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Cited by 82Bariatric Surgery and OutcomesGallbladder and Bile Duct DisordersBiliary and Gastrointestinal Fistulas

The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index; 5 of the 25 sources its claims cite were checked for support.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial

Open access
Haal, Sylke, Guman, Maimoena S S, Boerlage, Thomas C C, Acherman, Yair I Z, de Brauw, L Maurits, Bruin, Sjoerd, de Castro, Steve M M, van Hooft, Jeanin E, van de Laar, Arnold W J M, Moes, Daan E, Schouten, Manon, Schouten, Ruben, van Soest, Ellert J, van Veen, Ruben N, de Vries, Claire E E, Fockens, Paul, Dijkgraaf, Marcel G W, Gerdes, Victor E A, Voermans, Rogier P·2021·The Lancet Gastroenterology & Hepatology
DOI 10.1016/s2468-1253(21)00301-0
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Abstract

Background Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. Methods This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. Findings Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. Interpretation Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. Funding The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In the UPGRADE trial, ursodeoxycholic acid (UDCA) 900 mg daily for 6 months did not significantly reduce symptomatic gallstone disease within 24 months after bariatric surgery overall (6.5% vs 9.7%, RR 0.67, p=0.071). In patients without gallstones at baseline, UDCA significantly reduced symptomatic gallstone disease (4.2% vs 8.9%, RR 0.47, p=0.0081), with no benefit in those with asymptomatic gallstones at baseline.

Key findings

  • Primary endpoint symptomatic gallstone disease within 24 months occurred in 31/475 (6.5%) UDCA patients vs 47/484 (9.7%) placebo patients (RR 0.67, 95% CI 0.43–1.04, p=0.071).
  • Prespecified subgroup analysis showed a significant interaction with baseline asymptomatic gallstones (p=0.046): in patients without gallstones at baseline, symptomatic gallstone disease occurred in 16/381 (4.2%) vs 35/392 (8.9%) (RR 0.47, 95% CI 0.26–0.84, p=0.0081; NNT 21); in patients with asymptomatic gallstones at baseline, 15/94 (16.0%) vs 12/92 (13.0%) (RR 1.22, 95% CI 0.61–2.47, p=0.57).
  • Cholecystectomy within 24 months was performed in 25/475 (5.3%) UDCA patients vs 44/484 (9.1%) placebo patients (RR 0.58, 95% CI 0.36–0.93, p=0.022); gallstones or sludge on postoperative ultrasonography were present in 112/419 (26.7%) vs 138/415 (33.3%) (RR 0.80, 95% CI 0.65–0.99, p=0.040).
  • In patients who underwent RYGB, UDCA was beneficial for symptomatic gallstone disease (RR 0.61, 95% CI 0.38–0.98, p=0.039); the sleeve gastrectomy subgroup was too small to draw clear conclusions (RR 1.32, 95% CI 0.38–4.54, p=0.66).

Methods

  • Multicentre, double-blind, randomised, placebo-controlled superiority trial in three hospitals in the Netherlands; 985 patients were enrolled and 967 were included in the modified intention-to-treat population (477 UDCA, 490 placebo).
  • Adults scheduled for laparoscopic RYGB or sleeve gastrectomy were randomly assigned 1:1 to 900 mg UDCA daily for 6 months or placebo, stratified by baseline asymptomatic gallstones and type of scheduled surgery.
  • The primary endpoint was the proportion of patients with symptomatic gallstone disease within 24 months, adjudicated by a masked committee; secondary endpoints included gallstones/sludge on ultrasonography, cholecystectomy, time-to-event outcomes, compliance, quality of life, and costs. Analysis used χ² tests, relative risks with 95% CIs, logistic regression for interactions, and Kaplan-Meier/Cox methods.

Limitations

  • The paper states that results cannot be extrapolated to patients undergoing sleeve gastrectomy, that the sleeve gastrectomy subgroup was too small and had poor treatment compliance, and that follow-up was limited to 24 months, leaving longer-term effects uncertain.
  • The paper states that the overall primary endpoint was not statistically significant and that gallstone-related secondary endpoint results were not adjusted for multiple testing, so they should not be used to infer definitive treatment effects.
  • The text makes evident additional limitations: overall therapy compliance was moderate (63%), postoperative ultrasonography was missing in 58 UDCA and 75 placebo patients, and some baseline differences existed between groups (type 2 diabetes and health utility score), although post-hoc analyses found these did not impact the beneficial effect of UDCA.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s2468-1253(21)00301-0

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

5 of 25 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Interpretationreasoning

    Patients undergoing bariatric surgery experienced difficulty in tolerating either the size or structure of the tablet, rather than the content.

    “indicating that patients undergoing bariatric surgery experienced difficulty in tolerating either the size or structure of the tablet, rather than the content.8,37,38”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [8] Sakran, 2020, The use of Ursolit for gallstone prophylaxis following bariatric surgery: a randomized-controlled trial, Updates Surg source
    • cites [37] Miller, 2003, Gallstone formation prophylaxis after gastric restrictive procedures for weight loss: a randomized double-blind placebo-controlled trial, Ann Surg source

      The Results report that 24 protocol violators could not swallow the medication and that placebo and treatment patients dropped out for similar reasons at similar rates. The Discussion suggests capsule size may have contributed, but treats that explanation as possible rather than established; it does not specifically assess tablet structure. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [38] Sugerman, 1995, A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss, Am J Surg source
  • Findingown data

    There were three deaths in the safety population, two in the ursodeoxycholic acid group and one in the placebo group.

    “There were three deaths in the safety population, two in the ursodeoxycholic acid group, and one in the placebo group.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group).

    “The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group).”
    Quote in the paperNot a substantial claim
  • Findingown data

    No serious adverse event was attributed to the study drug.

    “No serious adverse event was attributed to the study drug (appendix pp 19-20).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo.

    “However, in patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 31
  • It may state two separate claims as one. 22

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Bariatric surgery is safe and the only treatment that achieves long-term weight loss and reduction of obesity-related diseases.

    “Bariatric surgery is safe and the only treatment that achieves long-term weight loss and reduction of obesity-related diseases.3”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [3] Colquitt, 2014, Surgery for weight loss in adults, Cochrane Database Syst Rev source

      The Discussion (page unavailable) reports that surgery produces greater weight loss and reductions in some comorbidities than conventional treatment. But the Background describes risks of significant morbidity and perioperative mortality, while the Discussion says the longer-term effects remain unclear. The review does not establish that surgery is safe or the only treatment with long-term benefits. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    A prespecified sensitivity analysis of the primary endpoint in four other predefined analysis sets was done.

    “A prespecified sensitivity analysis of the primary endpoint in four other predefined analysis sets, with an increasing compliance rate or earlier initiation of the study drug in each successive analysis set, was also done (see statistical analysis plan for detailed information).18”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Haal, 2020, Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: statistical analysis plan for a randomised controlled trial (UPGRADE trial), Trials source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    The trial was done according to the previously published trial protocol and statistical analysis plan.

    “The trial was done according to the previously published trial protocol and statistical analysis plan.17,18”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [17] Boerlage, 2017, Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial), BMC Gastroenterol source
    • cites [18] Haal, 2020, Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: statistical analysis plan for a randomised controlled trial (UPGRADE trial), Trials source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    In both trial groups, health-related quality of life was improved after bariatric surgery.

    “In both trial groups, health-related quality of life was improved after bariatric surgery (appendix p 5).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Similar results were found in the imputed datasets.

    “Similar results were found in the imputed datasets (appendix p 5).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The effect of ursodeoxycholic acid in patients without gallstones at baseline was robust and increased with every successive analysis set in the prespecified sensitivity analysis.

    “The effect of ursodeoxycholic acid in patients without gallstones at baseline was robust and increased with every successive analysis set in the prespecified sensitivity analysis (appendix p 6).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Cholecystectomy was delayed in 12 symptomatic patients with biliary colic (six in each group) and was done without meeting the definition for symptomatic gallstone disease in three patients (placebo group).

    “Cholecystectomy was delayed in 12 (six each in the ursodeoxycholic acid and placebo groups) symptomatic patients with biliary colic and done without meeting the definition for symptomatic gallstone disease in three patients (placebo group; appendix p 5).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    None of the deaths were surgery or treatment-related, and all three occurred after 6 months of follow-up.

    “None of the deaths were surgery or treatment-related, and all three occurred after 6 months of follow-up.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Side-effects and compliance were similar in both trial groups.

    “Side-effects and compliance were similar in both trial groups”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In the ursodeoxycholic acid group, 95% of patients were free of symptomatic gallstone disease until 481 days of follow-up, and free of cholecystectomy until 657 days.

    “In the ursodeoxycholic acid group, 95% of the patients were free of symptomatic gallstone disease until 481 days of follow-up, and free of cholecystectomy until 657 days.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingcitation

    The moderate overall compliance of 63% in our trial is consistent with compliance rates reported in other trials.

    “The moderate overall compliance of 63% in our trial is consistent with compliance rates reported in other trials, 6,8,35,36 although higher rates have been reported as well.7,25,37,38”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [6] Adams, 2016, Randomized, prospective comparison of ursodeoxycholic acid for the prevention of gallstones after sleeve gastrectomy, Obes Surg source
    • cites [8] Sakran, 2020, The use of Ursolit for gallstone prophylaxis following bariatric surgery: a randomized-controlled trial, Updates Surg source
    • cites [35] Williams, 1993, A double-blind placebo-controlled trial of ursodeoxycholic acid in the prevention of gallstones during weight loss after vertical banded gastroplasty, Obes Surg source
    • cites [36] Wudel, 2002, Prevention of gallstone formation in morbidly obese patients undergoing rapid weight loss: results of a randomized controlled pilot study, J Surg Res source

  • It may state two separate claims as one.

    Findingown data

    In the ursodeoxycholic acid group, diarrhoea occurred in 4/444 (0.9%) patients and skin rash in 2/444 (0.5%) patients.

    “In the ursodeoxycholic acid group, diarrhoea occurred in four (0•9%) of 444 patients and skin rash in two (0•5%) patients.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In the placebo group, 95% of patients were free of symptomatic gallstone disease until 311 days, and free of cholecystectomy until 354 days.

    “In the placebo group, 95% of the patients were free of symptomatic gallstone disease until 311 days, and free of cholecys tectomy until 354 days (figure 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In the placebo group, diarrhoea occurred in 2/453 (0.4%) patients and skin rash in 2/453 (0.4%) patients.

    “In the placebo group, diarrhoea occurred in two (0•4%) of 453 patients and skin rash in two (0•4%) patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    The most common serious adverse events were abdominal pain and internal hernia.

    “The most common serious adverse events were abdominal pain and internal hernia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Based on an expected reduction in symptomatic gallstone disease from 11% to 5.5% with a two-sided α of 5%, power of 80%, and drop-out of 20%, the trial calculated a total sample size of 980 patients.

    “Based on an expected reduction in symptomatic gallstone disease from 11% to 5•5% with a two-sided α of 5%, power of 80%, and drop-out of 20%, we calculated a total sample size of 980 patients.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Boerlage, 2017, Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial), BMC Gastroenterol source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    All participants were masked until the last patient completed 24 months of follow-up and the primary endpoint adjudication was done.

    “All were masked until the last patient completed 24 months of follow-up and the primary endpoint adjudication was done.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Similar incidences of symptomatic gallstone disease and a similar effect of ursodeoxycholic acid on gallstone formation are reported.

    “Consequently, similar incidences of symptomatic gallstone disease, 40 and a similar effect of ursodeoxycholic acid on gallstone formation are reported.7,23,24,26”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [40] Coupaye, 2015, Comparison of the incidence of cholelithiasis after sleeve gastrectomy and Roux-en-Y gastric bypass in obese patients: a prospective study, Surg Obes Relat Dis source
    • cites [7] Nabil, 2019, Effect of oral ursodeoxycholic acid on cholelithiasis following laparoscopic sleeve gastrectomy for morbid obesity, Surg Obes Relat Dis source
    • cites [23] Coupaye, 2019, Effectiveness of ursodeoxycholic acid in the prevention of cholelithiasis after sleeve gastrectomy, Obes Surg source
    • cites [24] Magouliotis, 2017, Ursodeoxycholic acid in the prevention of gallstone formation after bariatric surgery: an updated systematic review and meta-analysis, Obes Surg source
    • cites [26] Talha, 2020, Cholelithiasis after bariatric surgery, incidence, and prophylaxis: randomized controlled trial, Surg Endosc source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The result of pre-operative ultrasonography was blinded for the patients and clinicians.

    “Moreover, the result of pre-operative ultrasonography was blinded for the patients and clinicians.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Post-hoc sensitivity analyses were done by imputing missing primary endpoint values and missing postoperative ultrasonography data.

    “Lastly, post-hoc sensitivity analyses were done by imputing missing primary endpoint values and missing postoperative ultrasonography data (appendix pp 3-4).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    Placebo tablets were identical in appearance to ursodeoxycholic acid tablets and each package was given a randomisation number to ensure masking of patients, clinicians, and study staff.

    “Placebo tablets were identical in appearance to ursodeoxycholic acid tablets and each package was given a randomisation number to ensure masking of patients, clinicians, and study staff.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Interpretationown data

    Whether ursodeoxycholic acid is able to reduce the occurrence of symptomatic gallstone disease after sleeve gastrectomy is uncertain.

    “However, whether ursodeoxycholic acid is also able to reduce the occurrence of symptomatic gallstone disease after sleeve gastrectomy is uncertain”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    A masked adjudication committee of two gastroenterologists evaluated all primary endpoints individually.

    “A masked adjudication committee of two gastroenterologists (JEvH, EJvS) evaluated all primary endpoints individually.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Two post-hoc exploratory logistic regression analyses of the primary endpoint were done to account for significant baseline differences and variables of known clinical importance.

    “Furthermore, two post-hoc exploratory logistic regression analyses of the primary endpoint were done to account for significant baseline differences and variables of known clinical importance (ie, presence of type 2 diabetes, health utility score, age, gender, statin use at baseline, observed therapy compliance [compliant versus non-compliant], and percentage total weight loss at 6 months).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    The trial had a double-blind, randomised design.

    “Strengths of our trial include its double-blind, randomised design”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    A masked and independent reviewer assessed patient safety after 50% of the patients had completed 6 months of treatment.

    “A masked and independent reviewer assessed patient safety after 50% of the patients had completed 6 months of treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductown data

    The reported analyses were done in the predefined modified intention-to-treat population.

    “The reported analyses were done in the predefined modified intention-to-treat (ITT) population (ie, the analysis set of all randomly assigned eligible patients with any post-randomisation measurement).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    As prespecified, a formal test of interaction using logistic regression was done to assess whether treatment effects differed significantly between predefined subgroups.

    “As prespecified, we did a formal test of interaction using logistic regression to assess whether treatment effects differed significantly between predefined subgroups (ie, stratification groups).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisereasoning

    In all trials of ursodeoxycholic acid after bariatric surgery, the primary endpoint was gallstone formation, which is not a clinically relevant endpoint since many patients remain asymptomatic.

    “However, in all trials the primary endpoint was gallstone formation, which is not a clinically relevant endpoint since many patients remain asymptomatic.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

    “The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Patients with a RYGB were more often compliant than patients with a sleeve gastrectomy (64% vs 48%, p=0.0028).

    “Patients with a RYGB were more often compliant than patients with a sleeve gastrectomy (64% [573 patients] vs 48% [37 patients], p=0•0028).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    The mechanisms of weight loss differ between RYGB and sleeve gastrectomy, but the actual weight loss is almost comparable.

    “Although the mechanisms of weight loss differ between RYGB and sleeve gastrectomy, the actual weight loss, which predisposes patients undergoing bariatric surgery to gallstones formation, is almost comparable.39”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Peterli, 2018, Effect of laparoscopic sleeve gastrectomy vs laparoscopic Roux-en-Y gastric bypass on weight loss in patients with morbid obesity: the SM-BOSS randomized clinical trial, JAMA source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The ethical committee of the Slotervaart Hospital and Reade and the boards of directors at each hospital approved the trial protocol before local conduct started.

    “The ethical committee of the Slotervaart Hospital and Reade (Amsterdam, Netherlands) and the boards of directors at each hospital approved the trial protocol before local conduct started.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    Randomisation was done before surgery by central study coordinators using a web-based randomisation module with randomly varying block sizes and stratified by presence of asymptomatic gallstones at baseline and type of scheduled surgery.

    “Randomisation was done before surgery by central study coordinators using a web-based randomisation module with randomly varying block sizes (4, 6, and 8), and stratified by the presence of asymptomatic gallstones at baseline (present or not) and the type of scheduled surgery (RYGB or sleeve gastrectomy).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisenone given

    Most previous trials of ursodeoxycholic acid after bariatric surgery were underpowered and showed a high loss of follow-up.

    “Additionally, most trials were underpowered and showed a high loss of follow-up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The UPGRADE trial was done in accordance with the Declaration of Helsinki and the Dutch Law for Research Involving Human Subjects.

    “The UPGRADE trial was done in accordance with the Declaration of Helsinki and the Dutch Law for Research Involving Human Subjects.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Obesity and rapid weight loss are risk factors for the formation of cholesterol gallstones.

    “Obesity and rapid weight loss are both well known risk factors for the formation of cholesterol gallstones.5”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Lammert, 2016, Gallstones, Nat Rev Dis Primers source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    834 (86.2%) patients underwent postoperative ultrasonography.

    “834 (86•2%) patients underwent postoperative ultrasonography (table 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    An independent monitor, masked to treatment allocation, assessed the study documents and compared them with source documents.

    “An independent monitor, masked to treatment allocation, assessed the study documents, and compared them with the source documents.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    The UPGRADE trial was a multicentre, double-blind, randomised, placebo-controlled superiority trial done in three hospitals in the Netherlands.

    “The Ursodeoxycholic Acid for the Prevention of Symptomatic Gallstone Disease after Bariatric Surgery (UPGRADE) trial was a multicentre, double-blind, randomised, placebo-controlled superiority trial done in three hospitals in the Netherlands (appendix p 3).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    The trial is registered with the Netherlands Trial Register, NL5954.

    “The trial is registered with the Netherlands Trial Register, NL5954.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All participants gave written informed consent.

    “All participants gave written informed consent.”
    Quote in the paperNot a substantial claim
42 of 42

  • The paper relies on this without support.

    Ursodeoxycholic acid induces unsaturated gallbladder bile that hampers the nucleation of cholesterol crystals.

    “Ursodeoxycholic acid is known to induce unsaturated gallbladder bile that hampers the nucleation of cholesterol crystals.”

  • The paper relies on this without support.

    Ursodeoxycholic acid is not routinely prescribed in most countries.

    “Hence, ursodeoxycholic acid is not routinely prescribed in most countries.”

  • The paper relies on this without support.

    Weight loss already stabilises after approximately 12 months.

    “weight loss already stabilises after approximately 12 months”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Only 11 randomized controlled trials have reported the effect of UDCA on gallstone formation after bariatric surgery.

    “However, only 11 randomized controlled trials have reported the effect of UDCA on gallstone formation after bariatric surgery (Table 3) [1225264849505152535455].”

    From Prevention of Gallstones After Bariatric Surgery using Ursodeoxycholic Acid: A Narrative Review of Literatures (2022) · cites this paper as [12]

    The Research in context section reports that a search through March 1, 2016 found six randomised controlled trials of UDCA after bariatric surgery, all with gallstone formation as the primary endpoint. It supports the existence of such trials, but not the claimed total of 11; the earlier search cutoff also means its count does not establish a contrary total for a later date. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Younger patients have a higher risk of gallstone formation after bariatric surgery.

    “Age: Younger patients have a higher risk of gallstone formation after bariatric surgery [12,13].”

    From Prevention of Gallstones After Bariatric Surgery using Ursodeoxycholic Acid: A Narrative Review of Literatures (2022) · cites this paper as [12]

    The Introduction identifies obesity and rapid weight loss as risk factors for gallstone formation after bariatric surgery, but does not compare risk by patient age. Searches for younger patients and age-related risk found no passage in our copy supporting that comparison. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

Citations

Cites

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Metadata

Authors
Haal, S., Guman, M. S. S., Boerlage, T. C. C., Acherman, Y. I. Z., de Brauw, L. M., Bruin, S., de Castro, S. M. M., van Hooft, J. E., van de Laar, A. W. J. M., Moes, D. E., Schouten, M., Schouten, R., van Soest, E. J., van Veen, R. N., de Vries, C. E. E., Fockens, P., Dijkgraaf, M. G. W., Gerdes, V. E. A., & Voermans, R. P.
Affiliations
  • Spaarne Ziekenhuis (NL)
  • University Medical Center Utrecht (NL)
  • OLVG (NL)
  • Leiden University Medical Center (NL)
  • Dijklander Ziekenhuis (NL)
  • Flevoziekenhuis (NL)
  • Amsterdam University Medical Centers (NL)
Corresponding author
Voermans, Rogier P
ORCID
Venue
The Lancet Gastroenterology & Hepatology
Publisher
Elsevier BV
Published
2021-12
Volume
6
Issue
12
Pages
993-1001
ISSN
  • 2468-1156 (ISSN-L)
  • 2468-1253
DOI
10.1016/s2468-1253(21)00301-0
OpenAlex
W3210565781
Cited by
82
References
36
Citations by year
2026: 19 · 2025: 19 · 2024: 14 · 2023: 10 · 2022: 17 · 2021: 2
FWCI
9.80
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet. Gastroenterology & hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
ZonMw (848015003)
Topics
  • Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
  • Health Sciences › Medicine › Gastroenterology › Gallbladder and Bile Duct Disorders
  • Health Sciences › Medicine › Gastroenterology › Biliary and Gastrointestinal Fistulas
Keywords
symptomatic gallstones, bariatric surgery, morbid obesity, laparoscopic Roux-en-Y gastric bypass, sleeve gastrectomy, cholesterol gallstones, weight loss, gallstone prevention, asymptomatic gallstones, drug safety, gallstones, bile acid therapy, postoperative complications, gallbladder
MeSH terms
Adult, Cholagogues and Choleretics, Cholelithiasis, Double-Blind Method, Female, Gastrectomy, Humans, Male, Middle Aged, Netherlands, Obesity, Morbid, Laparoscopy, Placebos, Postoperative Complications, Safety, Ursodeoxycholic Acid, Gastric Bypass, Case-Control Studies, Treatment Outcome, Outcome Assessment, Health Care, Bariatric Surgery

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-08, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-08 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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