0% with 0 mg/day vs 2.6% with 5 mg/day; P = .023).
A higher percentage of patients taking prednisone 0 mg/day had disease relapses that were considered minor (14.1% and 4.2%; P = .0391). Major relapses occurred in none of the patients taking 5 mg/day and in 1.4% receiving 0 mg/day. About 90% of patients in either treatment arm completed the trial.
The study, funded by the National Institute of Arthritis and Musculoskelatal and Skin Diseases and the National Heart Lung and Blood Institute, was unique in that half of patients randomized in the study were enrolled at community clinics and half were enrolled at Vasculitis Clinical Research Consortium clinical centers.
Abatacept Falls Short for Preventing Relapse in GPA
Adding abatacept to glucocorticoids failed to reduce risk of relapse, worsening disease, or failure to reach remission in adults with relapsing, nonsevere GPA, based on data from a randomized trial of 65 individuals.
In the 20-site, randomized, double-blind ABROGATE (Abatacept for the Treatment of Relapsing, Non-Severe, Granulomatosis With Polyangiitis) study, 34 patients received 125 mg subcutaneous abatacept once a week or a placebo in addition to 30 mg/day of prednisone that was tapered and discontinued after 12 weeks. Patients who were receiving methotrexate, azathioprine, mycophenolate, or leflunomide at baseline continued the medication at a stable dose.
The primary outcome of disease worsening or relapse occurred in 62% of the abatacept group and 68% of the placebo group, and no significant difference in treatment failure rate appeared between the groups. In addition, key secondary endpoints of time to full remission, duration of glucocorticoid-free remission, relapse severity, prevention of damage, and patient-reported quality of life outcomes were not significantly different between the groups.
A total of 112 adverse events occurred, with similar type and severity between the groups, including incidence of infections.
The findings were limited by the relatively small sample size, but the results suggest a need for further research to determine mechanisms of disease and explore additional novel treatments for this rare patient population, the researchers wrote in their abstract.
The study was funded by the National Institutes of Health and Bristol-Myers Squibb.
Plasma Exchange Improves Kidney Function in AAV
Use of therapeutic plasma exchange (PLEX) as an adjunct treatment improved early kidney function in adults with AAV and glomerulonephritis but did not extend beyond 8 weeks, and recovery of kidney function was no different between patients receiving a regular glucocorticoid regimen versus a reduced course, based on a post-hoc analysis of 691 individuals in the international randomized controlled trial called PEXIVAS.
The primary outcomes of change in kidney function based on estimated glomerular filtration rate (eGFR) from baseline over 1 year and the percentage of patients with improvement in eGFR of at least 15 mL/min/1.73 m2 at weeks 12, 26, and 52.
The rate of improved eGFR was significantly greater in the PLEX group, compared with controls, at 2, 4, and 8 weeks. At 4 weeks, significantly more patients in the PLEX group had an increase in eGFR by at least 15 mL/min/1.73 m2, compared with the control group (relative risk [RR], 1.41; P = .008). In addition, improved kidney function within 4 weeks was significantly associated with lower risk of kidney failure within 1 year, regardless of treatment group.
The original PEXIVAS trial was supported by various government institutes and agencies from multiple countries.
Reinforced Vaccine Strategy with Rituximab Improved Antibody Response in AAV
A vaccine strategy consisting of a double dose of 13-valent antipneumococcal conjugate vaccine (PCV13) at day 0 and day 7 followed by a single dose of 23-valent unconjugated pneumococcal polysaccharide vaccine (PPV23) at 5 months significantly improved antibody responses against Streptococcus pneumoniae in patients with AAV, compared with standard treatment, based on data from 95 individuals in the multicenter, open-label study called PNEUMOVAS.
Adults with newly diagnosed AAV were randomly assigned to one of three treatment arms: a standard regimen of one dose of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 1); a double dose of PCV13 at day 0 and day 7 with a dose of PPV23 at month 5 (arm 2); or four doses of PCV13 at day 0 and one dose of PPV23 at month 5 (arm 3). These patients received PCV13 within 2 days before or after their first infusion of rituximab.
The primary endpoint was positive antibody response against 12 pneumococcal subtypes common to the PCV13 and PCV23 vaccines at 6 months. At 6 months, the immune response to 0-3, 4-6, 7-9, or 10-12 serotypes was 83.3%, 13.3%, 3.3%, and 0%, respectively, in arm 1; 56.3%, 28.1%, 15.6%, and 0% in arm 2; and 60.6%, 33.3%, 6.1%, and 0% in arm 3.
No severe adverse events related to vaccination were observed in any of the groups; a total of eight AAV flares occurred in six patients (one in arm 1, two in arm 2, and three in arm 3). Local and systemic reactions occurred more frequently with the reinforced dose regimens, but these were mostly grade 1 or 2 local reactions.
The study was supported by the French Ministry of Health.
How Medicare Reimbursement Trends Could Affect Breast Surgeries
These were findings of new research presented by Terry P. Gao, MD, at the American Society of Breast Surgeons annual meeting.
Medicare reimbursements often set a benchmark that is followed by private insurers, and the impact of changes on various breast surgeries have not been examined, Dr. Gao, a research resident at Temple University Hospital, Philadelphia, said during a press briefing in advance of the meeting.
“This study is important because it is the first to analyze trends in Medicare reimbursement for breast cancer surgery over a long period,” Dr. Gao said during an interview. The findings highlight a critical issue that could impact access to quality care, especially for vulnerable populations, she said.
How Were the Data Analyzed?
Dr. Gao and colleagues reviewed percent changes in reimbursement procedures over a 20-year period and compared them to changes in the consumer price index (CPI) to show the real-life impact of inflation.
The study examined reimbursements based on the Medicare Physician Fee Schedule Look-Up Tool from 2003 to 2023 for 10 procedures. The procedures were core needle biopsy, open incisional breast biopsy, open excisional breast biopsy, lumpectomy, lumpectomy with axillary lymph node dissection (ALND), simple mastectomy, radical mastectomy, modified radical mastectomy, biopsy/removal of lymph nodes, and sentinel lymph node biopsy.
What Does the New Study Show?
“Reimbursements did not keep pace with the price of goods and services,” Dr. Gao said during the press briefing.
After the researchers corrected data for inflation, the overall mean Medicare reimbursement for breast cancer surgeries decreased by approximately 21%, based in part on the 69% increase in the CPI over the study period, Dr. Gao said. The greatest change was in core needle biopsy, for which reimbursement decreased by 36%.
After inflation adjustment, reimbursement increases were seen for only two procedures, lumpectomy and simple mastectomy, of 0.37% and 3.58%, respectively, but these do not represent meaningful gains, Dr. Gao said.
The researchers also used a model to estimate the real-life impact of decreased reimbursement on clinicians. They subtracted the actual 2023 compensation from expected 2023 compensation based on inflation for a breast cancer case incidence of 297,790 patients who underwent axillary surgery, breast lumpectomy, or simple mastectomy. The calculated potential real-world compensation loss for that year was $107,604,444.
What are the Clinical Implications?
The current study is the first to put specific numbers on the trend in declining breast cancer payments, and the findings should encourage physicians to advocate for equitable policies, Dr. Gao noted during the briefing.
The substantial decrease in inflation-adjusted reimbursement rates was significant, she said during the interview. Although the decrease reflects similar trends seen in other specialties, the magnitude is a potential cause for concern, she said.
Declining reimbursements could disproportionately hurt safety-net hospitals serving vulnerable populations by limiting their ability to invest in better care and potentially worsening existing racial disparities, Dr. Gao told this publication. “Additionally, surgeons may opt out of Medicare networks due to low rates, leading to access issues and longer wait times. Finally, these trends could discourage future generations from specializing in breast cancer surgery.”
The study findings should be considered in the context of the complex and rapidly changing clinical landscape in which breast cancer care is evolving, Mediget Teshome, MD, chief of breast surgery at UCLA Health, said during an interview.
“Surgery remains a critically important aspect to curative treatment,” Dr. Teshome said.
Surgical decision-making tailored to each patient’s goals involves coordination from a multidisciplinary team as well as skill and attention from surgeons, she added.
“This degree of specialization and nuance is not always captured in reimbursement models for breast surgery,” Dr. Teshome emphasized. The policy implications of any changes in Medicare reimbursement will be important given the American Cancer Society reports breast cancer as the most commonly diagnosed cancer in women in the United States, and as the second leading cause of cancer death in US women, she noted.
What Additional Research Is Needed?
Research is needed to understand how declining reimbursements affect patients’ access to care, treatment choices, and long-term outcomes, Dr. Gao said in the interview. Future studies also are needed to examine provider overhead costs, staffing structures, and profit margins to offer a more comprehensive understanding of financial sustainability.
Dr. Gao and Dr. Teshome had no financial conflicts to disclose.
These were findings of new research presented by Terry P. Gao, MD, at the American Society of Breast Surgeons annual meeting.
Medicare reimbursements often set a benchmark that is followed by private insurers, and the impact of changes on various breast surgeries have not been examined, Dr. Gao, a research resident at Temple University Hospital, Philadelphia, said during a press briefing in advance of the meeting.
“This study is important because it is the first to analyze trends in Medicare reimbursement for breast cancer surgery over a long period,” Dr. Gao said during an interview. The findings highlight a critical issue that could impact access to quality care, especially for vulnerable populations, she said.
How Were the Data Analyzed?
Dr. Gao and colleagues reviewed percent changes in reimbursement procedures over a 20-year period and compared them to changes in the consumer price index (CPI) to show the real-life impact of inflation.
The study examined reimbursements based on the Medicare Physician Fee Schedule Look-Up Tool from 2003 to 2023 for 10 procedures. The procedures were core needle biopsy, open incisional breast biopsy, open excisional breast biopsy, lumpectomy, lumpectomy with axillary lymph node dissection (ALND), simple mastectomy, radical mastectomy, modified radical mastectomy, biopsy/removal of lymph nodes, and sentinel lymph node biopsy.
What Does the New Study Show?
“Reimbursements did not keep pace with the price of goods and services,” Dr. Gao said during the press briefing.
After the researchers corrected data for inflation, the overall mean Medicare reimbursement for breast cancer surgeries decreased by approximately 21%, based in part on the 69% increase in the CPI over the study period, Dr. Gao said. The greatest change was in core needle biopsy, for which reimbursement decreased by 36%.
After inflation adjustment, reimbursement increases were seen for only two procedures, lumpectomy and simple mastectomy, of 0.37% and 3.58%, respectively, but these do not represent meaningful gains, Dr. Gao said.
The researchers also used a model to estimate the real-life impact of decreased reimbursement on clinicians. They subtracted the actual 2023 compensation from expected 2023 compensation based on inflation for a breast cancer case incidence of 297,790 patients who underwent axillary surgery, breast lumpectomy, or simple mastectomy. The calculated potential real-world compensation loss for that year was $107,604,444.
What are the Clinical Implications?
The current study is the first to put specific numbers on the trend in declining breast cancer payments, and the findings should encourage physicians to advocate for equitable policies, Dr. Gao noted during the briefing.
The substantial decrease in inflation-adjusted reimbursement rates was significant, she said during the interview. Although the decrease reflects similar trends seen in other specialties, the magnitude is a potential cause for concern, she said.
Declining reimbursements could disproportionately hurt safety-net hospitals serving vulnerable populations by limiting their ability to invest in better care and potentially worsening existing racial disparities, Dr. Gao told this publication. “Additionally, surgeons may opt out of Medicare networks due to low rates, leading to access issues and longer wait times. Finally, these trends could discourage future generations from specializing in breast cancer surgery.”
The study findings should be considered in the context of the complex and rapidly changing clinical landscape in which breast cancer care is evolving, Mediget Teshome, MD, chief of breast surgery at UCLA Health, said during an interview.
“Surgery remains a critically important aspect to curative treatment,” Dr. Teshome said.
Surgical decision-making tailored to each patient’s goals involves coordination from a multidisciplinary team as well as skill and attention from surgeons, she added.
“This degree of specialization and nuance is not always captured in reimbursement models for breast surgery,” Dr. Teshome emphasized. The policy implications of any changes in Medicare reimbursement will be important given the American Cancer Society reports breast cancer as the most commonly diagnosed cancer in women in the United States, and as the second leading cause of cancer death in US women, she noted.
What Additional Research Is Needed?
Research is needed to understand how declining reimbursements affect patients’ access to care, treatment choices, and long-term outcomes, Dr. Gao said in the interview. Future studies also are needed to examine provider overhead costs, staffing structures, and profit margins to offer a more comprehensive understanding of financial sustainability.
Dr. Gao and Dr. Teshome had no financial conflicts to disclose.
These were findings of new research presented by Terry P. Gao, MD, at the American Society of Breast Surgeons annual meeting.
Medicare reimbursements often set a benchmark that is followed by private insurers, and the impact of changes on various breast surgeries have not been examined, Dr. Gao, a research resident at Temple University Hospital, Philadelphia, said during a press briefing in advance of the meeting.
“This study is important because it is the first to analyze trends in Medicare reimbursement for breast cancer surgery over a long period,” Dr. Gao said during an interview. The findings highlight a critical issue that could impact access to quality care, especially for vulnerable populations, she said.
How Were the Data Analyzed?
Dr. Gao and colleagues reviewed percent changes in reimbursement procedures over a 20-year period and compared them to changes in the consumer price index (CPI) to show the real-life impact of inflation.
The study examined reimbursements based on the Medicare Physician Fee Schedule Look-Up Tool from 2003 to 2023 for 10 procedures. The procedures were core needle biopsy, open incisional breast biopsy, open excisional breast biopsy, lumpectomy, lumpectomy with axillary lymph node dissection (ALND), simple mastectomy, radical mastectomy, modified radical mastectomy, biopsy/removal of lymph nodes, and sentinel lymph node biopsy.
What Does the New Study Show?
“Reimbursements did not keep pace with the price of goods and services,” Dr. Gao said during the press briefing.
After the researchers corrected data for inflation, the overall mean Medicare reimbursement for breast cancer surgeries decreased by approximately 21%, based in part on the 69% increase in the CPI over the study period, Dr. Gao said. The greatest change was in core needle biopsy, for which reimbursement decreased by 36%.
After inflation adjustment, reimbursement increases were seen for only two procedures, lumpectomy and simple mastectomy, of 0.37% and 3.58%, respectively, but these do not represent meaningful gains, Dr. Gao said.
The researchers also used a model to estimate the real-life impact of decreased reimbursement on clinicians. They subtracted the actual 2023 compensation from expected 2023 compensation based on inflation for a breast cancer case incidence of 297,790 patients who underwent axillary surgery, breast lumpectomy, or simple mastectomy. The calculated potential real-world compensation loss for that year was $107,604,444.
What are the Clinical Implications?
The current study is the first to put specific numbers on the trend in declining breast cancer payments, and the findings should encourage physicians to advocate for equitable policies, Dr. Gao noted during the briefing.
The substantial decrease in inflation-adjusted reimbursement rates was significant, she said during the interview. Although the decrease reflects similar trends seen in other specialties, the magnitude is a potential cause for concern, she said.
Declining reimbursements could disproportionately hurt safety-net hospitals serving vulnerable populations by limiting their ability to invest in better care and potentially worsening existing racial disparities, Dr. Gao told this publication. “Additionally, surgeons may opt out of Medicare networks due to low rates, leading to access issues and longer wait times. Finally, these trends could discourage future generations from specializing in breast cancer surgery.”
The study findings should be considered in the context of the complex and rapidly changing clinical landscape in which breast cancer care is evolving, Mediget Teshome, MD, chief of breast surgery at UCLA Health, said during an interview.
“Surgery remains a critically important aspect to curative treatment,” Dr. Teshome said.
Surgical decision-making tailored to each patient’s goals involves coordination from a multidisciplinary team as well as skill and attention from surgeons, she added.
“This degree of specialization and nuance is not always captured in reimbursement models for breast surgery,” Dr. Teshome emphasized. The policy implications of any changes in Medicare reimbursement will be important given the American Cancer Society reports breast cancer as the most commonly diagnosed cancer in women in the United States, and as the second leading cause of cancer death in US women, she noted.
What Additional Research Is Needed?
Research is needed to understand how declining reimbursements affect patients’ access to care, treatment choices, and long-term outcomes, Dr. Gao said in the interview. Future studies also are needed to examine provider overhead costs, staffing structures, and profit margins to offer a more comprehensive understanding of financial sustainability.
Dr. Gao and Dr. Teshome had no financial conflicts to disclose.
FROM THE AMERICAN SOCIETY OF BREAST SURGEONS ANNUAL MEETING
Mandibular Device Comparable to CPAP to Reduce BP in Hypertension, OSA
Use of a mandibular advancement device (MAD) proved non-inferior to guideline-recommended continuous positive airway pressure (CPAP) to reduce blood pressure in patients with hypertension and obstructive sleep apnea (OSA), in a randomized trial.
“These findings suggest that MAD could be considered an alternative to CPAP for optimizing blood pressure control in OSA patients with hypertension and high cardiovascular risk,” the researchers conclude.
“Looking at the totality of evidence available in the literature, it is still reasonable to say that CPAP is the first-line treatment until we have more data on the MAD,” said Ronald Lee Chi-Hang, MD, professor of medicine at Yong Loo Lin School of Medicine, National University of Singapore, who presented the results.
“However, for patients who truly cannot tolerate or accept using a CPAP, we should be more open-minded in looking for an alternative therapy such as a MAD, which based on our study, numerically had a better blood pressure reduction in patients compared with a CPAP,” said Dr. Chi-Hang, who is also a senior consultant in the Department of Cardiology at Singapore’s National University Heart Centre.
The results were presented April 6 at the American College of Cardiology Scientific Sessions 2024 and published online simultaneously in the Journal of the American College of Cardiology
Oral Appliance
OSA is increasingly recognized as “an underdiagnosed and modifiable cause of hypertension,” the researchers note in their report. “Patients with OSA develop recurrent collapse of the upper airway during sleep, resulting in hypoxemia, sympathetic hyperactivity, and BP surges.”
Current guidelines recommend screening and treatment of OSA in patients with hypertension, and CPAP is considered first-line therapy, they note.
“Despite being effective, unfortunately, many patients decline to use a CPAP or find it challenging to stick to the therapy,” Dr. Chi-Hang said, particularly those without daytime sleepiness.
MADs are oral appliances that work by advancing the mandible about 5 to 10 mm during sleep, he said. They provide an alternative to OSA patients and have been shown to improve daytime sleepiness and quality of life, “and in general, is better accepted and tolerated than CPAP.”
However, early studies are small, with short follow up, included patients with and without hypertension, and didn’t specify BP reduction as the primary outcome.
The CRESCENT trial was an investigator-initiated, randomized, non-inferiority trial that aimed to compare the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure in patients with moderate-to-severe OSA, hypertension and high cardiovascular risk. The prespecified margin for non-inferiority was 1.5 mm Hg.
A total of 321 participants were recruited at three public hospitals for polysomnography. All were older than age 40 years, had hypertension, and were at increased cardiovascular risk. Of these, 220 with moderate-to-severe OSA, defined as an apnea–hypopnea index (AHI) of ≥ 15 events/hour, were randomly assigned to either MAD or CPAP treatment.
The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. The median age was 61 years, most patients (85.5%) were male, and all were Chinese. All had essential hypertension and were on one or more antihypertensive medications. Hypertension was relatively well controlled at baseline.
At 6 months, 24-hour mean arterial BP decreased by 2.5 mm Hg in the MAD group (P = .003) compared to no change from baseline in the CPAP group (P = .374).
The between-group difference was -1.6 mm Hg (95% CI, -3.51 to 0.24, non-inferiority P < .001).
There was a larger between-group reduction in all secondary ambulatory BP parameters in the MAD versus the CPAP group, with the most pronounced effects seen in the asleep BP parameters.
Both the MAD and CPAP significantly improved daytime sleepiness, with no between-group differences (P =.384). There were no between-group differences in cardiovascular biomarkers.
During the presentation, panel discussant Julie B. Damp, MD, associate professor of medicine at Vanderbilt Health in Nashville, Tennessee, called CRESCENT “a really interesting study, and I think it has a lot of information to add [regarding] what we know about this comparison in the literature, because this is a big study and it also followed these patients for longer than we’ve seen in some of the previous studies.”
Dr. Damp asked, however, about how these results might be extrapolated to other populations, since the vast majority of participants were male.
Dr. Chi-Hang pointed out that most OSA studies include mostly male patients, but noted that particularly in Asian culture, female patients may be more conservative in seeking treatment for problems with snoring, poor quality of sleep, or extensive daytime sleepiness. “Therefore, lots of times, even in clinical practice, we see that over 80 or 90% of patients are male patients,” he said.
Dr. Damp followed up by asking about the differential effectiveness of CPAP vs MAD. “Just in thinking about these two therapies, there is some evidence that the mandibular devices are potentially less effective on some of the sleep apnea-specific measures, so how much of this do you think is an issue of a better vs a not better treatment as opposed to an issue truly of compliance and what patients are able to tolerate?”
Dr. Chi-Hang agreed that in terms of reducing the AHI, CPAP is more effective than MAD. “In fact, in our data, the residual AHI was 10 for the MAD group and 2 for the CPAP group. Clearly, CPAP is more effective,” he said. “But the problem we are facing in this area is the value of AHI as an index is being questioned.”
AHI considers only the number of events, without taking into account the duration or the depth of the apnea, he said. “AHI is simply not an ideal index to document the disease severity,” or the impact on cardiovascular outcomes.
A Tailored Approach
In an editorial accompanying the JACC publication, Michele Emdin, MD, PhD, Francesco Gentile, MD, and Alberto Giannoni, MD, PhD, all from the Health Science Interdisciplinary Center, Scuola Superiore Sant’ Anna, and Fondazione Toscana Gabriele Monasterio, in Pisa, Italy, commend the researchers for designing and conducting “such a pragmatic and informative trial, which confirms and extends previous findings.”
They also discuss the compliance vs effectiveness issue, pointing out that although CPAP appeared to be more effective in reducing apnea burden, there was higher adherence to MAD — with 57% using the device 6 or more hours per night, vs 23% for CPAP — which might have offset the greater reduction in apnea burden and resulted in the reduction in blood pressure seen in the trial.
“Addressing poor adherence to OSA treatments seems therefore necessary, particularly in the case of less symptomatic patients, who often have a lower perception of the related risks,” they write.
“Currently, a tailored approach seems reasonable, based on updated evidence, considering: a) the differential effects of CPAP or MAD on OSA, blood pressure; b) the treatment feasibility; c) the individual baseline demographic and clinical characteristics, including the presence of resistant hypertension; and d) compliance with the therapeutic tool and patient’s preferences,” the editorialists conclude.
The study was funded by the Singapore Ministry of Health. The authors and editorialists report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Use of a mandibular advancement device (MAD) proved non-inferior to guideline-recommended continuous positive airway pressure (CPAP) to reduce blood pressure in patients with hypertension and obstructive sleep apnea (OSA), in a randomized trial.
“These findings suggest that MAD could be considered an alternative to CPAP for optimizing blood pressure control in OSA patients with hypertension and high cardiovascular risk,” the researchers conclude.
“Looking at the totality of evidence available in the literature, it is still reasonable to say that CPAP is the first-line treatment until we have more data on the MAD,” said Ronald Lee Chi-Hang, MD, professor of medicine at Yong Loo Lin School of Medicine, National University of Singapore, who presented the results.
“However, for patients who truly cannot tolerate or accept using a CPAP, we should be more open-minded in looking for an alternative therapy such as a MAD, which based on our study, numerically had a better blood pressure reduction in patients compared with a CPAP,” said Dr. Chi-Hang, who is also a senior consultant in the Department of Cardiology at Singapore’s National University Heart Centre.
The results were presented April 6 at the American College of Cardiology Scientific Sessions 2024 and published online simultaneously in the Journal of the American College of Cardiology
Oral Appliance
OSA is increasingly recognized as “an underdiagnosed and modifiable cause of hypertension,” the researchers note in their report. “Patients with OSA develop recurrent collapse of the upper airway during sleep, resulting in hypoxemia, sympathetic hyperactivity, and BP surges.”
Current guidelines recommend screening and treatment of OSA in patients with hypertension, and CPAP is considered first-line therapy, they note.
“Despite being effective, unfortunately, many patients decline to use a CPAP or find it challenging to stick to the therapy,” Dr. Chi-Hang said, particularly those without daytime sleepiness.
MADs are oral appliances that work by advancing the mandible about 5 to 10 mm during sleep, he said. They provide an alternative to OSA patients and have been shown to improve daytime sleepiness and quality of life, “and in general, is better accepted and tolerated than CPAP.”
However, early studies are small, with short follow up, included patients with and without hypertension, and didn’t specify BP reduction as the primary outcome.
The CRESCENT trial was an investigator-initiated, randomized, non-inferiority trial that aimed to compare the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure in patients with moderate-to-severe OSA, hypertension and high cardiovascular risk. The prespecified margin for non-inferiority was 1.5 mm Hg.
A total of 321 participants were recruited at three public hospitals for polysomnography. All were older than age 40 years, had hypertension, and were at increased cardiovascular risk. Of these, 220 with moderate-to-severe OSA, defined as an apnea–hypopnea index (AHI) of ≥ 15 events/hour, were randomly assigned to either MAD or CPAP treatment.
The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. The median age was 61 years, most patients (85.5%) were male, and all were Chinese. All had essential hypertension and were on one or more antihypertensive medications. Hypertension was relatively well controlled at baseline.
At 6 months, 24-hour mean arterial BP decreased by 2.5 mm Hg in the MAD group (P = .003) compared to no change from baseline in the CPAP group (P = .374).
The between-group difference was -1.6 mm Hg (95% CI, -3.51 to 0.24, non-inferiority P < .001).
There was a larger between-group reduction in all secondary ambulatory BP parameters in the MAD versus the CPAP group, with the most pronounced effects seen in the asleep BP parameters.
Both the MAD and CPAP significantly improved daytime sleepiness, with no between-group differences (P =.384). There were no between-group differences in cardiovascular biomarkers.
During the presentation, panel discussant Julie B. Damp, MD, associate professor of medicine at Vanderbilt Health in Nashville, Tennessee, called CRESCENT “a really interesting study, and I think it has a lot of information to add [regarding] what we know about this comparison in the literature, because this is a big study and it also followed these patients for longer than we’ve seen in some of the previous studies.”
Dr. Damp asked, however, about how these results might be extrapolated to other populations, since the vast majority of participants were male.
Dr. Chi-Hang pointed out that most OSA studies include mostly male patients, but noted that particularly in Asian culture, female patients may be more conservative in seeking treatment for problems with snoring, poor quality of sleep, or extensive daytime sleepiness. “Therefore, lots of times, even in clinical practice, we see that over 80 or 90% of patients are male patients,” he said.
Dr. Damp followed up by asking about the differential effectiveness of CPAP vs MAD. “Just in thinking about these two therapies, there is some evidence that the mandibular devices are potentially less effective on some of the sleep apnea-specific measures, so how much of this do you think is an issue of a better vs a not better treatment as opposed to an issue truly of compliance and what patients are able to tolerate?”
Dr. Chi-Hang agreed that in terms of reducing the AHI, CPAP is more effective than MAD. “In fact, in our data, the residual AHI was 10 for the MAD group and 2 for the CPAP group. Clearly, CPAP is more effective,” he said. “But the problem we are facing in this area is the value of AHI as an index is being questioned.”
AHI considers only the number of events, without taking into account the duration or the depth of the apnea, he said. “AHI is simply not an ideal index to document the disease severity,” or the impact on cardiovascular outcomes.
A Tailored Approach
In an editorial accompanying the JACC publication, Michele Emdin, MD, PhD, Francesco Gentile, MD, and Alberto Giannoni, MD, PhD, all from the Health Science Interdisciplinary Center, Scuola Superiore Sant’ Anna, and Fondazione Toscana Gabriele Monasterio, in Pisa, Italy, commend the researchers for designing and conducting “such a pragmatic and informative trial, which confirms and extends previous findings.”
They also discuss the compliance vs effectiveness issue, pointing out that although CPAP appeared to be more effective in reducing apnea burden, there was higher adherence to MAD — with 57% using the device 6 or more hours per night, vs 23% for CPAP — which might have offset the greater reduction in apnea burden and resulted in the reduction in blood pressure seen in the trial.
“Addressing poor adherence to OSA treatments seems therefore necessary, particularly in the case of less symptomatic patients, who often have a lower perception of the related risks,” they write.
“Currently, a tailored approach seems reasonable, based on updated evidence, considering: a) the differential effects of CPAP or MAD on OSA, blood pressure; b) the treatment feasibility; c) the individual baseline demographic and clinical characteristics, including the presence of resistant hypertension; and d) compliance with the therapeutic tool and patient’s preferences,” the editorialists conclude.
The study was funded by the Singapore Ministry of Health. The authors and editorialists report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Use of a mandibular advancement device (MAD) proved non-inferior to guideline-recommended continuous positive airway pressure (CPAP) to reduce blood pressure in patients with hypertension and obstructive sleep apnea (OSA), in a randomized trial.
“These findings suggest that MAD could be considered an alternative to CPAP for optimizing blood pressure control in OSA patients with hypertension and high cardiovascular risk,” the researchers conclude.
“Looking at the totality of evidence available in the literature, it is still reasonable to say that CPAP is the first-line treatment until we have more data on the MAD,” said Ronald Lee Chi-Hang, MD, professor of medicine at Yong Loo Lin School of Medicine, National University of Singapore, who presented the results.
“However, for patients who truly cannot tolerate or accept using a CPAP, we should be more open-minded in looking for an alternative therapy such as a MAD, which based on our study, numerically had a better blood pressure reduction in patients compared with a CPAP,” said Dr. Chi-Hang, who is also a senior consultant in the Department of Cardiology at Singapore’s National University Heart Centre.
The results were presented April 6 at the American College of Cardiology Scientific Sessions 2024 and published online simultaneously in the Journal of the American College of Cardiology
Oral Appliance
OSA is increasingly recognized as “an underdiagnosed and modifiable cause of hypertension,” the researchers note in their report. “Patients with OSA develop recurrent collapse of the upper airway during sleep, resulting in hypoxemia, sympathetic hyperactivity, and BP surges.”
Current guidelines recommend screening and treatment of OSA in patients with hypertension, and CPAP is considered first-line therapy, they note.
“Despite being effective, unfortunately, many patients decline to use a CPAP or find it challenging to stick to the therapy,” Dr. Chi-Hang said, particularly those without daytime sleepiness.
MADs are oral appliances that work by advancing the mandible about 5 to 10 mm during sleep, he said. They provide an alternative to OSA patients and have been shown to improve daytime sleepiness and quality of life, “and in general, is better accepted and tolerated than CPAP.”
However, early studies are small, with short follow up, included patients with and without hypertension, and didn’t specify BP reduction as the primary outcome.
The CRESCENT trial was an investigator-initiated, randomized, non-inferiority trial that aimed to compare the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure in patients with moderate-to-severe OSA, hypertension and high cardiovascular risk. The prespecified margin for non-inferiority was 1.5 mm Hg.
A total of 321 participants were recruited at three public hospitals for polysomnography. All were older than age 40 years, had hypertension, and were at increased cardiovascular risk. Of these, 220 with moderate-to-severe OSA, defined as an apnea–hypopnea index (AHI) of ≥ 15 events/hour, were randomly assigned to either MAD or CPAP treatment.
The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. The median age was 61 years, most patients (85.5%) were male, and all were Chinese. All had essential hypertension and were on one or more antihypertensive medications. Hypertension was relatively well controlled at baseline.
At 6 months, 24-hour mean arterial BP decreased by 2.5 mm Hg in the MAD group (P = .003) compared to no change from baseline in the CPAP group (P = .374).
The between-group difference was -1.6 mm Hg (95% CI, -3.51 to 0.24, non-inferiority P < .001).
There was a larger between-group reduction in all secondary ambulatory BP parameters in the MAD versus the CPAP group, with the most pronounced effects seen in the asleep BP parameters.
Both the MAD and CPAP significantly improved daytime sleepiness, with no between-group differences (P =.384). There were no between-group differences in cardiovascular biomarkers.
During the presentation, panel discussant Julie B. Damp, MD, associate professor of medicine at Vanderbilt Health in Nashville, Tennessee, called CRESCENT “a really interesting study, and I think it has a lot of information to add [regarding] what we know about this comparison in the literature, because this is a big study and it also followed these patients for longer than we’ve seen in some of the previous studies.”
Dr. Damp asked, however, about how these results might be extrapolated to other populations, since the vast majority of participants were male.
Dr. Chi-Hang pointed out that most OSA studies include mostly male patients, but noted that particularly in Asian culture, female patients may be more conservative in seeking treatment for problems with snoring, poor quality of sleep, or extensive daytime sleepiness. “Therefore, lots of times, even in clinical practice, we see that over 80 or 90% of patients are male patients,” he said.
Dr. Damp followed up by asking about the differential effectiveness of CPAP vs MAD. “Just in thinking about these two therapies, there is some evidence that the mandibular devices are potentially less effective on some of the sleep apnea-specific measures, so how much of this do you think is an issue of a better vs a not better treatment as opposed to an issue truly of compliance and what patients are able to tolerate?”
Dr. Chi-Hang agreed that in terms of reducing the AHI, CPAP is more effective than MAD. “In fact, in our data, the residual AHI was 10 for the MAD group and 2 for the CPAP group. Clearly, CPAP is more effective,” he said. “But the problem we are facing in this area is the value of AHI as an index is being questioned.”
AHI considers only the number of events, without taking into account the duration or the depth of the apnea, he said. “AHI is simply not an ideal index to document the disease severity,” or the impact on cardiovascular outcomes.
A Tailored Approach
In an editorial accompanying the JACC publication, Michele Emdin, MD, PhD, Francesco Gentile, MD, and Alberto Giannoni, MD, PhD, all from the Health Science Interdisciplinary Center, Scuola Superiore Sant’ Anna, and Fondazione Toscana Gabriele Monasterio, in Pisa, Italy, commend the researchers for designing and conducting “such a pragmatic and informative trial, which confirms and extends previous findings.”
They also discuss the compliance vs effectiveness issue, pointing out that although CPAP appeared to be more effective in reducing apnea burden, there was higher adherence to MAD — with 57% using the device 6 or more hours per night, vs 23% for CPAP — which might have offset the greater reduction in apnea burden and resulted in the reduction in blood pressure seen in the trial.
“Addressing poor adherence to OSA treatments seems therefore necessary, particularly in the case of less symptomatic patients, who often have a lower perception of the related risks,” they write.
“Currently, a tailored approach seems reasonable, based on updated evidence, considering: a) the differential effects of CPAP or MAD on OSA, blood pressure; b) the treatment feasibility; c) the individual baseline demographic and clinical characteristics, including the presence of resistant hypertension; and d) compliance with the therapeutic tool and patient’s preferences,” the editorialists conclude.
The study was funded by the Singapore Ministry of Health. The authors and editorialists report no relevant financial relationships.
A version of this article appeared on Medscape.com.
Salt Substitutes May Cut All-Cause And Cardiovascular Mortality
Large-scale salt substitution holds promise for reducing mortality with no elevated risk of serious harms, especially for older people at increased cardiovascular disease (CVD) risk, a systematic review and meta-analysis by Australian researchers suggested.
The study, published in Annals of Internal Medicine, adds more evidence that broad adoption of potassium-rich salt substitutes for food preparation could have a significant effect on population health.
Although the supporting evidence was of low certainty, the analysis of 16 international randomized controlled trials of various interventions with 35,321 participants found salt substitution to be associated with an absolute reduction of 5 in 1000 in all-cause mortality (confidence interval, –3 to –7) and 3 in 1000 in CVD mortality (CI, –1 to –5).
Led by Hannah Greenwood, BPsychSc, a cardiovascular researcher at the Institute for Evidence-Based Healthcare at Bond University in Gold Coast, Queensland, the investigators also found very low certainty evidence of an absolute reduction of 8 in 1000 in major adverse cardiovascular events (CI, 0 to –15), with a 1 in 1000 decrease in more serious adverse events (CI, 4 to –2) in the same population.
Seven of the 16 studies were conducted in China and Taiwan and seven were conducted in populations of older age (mean age 62 years) and/or at higher cardiovascular risk.
With most of the data deriving from populations of older age at higher-than-average CV risk and/or eating an Asian diet, the findings’ generalizability to populations following a Western diet and/or at average CVD risk is limited, the researchers acknowledged.
“We are less certain about the effects in Western, younger, and healthy population groups,” corresponding author Loai Albarqouni, MD, MSc, PhD, assistant professor at the Institute for Evidence-Based Healthcare, said in an interview. “While we saw small, clinically meaningful reductions in cardiovascular deaths and events, effectiveness should be better established before salt substitutes are recommended more broadly, though they are promising.”
In addition, he said, since the longest follow-up of substitute use was 10 years, “we can’t speak to benefits or harms beyond this time frame.”
Still, recommending salt substitutes may be an effective way for physicians to help patients reduce CVD risk, especially those hesitant to start medication, he said. “But physicians should take into account individual circumstances and other factors like kidney disease before recommending salt substitutes. Other non-drug methods of reducing cardiovascular risk, such as diet or exercise, may also be considered.”
Dr. Albarqouni stressed that sodium intake is not the only driver of CVD and reducing intake is just one piece of the puzzle. He cautioned that substitutes themselves can contain high levels of sodium, “so if people are using them in large volumes, they may still present similar risks to the sodium in regular salt.”
While the substitutes appear safe as evidenced by low incidence of hyperkalemia or renal dysfunction, the evidence is scarce, heterogeneous, and weak, the authors stressed.
“They can pose a health risk among people who have kidney disease, diabetes, and heart failure or who take certain medications, including ACE inhibitors and potassium-sparing diuretics,” said Emma Laing, PhD, RDN, director of dietetics at the University of Georgia in Athens. And while their salty flavor makes these a reasonable alternate to sodium chloride, “the downsides include a higher cost and bitter or metallic taste in high amounts. These salt substitutes tend to be better accepted by patients if they contain less than 30% potassium chloride.”
She noted that flavorful salt-free spices, herbs, lemon and lime juices, and vinegars can be effective in lowering dietary sodium when used in lieu of cooking salt.
In similar findings, a recent Chinese study of elderly normotensive people in residential care facilities observed a decrease in the incidence of hypertension with salt substitution.
Approximately one-third of otherwise health individuals are salt-sensitive, rising to more than 50% those with hypertension, and excessive salt intake is estimated to be responsible for nearly 5 million deaths per year globally.
How much impact could household food preparation with salt substitutes really have in North America where sodium consumption is largely driven by processed and takeout food? “While someone may make the switch to a salt substitute for home cooking, their sodium intake might still be very high if a lot of processed or takeaway foods are eaten,” Dr. Albarqouni said. “To see large population impacts, we will likely need policy and institutional-level change as to how sodium is used in food processing, alongside individuals’ switching from regular salt to salt substitutes.”
In agreement, an accompanying editorial by researchers from the universities of Sydney, New South Wales, and California, San Diego, noted the failure of governments and industry to address the World Health Organization’s call for a 30% reduction in global sodium consumption by 2025. With hypertension a major global health burden, the editorialists, led by J. Jaime Miranda, MD, MSc, PhD, of the Sydney School of Public Health at the University of Sydney, believe salt substitutes could be an accessible path toward that goal for food production companies.
“Although the benefits of reducing salt intake have been known for decades, little progress has been made in the quest to lower salt intake on the industry and commercial fronts with existing regulatory tools,” they wrote. “Consequently, we must turn our attention to effective evidence-based alternatives, such as the use of potassium-enriched salts.”
Given the high rates of nonadherence to antihypertensive medication, nonpharmacologic measures to improve blood pressure control are required, they added. “Expanding the routine use of potassium-enriched salts across households and the food industry would benefit not only persons with existing hypertension but all members of the household and communities. An entire shift of the population’s blood pressure curve is possible.”
The study authors called for research to determine the cost-effectiveness of salt substitution in older Asian populations and its efficacy in groups at average cardiovascular risk or following a Western diet.
This research was supported by the National Health and Medical Research Council of Australia and an Australian Government Research Training Program Scholarship. Coauthor Dr. Lauren Ball disclosed support from the National Health and Medical Research Council of Australia. Ms. Hannah Greenwood received support from the Australian government and Bond University. Dr. Miranda disclosed numerous consulting, advisory, and research-funding relationships with government, academic, philanthropic, and nonprofit organizations. Editorial commentator Dr. Kathy Trieu reported research support from multiple government and non-profit research-funding organizations. Dr. Cheryl Anderson disclosed ties to Weight Watchers and the McCormick Science Institute, as well support from numerous government, academic, and nonprofit research-funding agencies.
Large-scale salt substitution holds promise for reducing mortality with no elevated risk of serious harms, especially for older people at increased cardiovascular disease (CVD) risk, a systematic review and meta-analysis by Australian researchers suggested.
The study, published in Annals of Internal Medicine, adds more evidence that broad adoption of potassium-rich salt substitutes for food preparation could have a significant effect on population health.
Although the supporting evidence was of low certainty, the analysis of 16 international randomized controlled trials of various interventions with 35,321 participants found salt substitution to be associated with an absolute reduction of 5 in 1000 in all-cause mortality (confidence interval, –3 to –7) and 3 in 1000 in CVD mortality (CI, –1 to –5).
Led by Hannah Greenwood, BPsychSc, a cardiovascular researcher at the Institute for Evidence-Based Healthcare at Bond University in Gold Coast, Queensland, the investigators also found very low certainty evidence of an absolute reduction of 8 in 1000 in major adverse cardiovascular events (CI, 0 to –15), with a 1 in 1000 decrease in more serious adverse events (CI, 4 to –2) in the same population.
Seven of the 16 studies were conducted in China and Taiwan and seven were conducted in populations of older age (mean age 62 years) and/or at higher cardiovascular risk.
With most of the data deriving from populations of older age at higher-than-average CV risk and/or eating an Asian diet, the findings’ generalizability to populations following a Western diet and/or at average CVD risk is limited, the researchers acknowledged.
“We are less certain about the effects in Western, younger, and healthy population groups,” corresponding author Loai Albarqouni, MD, MSc, PhD, assistant professor at the Institute for Evidence-Based Healthcare, said in an interview. “While we saw small, clinically meaningful reductions in cardiovascular deaths and events, effectiveness should be better established before salt substitutes are recommended more broadly, though they are promising.”
In addition, he said, since the longest follow-up of substitute use was 10 years, “we can’t speak to benefits or harms beyond this time frame.”
Still, recommending salt substitutes may be an effective way for physicians to help patients reduce CVD risk, especially those hesitant to start medication, he said. “But physicians should take into account individual circumstances and other factors like kidney disease before recommending salt substitutes. Other non-drug methods of reducing cardiovascular risk, such as diet or exercise, may also be considered.”
Dr. Albarqouni stressed that sodium intake is not the only driver of CVD and reducing intake is just one piece of the puzzle. He cautioned that substitutes themselves can contain high levels of sodium, “so if people are using them in large volumes, they may still present similar risks to the sodium in regular salt.”
While the substitutes appear safe as evidenced by low incidence of hyperkalemia or renal dysfunction, the evidence is scarce, heterogeneous, and weak, the authors stressed.
“They can pose a health risk among people who have kidney disease, diabetes, and heart failure or who take certain medications, including ACE inhibitors and potassium-sparing diuretics,” said Emma Laing, PhD, RDN, director of dietetics at the University of Georgia in Athens. And while their salty flavor makes these a reasonable alternate to sodium chloride, “the downsides include a higher cost and bitter or metallic taste in high amounts. These salt substitutes tend to be better accepted by patients if they contain less than 30% potassium chloride.”
She noted that flavorful salt-free spices, herbs, lemon and lime juices, and vinegars can be effective in lowering dietary sodium when used in lieu of cooking salt.
In similar findings, a recent Chinese study of elderly normotensive people in residential care facilities observed a decrease in the incidence of hypertension with salt substitution.
Approximately one-third of otherwise health individuals are salt-sensitive, rising to more than 50% those with hypertension, and excessive salt intake is estimated to be responsible for nearly 5 million deaths per year globally.
How much impact could household food preparation with salt substitutes really have in North America where sodium consumption is largely driven by processed and takeout food? “While someone may make the switch to a salt substitute for home cooking, their sodium intake might still be very high if a lot of processed or takeaway foods are eaten,” Dr. Albarqouni said. “To see large population impacts, we will likely need policy and institutional-level change as to how sodium is used in food processing, alongside individuals’ switching from regular salt to salt substitutes.”
In agreement, an accompanying editorial by researchers from the universities of Sydney, New South Wales, and California, San Diego, noted the failure of governments and industry to address the World Health Organization’s call for a 30% reduction in global sodium consumption by 2025. With hypertension a major global health burden, the editorialists, led by J. Jaime Miranda, MD, MSc, PhD, of the Sydney School of Public Health at the University of Sydney, believe salt substitutes could be an accessible path toward that goal for food production companies.
“Although the benefits of reducing salt intake have been known for decades, little progress has been made in the quest to lower salt intake on the industry and commercial fronts with existing regulatory tools,” they wrote. “Consequently, we must turn our attention to effective evidence-based alternatives, such as the use of potassium-enriched salts.”
Given the high rates of nonadherence to antihypertensive medication, nonpharmacologic measures to improve blood pressure control are required, they added. “Expanding the routine use of potassium-enriched salts across households and the food industry would benefit not only persons with existing hypertension but all members of the household and communities. An entire shift of the population’s blood pressure curve is possible.”
The study authors called for research to determine the cost-effectiveness of salt substitution in older Asian populations and its efficacy in groups at average cardiovascular risk or following a Western diet.
This research was supported by the National Health and Medical Research Council of Australia and an Australian Government Research Training Program Scholarship. Coauthor Dr. Lauren Ball disclosed support from the National Health and Medical Research Council of Australia. Ms. Hannah Greenwood received support from the Australian government and Bond University. Dr. Miranda disclosed numerous consulting, advisory, and research-funding relationships with government, academic, philanthropic, and nonprofit organizations. Editorial commentator Dr. Kathy Trieu reported research support from multiple government and non-profit research-funding organizations. Dr. Cheryl Anderson disclosed ties to Weight Watchers and the McCormick Science Institute, as well support from numerous government, academic, and nonprofit research-funding agencies.
Large-scale salt substitution holds promise for reducing mortality with no elevated risk of serious harms, especially for older people at increased cardiovascular disease (CVD) risk, a systematic review and meta-analysis by Australian researchers suggested.
The study, published in Annals of Internal Medicine, adds more evidence that broad adoption of potassium-rich salt substitutes for food preparation could have a significant effect on population health.
Although the supporting evidence was of low certainty, the analysis of 16 international randomized controlled trials of various interventions with 35,321 participants found salt substitution to be associated with an absolute reduction of 5 in 1000 in all-cause mortality (confidence interval, –3 to –7) and 3 in 1000 in CVD mortality (CI, –1 to –5).
Led by Hannah Greenwood, BPsychSc, a cardiovascular researcher at the Institute for Evidence-Based Healthcare at Bond University in Gold Coast, Queensland, the investigators also found very low certainty evidence of an absolute reduction of 8 in 1000 in major adverse cardiovascular events (CI, 0 to –15), with a 1 in 1000 decrease in more serious adverse events (CI, 4 to –2) in the same population.
Seven of the 16 studies were conducted in China and Taiwan and seven were conducted in populations of older age (mean age 62 years) and/or at higher cardiovascular risk.
With most of the data deriving from populations of older age at higher-than-average CV risk and/or eating an Asian diet, the findings’ generalizability to populations following a Western diet and/or at average CVD risk is limited, the researchers acknowledged.
“We are less certain about the effects in Western, younger, and healthy population groups,” corresponding author Loai Albarqouni, MD, MSc, PhD, assistant professor at the Institute for Evidence-Based Healthcare, said in an interview. “While we saw small, clinically meaningful reductions in cardiovascular deaths and events, effectiveness should be better established before salt substitutes are recommended more broadly, though they are promising.”
In addition, he said, since the longest follow-up of substitute use was 10 years, “we can’t speak to benefits or harms beyond this time frame.”
Still, recommending salt substitutes may be an effective way for physicians to help patients reduce CVD risk, especially those hesitant to start medication, he said. “But physicians should take into account individual circumstances and other factors like kidney disease before recommending salt substitutes. Other non-drug methods of reducing cardiovascular risk, such as diet or exercise, may also be considered.”
Dr. Albarqouni stressed that sodium intake is not the only driver of CVD and reducing intake is just one piece of the puzzle. He cautioned that substitutes themselves can contain high levels of sodium, “so if people are using them in large volumes, they may still present similar risks to the sodium in regular salt.”
While the substitutes appear safe as evidenced by low incidence of hyperkalemia or renal dysfunction, the evidence is scarce, heterogeneous, and weak, the authors stressed.
“They can pose a health risk among people who have kidney disease, diabetes, and heart failure or who take certain medications, including ACE inhibitors and potassium-sparing diuretics,” said Emma Laing, PhD, RDN, director of dietetics at the University of Georgia in Athens. And while their salty flavor makes these a reasonable alternate to sodium chloride, “the downsides include a higher cost and bitter or metallic taste in high amounts. These salt substitutes tend to be better accepted by patients if they contain less than 30% potassium chloride.”
She noted that flavorful salt-free spices, herbs, lemon and lime juices, and vinegars can be effective in lowering dietary sodium when used in lieu of cooking salt.
In similar findings, a recent Chinese study of elderly normotensive people in residential care facilities observed a decrease in the incidence of hypertension with salt substitution.
Approximately one-third of otherwise health individuals are salt-sensitive, rising to more than 50% those with hypertension, and excessive salt intake is estimated to be responsible for nearly 5 million deaths per year globally.
How much impact could household food preparation with salt substitutes really have in North America where sodium consumption is largely driven by processed and takeout food? “While someone may make the switch to a salt substitute for home cooking, their sodium intake might still be very high if a lot of processed or takeaway foods are eaten,” Dr. Albarqouni said. “To see large population impacts, we will likely need policy and institutional-level change as to how sodium is used in food processing, alongside individuals’ switching from regular salt to salt substitutes.”
In agreement, an accompanying editorial by researchers from the universities of Sydney, New South Wales, and California, San Diego, noted the failure of governments and industry to address the World Health Organization’s call for a 30% reduction in global sodium consumption by 2025. With hypertension a major global health burden, the editorialists, led by J. Jaime Miranda, MD, MSc, PhD, of the Sydney School of Public Health at the University of Sydney, believe salt substitutes could be an accessible path toward that goal for food production companies.
“Although the benefits of reducing salt intake have been known for decades, little progress has been made in the quest to lower salt intake on the industry and commercial fronts with existing regulatory tools,” they wrote. “Consequently, we must turn our attention to effective evidence-based alternatives, such as the use of potassium-enriched salts.”
Given the high rates of nonadherence to antihypertensive medication, nonpharmacologic measures to improve blood pressure control are required, they added. “Expanding the routine use of potassium-enriched salts across households and the food industry would benefit not only persons with existing hypertension but all members of the household and communities. An entire shift of the population’s blood pressure curve is possible.”
The study authors called for research to determine the cost-effectiveness of salt substitution in older Asian populations and its efficacy in groups at average cardiovascular risk or following a Western diet.
This research was supported by the National Health and Medical Research Council of Australia and an Australian Government Research Training Program Scholarship. Coauthor Dr. Lauren Ball disclosed support from the National Health and Medical Research Council of Australia. Ms. Hannah Greenwood received support from the Australian government and Bond University. Dr. Miranda disclosed numerous consulting, advisory, and research-funding relationships with government, academic, philanthropic, and nonprofit organizations. Editorial commentator Dr. Kathy Trieu reported research support from multiple government and non-profit research-funding organizations. Dr. Cheryl Anderson disclosed ties to Weight Watchers and the McCormick Science Institute, as well support from numerous government, academic, and nonprofit research-funding agencies.
FROM ANNALS OF INTERNAL MEDICINE
Environmental Chemicals Linked to Parkinson’s Disease in Urban Areas
DENVER — , according to results from a new nationwide analysis of a Medicare population.
TCE has long been used as an industrial solvent, and it is a component of several household cleaning products. Case reports have suggested that workers exposed to it have increased risk of Parkinson’s disease, with risk increases as high as 500%.
Exposure can come through air or water, but 97% of environmental TCE is found in the air, according to Brittany Krzyzanowski, PhD, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
Previous studies of TCE had looked primarily at occupational exposure, such as workers at TCE-emitting facilities, or soldiers stationed at Camp Lejeune in North Carolina, where levels of TCE were more than 70-fold higher than EPA-permissible levels. A recent study found a 70% increase in risk of Parkinson’s disease associated with individuals who were stationed there.
From Population Data to Individual Risk
In an interview, Dr. Krzyzanowski pointed out that the Camp Lejeune studies didn’t assign TCE exposure to individuals — instead, researchers noted whether an individual was stationed at that base or another. “Our study adds to the previous work by investigating environmental exposure using TCE estimates that we are able to assign to individuals. [It shows that] you don’t have to work in a facility with TCE, you don’t have to be stationed on a military base with tainted water, you just have to live in a census tract with higher levels of TCE to have increased risk,” said Dr. Krzyzanowski, a research assistant professor at Barrow Neurological Institute in Phoenix.
In the new study, Dr. Krzyzanowski and her colleagues analyzed data from 1,559,135 Medicare beneficiaries with no other health coverage, who had a valid US ZIP code. There were 252,700 incident cases of Parkinson’s disease who were initially diagnosed between 2016 and 2018. These individuals were matched 1:5 with 1,306,435 healthy controls.
Airborne TCE exposure data was drawn the Environmental Protection Agency’s National Air Toxics Assessment data from 2005, about 12 years prior to the start of the study and in line with the expected latency between exposure and development of Parkinson’s disease.
“We found a nationwide association between airborne TCE exposure and Parkinson’s disease risks, but this was only true for the metropolitan areas. Within these metro areas, there was a dose-response effect, where increasing levels of TCE were associated with increasing risk of Parkinson’s disease. In particular, those living in the metros with the highest levels of TCE had a 24% greater risk of Parkinson’s compared with those in metros with the lowest levels of TCE,” Dr. Krzyzanowski said during her presentation. The P-value for the trend was less than .0001.
The census tracts in metropolitan areas are smaller than those in rural areas because of differences in population density, and this leads to greater precision of TCE exposure estimates in urban environments, according to Dr. Krzyzanowski, and this could explain the lack of a statistically significant association seen among rural populations.
‘More Substantial’ Data Adds to Previous Evidence
The new study is an important addition to the literature examining TCE exposure and Parkinson’s disease, according to session moderator Jeff Bronstein, MD, PhD, who was asked for comment. “It’s more substantial data making that association between TCE and Parkinson’s. It’s been growing over the past decade, and this is a more objective, big data association, so it adds more strength to the body of knowledge that we already have. It’s unbiased, which is nice,” said Dr. Bronstein, professor of neurology and director of movement disorders at UCLA.
It remains uncertain whether TCE is a direct cause of Parkinson’s disease, but “a lot of us believe it’s causal. There’s a lot of evidence now. There are some very good studies with inhalation models that show it affects autophagy, or the way we break down proteins, and that it also involves LRRK2 [leucine-rich repeat kinase 2], which is one of the proteins involved in some of the genetic forms [of Parkinson’s disease], and it might affect mitochondria. They’re all linked in network and right now the animal studies point to that network,” said Dr. Bronstein.
Dr. Krzyzanowski has no relevant financial disclosures. Dr. Bronstein consults for a legal firm involved in the Camp Lejeune litigation.
DENVER — , according to results from a new nationwide analysis of a Medicare population.
TCE has long been used as an industrial solvent, and it is a component of several household cleaning products. Case reports have suggested that workers exposed to it have increased risk of Parkinson’s disease, with risk increases as high as 500%.
Exposure can come through air or water, but 97% of environmental TCE is found in the air, according to Brittany Krzyzanowski, PhD, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
Previous studies of TCE had looked primarily at occupational exposure, such as workers at TCE-emitting facilities, or soldiers stationed at Camp Lejeune in North Carolina, where levels of TCE were more than 70-fold higher than EPA-permissible levels. A recent study found a 70% increase in risk of Parkinson’s disease associated with individuals who were stationed there.
From Population Data to Individual Risk
In an interview, Dr. Krzyzanowski pointed out that the Camp Lejeune studies didn’t assign TCE exposure to individuals — instead, researchers noted whether an individual was stationed at that base or another. “Our study adds to the previous work by investigating environmental exposure using TCE estimates that we are able to assign to individuals. [It shows that] you don’t have to work in a facility with TCE, you don’t have to be stationed on a military base with tainted water, you just have to live in a census tract with higher levels of TCE to have increased risk,” said Dr. Krzyzanowski, a research assistant professor at Barrow Neurological Institute in Phoenix.
In the new study, Dr. Krzyzanowski and her colleagues analyzed data from 1,559,135 Medicare beneficiaries with no other health coverage, who had a valid US ZIP code. There were 252,700 incident cases of Parkinson’s disease who were initially diagnosed between 2016 and 2018. These individuals were matched 1:5 with 1,306,435 healthy controls.
Airborne TCE exposure data was drawn the Environmental Protection Agency’s National Air Toxics Assessment data from 2005, about 12 years prior to the start of the study and in line with the expected latency between exposure and development of Parkinson’s disease.
“We found a nationwide association between airborne TCE exposure and Parkinson’s disease risks, but this was only true for the metropolitan areas. Within these metro areas, there was a dose-response effect, where increasing levels of TCE were associated with increasing risk of Parkinson’s disease. In particular, those living in the metros with the highest levels of TCE had a 24% greater risk of Parkinson’s compared with those in metros with the lowest levels of TCE,” Dr. Krzyzanowski said during her presentation. The P-value for the trend was less than .0001.
The census tracts in metropolitan areas are smaller than those in rural areas because of differences in population density, and this leads to greater precision of TCE exposure estimates in urban environments, according to Dr. Krzyzanowski, and this could explain the lack of a statistically significant association seen among rural populations.
‘More Substantial’ Data Adds to Previous Evidence
The new study is an important addition to the literature examining TCE exposure and Parkinson’s disease, according to session moderator Jeff Bronstein, MD, PhD, who was asked for comment. “It’s more substantial data making that association between TCE and Parkinson’s. It’s been growing over the past decade, and this is a more objective, big data association, so it adds more strength to the body of knowledge that we already have. It’s unbiased, which is nice,” said Dr. Bronstein, professor of neurology and director of movement disorders at UCLA.
It remains uncertain whether TCE is a direct cause of Parkinson’s disease, but “a lot of us believe it’s causal. There’s a lot of evidence now. There are some very good studies with inhalation models that show it affects autophagy, or the way we break down proteins, and that it also involves LRRK2 [leucine-rich repeat kinase 2], which is one of the proteins involved in some of the genetic forms [of Parkinson’s disease], and it might affect mitochondria. They’re all linked in network and right now the animal studies point to that network,” said Dr. Bronstein.
Dr. Krzyzanowski has no relevant financial disclosures. Dr. Bronstein consults for a legal firm involved in the Camp Lejeune litigation.
DENVER — , according to results from a new nationwide analysis of a Medicare population.
TCE has long been used as an industrial solvent, and it is a component of several household cleaning products. Case reports have suggested that workers exposed to it have increased risk of Parkinson’s disease, with risk increases as high as 500%.
Exposure can come through air or water, but 97% of environmental TCE is found in the air, according to Brittany Krzyzanowski, PhD, who presented the study at the 2024 annual meeting of the American Academy of Neurology.
Previous studies of TCE had looked primarily at occupational exposure, such as workers at TCE-emitting facilities, or soldiers stationed at Camp Lejeune in North Carolina, where levels of TCE were more than 70-fold higher than EPA-permissible levels. A recent study found a 70% increase in risk of Parkinson’s disease associated with individuals who were stationed there.
From Population Data to Individual Risk
In an interview, Dr. Krzyzanowski pointed out that the Camp Lejeune studies didn’t assign TCE exposure to individuals — instead, researchers noted whether an individual was stationed at that base or another. “Our study adds to the previous work by investigating environmental exposure using TCE estimates that we are able to assign to individuals. [It shows that] you don’t have to work in a facility with TCE, you don’t have to be stationed on a military base with tainted water, you just have to live in a census tract with higher levels of TCE to have increased risk,” said Dr. Krzyzanowski, a research assistant professor at Barrow Neurological Institute in Phoenix.
In the new study, Dr. Krzyzanowski and her colleagues analyzed data from 1,559,135 Medicare beneficiaries with no other health coverage, who had a valid US ZIP code. There were 252,700 incident cases of Parkinson’s disease who were initially diagnosed between 2016 and 2018. These individuals were matched 1:5 with 1,306,435 healthy controls.
Airborne TCE exposure data was drawn the Environmental Protection Agency’s National Air Toxics Assessment data from 2005, about 12 years prior to the start of the study and in line with the expected latency between exposure and development of Parkinson’s disease.
“We found a nationwide association between airborne TCE exposure and Parkinson’s disease risks, but this was only true for the metropolitan areas. Within these metro areas, there was a dose-response effect, where increasing levels of TCE were associated with increasing risk of Parkinson’s disease. In particular, those living in the metros with the highest levels of TCE had a 24% greater risk of Parkinson’s compared with those in metros with the lowest levels of TCE,” Dr. Krzyzanowski said during her presentation. The P-value for the trend was less than .0001.
The census tracts in metropolitan areas are smaller than those in rural areas because of differences in population density, and this leads to greater precision of TCE exposure estimates in urban environments, according to Dr. Krzyzanowski, and this could explain the lack of a statistically significant association seen among rural populations.
‘More Substantial’ Data Adds to Previous Evidence
The new study is an important addition to the literature examining TCE exposure and Parkinson’s disease, according to session moderator Jeff Bronstein, MD, PhD, who was asked for comment. “It’s more substantial data making that association between TCE and Parkinson’s. It’s been growing over the past decade, and this is a more objective, big data association, so it adds more strength to the body of knowledge that we already have. It’s unbiased, which is nice,” said Dr. Bronstein, professor of neurology and director of movement disorders at UCLA.
It remains uncertain whether TCE is a direct cause of Parkinson’s disease, but “a lot of us believe it’s causal. There’s a lot of evidence now. There are some very good studies with inhalation models that show it affects autophagy, or the way we break down proteins, and that it also involves LRRK2 [leucine-rich repeat kinase 2], which is one of the proteins involved in some of the genetic forms [of Parkinson’s disease], and it might affect mitochondria. They’re all linked in network and right now the animal studies point to that network,” said Dr. Bronstein.
Dr. Krzyzanowski has no relevant financial disclosures. Dr. Bronstein consults for a legal firm involved in the Camp Lejeune litigation.
FROM AAN 2024
No Routine Cancer Screening Option? New MCED Tests May Help
Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.
The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.
That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.
The Early Data
One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.
Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.
However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.
The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.
Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up.
The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.
Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.
The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%).
The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.
Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.
Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported.
“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.
Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.
The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.
The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.
The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”
MCED in Low-Income Settings
The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.
The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.
The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.
This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”
Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.
To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.
Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.
To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.
The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.
The test could predict the tissue of origin in about two thirds of cases.
Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded.
Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.
Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said.
Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.
And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.
Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.
A version of this article appeared on Medscape.com.
Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.
The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.
That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.
The Early Data
One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.
Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.
However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.
The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.
Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up.
The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.
Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.
The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%).
The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.
Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.
Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported.
“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.
Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.
The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.
The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.
The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”
MCED in Low-Income Settings
The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.
The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.
The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.
This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”
Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.
To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.
Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.
To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.
The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.
The test could predict the tissue of origin in about two thirds of cases.
Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded.
Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.
Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said.
Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.
And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.
Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.
A version of this article appeared on Medscape.com.
Analyses presented during a session at the American Association for Cancer Research annual meeting, revealed that three new MCED tests — CanScan, MERCURY, and OncoSeek — could detect a range of cancers and recognize the tissue of origin with high accuracy. One — OncoSeek — could also provide an affordable cancer screening option for individuals living in lower-income countries.
The need for these noninvasive liquid biopsy tests that can accurately identify multiple cancer types with a single blood draw, especially cancers without routine screening strategies, is pressing. “We know that the current cancer standard of care screening will identify less than 50% of all cancers, while more than 50% of all cancer deaths occur in types of cancer with no recommended screening,” said co-moderator Marie E. Wood, MD, of the University of Colorado Anschutz Medical Campus, in Aurora, Colorado.
That being said, “the clinical utility of multicancer detection tests has not been established and we’re concerned about issues of overdiagnosis and overtreatment,” she noted.
The Early Data
One new MCED test called CanScan, developed by Geneseeq Technology, uses plasma cell-free DNA fragment patterns to detect cancer signals as well as identify the tissue of origin across 13 cancer types.
Overall, the CanScan test covers cancer types that contribute to two thirds of new cancer cases and 74% of morality globally, said presenter Shanshan Yang, of Geneseeq Research Institute, in Nanjing, China.
However, only five of these cancer types have screening recommendations issued by the US Preventive Services Task Force (USPSTF), Dr. Yang added.
The interim data comes from an ongoing large-scale prospective study evaluating the MCED test in a cohort of asymptomatic individuals between ages 45 and 75 years with an average risk for cancer and no cancer-related symptoms on enrollment.
Patients at baseline had their blood collected for the CanScan test and subsequently received annual routine physical exams once a year for 3 consecutive years, with an additional 2 years of follow-up.
The analysis included 3724 participants with analyzable samples at the data cutoff in September 2023. Among the 3724 participants, 29 had confirmed cancer diagnoses. Among these cases, 14 patients had their cancer confirmed through USPSTF recommended screening and 15 were detected through outside of standard USPSTF screening, such as a thyroid ultrasound, Dr. Yang explained.
Almost 90% of the cancers (26 of 29) were detected in the stage I or II, and eight (27.5%) were not one of the test’s 13 targeted cancer types.
The CanScan test had a sensitivity of 55.2%, identifying 16 of 29 of the patients with cancer, including 10 of 21 individuals with stage I (47.6%), and two of three with stage II (66.7%).
The test had a high specificity of 97.9%, meaning out of 100 people screened, only two had false negative findings.
Among the 15 patients who had their cancer detected outside of USPSTF screening recommendations, eight (53.3%) were found using a CanScan test, including patients with liver and endometrial cancers.
Compared with a positive predictive value of (PPV) of 1.6% with screening or physical exam methods alone, the CanScan test had a PPV of 17.4%, Dr. Yang reported.
“The MCED test holds significant potential for early cancer screening in asymptomatic populations,” Dr. Yang and colleagues concluded.
Another new MCED test called MERCURY, also developed by Geneseeq Technology and presented during the session, used a similar method to detect cancer signals and predict the tissue of origin across 13 cancer types.
The researchers initially validated the test using 3076 patients with cancer and 3477 healthy controls with a target specificity of 99%. In this group, researchers reported a sensitivity of 0.865 and a specificity of 0.989.
The team then performed an independent validation analysis with 1465 participants, 732 with cancer and 733 with no cancer, and confirmed a high sensitivity and specificity of 0.874 and 0.978, respectively. The sensitivity increased incrementally by cancer stage — 0.768 for stage I, 0.840 for stage II, 0.923 for stage III, and 0.971 for stage IV.
The test identified the tissue of origin with high accuracy, the researchers noted, but cautioned that the test needs “to be further validated in a prospective cohort study.”
MCED in Low-Income Settings
The session also featured findings on a new affordable MCED test called OncoSeek, which could provide greater access to cancer testing in low- and middle-income countries.
The OncoSeek algorithm identifies the presence of cancer using seven protein tumor markers alongside clinical information, such as gender and age. Like other tests, the test also predicts the possible tissue of origin.
The test can be run on clinical protein assay instruments that are already widely available, such as Roche cobas analyzer, Mao Mao, MD, PhD, the founder and CEO of SeekIn, of Shenzhen, China, told this news organization.
This “feature makes the test accessible worldwide, even in low- and middle-income countries,” he said. “These instruments are fully-automated and part of today’s clinical practice. Therefore, the test does not require additional infrastructure building and lab personal training.”
Another notable advantage: the OncoSeek test only costs about $20, compared with other MCED tests, which can cost anywhere from $200 to $1000.
To validate the technology in a large, diverse cohort, Dr. Mao and colleagues enrolled approximately 10,000 participants, including 2003 cancer cases and 7888 non-cancer cases.
Peripheral blood was collected from each participant and analyzed using a panel of the seven protein tumor markers — AFP, CA125, CA15-3, CA19-9, CA72-4, CEA, and CYFRA 21-1.
To reduce the risk for false positive findings, the team designed the OncoSeek algorithm to achieve a specificity of 93%. Dr. Mao and colleagues found a sensitivity of 51.7%, resulting in an overall accuracy of 84.6%.
The performance was consistent in additional validation cohorts in Brazil, China, and the United States, with sensitivities ranging from 39.0% to 77.6% for detecting nine common cancer types, including breast, colorectal, liver, lung, lymphoma, esophagus, ovary, pancreas, and stomach. The sensitivity for pancreatic cancer was at the high end of 77.6%.
The test could predict the tissue of origin in about two thirds of cases.
Given its low cost, OncoSeek represents an affordable and accessible option for cancer screening, the authors concluded.
Overall, “I think MCEDs have the potential to enhance cancer screening,” Dr. Wood told this news organization.
Still, questions remain about the optimal use of these tests, such as whether they are best for average-risk or higher risk populations, and how to integrate them into standard screening, she said.
Dr. Wood also cautioned that the studies presented in the session represent early data, and it is likely that the numbers, such as sensitivity and specificity, will change with further prospective analyses.
And ultimately, these tests should complement, not replace, standard screening. “A negative testing should not be taken as a sign to avoid standard screening,” Dr. Wood said.
Dr. Yang is an employee of Geneseeq Technology, Inc., and Dr. Mao is an employee of SeekIn. Dr. Wood had no disclosures to report.
A version of this article appeared on Medscape.com.