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UPGRADE trial

Ursodeoxycholic acid, gallstones and bariatric surgery

An estimated 11 % of patients who have a Roux-en-Y gastric bypass develop symptomatic gallstone disease, leading to severe complications and sometimes hospitalisation and surgery

Researchers from the Netherlands have established a randomised controlled trial to assess whether Ursodeoxycholic acid (UDCA) reduces the incidence of symptomatic gallstone disease after Roux-en-Y gastric bypass or sleeve gastrectomy. The study will also determine if treatment with UDCA is cost-effective. The paper describing the clinical trial, ‘Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: study protocol for a randomized controlled trial (UPGRADE trial),’ was published in BMC Gastroenterology.

The paper’s authors from MC Slotervaart, the University of Amsterdam and OLVG, Amsterdam, and MC Zuiderzee, Lelystad, the Netherlands, state that an estimated 11 % of patients who have a Roux-en-Y gastric bypass develop symptomatic gallstone disease, leading to severe complications and sometimes hospitalisation and surgery. It is known that UDCA prevents the formation of gallstones after bariatric surgery although, no randomised controlled trial with symptomatic gallstone disease as primary endpoint has been conducted. In addition, current major guidelines make no definite statement about postoperative UDCA prophylaxis and most bariatric centres (in the Netherlands) do not prescribe UDCA.

The UPGRADE trial, a randomised, placebo-controlled, double-blind multi-centre trial is planning to recruit 980 patients scheduled to undergo Roux-en-Y gastric bypass or sleeve gastrectomy (Figure 1) in three bariatric centres in the Netherlands. Patients will undergo a preoperative ultrasound and randomisation will be stratified for pre-existing gallstones and for type of surgery. The intervention group will receive UDCA 900mg once daily for six months. The placebo group will receive similar-looking placebo tablets.

Figure 1: Study flowchart

The primary endpoint is symptomatic gallstone disease after 24 months, defined as admission or hospital visit for symptomatic gallstone disease. Secondary endpoints consist of the development of gallstones on ultrasound at 24 months, number of cholecystectomies, side-effects of UDCA and quality of life. Furthermore, cost-effectiveness, cost-utility and budget impact analyses will be performed.

The increased risk of gallstone development involves several determinants, such as rapid weight loss that causes a change in cholesterol metabolism and consequently increases the concentration of cholesterol in the bile to a level at which not all cholesterol can be dissolved by the bile salts. This undissolved cholesterol is prone to crystallise into stones and the concentration of mucin in the bile increases 10–20 fold after bariatric surgery, although the exact mechanism behind this increase is unknown.

UDCA is an orally taken bile acid that is known to prevent the formation of gallstones by increasing bile flow and reducing its lithogenicity. It is well tolerated with few side effects, the most prevalent of which is diarrhoea in 2–9% of patients.

The authors note that to date, five trials have studied the use of UDCA for gallstone prophylaxis after bariatric surgery (RYGB, vertical banded gastroplasty or adjustable gastric banding). The trials reported tha UDCA for three to six months effectively prevents the formation of gallstones up to 24 months after bariatric surgery. Nevertheless, the primary endpoint of all studies consisted of the formation of gallstones on ultrasound and not symptoms of, or medical interventions for gallstones. Therefore, the athours state that the studies not provide definite evidence regarding the use of UDCA, as 60–80% of patients with gallstones will remain asymptomatic.

They also caution that there is a degree of uncertainty about the use of postoperative gallstone prophylaxis is reflected in the different guidelines. For example, the note that the 2013 guidelines by the American Society of Metabolic and Bariatric Surgeons states that both prophylactic cholecystectomy and the postoperative use of ursodeoxycholic acid may be considered but makes no definitive statement about either of the preventive strategies. Therefore, they have designed this study designed to provide evidence regarding the prophylactic use of UDCA in preventing symptomatic gallstone disease post-operatively.

For the cost-effectivity and cost-utility analysis, incremental cost-effectiveness ratios will be calculated as the extra costs per additional patient without symptomatic gallstone disease and as the extra costs per QALY gained. Medical, patient and employer costs will be included in the evaluation.

“This randomised controlled trial is designed to provide evidence regarding the effectiveness of UDCA for the prevention of symptomatic gallstone disease after bariatric surgery,” the authors conclude. “The main advantage over previous studies is the presence of a clinically relevant endpoint, namely symptomatic gallstone disease, and the follow-up duration of 24 months.”

This study is funded by ZonMW (The Netherlands Organisation for Health Research and Development) and the foundation for clinical research Slotervaart hospital (Stichting Klinisch Wetenschappelijk Onderzoek Slotervaartziekenhuis, SKWOSZ). Zambon BV the Netherlands provided research support consisting of all necessary UDCA tablets and the ultrasound device.

To access this paper, please click here

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