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Common Crohn’s Immune Response to Gut Bacteria Suggests Therapeutic Target
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
Many patients with Crohn’s disease (CD) have a heightened immune response to flagellins expressed by commensal gut bacteria Lachnospiraceae, with seroreactivity appearing up to 5 years prior to development of Crohn’s complications, according to investigators.
These findings suggest that lead author Qing Zhao, MD, PhD, of the University of Alabama at Birmingham, and colleagues reported.
Previously, Zhao and colleagues found that about 30% of patients with CD had elevated IgG responses to multiple Lachnospiraceae flagellins, and stronger reactivity was associated with higher flagellin-specific CD4+ T cells in circulation.
“In this study, we aimed to identify immunodominant B cell peptide epitopes shared among Lachnospiraceae bacterial flagellins in patients with CD and to correlate this immune reactivity with the clinical disease course,” the investigators wrote in Gastroenterology.
To this end, the investigators analyzed serum samples from adult CD patients, pediatric CD patients, and healthy infants without inflammatory bowel disease, with data derived from multiple sources. Adult patients with CD were part of a regional cohort recruited at the University of Alabama at Birmingham, while pediatric patients with CD came from the RISK Stratification Study, a multisite cohort study across the United States and Canada. Samples from healthy infants were collected from three diverse geographic locations: Uganda, Sweden, and the United States, providing a broad comparison of immune responses to Lachnospiraceae flagellin across populations.
Samples were analyzed via two main methods: a flagellin peptide microarray and a cytometric bead array. The microarray, comprising sequential Lachnospiraceae-derived peptides, enabled identification of IgG responses specific to individual bacterial peptides. The cytometric bead array allowed for multiplexed detection of IgG, IgA, and IgM antibodies to these peptides, quantifying immune reactivity and enabling correlation with clinical disease data.
This approach revealed that nearly half of patients with CD — both adults and children — had a strong IgG immune response targeting a specific bacterial peptide in the Lachnospiraceae flagellin hinge region. This response was linked to an increased risk of disease complications over time, suggesting the peptide’s potential as a biomarker for CD severity and progression, according to the investigators.
Of note, healthy infants also exhibited an elevated IgG response to the same bacterial peptide at around 1 year of age, but this response declined as they grew older, in contrast to its persistence in CD patients. This difference points to a possible failure in immune tolerance in CD, where the natural immune response to gut bacteria in infancy may become dysregulated, Zhao and colleagues explained.
“The flagellin cytometric bead array used in this study holds potential for a simplified yet robust diagnostic and prognostic assay for Crohn’s disease,” they concluded. “Given that reactivity to the dominant flagellin epitope is strongly associated with the development of disease complications, this technique may also assist in identifying patients with Crohn’s disease who would benefit from early therapy.”
Zhao and colleagues also called for future studies to characterize the role of flagellin hinge peptide–specific IgG antibodies in CD pathogenesis, and to explore the hinge peptide as a potential therapeutic target.The study was supported by a Synergy Award from the Kenneth Rainin Foundation, a Career Development Award from the Crohn’s and Colitis Foundation, and grants from the Department of Veterans Affairs, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and National Institute of Diabetes and Digestive and Kidney Diseases. One coauthor and the University of Alabama at Birmingham hold a patent on Lachnospiraceae A4 Fla2, licensed for clinical application by Prometheus Laboratories. Four study coauthors have filed a patent for the flagellin peptide cytometric bead array. One coauthor serves as the founder and chief scientific officer of ImmPrev Bio, a company developing an antigen-directed immunotherapy for Crohn’s disease.
FROM GASTROENTEROLOGY
Liquid Fasting Mitigates Negative Pre-Surgery Impact of Semaglutide
These findings suggest that patients taking GLP-1 receptor agonists (GLP-1RAs) may benefit from a 24-hour liquid fast before anesthetic procedures without the need for a medication hold, reported lead author Haarika Korlipara, MD, of NewYork–Presbyterian/Weill Cornell Medical Center, New York, and colleagues.
“[T]he effects of delayed gastric emptying in patients on long-acting GLP-1RAs are clinically important in the management of anesthetized patients, who may develop periprocedural complications in the setting of retained solid gastric contents,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy.
The researchers retrospectively analyzed clinical data from 1,212 patients undergoing upper endoscopy at a tertiary care center. Among them, 602 were on semaglutide for more than four weeks, while 610 were controls not taking the medication.
The primary outcome was the presence of retained solid gastric contents. Secondary outcomes included the need for intubation, early procedure termination, and recommendations for repeat endoscopy.
Semaglutide use was an independent predictor of retained solid gastric contents (odds ratio [OR], 4.74; 95% CI, 2.40-9.35; P less than .0001). Multivariable propensity-matched analysis showed a 6% absolute increase in retained gastric contents in the semaglutide group compared to controls (P less than .0001).
This increase appeared clinically relevant, as semaglutide use was associated with a higher rate of early procedure termination (OR, 3.09; P = 0.02) and recommendations for repeat endoscopies (OR, 3.61; P = 0.02), “indicating the degree of retained solid gastric contents was enough to limit the intended gastric mucosal examination,” the investigators wrote.
However, patients who underwent same-day colonoscopy, which included a 24-hour clear liquid fast leading up to the procedure, were less likely to have retained gastric contents (OR, 0.41; 95% CI, 0.23-0.73; P = 0.003), suggesting that extended fasting protocols may mitigate the risk of procedural complications.
“Patients with a history of gastroparesis are often advised to stop ingesting solid foods and maintain a clear liquid diet for a longer period than standard ASA guidance before anesthetized procedures,” Dr. Korlipara and colleagues wrote. “In our opinion, this recommendation should be considered in patients on long-term GLP-1RA therapy, in response to the findings reported in this study and others about the protective effects of a 24-hour liquid fast.”
Point-of-care gastric ultrasound may also be considered to evaluate patients at higher risk of retained stomach contents, they added, especially in patients with additional risk factors for delayed gastric emptying.
“Previously published data have linked prolonged gastric emptying delays in patients chronically using these medications,” they wrote. “Considering the effect on blood sugar and associated procedural risk, especially in patients taking this medication for diabetes management, more studies are warranted to determine the effect of medication on periprocedural complications and recommend repeat evaluation.”
After this study was released, new clinical guidance on the use of GLP-1RAs before surgery was co-published by AGA and four other societies. The guidance notes that, in most cases, patients can continue to take GLP-1RAs, but individual risk factors for complications should be assessed prior to surgery. The guidance cautions that patients at high risk for significant GI side effects should follow a liquid diet for 24 hours before a procedure and the anesthesia plan be adjusted accordingly. In rare cases, the procedure should be delayed.
Dr. Korlipara disclosed no conflicts of interest.
These findings suggest that patients taking GLP-1 receptor agonists (GLP-1RAs) may benefit from a 24-hour liquid fast before anesthetic procedures without the need for a medication hold, reported lead author Haarika Korlipara, MD, of NewYork–Presbyterian/Weill Cornell Medical Center, New York, and colleagues.
“[T]he effects of delayed gastric emptying in patients on long-acting GLP-1RAs are clinically important in the management of anesthetized patients, who may develop periprocedural complications in the setting of retained solid gastric contents,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy.
The researchers retrospectively analyzed clinical data from 1,212 patients undergoing upper endoscopy at a tertiary care center. Among them, 602 were on semaglutide for more than four weeks, while 610 were controls not taking the medication.
The primary outcome was the presence of retained solid gastric contents. Secondary outcomes included the need for intubation, early procedure termination, and recommendations for repeat endoscopy.
Semaglutide use was an independent predictor of retained solid gastric contents (odds ratio [OR], 4.74; 95% CI, 2.40-9.35; P less than .0001). Multivariable propensity-matched analysis showed a 6% absolute increase in retained gastric contents in the semaglutide group compared to controls (P less than .0001).
This increase appeared clinically relevant, as semaglutide use was associated with a higher rate of early procedure termination (OR, 3.09; P = 0.02) and recommendations for repeat endoscopies (OR, 3.61; P = 0.02), “indicating the degree of retained solid gastric contents was enough to limit the intended gastric mucosal examination,” the investigators wrote.
However, patients who underwent same-day colonoscopy, which included a 24-hour clear liquid fast leading up to the procedure, were less likely to have retained gastric contents (OR, 0.41; 95% CI, 0.23-0.73; P = 0.003), suggesting that extended fasting protocols may mitigate the risk of procedural complications.
“Patients with a history of gastroparesis are often advised to stop ingesting solid foods and maintain a clear liquid diet for a longer period than standard ASA guidance before anesthetized procedures,” Dr. Korlipara and colleagues wrote. “In our opinion, this recommendation should be considered in patients on long-term GLP-1RA therapy, in response to the findings reported in this study and others about the protective effects of a 24-hour liquid fast.”
Point-of-care gastric ultrasound may also be considered to evaluate patients at higher risk of retained stomach contents, they added, especially in patients with additional risk factors for delayed gastric emptying.
“Previously published data have linked prolonged gastric emptying delays in patients chronically using these medications,” they wrote. “Considering the effect on blood sugar and associated procedural risk, especially in patients taking this medication for diabetes management, more studies are warranted to determine the effect of medication on periprocedural complications and recommend repeat evaluation.”
After this study was released, new clinical guidance on the use of GLP-1RAs before surgery was co-published by AGA and four other societies. The guidance notes that, in most cases, patients can continue to take GLP-1RAs, but individual risk factors for complications should be assessed prior to surgery. The guidance cautions that patients at high risk for significant GI side effects should follow a liquid diet for 24 hours before a procedure and the anesthesia plan be adjusted accordingly. In rare cases, the procedure should be delayed.
Dr. Korlipara disclosed no conflicts of interest.
These findings suggest that patients taking GLP-1 receptor agonists (GLP-1RAs) may benefit from a 24-hour liquid fast before anesthetic procedures without the need for a medication hold, reported lead author Haarika Korlipara, MD, of NewYork–Presbyterian/Weill Cornell Medical Center, New York, and colleagues.
“[T]he effects of delayed gastric emptying in patients on long-acting GLP-1RAs are clinically important in the management of anesthetized patients, who may develop periprocedural complications in the setting of retained solid gastric contents,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy.
The researchers retrospectively analyzed clinical data from 1,212 patients undergoing upper endoscopy at a tertiary care center. Among them, 602 were on semaglutide for more than four weeks, while 610 were controls not taking the medication.
The primary outcome was the presence of retained solid gastric contents. Secondary outcomes included the need for intubation, early procedure termination, and recommendations for repeat endoscopy.
Semaglutide use was an independent predictor of retained solid gastric contents (odds ratio [OR], 4.74; 95% CI, 2.40-9.35; P less than .0001). Multivariable propensity-matched analysis showed a 6% absolute increase in retained gastric contents in the semaglutide group compared to controls (P less than .0001).
This increase appeared clinically relevant, as semaglutide use was associated with a higher rate of early procedure termination (OR, 3.09; P = 0.02) and recommendations for repeat endoscopies (OR, 3.61; P = 0.02), “indicating the degree of retained solid gastric contents was enough to limit the intended gastric mucosal examination,” the investigators wrote.
However, patients who underwent same-day colonoscopy, which included a 24-hour clear liquid fast leading up to the procedure, were less likely to have retained gastric contents (OR, 0.41; 95% CI, 0.23-0.73; P = 0.003), suggesting that extended fasting protocols may mitigate the risk of procedural complications.
“Patients with a history of gastroparesis are often advised to stop ingesting solid foods and maintain a clear liquid diet for a longer period than standard ASA guidance before anesthetized procedures,” Dr. Korlipara and colleagues wrote. “In our opinion, this recommendation should be considered in patients on long-term GLP-1RA therapy, in response to the findings reported in this study and others about the protective effects of a 24-hour liquid fast.”
Point-of-care gastric ultrasound may also be considered to evaluate patients at higher risk of retained stomach contents, they added, especially in patients with additional risk factors for delayed gastric emptying.
“Previously published data have linked prolonged gastric emptying delays in patients chronically using these medications,” they wrote. “Considering the effect on blood sugar and associated procedural risk, especially in patients taking this medication for diabetes management, more studies are warranted to determine the effect of medication on periprocedural complications and recommend repeat evaluation.”
After this study was released, new clinical guidance on the use of GLP-1RAs before surgery was co-published by AGA and four other societies. The guidance notes that, in most cases, patients can continue to take GLP-1RAs, but individual risk factors for complications should be assessed prior to surgery. The guidance cautions that patients at high risk for significant GI side effects should follow a liquid diet for 24 hours before a procedure and the anesthesia plan be adjusted accordingly. In rare cases, the procedure should be delayed.
Dr. Korlipara disclosed no conflicts of interest.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
MASH: Experts Offer Noninvasive Cutoffs for Prescribing Resmetirom
This guidance document allows clinicians to use a variety of NITs to start and monitor resmetirom therapy, precluding the need for a biopsy, lead author Mazen Noureddin, MD, of Houston Research Institute, Houston Methodist Hospital in Texas, and colleagues reported.
“The recent conditional approval by the [Food and Drug Administration] of resmetirom ... presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH,” the investigators wrote in Clinical Gastroenterology and Hepatology.
However, the approval also “presents important challenges,” they noted, “including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population.”
To help identify which patients should get this new intervention, Noureddin and colleagues considered benchmarks from published literature, and conducted a post hoc analysis of phase 3 MASTERO-NASH trial data. Trial enrollment required at least three cardiometabolic risk factors and a vibration-controlled transient elastography (VCTE) prescreening within the past 3 months. The population included 888 patients with F2 or F3 disease.
Recommendations were split into three categories: treat with resmetirom, consider treating with resmetirom, and do not treat with resmetirom.
The recommendation to treat calls for a VCTE of 10-15 kPa, a magnetic resonance elastography (MRE) of 3.3-4.2 kPa, or an Enhanced Liver Fibrosis (ELF) score of 9.2-10.4, with the caveat that an ELF score below 9.8 requires a second NIT for confirmation. Alternatively, a positive composite score such as FibroScan–aspartate aminotransferase (FAST), MRI–AST (MAST), or MRE + Fibrosis-4 (MEFIB) may serve as grounds for treatment. For any of the previous, platelets must concurrently be at least 140 with no evidence of portal hypertension.
The recommendation to consider treatment depends upon a VCTE of 15.1-19.9 kPa, an MRE of 4.3-4.9 kPa, an ELF score of 10.5-11.3, or positive FAST, MAST, or MEFIB. Again, these require a concurrent platelet count of 140 and no portal hypertension.
Finally, patients should not be treated with resmetirom if they have a VCTE of 20 kPa or greater, an MRE of 5 kPa or greater, and an ELF score greater than 11.3.
Noureddin and colleagues also offered guidance on monitoring strategies, including follow-up at 3, 6, and 12 months.
At 3 months, the focus should be safety, including screening for drug-related liver injury and other adverse events that warrant cessation.
At 6 months, alanine aminotransferase (ALT) levels, VCTE, or MRI–proton density fat fraction (PDFF) tests can indicate early response, but treatment should generally continue regardless of results.
At 12 months, efficacy can be fully evaluated. ALT normalization, or improvement of more than 17 IU/L or more than 20%, along with a 30% or greater drop in VCTE, or at least 30% drop in liver fat on MRI-PDFF, serve as grounds for continuation.
Noureddin and colleagues noted that ALT improvement should be paired with corresponding improvements in imaging, such as a 30% reduction in MRI-PDFF. Even if ALT levels do not improve, a 30% or greater reduction in MRI-PDFF can still indicate a positive response; however, VCTE alone may not be sufficient to fully assess treatment response.
“Emerging data, particularly regarding the noninvasive assessment of treatment response, are likely to further modify patient selection, safety signals, and efficacy algorithms,” they concluded.This study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, the John C. Martin Foundation, and the National Institute on Alcohol Abuse and Alcoholism. The investigators disclosed additional relationships with Novo Nordisk, Pfizer, Shire, and others.
The approval of resmetirom as the first registered treatment for metabolic dysfunction–associated steatohepatitis (MASH) marks a historic moment. This expert panel recommendation document offers valuable guidance on patient selection for resmetirom treatment, monitoring responses, and managing potential side effects and drug-drug interactions. It also highlights the complexities of applying noninvasive tests for treatment initiation. Clinicians must identify MASH patients with significant or advanced fibrosis while avoiding those with cirrhosis and hepatic decompensation. Management will be simplified if the MAESTRO-OUTCOMES trial confirms that resmetirom is safe and effective for patients with compensated MASH cirrhosis.
The most reliable response biomarkers in the MAESTRO-NASH trial include reductions in MRI–proton density fat fraction (MRI-PDFF) and serum alanine aminotransferase, despite MRI-PDFF being limited by cost and availability. Worsening liver stiffness measurement via vibration-controlled transient elastography is suggested as a stopping rule, although this is not supported by resmetirom trial data. Short-term increases in liver stiffness may yield false positives, so it is advisable to repeat or use alternative noninvasive tests before discontinuing treatment.
Vincent Wai-Sun Wong, MD, is Mok Hing Yiu Professor of Medicine at the Chinese University of Hong Kong, China. He reported his role as a consultant or advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Intercept, Inventiva, Merck, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences, and is the cofounder of Illuminatio Medical Technology.
The approval of resmetirom as the first registered treatment for metabolic dysfunction–associated steatohepatitis (MASH) marks a historic moment. This expert panel recommendation document offers valuable guidance on patient selection for resmetirom treatment, monitoring responses, and managing potential side effects and drug-drug interactions. It also highlights the complexities of applying noninvasive tests for treatment initiation. Clinicians must identify MASH patients with significant or advanced fibrosis while avoiding those with cirrhosis and hepatic decompensation. Management will be simplified if the MAESTRO-OUTCOMES trial confirms that resmetirom is safe and effective for patients with compensated MASH cirrhosis.
The most reliable response biomarkers in the MAESTRO-NASH trial include reductions in MRI–proton density fat fraction (MRI-PDFF) and serum alanine aminotransferase, despite MRI-PDFF being limited by cost and availability. Worsening liver stiffness measurement via vibration-controlled transient elastography is suggested as a stopping rule, although this is not supported by resmetirom trial data. Short-term increases in liver stiffness may yield false positives, so it is advisable to repeat or use alternative noninvasive tests before discontinuing treatment.
Vincent Wai-Sun Wong, MD, is Mok Hing Yiu Professor of Medicine at the Chinese University of Hong Kong, China. He reported his role as a consultant or advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Intercept, Inventiva, Merck, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences, and is the cofounder of Illuminatio Medical Technology.
The approval of resmetirom as the first registered treatment for metabolic dysfunction–associated steatohepatitis (MASH) marks a historic moment. This expert panel recommendation document offers valuable guidance on patient selection for resmetirom treatment, monitoring responses, and managing potential side effects and drug-drug interactions. It also highlights the complexities of applying noninvasive tests for treatment initiation. Clinicians must identify MASH patients with significant or advanced fibrosis while avoiding those with cirrhosis and hepatic decompensation. Management will be simplified if the MAESTRO-OUTCOMES trial confirms that resmetirom is safe and effective for patients with compensated MASH cirrhosis.
The most reliable response biomarkers in the MAESTRO-NASH trial include reductions in MRI–proton density fat fraction (MRI-PDFF) and serum alanine aminotransferase, despite MRI-PDFF being limited by cost and availability. Worsening liver stiffness measurement via vibration-controlled transient elastography is suggested as a stopping rule, although this is not supported by resmetirom trial data. Short-term increases in liver stiffness may yield false positives, so it is advisable to repeat or use alternative noninvasive tests before discontinuing treatment.
Vincent Wai-Sun Wong, MD, is Mok Hing Yiu Professor of Medicine at the Chinese University of Hong Kong, China. He reported his role as a consultant or advisory board member for AbbVie, AstraZeneca, Boehringer Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Intercept, Inventiva, Merck, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences, and is the cofounder of Illuminatio Medical Technology.
This guidance document allows clinicians to use a variety of NITs to start and monitor resmetirom therapy, precluding the need for a biopsy, lead author Mazen Noureddin, MD, of Houston Research Institute, Houston Methodist Hospital in Texas, and colleagues reported.
“The recent conditional approval by the [Food and Drug Administration] of resmetirom ... presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH,” the investigators wrote in Clinical Gastroenterology and Hepatology.
However, the approval also “presents important challenges,” they noted, “including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population.”
To help identify which patients should get this new intervention, Noureddin and colleagues considered benchmarks from published literature, and conducted a post hoc analysis of phase 3 MASTERO-NASH trial data. Trial enrollment required at least three cardiometabolic risk factors and a vibration-controlled transient elastography (VCTE) prescreening within the past 3 months. The population included 888 patients with F2 or F3 disease.
Recommendations were split into three categories: treat with resmetirom, consider treating with resmetirom, and do not treat with resmetirom.
The recommendation to treat calls for a VCTE of 10-15 kPa, a magnetic resonance elastography (MRE) of 3.3-4.2 kPa, or an Enhanced Liver Fibrosis (ELF) score of 9.2-10.4, with the caveat that an ELF score below 9.8 requires a second NIT for confirmation. Alternatively, a positive composite score such as FibroScan–aspartate aminotransferase (FAST), MRI–AST (MAST), or MRE + Fibrosis-4 (MEFIB) may serve as grounds for treatment. For any of the previous, platelets must concurrently be at least 140 with no evidence of portal hypertension.
The recommendation to consider treatment depends upon a VCTE of 15.1-19.9 kPa, an MRE of 4.3-4.9 kPa, an ELF score of 10.5-11.3, or positive FAST, MAST, or MEFIB. Again, these require a concurrent platelet count of 140 and no portal hypertension.
Finally, patients should not be treated with resmetirom if they have a VCTE of 20 kPa or greater, an MRE of 5 kPa or greater, and an ELF score greater than 11.3.
Noureddin and colleagues also offered guidance on monitoring strategies, including follow-up at 3, 6, and 12 months.
At 3 months, the focus should be safety, including screening for drug-related liver injury and other adverse events that warrant cessation.
At 6 months, alanine aminotransferase (ALT) levels, VCTE, or MRI–proton density fat fraction (PDFF) tests can indicate early response, but treatment should generally continue regardless of results.
At 12 months, efficacy can be fully evaluated. ALT normalization, or improvement of more than 17 IU/L or more than 20%, along with a 30% or greater drop in VCTE, or at least 30% drop in liver fat on MRI-PDFF, serve as grounds for continuation.
Noureddin and colleagues noted that ALT improvement should be paired with corresponding improvements in imaging, such as a 30% reduction in MRI-PDFF. Even if ALT levels do not improve, a 30% or greater reduction in MRI-PDFF can still indicate a positive response; however, VCTE alone may not be sufficient to fully assess treatment response.
“Emerging data, particularly regarding the noninvasive assessment of treatment response, are likely to further modify patient selection, safety signals, and efficacy algorithms,” they concluded.This study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, the John C. Martin Foundation, and the National Institute on Alcohol Abuse and Alcoholism. The investigators disclosed additional relationships with Novo Nordisk, Pfizer, Shire, and others.
This guidance document allows clinicians to use a variety of NITs to start and monitor resmetirom therapy, precluding the need for a biopsy, lead author Mazen Noureddin, MD, of Houston Research Institute, Houston Methodist Hospital in Texas, and colleagues reported.
“The recent conditional approval by the [Food and Drug Administration] of resmetirom ... presents a much-anticipated therapeutic option for patients with noncirrhotic advanced MASH,” the investigators wrote in Clinical Gastroenterology and Hepatology.
However, the approval also “presents important challenges,” they noted, “including how to noninvasively identify patients with fibrosis stages 2-3, and how to exclude patients with more advanced disease who should not be treated until further data emerge on the use of resmetirom in this population.”
To help identify which patients should get this new intervention, Noureddin and colleagues considered benchmarks from published literature, and conducted a post hoc analysis of phase 3 MASTERO-NASH trial data. Trial enrollment required at least three cardiometabolic risk factors and a vibration-controlled transient elastography (VCTE) prescreening within the past 3 months. The population included 888 patients with F2 or F3 disease.
Recommendations were split into three categories: treat with resmetirom, consider treating with resmetirom, and do not treat with resmetirom.
The recommendation to treat calls for a VCTE of 10-15 kPa, a magnetic resonance elastography (MRE) of 3.3-4.2 kPa, or an Enhanced Liver Fibrosis (ELF) score of 9.2-10.4, with the caveat that an ELF score below 9.8 requires a second NIT for confirmation. Alternatively, a positive composite score such as FibroScan–aspartate aminotransferase (FAST), MRI–AST (MAST), or MRE + Fibrosis-4 (MEFIB) may serve as grounds for treatment. For any of the previous, platelets must concurrently be at least 140 with no evidence of portal hypertension.
The recommendation to consider treatment depends upon a VCTE of 15.1-19.9 kPa, an MRE of 4.3-4.9 kPa, an ELF score of 10.5-11.3, or positive FAST, MAST, or MEFIB. Again, these require a concurrent platelet count of 140 and no portal hypertension.
Finally, patients should not be treated with resmetirom if they have a VCTE of 20 kPa or greater, an MRE of 5 kPa or greater, and an ELF score greater than 11.3.
Noureddin and colleagues also offered guidance on monitoring strategies, including follow-up at 3, 6, and 12 months.
At 3 months, the focus should be safety, including screening for drug-related liver injury and other adverse events that warrant cessation.
At 6 months, alanine aminotransferase (ALT) levels, VCTE, or MRI–proton density fat fraction (PDFF) tests can indicate early response, but treatment should generally continue regardless of results.
At 12 months, efficacy can be fully evaluated. ALT normalization, or improvement of more than 17 IU/L or more than 20%, along with a 30% or greater drop in VCTE, or at least 30% drop in liver fat on MRI-PDFF, serve as grounds for continuation.
Noureddin and colleagues noted that ALT improvement should be paired with corresponding improvements in imaging, such as a 30% reduction in MRI-PDFF. Even if ALT levels do not improve, a 30% or greater reduction in MRI-PDFF can still indicate a positive response; however, VCTE alone may not be sufficient to fully assess treatment response.
“Emerging data, particularly regarding the noninvasive assessment of treatment response, are likely to further modify patient selection, safety signals, and efficacy algorithms,” they concluded.This study was supported by the National Center for Advancing Translational Sciences, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, the John C. Martin Foundation, and the National Institute on Alcohol Abuse and Alcoholism. The investigators disclosed additional relationships with Novo Nordisk, Pfizer, Shire, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Family Medicine–Led Obstetric Units Achieve Lower C-Section Rates, Better Safety Culture
Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.
These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.
“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.
This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.
The role of FM in these initiatives therefore remains unexplored.
This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers
To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).
The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.
The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).
In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.
“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.
She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.
“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.
“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
The Model Itself Could Be the Biggest Finding
According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.
“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”
This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.
“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”
Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.
“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
Barriers May Block FM Providers From Obstetric Practice
In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?
Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.
In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.
“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.
Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.
“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.
“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”
Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.
Until then, this gap in maternity care remains an ongoing, and often personal, concern.
“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”
This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.
These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.
“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.
This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.
The role of FM in these initiatives therefore remains unexplored.
This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers
To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).
The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.
The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).
In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.
“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.
She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.
“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.
“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
The Model Itself Could Be the Biggest Finding
According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.
“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”
This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.
“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”
Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.
“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
Barriers May Block FM Providers From Obstetric Practice
In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?
Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.
In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.
“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.
Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.
“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.
“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”
Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.
Until then, this gap in maternity care remains an ongoing, and often personal, concern.
“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”
This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.
These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.
“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.
This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.
The role of FM in these initiatives therefore remains unexplored.
This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers
To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).
The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.
The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).
In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.
“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.
She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.
“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.
“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
The Model Itself Could Be the Biggest Finding
According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.
“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”
This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.
“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”
Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.
“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
Barriers May Block FM Providers From Obstetric Practice
In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?
Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.
In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.
“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.
Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.
“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.
“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”
Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.
Until then, this gap in maternity care remains an ongoing, and often personal, concern.
“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”
This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF FAMILY MEDICINE
Should First-Line Dual Checkpoint Blockade Be Used for NSCLC With Specific Mutations?
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.
according to the authors of a new paper.
These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.
“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.
Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
What Were the Original Findings of POSEIDON?
The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.
Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.
These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
What Did Post Hoc Analysis Highlight About POSEIDON?
The present analysis aimed to validate two actionable biomarkers.
“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.
From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.
As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.
This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.
Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
How Do Findings Relate to Previous NSCLC Subgroup Research?
Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.
“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.
Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.
“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”
Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.
MASLD Healthcare Costs Climbing Fast in Canada
according to a new study.
The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.
“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”
Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.
Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).
The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.
The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.
Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.
The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.
Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.
“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its clinical burden is expected to mirror the rising rates of obesity and diabetes over the next couple decades. The cost analysis by Memdovich and colleagues provides a timely report on the healthcare burden of MASLD in Canada. Their results are, nevertheless, generalizable to other healthcare systems.
The authors found that nearly 98% of total healthcare costs of patients with MASLD were not specifically related to liver treatment, but rather linked to the management of patients’ cardiometabolic comorbidities. Projection estimates based on this cohort suggests a steep rise in the total healthcare costs over the coming decades reflecting increasing rates of comorbidities, with largest changes expected in the advanced fibrosis patient group. These findings highlight the need for early recognition of MASLD followed by a collaborative effort in management of MASLD in conjunction with its associated cardiometabolic comorbidities.
As rates for obesity, diabetes, and MASLD continue to rise, there is an urgency to create a global strategy for MASLD management that focuses on both prevention and treatment. Public health strategies are needed to increase awareness and focus on the treatment and prevention cardiometabolic risk factors that appear to be the main drivers of healthcare costs among patients with MASLD. A concerted effort is needed from providers, both primary care and specialists, for early recognition and treatment of MASLD. Such a public health response combined with recent advent in pharmacotherapy for weight loss and metabolic dysfunction–associated steatohepatitis may alter the projected costs and hopefully decrease the disease burden associated advanced MASLD.
Akshay Shetty, MD, is assistant professor of medicine and surgery at the David Geffen School of Medicine, University of California, San Francisco. He has no conflicts of interest to declare. Sammy Saab, MD, MPH, AGAF, is professor of medicine and surgery at the David Geffen School of Medicine at UCLA. He is on the speakers bureau for AbbVie, Gilead, Eisai, Intercept, Ipsen, Salix, Mallinckrodt, and Takeda, and has been a consultant for Gilead, Ipsen, Mallinckrodt, Madrigal, and Orphalan.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its clinical burden is expected to mirror the rising rates of obesity and diabetes over the next couple decades. The cost analysis by Memdovich and colleagues provides a timely report on the healthcare burden of MASLD in Canada. Their results are, nevertheless, generalizable to other healthcare systems.
The authors found that nearly 98% of total healthcare costs of patients with MASLD were not specifically related to liver treatment, but rather linked to the management of patients’ cardiometabolic comorbidities. Projection estimates based on this cohort suggests a steep rise in the total healthcare costs over the coming decades reflecting increasing rates of comorbidities, with largest changes expected in the advanced fibrosis patient group. These findings highlight the need for early recognition of MASLD followed by a collaborative effort in management of MASLD in conjunction with its associated cardiometabolic comorbidities.
As rates for obesity, diabetes, and MASLD continue to rise, there is an urgency to create a global strategy for MASLD management that focuses on both prevention and treatment. Public health strategies are needed to increase awareness and focus on the treatment and prevention cardiometabolic risk factors that appear to be the main drivers of healthcare costs among patients with MASLD. A concerted effort is needed from providers, both primary care and specialists, for early recognition and treatment of MASLD. Such a public health response combined with recent advent in pharmacotherapy for weight loss and metabolic dysfunction–associated steatohepatitis may alter the projected costs and hopefully decrease the disease burden associated advanced MASLD.
Akshay Shetty, MD, is assistant professor of medicine and surgery at the David Geffen School of Medicine, University of California, San Francisco. He has no conflicts of interest to declare. Sammy Saab, MD, MPH, AGAF, is professor of medicine and surgery at the David Geffen School of Medicine at UCLA. He is on the speakers bureau for AbbVie, Gilead, Eisai, Intercept, Ipsen, Salix, Mallinckrodt, and Takeda, and has been a consultant for Gilead, Ipsen, Mallinckrodt, Madrigal, and Orphalan.
Metabolic dysfunction–associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its clinical burden is expected to mirror the rising rates of obesity and diabetes over the next couple decades. The cost analysis by Memdovich and colleagues provides a timely report on the healthcare burden of MASLD in Canada. Their results are, nevertheless, generalizable to other healthcare systems.
The authors found that nearly 98% of total healthcare costs of patients with MASLD were not specifically related to liver treatment, but rather linked to the management of patients’ cardiometabolic comorbidities. Projection estimates based on this cohort suggests a steep rise in the total healthcare costs over the coming decades reflecting increasing rates of comorbidities, with largest changes expected in the advanced fibrosis patient group. These findings highlight the need for early recognition of MASLD followed by a collaborative effort in management of MASLD in conjunction with its associated cardiometabolic comorbidities.
As rates for obesity, diabetes, and MASLD continue to rise, there is an urgency to create a global strategy for MASLD management that focuses on both prevention and treatment. Public health strategies are needed to increase awareness and focus on the treatment and prevention cardiometabolic risk factors that appear to be the main drivers of healthcare costs among patients with MASLD. A concerted effort is needed from providers, both primary care and specialists, for early recognition and treatment of MASLD. Such a public health response combined with recent advent in pharmacotherapy for weight loss and metabolic dysfunction–associated steatohepatitis may alter the projected costs and hopefully decrease the disease burden associated advanced MASLD.
Akshay Shetty, MD, is assistant professor of medicine and surgery at the David Geffen School of Medicine, University of California, San Francisco. He has no conflicts of interest to declare. Sammy Saab, MD, MPH, AGAF, is professor of medicine and surgery at the David Geffen School of Medicine at UCLA. He is on the speakers bureau for AbbVie, Gilead, Eisai, Intercept, Ipsen, Salix, Mallinckrodt, and Takeda, and has been a consultant for Gilead, Ipsen, Mallinckrodt, Madrigal, and Orphalan.
according to a new study.
The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.
“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”
Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.
Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).
The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.
The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.
Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.
The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.
Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.
“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.
according to a new study.
The expected surge reflects the growing prevalence of MASLD and its associated conditions, emphasizing the necessity for a comprehensive approach to address this escalating public health issue, reported lead author K. Ally Memedovich, BHSc, of the University of Calgary in Alberta, Canada, and colleagues.
“The costs associated with the management of MASLD in Canada remain unknown but have been estimated as being very high,” the investigators wrote in Gastro Hep Advances. “Specifically, in one study from the United States, the healthcare costs and utilization of those with MASLD was nearly double that of patients without MASLD but with similar health status. This difference was largely due to increases in imaging, hospitalization, liver fibrosis assessment, laboratory tests, and outpatient visits.”
Although projections are available to estimate the future prevalence of MASLD in Canada, no models are available to predict the growing national economic burden, prompting the present study.
Memedovich and colleagues analyzed healthcare usage data from 6,358 patients diagnosed with MASLD disease in Calgary from 2018 to 2020. Using provincial administrative data, they calculated both liver-specific and total healthcare costs associated with different stages of liver fibrosis, ranging from F0/F1 (minimal fibrosis) to F4 (advanced fibrosis or cirrhosis).
The patients’ liver fibrosis stages were determined using liver stiffness measurements obtained through shear wave elastography. Average annual cost per patient was then calculated for each fibrosis stage by analyzing hospitalizations, ambulatory care, and physician claims data.
The annual average liver-specific cost per patient increased with severity of liver fibrosis; costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$7.02, C$35.30, C$60.46, and C$72.55, respectively. By 2050, liver-specific healthcare costs are projected to increase by C$51 million, reaching C$136 million Canada-wide.
Total healthcare costs were markedly higher; annual costs for patients with fibrosis stages F0/F1, F2, F3, and F4 were C$397.90, C$781.53, C$2,881.84, and C$1,598.82, respectively. As a result, total healthcare costs are expected to rise by nearly C$2 billion, contributing to a Canadian healthcare burden of C$5.81 billion annually by 2050.
The study revealed that over 90% of the healthcare costs for MASLD patients were attributed not to liver disease itself but to the management of associated comorbidities such as diabetes, hypertension, mental illness, and obesity. For instance, diabetes was the most common reason for physician visits among MASLD patients, accounting for 65.2% of cases. One study limitation was exclusion of decompensated cirrhosis, liver cancer, or a liver transplant recipient because of low prevalence in this cohort, potentially contributing to low liver specific healthcare costs.
Memedovich and colleagues noted that chronic diseases account for approximately C$68 billion annually in direct healthcare costs in Canada, representing around 58% of total healthcare expenditures. Estimates suggest that 1% annual reduction in chronic disease prevalence could save C$107 billion over the course of 20 years.
“Therefore, an approach that focuses on preventing and managing chronic diseases overall is needed to reduce the burden of MASLD on the healthcare system,” they wrote. This study was funded by LiveRx via an Alberta Innovates grant. The investigators disclosed relationships with Gilead, Abbott, GSK, and others.
FROM GASTRO HEP ADVANCES
Vonoprazan Offers PPI Alternative for Heartburn with Non-Erosive Reflux
according to investigators.
Benefits of vonoprazan were seen as soon as the first day of treatment and persisted through the 20-week extension period, lead author Loren Laine, MD, AGAF, of Yale School of Medicine, New Haven, Connecticut, and colleagues reported.
“A potential alternative to PPI therapy is a potassium-competitive acid blocker, a new class of antisecretory agents that provide more potent inhibition of gastric acid secretion than PPIs,” the investigators wrote in Clinical Gastroenterology and Hepatology.
While a small observational study found that 18 out of 26 patients (69%) with PPI-resistant NERD had improved symptoms with vonoprazan, subsequent randomized trials in Japan failed to meet their primary endpoints, Laine and colleagues noted. The present randomized trial was therefore conducted to determine how vonoprazan might help a US patient population.
The study involved 772 patients who reported heartburn at least 4 days per week during screening, but without erosive esophagitis on endoscopy. Participants were randomized into three groups: placebo, vonoprazan 10 mg, or vonoprazan 20 mg. These protocols were administered for 4 weeks, followed by a 20-week extension, in which placebo patients were rerandomized to receive one of the two vonoprazan dose levels.
The primary endpoint was the percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days) during the initial 4-week treatment period. The secondary endpoint, assessed during the same timeframe, was percentage of days without need for a rescue antacid.
In the 4-week placebo-controlled period, patients treated with vonoprazan 10 mg and 20 mg showed a significant improvement in heartburn-free days, compared with placebo. The percentage of 24-hour heartburn-free days was 27.7% in the placebo group vs 44.8% in the 10-mg vonoprazan group (least squares mean difference 17.1%; P < .0001) and 44.4% in the 20 mg vonoprazan group (least squares mean difference 16.7%; P < .0001).
Benefits of vonoprazan were seen as early as the first day of treatment, with 8.3% and 11.6% more patients in the 10-mg and 20-mg groups, respectively, experiencing a heartburn-free day, compared with placebo. By day 2, these differences increased to 18.1% and 23.2%, respectively.
The percentage of days without rescue antacid use was also significantly higher in both vonoprazan groups. Patients in the 10 mg and 20 mg groups had 63.3% and 61.2% of days without antacid use, respectively, compared with 47.6% in the placebo group (P < .0001 for both comparisons).
These benefits persisted throughout the 20-week extension period, with similar percentages of heartburn-free days across all groups. Mean percentages of 24-hour heartburn-free days ranged from 61% to 63% in the extension phase, while median percentages spanned 76%-79%.
Adverse events were infrequent and comparable across all groups. The most common adverse event was nausea, occurring slightly more frequently in the vonoprazan groups (2.3% in the 10-mg group and 3.1% in the 20-mg group) vs placebo (0.4%). Serious adverse events were rare and were deemed unrelated to treatment. No new safety signals were identified during the 20-week extension period. Increases in serum gastrin levels, a marker of acid suppression, returned to near baseline after discontinuation of vonoprazan.
“In conclusion, the potassium-competitive acid blocker vonoprazan was efficacious in reducing heartburn symptoms in patients with NERD, with the benefit appearing to begin as early as the first day of therapy,” Laine and colleagues wrote.
In July 2024, the Food and Drug Administration approved vonoprazan for treating heartburn in patients with nonerosive gastroesophageal reflux disease.This study was funded by Phathom Pharmaceuticals. The investigators disclosed additional relationships with Takeda, Medtronic, Carnot, and others.
Proton pump inhibitors (PPIs) have revolutionized the treatment of gastroesophageal reflux disease (GERD). One might ask what the reason would be to challenge this giant of the pharmacopeia with another medication for GERD.
In this important study by Laine et al, vonoprazan is expectedly efficacious in treating nonerosive GERD (NERD) but notably less so when compared with the authors’ trial for erosive GERD. This is not surprising owing to the multiple and common acid independent etiologies of NERD, such as esophageal hypersensitivity. The high placebo response supports this. Two notable results, however, merit emphasis in potential advantages over PPIs.
First, vonoprazan is effective at day 1 of therapy by eliminating the need for loading. Second, nocturnal reflux, a purer form of GERD, is better controlled with a morning dose of vonopazan mitigating against nocturnal acid breakthrough and the need for twice-daily dosing with PPIs and/or addition of an H2 antagonist. These results by no means advocate for replacement of PPIs with PCABs, but at least suggest specific populations of GERD patients who may specifically benefit from PCAB use. The study also indirectly emphasizes that careful selection of NERD patients whose GERD symptoms are predominantly caused by increased esophageal acid exposure are the most appropriate candidates. The ultimate answer as to where vonoprazan will be used in our practice is evolving.
David Katzka, MD, is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City. He has received research support from Takeda, Sanofi, and Regeneron. He is also an associate editor for GI & Hepatology News.
Proton pump inhibitors (PPIs) have revolutionized the treatment of gastroesophageal reflux disease (GERD). One might ask what the reason would be to challenge this giant of the pharmacopeia with another medication for GERD.
In this important study by Laine et al, vonoprazan is expectedly efficacious in treating nonerosive GERD (NERD) but notably less so when compared with the authors’ trial for erosive GERD. This is not surprising owing to the multiple and common acid independent etiologies of NERD, such as esophageal hypersensitivity. The high placebo response supports this. Two notable results, however, merit emphasis in potential advantages over PPIs.
First, vonoprazan is effective at day 1 of therapy by eliminating the need for loading. Second, nocturnal reflux, a purer form of GERD, is better controlled with a morning dose of vonopazan mitigating against nocturnal acid breakthrough and the need for twice-daily dosing with PPIs and/or addition of an H2 antagonist. These results by no means advocate for replacement of PPIs with PCABs, but at least suggest specific populations of GERD patients who may specifically benefit from PCAB use. The study also indirectly emphasizes that careful selection of NERD patients whose GERD symptoms are predominantly caused by increased esophageal acid exposure are the most appropriate candidates. The ultimate answer as to where vonoprazan will be used in our practice is evolving.
David Katzka, MD, is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City. He has received research support from Takeda, Sanofi, and Regeneron. He is also an associate editor for GI & Hepatology News.
Proton pump inhibitors (PPIs) have revolutionized the treatment of gastroesophageal reflux disease (GERD). One might ask what the reason would be to challenge this giant of the pharmacopeia with another medication for GERD.
In this important study by Laine et al, vonoprazan is expectedly efficacious in treating nonerosive GERD (NERD) but notably less so when compared with the authors’ trial for erosive GERD. This is not surprising owing to the multiple and common acid independent etiologies of NERD, such as esophageal hypersensitivity. The high placebo response supports this. Two notable results, however, merit emphasis in potential advantages over PPIs.
First, vonoprazan is effective at day 1 of therapy by eliminating the need for loading. Second, nocturnal reflux, a purer form of GERD, is better controlled with a morning dose of vonopazan mitigating against nocturnal acid breakthrough and the need for twice-daily dosing with PPIs and/or addition of an H2 antagonist. These results by no means advocate for replacement of PPIs with PCABs, but at least suggest specific populations of GERD patients who may specifically benefit from PCAB use. The study also indirectly emphasizes that careful selection of NERD patients whose GERD symptoms are predominantly caused by increased esophageal acid exposure are the most appropriate candidates. The ultimate answer as to where vonoprazan will be used in our practice is evolving.
David Katzka, MD, is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York City. He has received research support from Takeda, Sanofi, and Regeneron. He is also an associate editor for GI & Hepatology News.
according to investigators.
Benefits of vonoprazan were seen as soon as the first day of treatment and persisted through the 20-week extension period, lead author Loren Laine, MD, AGAF, of Yale School of Medicine, New Haven, Connecticut, and colleagues reported.
“A potential alternative to PPI therapy is a potassium-competitive acid blocker, a new class of antisecretory agents that provide more potent inhibition of gastric acid secretion than PPIs,” the investigators wrote in Clinical Gastroenterology and Hepatology.
While a small observational study found that 18 out of 26 patients (69%) with PPI-resistant NERD had improved symptoms with vonoprazan, subsequent randomized trials in Japan failed to meet their primary endpoints, Laine and colleagues noted. The present randomized trial was therefore conducted to determine how vonoprazan might help a US patient population.
The study involved 772 patients who reported heartburn at least 4 days per week during screening, but without erosive esophagitis on endoscopy. Participants were randomized into three groups: placebo, vonoprazan 10 mg, or vonoprazan 20 mg. These protocols were administered for 4 weeks, followed by a 20-week extension, in which placebo patients were rerandomized to receive one of the two vonoprazan dose levels.
The primary endpoint was the percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days) during the initial 4-week treatment period. The secondary endpoint, assessed during the same timeframe, was percentage of days without need for a rescue antacid.
In the 4-week placebo-controlled period, patients treated with vonoprazan 10 mg and 20 mg showed a significant improvement in heartburn-free days, compared with placebo. The percentage of 24-hour heartburn-free days was 27.7% in the placebo group vs 44.8% in the 10-mg vonoprazan group (least squares mean difference 17.1%; P < .0001) and 44.4% in the 20 mg vonoprazan group (least squares mean difference 16.7%; P < .0001).
Benefits of vonoprazan were seen as early as the first day of treatment, with 8.3% and 11.6% more patients in the 10-mg and 20-mg groups, respectively, experiencing a heartburn-free day, compared with placebo. By day 2, these differences increased to 18.1% and 23.2%, respectively.
The percentage of days without rescue antacid use was also significantly higher in both vonoprazan groups. Patients in the 10 mg and 20 mg groups had 63.3% and 61.2% of days without antacid use, respectively, compared with 47.6% in the placebo group (P < .0001 for both comparisons).
These benefits persisted throughout the 20-week extension period, with similar percentages of heartburn-free days across all groups. Mean percentages of 24-hour heartburn-free days ranged from 61% to 63% in the extension phase, while median percentages spanned 76%-79%.
Adverse events were infrequent and comparable across all groups. The most common adverse event was nausea, occurring slightly more frequently in the vonoprazan groups (2.3% in the 10-mg group and 3.1% in the 20-mg group) vs placebo (0.4%). Serious adverse events were rare and were deemed unrelated to treatment. No new safety signals were identified during the 20-week extension period. Increases in serum gastrin levels, a marker of acid suppression, returned to near baseline after discontinuation of vonoprazan.
“In conclusion, the potassium-competitive acid blocker vonoprazan was efficacious in reducing heartburn symptoms in patients with NERD, with the benefit appearing to begin as early as the first day of therapy,” Laine and colleagues wrote.
In July 2024, the Food and Drug Administration approved vonoprazan for treating heartburn in patients with nonerosive gastroesophageal reflux disease.This study was funded by Phathom Pharmaceuticals. The investigators disclosed additional relationships with Takeda, Medtronic, Carnot, and others.
according to investigators.
Benefits of vonoprazan were seen as soon as the first day of treatment and persisted through the 20-week extension period, lead author Loren Laine, MD, AGAF, of Yale School of Medicine, New Haven, Connecticut, and colleagues reported.
“A potential alternative to PPI therapy is a potassium-competitive acid blocker, a new class of antisecretory agents that provide more potent inhibition of gastric acid secretion than PPIs,” the investigators wrote in Clinical Gastroenterology and Hepatology.
While a small observational study found that 18 out of 26 patients (69%) with PPI-resistant NERD had improved symptoms with vonoprazan, subsequent randomized trials in Japan failed to meet their primary endpoints, Laine and colleagues noted. The present randomized trial was therefore conducted to determine how vonoprazan might help a US patient population.
The study involved 772 patients who reported heartburn at least 4 days per week during screening, but without erosive esophagitis on endoscopy. Participants were randomized into three groups: placebo, vonoprazan 10 mg, or vonoprazan 20 mg. These protocols were administered for 4 weeks, followed by a 20-week extension, in which placebo patients were rerandomized to receive one of the two vonoprazan dose levels.
The primary endpoint was the percentage of days without daytime or nighttime heartburn (24-hour heartburn-free days) during the initial 4-week treatment period. The secondary endpoint, assessed during the same timeframe, was percentage of days without need for a rescue antacid.
In the 4-week placebo-controlled period, patients treated with vonoprazan 10 mg and 20 mg showed a significant improvement in heartburn-free days, compared with placebo. The percentage of 24-hour heartburn-free days was 27.7% in the placebo group vs 44.8% in the 10-mg vonoprazan group (least squares mean difference 17.1%; P < .0001) and 44.4% in the 20 mg vonoprazan group (least squares mean difference 16.7%; P < .0001).
Benefits of vonoprazan were seen as early as the first day of treatment, with 8.3% and 11.6% more patients in the 10-mg and 20-mg groups, respectively, experiencing a heartburn-free day, compared with placebo. By day 2, these differences increased to 18.1% and 23.2%, respectively.
The percentage of days without rescue antacid use was also significantly higher in both vonoprazan groups. Patients in the 10 mg and 20 mg groups had 63.3% and 61.2% of days without antacid use, respectively, compared with 47.6% in the placebo group (P < .0001 for both comparisons).
These benefits persisted throughout the 20-week extension period, with similar percentages of heartburn-free days across all groups. Mean percentages of 24-hour heartburn-free days ranged from 61% to 63% in the extension phase, while median percentages spanned 76%-79%.
Adverse events were infrequent and comparable across all groups. The most common adverse event was nausea, occurring slightly more frequently in the vonoprazan groups (2.3% in the 10-mg group and 3.1% in the 20-mg group) vs placebo (0.4%). Serious adverse events were rare and were deemed unrelated to treatment. No new safety signals were identified during the 20-week extension period. Increases in serum gastrin levels, a marker of acid suppression, returned to near baseline after discontinuation of vonoprazan.
“In conclusion, the potassium-competitive acid blocker vonoprazan was efficacious in reducing heartburn symptoms in patients with NERD, with the benefit appearing to begin as early as the first day of therapy,” Laine and colleagues wrote.
In July 2024, the Food and Drug Administration approved vonoprazan for treating heartburn in patients with nonerosive gastroesophageal reflux disease.This study was funded by Phathom Pharmaceuticals. The investigators disclosed additional relationships with Takeda, Medtronic, Carnot, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Celiac Screening in Kids Appears Cost-Effective
If these screening strategies are deemed feasible by clinicians and patients, then implementation in routine care is needed, lead author Jan Heijdra Suasnabar, MSc, of Leiden University Medical Centre in the Netherlands, and colleagues reported.
“Cohort studies have shown that CD likely develops early in life and can be easily diagnosed by detection of CD-specific antibodies against the enzyme tissue transglutaminase type 2 (IgA-TG2),” the investigators wrote in Gastroenterology.
Despite the ease of diagnosis, as few as one in five cases of CD are detected using current clinical strategies, meaning many cases are diagnosed years after symptom onset.
“Such high rates of missed/delayed diagnoses have been attributed to CD’s varied and nonspecific symptoms, lack of awareness, and the resource-intensive process necessary to establish the diagnosis,” Heijdra Suasnabar and colleagues wrote. “From an economic perspective, the burden of CD translates into substantial excess healthcare and societal costs.”
These practice gaps prompted the present study, which explored the long-term cost effectiveness of mass CD screening and active case finding among pediatric patients.
The investigators employed a model-based cost-effectiveness analysis with a hypothetical cohort representing all children with CD in the Netherlands. Iterations of this model evaluated long-term costs as these children moved through the healthcare system along various CD detection strategies.
The first strategy was based on the current Dutch approach, which is the same as that in the United States: Patients are only evaluated for CD if they present with symptoms that prompt suspicion of disease. Based on data from population-based studies, the model assumed that approximately one in three cases would be detected using this strategy.
The second strategy involved mass screening using IgA-TG2 point-of-care testing (sensitivity, 0.94; specificity, 0.944) via youth health care clinics, regardless of symptoms.
The third strategy, called “active case finding,” represented something of an intermediate approach, in which children with at least 1 CD-related symptom underwent point-of-care antibody testing.
For both mass screening and active case finding strategies, a positive antibody test was followed with confirmatory diagnostic testing.
Compared with current clinical approach, mass screening added 7.46 more quality-adjusted life-years (QALYs) per CD patient with an increased cost of €28,635 per CD patient. Active case finding gained 4.33 QALYs per CD patient while incurring an additional cost of €15,585 per CD patient.
Based on a willingness-to-pay threshold of €20,000 per QALY, the investigators deemed both strategies “highly cost effective,” compared with current standard of care. Some of these costs were offset by “substantial” reductions in productivity losses, they noted, including CD-related absences from work and school.
“Our results illustrate how an earlier detection of CD through screening or case finding, although more costly, leads to improved health outcomes and a reduction in disease burden, compared with current care,” Heijdra Suasnabar and colleagues wrote.
Their concluding remarks highlighted the conservative scenarios built into their model, and suggested that their findings offer solid evidence for implementing new CD-testing strategies.
“If found to be feasible and acceptable by clinicians and patients, these strategies should be implemented in the Netherlands,” they wrote.This study was supported by the Netherlands Organization for Health Research and Development. The investigators disclosed no conflicts of interest.
Celiac disease (CD) is common, affecting about 1% of the population, but it remains underdiagnosed because of its heterogeneous presentation and limited provider awareness. Most cases are detected only after patients develop gastrointestinal symptoms or laboratory abnormalities.
In this cost-effectiveness analysis, Suasnabar and colleagues demonstrate that screening children for celiac disease would be highly cost-effective relative to the current practice of clinical detection. They modeled point-of-care-testing using tissue transglutaminase IgA in all 3-year-old children in the Netherlands. While both mass screening and case-finding (via a standardized questionnaire) would increase healthcare costs relative to current care, both strategies would improve quality of life (QoL), reduce long-term complications (such as osteoporosis and non-Hodgkin lymphoma), and minimize productivity losses in individuals with CD. In sensitivity analyses accounting for uncertainty in QoL inputs and in the utility of diagnosing and treating asymptomatic CD, each screening strategy remained well below accepted willingness-to-pay thresholds.
John B. Doyle, MD, is a gastroenterology fellow in the Division of Digestive and Liver Diseases at Columbia University Medical Center, New York City. Benjamin Lebwohl, MD, MS, AGAF, is professor of medicine and epidemiology at Columbia University Medical Center and director of clinical research at The Celiac Disease Center at Columbia. They have no conflicts of interest to declare.
Celiac disease (CD) is common, affecting about 1% of the population, but it remains underdiagnosed because of its heterogeneous presentation and limited provider awareness. Most cases are detected only after patients develop gastrointestinal symptoms or laboratory abnormalities.
In this cost-effectiveness analysis, Suasnabar and colleagues demonstrate that screening children for celiac disease would be highly cost-effective relative to the current practice of clinical detection. They modeled point-of-care-testing using tissue transglutaminase IgA in all 3-year-old children in the Netherlands. While both mass screening and case-finding (via a standardized questionnaire) would increase healthcare costs relative to current care, both strategies would improve quality of life (QoL), reduce long-term complications (such as osteoporosis and non-Hodgkin lymphoma), and minimize productivity losses in individuals with CD. In sensitivity analyses accounting for uncertainty in QoL inputs and in the utility of diagnosing and treating asymptomatic CD, each screening strategy remained well below accepted willingness-to-pay thresholds.
John B. Doyle, MD, is a gastroenterology fellow in the Division of Digestive and Liver Diseases at Columbia University Medical Center, New York City. Benjamin Lebwohl, MD, MS, AGAF, is professor of medicine and epidemiology at Columbia University Medical Center and director of clinical research at The Celiac Disease Center at Columbia. They have no conflicts of interest to declare.
Celiac disease (CD) is common, affecting about 1% of the population, but it remains underdiagnosed because of its heterogeneous presentation and limited provider awareness. Most cases are detected only after patients develop gastrointestinal symptoms or laboratory abnormalities.
In this cost-effectiveness analysis, Suasnabar and colleagues demonstrate that screening children for celiac disease would be highly cost-effective relative to the current practice of clinical detection. They modeled point-of-care-testing using tissue transglutaminase IgA in all 3-year-old children in the Netherlands. While both mass screening and case-finding (via a standardized questionnaire) would increase healthcare costs relative to current care, both strategies would improve quality of life (QoL), reduce long-term complications (such as osteoporosis and non-Hodgkin lymphoma), and minimize productivity losses in individuals with CD. In sensitivity analyses accounting for uncertainty in QoL inputs and in the utility of diagnosing and treating asymptomatic CD, each screening strategy remained well below accepted willingness-to-pay thresholds.
John B. Doyle, MD, is a gastroenterology fellow in the Division of Digestive and Liver Diseases at Columbia University Medical Center, New York City. Benjamin Lebwohl, MD, MS, AGAF, is professor of medicine and epidemiology at Columbia University Medical Center and director of clinical research at The Celiac Disease Center at Columbia. They have no conflicts of interest to declare.
If these screening strategies are deemed feasible by clinicians and patients, then implementation in routine care is needed, lead author Jan Heijdra Suasnabar, MSc, of Leiden University Medical Centre in the Netherlands, and colleagues reported.
“Cohort studies have shown that CD likely develops early in life and can be easily diagnosed by detection of CD-specific antibodies against the enzyme tissue transglutaminase type 2 (IgA-TG2),” the investigators wrote in Gastroenterology.
Despite the ease of diagnosis, as few as one in five cases of CD are detected using current clinical strategies, meaning many cases are diagnosed years after symptom onset.
“Such high rates of missed/delayed diagnoses have been attributed to CD’s varied and nonspecific symptoms, lack of awareness, and the resource-intensive process necessary to establish the diagnosis,” Heijdra Suasnabar and colleagues wrote. “From an economic perspective, the burden of CD translates into substantial excess healthcare and societal costs.”
These practice gaps prompted the present study, which explored the long-term cost effectiveness of mass CD screening and active case finding among pediatric patients.
The investigators employed a model-based cost-effectiveness analysis with a hypothetical cohort representing all children with CD in the Netherlands. Iterations of this model evaluated long-term costs as these children moved through the healthcare system along various CD detection strategies.
The first strategy was based on the current Dutch approach, which is the same as that in the United States: Patients are only evaluated for CD if they present with symptoms that prompt suspicion of disease. Based on data from population-based studies, the model assumed that approximately one in three cases would be detected using this strategy.
The second strategy involved mass screening using IgA-TG2 point-of-care testing (sensitivity, 0.94; specificity, 0.944) via youth health care clinics, regardless of symptoms.
The third strategy, called “active case finding,” represented something of an intermediate approach, in which children with at least 1 CD-related symptom underwent point-of-care antibody testing.
For both mass screening and active case finding strategies, a positive antibody test was followed with confirmatory diagnostic testing.
Compared with current clinical approach, mass screening added 7.46 more quality-adjusted life-years (QALYs) per CD patient with an increased cost of €28,635 per CD patient. Active case finding gained 4.33 QALYs per CD patient while incurring an additional cost of €15,585 per CD patient.
Based on a willingness-to-pay threshold of €20,000 per QALY, the investigators deemed both strategies “highly cost effective,” compared with current standard of care. Some of these costs were offset by “substantial” reductions in productivity losses, they noted, including CD-related absences from work and school.
“Our results illustrate how an earlier detection of CD through screening or case finding, although more costly, leads to improved health outcomes and a reduction in disease burden, compared with current care,” Heijdra Suasnabar and colleagues wrote.
Their concluding remarks highlighted the conservative scenarios built into their model, and suggested that their findings offer solid evidence for implementing new CD-testing strategies.
“If found to be feasible and acceptable by clinicians and patients, these strategies should be implemented in the Netherlands,” they wrote.This study was supported by the Netherlands Organization for Health Research and Development. The investigators disclosed no conflicts of interest.
If these screening strategies are deemed feasible by clinicians and patients, then implementation in routine care is needed, lead author Jan Heijdra Suasnabar, MSc, of Leiden University Medical Centre in the Netherlands, and colleagues reported.
“Cohort studies have shown that CD likely develops early in life and can be easily diagnosed by detection of CD-specific antibodies against the enzyme tissue transglutaminase type 2 (IgA-TG2),” the investigators wrote in Gastroenterology.
Despite the ease of diagnosis, as few as one in five cases of CD are detected using current clinical strategies, meaning many cases are diagnosed years after symptom onset.
“Such high rates of missed/delayed diagnoses have been attributed to CD’s varied and nonspecific symptoms, lack of awareness, and the resource-intensive process necessary to establish the diagnosis,” Heijdra Suasnabar and colleagues wrote. “From an economic perspective, the burden of CD translates into substantial excess healthcare and societal costs.”
These practice gaps prompted the present study, which explored the long-term cost effectiveness of mass CD screening and active case finding among pediatric patients.
The investigators employed a model-based cost-effectiveness analysis with a hypothetical cohort representing all children with CD in the Netherlands. Iterations of this model evaluated long-term costs as these children moved through the healthcare system along various CD detection strategies.
The first strategy was based on the current Dutch approach, which is the same as that in the United States: Patients are only evaluated for CD if they present with symptoms that prompt suspicion of disease. Based on data from population-based studies, the model assumed that approximately one in three cases would be detected using this strategy.
The second strategy involved mass screening using IgA-TG2 point-of-care testing (sensitivity, 0.94; specificity, 0.944) via youth health care clinics, regardless of symptoms.
The third strategy, called “active case finding,” represented something of an intermediate approach, in which children with at least 1 CD-related symptom underwent point-of-care antibody testing.
For both mass screening and active case finding strategies, a positive antibody test was followed with confirmatory diagnostic testing.
Compared with current clinical approach, mass screening added 7.46 more quality-adjusted life-years (QALYs) per CD patient with an increased cost of €28,635 per CD patient. Active case finding gained 4.33 QALYs per CD patient while incurring an additional cost of €15,585 per CD patient.
Based on a willingness-to-pay threshold of €20,000 per QALY, the investigators deemed both strategies “highly cost effective,” compared with current standard of care. Some of these costs were offset by “substantial” reductions in productivity losses, they noted, including CD-related absences from work and school.
“Our results illustrate how an earlier detection of CD through screening or case finding, although more costly, leads to improved health outcomes and a reduction in disease burden, compared with current care,” Heijdra Suasnabar and colleagues wrote.
Their concluding remarks highlighted the conservative scenarios built into their model, and suggested that their findings offer solid evidence for implementing new CD-testing strategies.
“If found to be feasible and acceptable by clinicians and patients, these strategies should be implemented in the Netherlands,” they wrote.This study was supported by the Netherlands Organization for Health Research and Development. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Low Follow-up of Abnormal Urine Proteinuria Dipstick Tests in Primary Care
Only 1 in 15 urine dipstick tests showing proteinuria in the primary care setting are followed up with albuminuria quantification testing, according to investigators.
These findings expose a broad gap in screening for chronic kidney disease (CKD), which is especially concerning since newer kidney-protecting agents are more effective when prescribed earlier in the disease course, reported lead author Yunwen Xu, PhD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.
“Evidence-based prescription of renin-angiotensin system inhibitors, glucagon-like peptide-1 receptor (GLP-1) agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) relies on the level of albuminuria,” the investigators wrote in Annals of Internal Medicine.
“Although urine albumin-creatinine ratio (ACR) is the most accurate method for quantifying albuminuria, dipstick urinalysis tests are inexpensive and are often used as an initial screening test, with guidelines recommending follow-up ACR testing if the protein dipstick test result is abnormal.”
Despite this guidance, real-world follow-up rates have been unknown, prompting the present study. Real-world data show a low follow-up rate. Dr. Xu and colleagues analyzed data from 1 million patients in 33 health systems who underwent urine dipstick testing in a primary care setting.
Across this population, 13% of patients had proteinuria, but only 6.7% underwent follow-up albuminuria quantification testing within the next year. ACR was the most common method (86%).
Likelihood of follow-up increased slightly with the level of proteinuria detected; however, absolute differences were marginal, with a 3+ result yielding a follow-up rate of just 8%, compared with 7.3% for a 2+ result and 6.3% for a 1+ result. When albuminuria quantification tests were conducted, 1+, 2+, and 3+ dipstick results were associated with albuminuria rates of 36.3%, 53.0%, and 64.9%, respectively.
Patients with diabetes had the highest follow-up rate, at 16.6%, vs 3.8% for those without diabetes.
Reasons for Low Follow-up Unclear
The dataset did not include information about reasons for ordering urinalyses, whether primary care providers knew about the abnormal dipstick tests, or awareness of guideline recommendations.
“I think they know it should be done,” said principal investigator Alexander R. Chang, MD, associate professor in the department of nephrology and population health sciences at Geisinger Health, Danville, Pennsylvania.
He suggested that real-time awareness issues, especially within electronic health record (EHR) systems, could explain the low follow-up rates. Blood test abnormalities are often flagged in red in EHRs, he said in an interview, but urine dipstick results typically remain in plain black and white.
“So, then it sort of requires that extra cognitive step to kind of look at that [result], and say, okay, that is pretty abnormal; I should do something about that,” he said.
Neil S. Skolnik, MD, a primary care physician at Jefferson Health, Abington, Pennsylvania, was surprised by the findings. “If you get a urinalysis and there’s protein, normally you follow up,” Dr. Skolnik said in an interview. “I have a feeling that there’s something we’re not seeing here about what’s going on. It is hard to imagine that in only 1 out of 15 times that proteinuria is identified, is there any follow-up. I really don’t have a good explanation.”
Renee Marie Betancourt, MD, associate professor and vice chair of diversity, equity, and inclusion in the Department of Family Medicine and Community Health at the University of Pennsylvania Perelman School of Medicine, Philadelphia, said it is hard to draw conclusions from the available data, but agreed that low visibility of results could be partially to blame.
“The chart doesn’t tell me [a urine dipstick result] is abnormal,” Dr. Betancourt said in an interview. “The chart just reports it, agnostic of normal or abnormal.”
Beyond issues with visibility, Dr. Betancourt described how primary care physicians are often so flooded with other concerns that a positive dipstick test can become a low priority, particularly among patients with CKD, who typically have other health issues.
“I oftentimes spend the majority of my visit on the patient’s concerns, and sometimes, beyond their concerns, I have concerns, and [a urine dipstick result] might not make it to the top of the list,” she said.
EHR-Based Interventions Might Help Improve Follow-up
Dr. Chang suggested that improved visibility of dipstick results could help, or possibly EHR-integrated clinical decision tools.
Dr. Betancourt and colleagues at Penn Medicine are actively working on such a solution. Their EHR-based intervention is aimed at identifying and managing patients with CKD. The present design, slated for pilot testing at one or two primary care clinics beginning in January 2025, depends upon estimated glomerular filtration rate (eGFR) to flag CKD patients, with ACR testing recommended yearly to predict disease progression.
Although urine dipstick findings are not currently a part of this software pathway, the findings from the present study might influence future strategy.
“I’m going to take this to our collaborators and ask about opportunities to ... encourage providers to be more active with dipsticks,” Dr. Betancourt said.
Newer Medications Are Effective, but Prescribing Challenges Remain
Ideally, CKD screening improvements will unlock a greater goal: prescribing kidney-protecting medications to patients who need them — as soon as they need them.
Here might lie the real knowledge gap among experienced primary care physicians, Dr. Chang suggested. “In the past, there wasn’t quite as much that you could do about having proteinuria,” he said. “But now we have lots more medications ... it’s not just tracking that they have a bad prognostic factor. [Proteinuria is] actually something that we can act upon.”
Who exactly should be prescribing these kidney-protecting medications, however, remains contested, as agents like GLP-1 agonists and SGLT2 inhibitors yield benefits across specialties, including nephrology, cardiology, and endocrinology.
“Everyone’s going to have to work together,” Dr. Chang said. “You can’t really put it all on the [primary care physician] to quarterback everything.”
And, regardless of who throws the ball, a touchdown is not guaranteed.
Dr. Betancourt called out the high cost of these newer drugs and described how some of her patients, already facing multiple health inequities, are left without.
“I have patients who cannot fill these medications because the copay is too high,” she said. “Just last week I received a message from a patient who stopped taking his SGLT2 inhibitor because the cost was too high ... it was over $300 per month.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors’ conflicts of interests are available in the original paper. Dr. Skolnik and Dr. Betancourt reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
Only 1 in 15 urine dipstick tests showing proteinuria in the primary care setting are followed up with albuminuria quantification testing, according to investigators.
These findings expose a broad gap in screening for chronic kidney disease (CKD), which is especially concerning since newer kidney-protecting agents are more effective when prescribed earlier in the disease course, reported lead author Yunwen Xu, PhD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.
“Evidence-based prescription of renin-angiotensin system inhibitors, glucagon-like peptide-1 receptor (GLP-1) agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) relies on the level of albuminuria,” the investigators wrote in Annals of Internal Medicine.
“Although urine albumin-creatinine ratio (ACR) is the most accurate method for quantifying albuminuria, dipstick urinalysis tests are inexpensive and are often used as an initial screening test, with guidelines recommending follow-up ACR testing if the protein dipstick test result is abnormal.”
Despite this guidance, real-world follow-up rates have been unknown, prompting the present study. Real-world data show a low follow-up rate. Dr. Xu and colleagues analyzed data from 1 million patients in 33 health systems who underwent urine dipstick testing in a primary care setting.
Across this population, 13% of patients had proteinuria, but only 6.7% underwent follow-up albuminuria quantification testing within the next year. ACR was the most common method (86%).
Likelihood of follow-up increased slightly with the level of proteinuria detected; however, absolute differences were marginal, with a 3+ result yielding a follow-up rate of just 8%, compared with 7.3% for a 2+ result and 6.3% for a 1+ result. When albuminuria quantification tests were conducted, 1+, 2+, and 3+ dipstick results were associated with albuminuria rates of 36.3%, 53.0%, and 64.9%, respectively.
Patients with diabetes had the highest follow-up rate, at 16.6%, vs 3.8% for those without diabetes.
Reasons for Low Follow-up Unclear
The dataset did not include information about reasons for ordering urinalyses, whether primary care providers knew about the abnormal dipstick tests, or awareness of guideline recommendations.
“I think they know it should be done,” said principal investigator Alexander R. Chang, MD, associate professor in the department of nephrology and population health sciences at Geisinger Health, Danville, Pennsylvania.
He suggested that real-time awareness issues, especially within electronic health record (EHR) systems, could explain the low follow-up rates. Blood test abnormalities are often flagged in red in EHRs, he said in an interview, but urine dipstick results typically remain in plain black and white.
“So, then it sort of requires that extra cognitive step to kind of look at that [result], and say, okay, that is pretty abnormal; I should do something about that,” he said.
Neil S. Skolnik, MD, a primary care physician at Jefferson Health, Abington, Pennsylvania, was surprised by the findings. “If you get a urinalysis and there’s protein, normally you follow up,” Dr. Skolnik said in an interview. “I have a feeling that there’s something we’re not seeing here about what’s going on. It is hard to imagine that in only 1 out of 15 times that proteinuria is identified, is there any follow-up. I really don’t have a good explanation.”
Renee Marie Betancourt, MD, associate professor and vice chair of diversity, equity, and inclusion in the Department of Family Medicine and Community Health at the University of Pennsylvania Perelman School of Medicine, Philadelphia, said it is hard to draw conclusions from the available data, but agreed that low visibility of results could be partially to blame.
“The chart doesn’t tell me [a urine dipstick result] is abnormal,” Dr. Betancourt said in an interview. “The chart just reports it, agnostic of normal or abnormal.”
Beyond issues with visibility, Dr. Betancourt described how primary care physicians are often so flooded with other concerns that a positive dipstick test can become a low priority, particularly among patients with CKD, who typically have other health issues.
“I oftentimes spend the majority of my visit on the patient’s concerns, and sometimes, beyond their concerns, I have concerns, and [a urine dipstick result] might not make it to the top of the list,” she said.
EHR-Based Interventions Might Help Improve Follow-up
Dr. Chang suggested that improved visibility of dipstick results could help, or possibly EHR-integrated clinical decision tools.
Dr. Betancourt and colleagues at Penn Medicine are actively working on such a solution. Their EHR-based intervention is aimed at identifying and managing patients with CKD. The present design, slated for pilot testing at one or two primary care clinics beginning in January 2025, depends upon estimated glomerular filtration rate (eGFR) to flag CKD patients, with ACR testing recommended yearly to predict disease progression.
Although urine dipstick findings are not currently a part of this software pathway, the findings from the present study might influence future strategy.
“I’m going to take this to our collaborators and ask about opportunities to ... encourage providers to be more active with dipsticks,” Dr. Betancourt said.
Newer Medications Are Effective, but Prescribing Challenges Remain
Ideally, CKD screening improvements will unlock a greater goal: prescribing kidney-protecting medications to patients who need them — as soon as they need them.
Here might lie the real knowledge gap among experienced primary care physicians, Dr. Chang suggested. “In the past, there wasn’t quite as much that you could do about having proteinuria,” he said. “But now we have lots more medications ... it’s not just tracking that they have a bad prognostic factor. [Proteinuria is] actually something that we can act upon.”
Who exactly should be prescribing these kidney-protecting medications, however, remains contested, as agents like GLP-1 agonists and SGLT2 inhibitors yield benefits across specialties, including nephrology, cardiology, and endocrinology.
“Everyone’s going to have to work together,” Dr. Chang said. “You can’t really put it all on the [primary care physician] to quarterback everything.”
And, regardless of who throws the ball, a touchdown is not guaranteed.
Dr. Betancourt called out the high cost of these newer drugs and described how some of her patients, already facing multiple health inequities, are left without.
“I have patients who cannot fill these medications because the copay is too high,” she said. “Just last week I received a message from a patient who stopped taking his SGLT2 inhibitor because the cost was too high ... it was over $300 per month.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors’ conflicts of interests are available in the original paper. Dr. Skolnik and Dr. Betancourt reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
Only 1 in 15 urine dipstick tests showing proteinuria in the primary care setting are followed up with albuminuria quantification testing, according to investigators.
These findings expose a broad gap in screening for chronic kidney disease (CKD), which is especially concerning since newer kidney-protecting agents are more effective when prescribed earlier in the disease course, reported lead author Yunwen Xu, PhD, of Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.
“Evidence-based prescription of renin-angiotensin system inhibitors, glucagon-like peptide-1 receptor (GLP-1) agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) relies on the level of albuminuria,” the investigators wrote in Annals of Internal Medicine.
“Although urine albumin-creatinine ratio (ACR) is the most accurate method for quantifying albuminuria, dipstick urinalysis tests are inexpensive and are often used as an initial screening test, with guidelines recommending follow-up ACR testing if the protein dipstick test result is abnormal.”
Despite this guidance, real-world follow-up rates have been unknown, prompting the present study. Real-world data show a low follow-up rate. Dr. Xu and colleagues analyzed data from 1 million patients in 33 health systems who underwent urine dipstick testing in a primary care setting.
Across this population, 13% of patients had proteinuria, but only 6.7% underwent follow-up albuminuria quantification testing within the next year. ACR was the most common method (86%).
Likelihood of follow-up increased slightly with the level of proteinuria detected; however, absolute differences were marginal, with a 3+ result yielding a follow-up rate of just 8%, compared with 7.3% for a 2+ result and 6.3% for a 1+ result. When albuminuria quantification tests were conducted, 1+, 2+, and 3+ dipstick results were associated with albuminuria rates of 36.3%, 53.0%, and 64.9%, respectively.
Patients with diabetes had the highest follow-up rate, at 16.6%, vs 3.8% for those without diabetes.
Reasons for Low Follow-up Unclear
The dataset did not include information about reasons for ordering urinalyses, whether primary care providers knew about the abnormal dipstick tests, or awareness of guideline recommendations.
“I think they know it should be done,” said principal investigator Alexander R. Chang, MD, associate professor in the department of nephrology and population health sciences at Geisinger Health, Danville, Pennsylvania.
He suggested that real-time awareness issues, especially within electronic health record (EHR) systems, could explain the low follow-up rates. Blood test abnormalities are often flagged in red in EHRs, he said in an interview, but urine dipstick results typically remain in plain black and white.
“So, then it sort of requires that extra cognitive step to kind of look at that [result], and say, okay, that is pretty abnormal; I should do something about that,” he said.
Neil S. Skolnik, MD, a primary care physician at Jefferson Health, Abington, Pennsylvania, was surprised by the findings. “If you get a urinalysis and there’s protein, normally you follow up,” Dr. Skolnik said in an interview. “I have a feeling that there’s something we’re not seeing here about what’s going on. It is hard to imagine that in only 1 out of 15 times that proteinuria is identified, is there any follow-up. I really don’t have a good explanation.”
Renee Marie Betancourt, MD, associate professor and vice chair of diversity, equity, and inclusion in the Department of Family Medicine and Community Health at the University of Pennsylvania Perelman School of Medicine, Philadelphia, said it is hard to draw conclusions from the available data, but agreed that low visibility of results could be partially to blame.
“The chart doesn’t tell me [a urine dipstick result] is abnormal,” Dr. Betancourt said in an interview. “The chart just reports it, agnostic of normal or abnormal.”
Beyond issues with visibility, Dr. Betancourt described how primary care physicians are often so flooded with other concerns that a positive dipstick test can become a low priority, particularly among patients with CKD, who typically have other health issues.
“I oftentimes spend the majority of my visit on the patient’s concerns, and sometimes, beyond their concerns, I have concerns, and [a urine dipstick result] might not make it to the top of the list,” she said.
EHR-Based Interventions Might Help Improve Follow-up
Dr. Chang suggested that improved visibility of dipstick results could help, or possibly EHR-integrated clinical decision tools.
Dr. Betancourt and colleagues at Penn Medicine are actively working on such a solution. Their EHR-based intervention is aimed at identifying and managing patients with CKD. The present design, slated for pilot testing at one or two primary care clinics beginning in January 2025, depends upon estimated glomerular filtration rate (eGFR) to flag CKD patients, with ACR testing recommended yearly to predict disease progression.
Although urine dipstick findings are not currently a part of this software pathway, the findings from the present study might influence future strategy.
“I’m going to take this to our collaborators and ask about opportunities to ... encourage providers to be more active with dipsticks,” Dr. Betancourt said.
Newer Medications Are Effective, but Prescribing Challenges Remain
Ideally, CKD screening improvements will unlock a greater goal: prescribing kidney-protecting medications to patients who need them — as soon as they need them.
Here might lie the real knowledge gap among experienced primary care physicians, Dr. Chang suggested. “In the past, there wasn’t quite as much that you could do about having proteinuria,” he said. “But now we have lots more medications ... it’s not just tracking that they have a bad prognostic factor. [Proteinuria is] actually something that we can act upon.”
Who exactly should be prescribing these kidney-protecting medications, however, remains contested, as agents like GLP-1 agonists and SGLT2 inhibitors yield benefits across specialties, including nephrology, cardiology, and endocrinology.
“Everyone’s going to have to work together,” Dr. Chang said. “You can’t really put it all on the [primary care physician] to quarterback everything.”
And, regardless of who throws the ball, a touchdown is not guaranteed.
Dr. Betancourt called out the high cost of these newer drugs and described how some of her patients, already facing multiple health inequities, are left without.
“I have patients who cannot fill these medications because the copay is too high,” she said. “Just last week I received a message from a patient who stopped taking his SGLT2 inhibitor because the cost was too high ... it was over $300 per month.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. The authors’ conflicts of interests are available in the original paper. Dr. Skolnik and Dr. Betancourt reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF INTERNAL MEDICINE
Severe Maternal Morbidity Three Times Higher in Surrogate Gestational Carriers
Gestational carriers face a significantly higher risk for severe maternal morbidity and other pregnancy complications than those conceiving naturally or via in vitro fertilization (IVF), according to a recent Canadian study.
These findings suggest that more work is needed to ensure careful selection of gestational carriers, reported lead author Maria P. Velez, MD, PhD, of McGill University, Montreal, Quebec, Canada, and colleagues.
“Although a gestational carrier should ideally be a healthy person, with a demonstrated low-risk obstetric history, it is not clear whether this occurs in practice,” the investigators wrote in Annals of Internal Medicine. “Moreover, the risk for maternal and neonatal adversity is largely unknown in this group.”
Study Compared Gestational Carriage With IVF and Unassisted Conception
To address these knowledge gaps, Dr. Velez and colleagues conducted a population-based cohort study in Ontario using linked administrative datasets. All singleton births at more than 20 weeks’ gestation with mothers aged 18-50 years were included from April 2012 to March 2021. Multifetal pregnancies were excluded, as were women with a history of infertility diagnosis without fertility treatment, and those who underwent intrauterine insemination or ovulation induction.
Outcomes were compared across three groups: Unassisted conception, IVF, and gestational carriage. The primary maternal outcome was severe maternal morbidity, defined by a validated composite of 41 unique indicators. The primary infant outcome was severe neonatal morbidity, comprising 19 unique indicators.
Secondary outcomes were hypertensive disorders, elective cesarean delivery, emergent cesarean delivery, preterm birth at less than 37 weeks, preterm birth at more than 32 weeks, and postpartum hemorrhage.
Logistic regression analysis adjusted for a range of covariates, including age, obesity, tobacco/drug dependence, chronic hypertension, and others. The final dataset included 846,124 births by unassisted conception (97.6%), 16,087 by IVF (1.8%), and 806 by gestational carriage (0.1%).
The weighted relative risk (wRR) for severe maternal morbidity was more than three times higher in gestational carriers than in those conceiving naturally (wRR, 3.30; 95% CI, 2.59-4.20) and 86% higher than in those conceiving via IVF (wRR, 1.86; 95% CI, 1.36-2.55). These stem from absolute risks of 2.3%, 4.3%, and 7.8% for unassisted, IVF, and surrogate pregnancies, respectively.
Moreover, surrogates were 75% more likely to have hypertensive disorders, 79% more likely to have preterm birth at less than 37 weeks, and almost three times as likely to have postpartum hemorrhage.
These same three secondary outcomes were also significantly more common when comparing surrogate with IVF pregnancies, albeit to a lesser degree. In contrast, surrogate pregnancies were associated with a 21% lower risk for elective cesarean delivery than IVF pregnancies (wRR, 0.79; 95% CI, 0.68-0.93).
Severe neonatal morbidity was not significantly different between the groups. These findings add to a mixed body of evidence surrounding both maternal and neonatal outcomes with gestational carriers, according to the investigators.
“Prior small studies [by Söderström-Anttila et al. and Swanson et al.] reported varying risks for preterm birth in singleton gestational carriage pregnancies, whereas a recent large US registry reported no increased risk for preterm birth compared with IVF, after accounting for multifetal pregnancy,” they wrote. “This study excluded multifetal pregnancies, a common occurrence after IVF, with reported higher risks for adverse outcomes. Accordingly, adverse maternal and newborn outcomes may have been underestimated herein.”
Causes of Worse Outcomes Remain Unclear
While the present findings suggest greater maternal morbidity among surrogates, potential causes of these adverse outcomes remain unclear.
The investigators suggested that implantation of a nonautologous embryo could be playing a role, as oocyte donation has been linked with an increased risk for hypertensive disorders of pregnancy.
“We don’t know exactly why that can happen,” Dr. Velez said in an interview. “Maybe that embryo can be associated with an immunological response that could be associated with higher morbidity during pregnancy. We need, however, other studies that can continue testing that hypothesis.”
In the meantime, more care is needed in surrogate selection, according to Dr. Velez.
“In our study, we found that there were patients, for example, who had more than three prior C-sections, which is one of the contraindications for gestational carriers, and patients who had more than five [prior] pregnancies, which is also another limitation in the guidelines for choosing these patients,” she said. “Definitely we need to be more vigilant when we accept these gestational carriers.”
But improving surrogate selection may be easier said than done.
The quantitative thresholds cited by Dr. Velez come from the American Society for Reproductive Medicine guidelines. Alternative guidance documents from the Canadian Fertility and Andrology Society and American College of Obstetricians and Gynecologists are less prescriptive; instead, they offer qualitative recommendations concerning obstetric history and risk assessment.
And then there is the regulatory specter looming over the entire field, evidenced by the many times that these publications cite ethical and legal considerations — far more than the average medical guidance document — when making clinical decisions related to surrogacy.
Present Study Offers Much-Needed Data in Understudied Field
According to Kate Swanson, MD, a perinatologist, clinical geneticist, and associate professor at the University of California San Francisco, the present study may help steer medical societies and healthcare providers away from these potential sand traps and toward conversations grounded in scientific data.
“I think one of the reasons that the Society for Maternal-Fetal Medicine and the maternal-fetal medicine community in general hasn’t been interested in this subject is that they see it as a social/ethical/legal issue rather than a medical one,” Dr. Swanson said in an interview. “One of the real benefits of this article is that it shows that this is a medical issue that the obstetric community needs to pay attention to.”
These new data could help guide decisions about risk and candidacy with both potential gestational carriers and intended parents, she said.
Still, it’s hard — if not impossible — to disentangle the medical and legal aspects of surrogacy, as shown when analyzing the present study.
In Canada, where it was conducted, intended parents are forbidden from paying surrogates for their services beyond out-of-pocket costs directly related to pregnancy. Meanwhile, surrogacy laws vary widely across the United States; some states (eg, Louisiana) allow only altruistic surrogacy like Canada, while other states (eg, California) permit commercial surrogacy with no legal limits on compensation.
Dr. Swanson and Dr. Velez offered starkly different views on this topic.
“I think there should be more regulations in terms of compensating [gestational carriers],” Dr. Velez said. “I don’t think being a gestational carrier should be like a job or a way of making a living.”
Dr. Swanson, who has published multiple studies on gestational carriage and experienced the process as an intended parent, said compensation beyond expenses is essential.
“I do think it’s incredibly reasonable to pay someone — a woman is taking on quite a lot of inconvenience and risk — in order to perform this service for another family,” she said. “I think it’s incredibly appropriate to compensate her for all of that.”
Reasons for compensation go beyond the ethical, Dr. Swanson added, and may explain some of the findings from the present study.
“A lot of these gestational carriers [in the present dataset] wouldn’t necessarily meet criteria through the American Society of Reproductive Medicine,” Dr. Swanson said, pointing out surrogates who had never had a pregnancy before or reported the use of tobacco or other drugs. “Really, it shows me that a lot of the people participating as gestational carriers were maybe not ideal candidates. I think one of the reasons that we might see that in this Canadian population is ... that you can’t compensate someone, so I think their pool of people willing to be gestational carriers is a lot smaller, and they may be a little bit less selective sometimes.”
Dr. Velez acknowledged that the present study was limited by a shortage of potentially relevant information concerning the surrogacy selection process, including underlying reasons for becoming a gestational carrier. More work is needed to understand the health and outcomes of these women, she said, including topics ranging from immunologic mechanisms to mental health.
She also called for more discussions surrounding maternal safety, with participation from all stakeholders, including governments, surrogates, intended parents, and physicians too.
This study was funded by the Canadian Institutes of Health Research. The investigators disclosed no conflicts of interest. Dr. Swanson disclosed a relationship with Mitera.
A version of this article first appeared on Medscape.com.
Gestational carriers face a significantly higher risk for severe maternal morbidity and other pregnancy complications than those conceiving naturally or via in vitro fertilization (IVF), according to a recent Canadian study.
These findings suggest that more work is needed to ensure careful selection of gestational carriers, reported lead author Maria P. Velez, MD, PhD, of McGill University, Montreal, Quebec, Canada, and colleagues.
“Although a gestational carrier should ideally be a healthy person, with a demonstrated low-risk obstetric history, it is not clear whether this occurs in practice,” the investigators wrote in Annals of Internal Medicine. “Moreover, the risk for maternal and neonatal adversity is largely unknown in this group.”
Study Compared Gestational Carriage With IVF and Unassisted Conception
To address these knowledge gaps, Dr. Velez and colleagues conducted a population-based cohort study in Ontario using linked administrative datasets. All singleton births at more than 20 weeks’ gestation with mothers aged 18-50 years were included from April 2012 to March 2021. Multifetal pregnancies were excluded, as were women with a history of infertility diagnosis without fertility treatment, and those who underwent intrauterine insemination or ovulation induction.
Outcomes were compared across three groups: Unassisted conception, IVF, and gestational carriage. The primary maternal outcome was severe maternal morbidity, defined by a validated composite of 41 unique indicators. The primary infant outcome was severe neonatal morbidity, comprising 19 unique indicators.
Secondary outcomes were hypertensive disorders, elective cesarean delivery, emergent cesarean delivery, preterm birth at less than 37 weeks, preterm birth at more than 32 weeks, and postpartum hemorrhage.
Logistic regression analysis adjusted for a range of covariates, including age, obesity, tobacco/drug dependence, chronic hypertension, and others. The final dataset included 846,124 births by unassisted conception (97.6%), 16,087 by IVF (1.8%), and 806 by gestational carriage (0.1%).
The weighted relative risk (wRR) for severe maternal morbidity was more than three times higher in gestational carriers than in those conceiving naturally (wRR, 3.30; 95% CI, 2.59-4.20) and 86% higher than in those conceiving via IVF (wRR, 1.86; 95% CI, 1.36-2.55). These stem from absolute risks of 2.3%, 4.3%, and 7.8% for unassisted, IVF, and surrogate pregnancies, respectively.
Moreover, surrogates were 75% more likely to have hypertensive disorders, 79% more likely to have preterm birth at less than 37 weeks, and almost three times as likely to have postpartum hemorrhage.
These same three secondary outcomes were also significantly more common when comparing surrogate with IVF pregnancies, albeit to a lesser degree. In contrast, surrogate pregnancies were associated with a 21% lower risk for elective cesarean delivery than IVF pregnancies (wRR, 0.79; 95% CI, 0.68-0.93).
Severe neonatal morbidity was not significantly different between the groups. These findings add to a mixed body of evidence surrounding both maternal and neonatal outcomes with gestational carriers, according to the investigators.
“Prior small studies [by Söderström-Anttila et al. and Swanson et al.] reported varying risks for preterm birth in singleton gestational carriage pregnancies, whereas a recent large US registry reported no increased risk for preterm birth compared with IVF, after accounting for multifetal pregnancy,” they wrote. “This study excluded multifetal pregnancies, a common occurrence after IVF, with reported higher risks for adverse outcomes. Accordingly, adverse maternal and newborn outcomes may have been underestimated herein.”
Causes of Worse Outcomes Remain Unclear
While the present findings suggest greater maternal morbidity among surrogates, potential causes of these adverse outcomes remain unclear.
The investigators suggested that implantation of a nonautologous embryo could be playing a role, as oocyte donation has been linked with an increased risk for hypertensive disorders of pregnancy.
“We don’t know exactly why that can happen,” Dr. Velez said in an interview. “Maybe that embryo can be associated with an immunological response that could be associated with higher morbidity during pregnancy. We need, however, other studies that can continue testing that hypothesis.”
In the meantime, more care is needed in surrogate selection, according to Dr. Velez.
“In our study, we found that there were patients, for example, who had more than three prior C-sections, which is one of the contraindications for gestational carriers, and patients who had more than five [prior] pregnancies, which is also another limitation in the guidelines for choosing these patients,” she said. “Definitely we need to be more vigilant when we accept these gestational carriers.”
But improving surrogate selection may be easier said than done.
The quantitative thresholds cited by Dr. Velez come from the American Society for Reproductive Medicine guidelines. Alternative guidance documents from the Canadian Fertility and Andrology Society and American College of Obstetricians and Gynecologists are less prescriptive; instead, they offer qualitative recommendations concerning obstetric history and risk assessment.
And then there is the regulatory specter looming over the entire field, evidenced by the many times that these publications cite ethical and legal considerations — far more than the average medical guidance document — when making clinical decisions related to surrogacy.
Present Study Offers Much-Needed Data in Understudied Field
According to Kate Swanson, MD, a perinatologist, clinical geneticist, and associate professor at the University of California San Francisco, the present study may help steer medical societies and healthcare providers away from these potential sand traps and toward conversations grounded in scientific data.
“I think one of the reasons that the Society for Maternal-Fetal Medicine and the maternal-fetal medicine community in general hasn’t been interested in this subject is that they see it as a social/ethical/legal issue rather than a medical one,” Dr. Swanson said in an interview. “One of the real benefits of this article is that it shows that this is a medical issue that the obstetric community needs to pay attention to.”
These new data could help guide decisions about risk and candidacy with both potential gestational carriers and intended parents, she said.
Still, it’s hard — if not impossible — to disentangle the medical and legal aspects of surrogacy, as shown when analyzing the present study.
In Canada, where it was conducted, intended parents are forbidden from paying surrogates for their services beyond out-of-pocket costs directly related to pregnancy. Meanwhile, surrogacy laws vary widely across the United States; some states (eg, Louisiana) allow only altruistic surrogacy like Canada, while other states (eg, California) permit commercial surrogacy with no legal limits on compensation.
Dr. Swanson and Dr. Velez offered starkly different views on this topic.
“I think there should be more regulations in terms of compensating [gestational carriers],” Dr. Velez said. “I don’t think being a gestational carrier should be like a job or a way of making a living.”
Dr. Swanson, who has published multiple studies on gestational carriage and experienced the process as an intended parent, said compensation beyond expenses is essential.
“I do think it’s incredibly reasonable to pay someone — a woman is taking on quite a lot of inconvenience and risk — in order to perform this service for another family,” she said. “I think it’s incredibly appropriate to compensate her for all of that.”
Reasons for compensation go beyond the ethical, Dr. Swanson added, and may explain some of the findings from the present study.
“A lot of these gestational carriers [in the present dataset] wouldn’t necessarily meet criteria through the American Society of Reproductive Medicine,” Dr. Swanson said, pointing out surrogates who had never had a pregnancy before or reported the use of tobacco or other drugs. “Really, it shows me that a lot of the people participating as gestational carriers were maybe not ideal candidates. I think one of the reasons that we might see that in this Canadian population is ... that you can’t compensate someone, so I think their pool of people willing to be gestational carriers is a lot smaller, and they may be a little bit less selective sometimes.”
Dr. Velez acknowledged that the present study was limited by a shortage of potentially relevant information concerning the surrogacy selection process, including underlying reasons for becoming a gestational carrier. More work is needed to understand the health and outcomes of these women, she said, including topics ranging from immunologic mechanisms to mental health.
She also called for more discussions surrounding maternal safety, with participation from all stakeholders, including governments, surrogates, intended parents, and physicians too.
This study was funded by the Canadian Institutes of Health Research. The investigators disclosed no conflicts of interest. Dr. Swanson disclosed a relationship with Mitera.
A version of this article first appeared on Medscape.com.
Gestational carriers face a significantly higher risk for severe maternal morbidity and other pregnancy complications than those conceiving naturally or via in vitro fertilization (IVF), according to a recent Canadian study.
These findings suggest that more work is needed to ensure careful selection of gestational carriers, reported lead author Maria P. Velez, MD, PhD, of McGill University, Montreal, Quebec, Canada, and colleagues.
“Although a gestational carrier should ideally be a healthy person, with a demonstrated low-risk obstetric history, it is not clear whether this occurs in practice,” the investigators wrote in Annals of Internal Medicine. “Moreover, the risk for maternal and neonatal adversity is largely unknown in this group.”
Study Compared Gestational Carriage With IVF and Unassisted Conception
To address these knowledge gaps, Dr. Velez and colleagues conducted a population-based cohort study in Ontario using linked administrative datasets. All singleton births at more than 20 weeks’ gestation with mothers aged 18-50 years were included from April 2012 to March 2021. Multifetal pregnancies were excluded, as were women with a history of infertility diagnosis without fertility treatment, and those who underwent intrauterine insemination or ovulation induction.
Outcomes were compared across three groups: Unassisted conception, IVF, and gestational carriage. The primary maternal outcome was severe maternal morbidity, defined by a validated composite of 41 unique indicators. The primary infant outcome was severe neonatal morbidity, comprising 19 unique indicators.
Secondary outcomes were hypertensive disorders, elective cesarean delivery, emergent cesarean delivery, preterm birth at less than 37 weeks, preterm birth at more than 32 weeks, and postpartum hemorrhage.
Logistic regression analysis adjusted for a range of covariates, including age, obesity, tobacco/drug dependence, chronic hypertension, and others. The final dataset included 846,124 births by unassisted conception (97.6%), 16,087 by IVF (1.8%), and 806 by gestational carriage (0.1%).
The weighted relative risk (wRR) for severe maternal morbidity was more than three times higher in gestational carriers than in those conceiving naturally (wRR, 3.30; 95% CI, 2.59-4.20) and 86% higher than in those conceiving via IVF (wRR, 1.86; 95% CI, 1.36-2.55). These stem from absolute risks of 2.3%, 4.3%, and 7.8% for unassisted, IVF, and surrogate pregnancies, respectively.
Moreover, surrogates were 75% more likely to have hypertensive disorders, 79% more likely to have preterm birth at less than 37 weeks, and almost three times as likely to have postpartum hemorrhage.
These same three secondary outcomes were also significantly more common when comparing surrogate with IVF pregnancies, albeit to a lesser degree. In contrast, surrogate pregnancies were associated with a 21% lower risk for elective cesarean delivery than IVF pregnancies (wRR, 0.79; 95% CI, 0.68-0.93).
Severe neonatal morbidity was not significantly different between the groups. These findings add to a mixed body of evidence surrounding both maternal and neonatal outcomes with gestational carriers, according to the investigators.
“Prior small studies [by Söderström-Anttila et al. and Swanson et al.] reported varying risks for preterm birth in singleton gestational carriage pregnancies, whereas a recent large US registry reported no increased risk for preterm birth compared with IVF, after accounting for multifetal pregnancy,” they wrote. “This study excluded multifetal pregnancies, a common occurrence after IVF, with reported higher risks for adverse outcomes. Accordingly, adverse maternal and newborn outcomes may have been underestimated herein.”
Causes of Worse Outcomes Remain Unclear
While the present findings suggest greater maternal morbidity among surrogates, potential causes of these adverse outcomes remain unclear.
The investigators suggested that implantation of a nonautologous embryo could be playing a role, as oocyte donation has been linked with an increased risk for hypertensive disorders of pregnancy.
“We don’t know exactly why that can happen,” Dr. Velez said in an interview. “Maybe that embryo can be associated with an immunological response that could be associated with higher morbidity during pregnancy. We need, however, other studies that can continue testing that hypothesis.”
In the meantime, more care is needed in surrogate selection, according to Dr. Velez.
“In our study, we found that there were patients, for example, who had more than three prior C-sections, which is one of the contraindications for gestational carriers, and patients who had more than five [prior] pregnancies, which is also another limitation in the guidelines for choosing these patients,” she said. “Definitely we need to be more vigilant when we accept these gestational carriers.”
But improving surrogate selection may be easier said than done.
The quantitative thresholds cited by Dr. Velez come from the American Society for Reproductive Medicine guidelines. Alternative guidance documents from the Canadian Fertility and Andrology Society and American College of Obstetricians and Gynecologists are less prescriptive; instead, they offer qualitative recommendations concerning obstetric history and risk assessment.
And then there is the regulatory specter looming over the entire field, evidenced by the many times that these publications cite ethical and legal considerations — far more than the average medical guidance document — when making clinical decisions related to surrogacy.
Present Study Offers Much-Needed Data in Understudied Field
According to Kate Swanson, MD, a perinatologist, clinical geneticist, and associate professor at the University of California San Francisco, the present study may help steer medical societies and healthcare providers away from these potential sand traps and toward conversations grounded in scientific data.
“I think one of the reasons that the Society for Maternal-Fetal Medicine and the maternal-fetal medicine community in general hasn’t been interested in this subject is that they see it as a social/ethical/legal issue rather than a medical one,” Dr. Swanson said in an interview. “One of the real benefits of this article is that it shows that this is a medical issue that the obstetric community needs to pay attention to.”
These new data could help guide decisions about risk and candidacy with both potential gestational carriers and intended parents, she said.
Still, it’s hard — if not impossible — to disentangle the medical and legal aspects of surrogacy, as shown when analyzing the present study.
In Canada, where it was conducted, intended parents are forbidden from paying surrogates for their services beyond out-of-pocket costs directly related to pregnancy. Meanwhile, surrogacy laws vary widely across the United States; some states (eg, Louisiana) allow only altruistic surrogacy like Canada, while other states (eg, California) permit commercial surrogacy with no legal limits on compensation.
Dr. Swanson and Dr. Velez offered starkly different views on this topic.
“I think there should be more regulations in terms of compensating [gestational carriers],” Dr. Velez said. “I don’t think being a gestational carrier should be like a job or a way of making a living.”
Dr. Swanson, who has published multiple studies on gestational carriage and experienced the process as an intended parent, said compensation beyond expenses is essential.
“I do think it’s incredibly reasonable to pay someone — a woman is taking on quite a lot of inconvenience and risk — in order to perform this service for another family,” she said. “I think it’s incredibly appropriate to compensate her for all of that.”
Reasons for compensation go beyond the ethical, Dr. Swanson added, and may explain some of the findings from the present study.
“A lot of these gestational carriers [in the present dataset] wouldn’t necessarily meet criteria through the American Society of Reproductive Medicine,” Dr. Swanson said, pointing out surrogates who had never had a pregnancy before or reported the use of tobacco or other drugs. “Really, it shows me that a lot of the people participating as gestational carriers were maybe not ideal candidates. I think one of the reasons that we might see that in this Canadian population is ... that you can’t compensate someone, so I think their pool of people willing to be gestational carriers is a lot smaller, and they may be a little bit less selective sometimes.”
Dr. Velez acknowledged that the present study was limited by a shortage of potentially relevant information concerning the surrogacy selection process, including underlying reasons for becoming a gestational carrier. More work is needed to understand the health and outcomes of these women, she said, including topics ranging from immunologic mechanisms to mental health.
She also called for more discussions surrounding maternal safety, with participation from all stakeholders, including governments, surrogates, intended parents, and physicians too.
This study was funded by the Canadian Institutes of Health Research. The investigators disclosed no conflicts of interest. Dr. Swanson disclosed a relationship with Mitera.
A version of this article first appeared on Medscape.com.