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Can ursodeoxycholic acid administration prevent gallstone formation after gastrectomy in patients with gastric cancer?
In this randomized clinical trial of 521 adults, the use of 300 mg or 600 mg of ursodeoxycholic acid, compared with placebo, resulted in a significantly decreased proportion of patients developing gallstones within 12 months after gastrectomy (5.3% in the 300-mg group, 4.3% in the 600-mg group, and 16.7% in the placebo group).
Ursodeoxycholic acid administration may prevent gallstone formation after gastrectomy in patients with gastric cancer.
The incidence of gallstones has been reported to increase after gastrectomy. However, few studies have been conducted on the prevention of gallstone formation in patients who have undergone gastrectomy.
To evaluate the efficacy and safety of ursodeoxycholic acid (UDCA) in preventing gallstone formation after gastrectomy in patients with gastric cancer.
Design, Setting, and Participants
The PEGASUS-D study (Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study) was a randomized, double-blind, placebo-controlled clinical trial conducted at 12 institutions in the Republic of Korea. Adults (aged ≥19 years) with a diagnosis of gastric cancer who underwent total, distal, or proximal gastrectomy were enrolled between May 26, 2015, and January 9, 2017; follow-up ended January 8, 2018. Efficacy was evaluated by both the full analysis set, based on the intention-to-treat principle, and the per-protocol set; full analysis set findings were interpreted as the main results.
Eligible participants were randomly assigned to receive 300 mg of UDCA, 600 mg of UDCA, or placebo at a ratio of 1:1:1. Ursodeoxycholic acid and placebo were administered daily for 52 weeks.
Main Outcomes and Measures
Gallstone formation was assessed with abdominal ultrasonography every 3 months for 12 months. Randomization and allocation to trial groups were carried out by an interactive web-response system. The primary end point was the proportion of patients developing gallstones within 12 months after gastrectomy.
A total of 521 patients (175 received 300 mg of UDCA, 178 received 600 mg of UDCA, and 168 received placebo) were randomized. The full analysis set included 465 patients (311 men; median age, 56.0 years [interquartile range, 48.0-64.0 years]), with 151 patients in the 300-mg group, 164 patients in the 600-mg group, and 150 patients in the placebo group. The proportion of patients developing gallstones within 12 months after gastrectomy was 8 of 151 (5.3%) in the 300-mg group, 7 of 164 (4.3%) in the 600-mg group, and 25 of 150 (16.7%) in the placebo group. Compared with the placebo group, odds ratios for gallstone formation were 0.27 (95% CI, 0.12-0.62; P = .002) in the 300-mg group and 0.20 (95% CI, 0.08-0.50; P < .001) in the 600-mg group. No significant adverse drug reactions were detected among the enrolled patients.
Conclusions and Relevance
Administration of UDCA for 12 months significantly reduced the incidence of gallstones after gastrectomy for gastric cancer. These findings suggest that UDCA administration prevents gallstone formation after gastrectomy in patients with gastric cancer.
ClinicalTrials.gov Identifier: NCT02490111
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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.
Accepted for Publication: March 13, 2020.
Published Online: June 17, 2020. doi:10.1001/jamasurg.2020.1501
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Lee SH et al. JAMA Surgery.
Corresponding Author: Do Joong Park, MD, PhD, Department of Surgery and Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea (email@example.com).
Author Contributions: Dr D. J. Park had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: S. H. Lee, Jang, Yoo, Ryu, Y.S. Park, D. J. Park.
Acquisition, analysis, or interpretation of data: S. H. Lee, Jang, Yoo, Hwang, Ryu, Kwon, Hur, Yoon, Eom, H. S. Ahn, Son, Song, H. H. Lee, Choi, An, S.-I. Lee, K. H. Lee, S. Ahn, D. J. Park.
Drafting of the manuscript: S. H. Lee, Jang, Ryu, D. J. Park.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: S. H. Lee, H. S. Ahn, K. H. Lee, S. Ahn, D. J. Park.
Obtained funding: S. H. Lee, Ryu, D. J. Park.
Administrative, technical, or material support: S. H. Lee, Jang, Yoo, Ryu, Eom, H. S. Ahn, An, K. H. Lee, Y. S. Park, D. J. Park.
Supervision: S. H. Lee, Ryu, Song, An, D. J. Park.
Conflict of Interest Disclosures: Dr S.H. Lee reported receiving speaker honoraria and grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr Yoo reported receiving grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr Y. S. Park reported receiving grants from Daewoong Pharmaceutical Co Ltd during the conduct of the study. Dr D. J. Park reported receiving speaker honoraria from Daewoong Pharmaceutical Co Ltd during the conduct of the study; and a research grant from Medtronic outside the submitted work. No other disclosures were reported.
Funding/Support: This study was supported by a research grant from Daewoong Pharmaceutical Co Ltd.
Role of the Funder/Sponsor: The funding source, with guidance from the steering committee, was involved in the study design, data collection and analysis, and manuscript preparation process.
Group Information: The Efficacy and Safety of DWJ1319 in the Prevention of Gallstone Formation after Gastrectomy in Patient with Gastric Cancer: A Multicenter, Randomized, Double-blind, Placebo-controlled Study (PEGASUS-D) Group members are Do Joong Park (principal investigator [PI]), Sang Hyub Lee (co-PI), Moon-Won Yoo, Sun-Hwi Hwang, Seong-Yeob Ryu, Oh Kyoung Kwon, Hoon Hur, Hong Man Yoon, Bang Wool Eom, Hye Seong Ahn, Taeil Son, Kyo Young Song, Han Hong Lee, Min-Gew Choi, Ji Yeong An, Sang-Il Lee (all site PIs), Dong Kee Jang, Kyung Ho Lee, Young Suk Park (all investigators), and Soyeon Ahn (principal biostatistician).
Meeting Presentation: This paper was presented at the Lecture Presentation of Research Forum of the Digestive Disease Week; May 18, 2019; San Diego, California; at the International Gastric Cancer Congress; May 10, 2019; Prague, Czech Republic; and at the 39th Congress of the European Society of Surgical Oncology; October 10, 2019; Rotterdam, the Netherlands.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We thank the patients and their families for participating in the trial. Kyung Won Kim, MD, PhD, Asan Medical Center; Jee Hyun Baek, MD, Human Medical Imaging and Intervention Center; Hyun Sik Woo, MD, Boramae Medical Center; and Eun Sun Lee, MD, PhD, Chung-Ang University Hospital provided consultation regarding radiologic criteria. They were compensated for their contributions. Hyung-Ho Kim, MD, PhD, and Sang-Hoon Ahn, MD, Seoul National University Bundang Hospital; Beom-Su Kim, MD, PhD, and In Seob Lee, MD, PhD, Asan Medical Center; and Ji Yoen Park, MD, Kyoungpook National University Hospital were investigators for each institute. They were not compensated for their contributions. Hyun Ju Shin, BS, Daewoong Pharmaceutical Co Ltd, was clinical project leader and Bobae Jo, MS, Daewoong Pharmaceutical Co Ltd, was the statistician. They were not compensated for their contributions.
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