Elsevier

The Lancet

Volume 393, Issue 10188, 8–14 June 2019, Pages 2322-2330
The Lancet

Articles
Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial

https://doi.org/10.1016/S0140-6736(19)30941-9Get rights and content

Summary

Background

International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10–41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy.

Methods

We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18–95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15–30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022.

Findings

Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0–60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6–63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI −8·6%; pnon-inferiority=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526).

Interpretation

Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms.

Funding

The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.

Introduction

Symptomatic gallstone disease constitutes a substantial and increasing health problem in Western society.1 Yearly, there are more than 1·8 million ambulatory visits for symptomatic gallstones in the USA.2 5% of all patients with cholelithiasis develop complications such as cholecystitis, cholangitis, or biliary pancreatitis.3 The remaining 95% of patients are at risk for symptoms arising from cholecystolithiasis. Typically, these patients develop episodes of biliary colics, defined by the ROME III criteria as acute severe abdominal pain located in the right upper quadrant or epigastrium lasting 15–30 min or longer.4 Most patients do not develop typical attacks, but might report non-specific abdominal symptoms.3, 5

Research in context

Evidence before this study

International guidelines advise laparoscopic cholecystectomy as a treatment for uncomplicated symptomatic cholecystolithiasis. A systematic review published in 2013, two prospective studies published in 2011 and 2017, and the results of two randomised trials published in 2005 showed that 10–41% of all patients following cholecystectomy continued to have abdominal pain. Persistent postoperative pain is associated with a significant burden for health-care systems, especially from an economical viewpoint.

A systematic review of international guidelines published in 2017 showed no consensus on the criteria to select patients for elective cholecystectomy. The absence of consensus is further illustrated in studies showing large variation in clinical practice among and within countries. We found no studies or trials assessing different criteria for indication of cholecystectomy for uncomplicated symptomatic cholecystolithiasis, or studies assessing the effectiveness of a more restrictive strategy for selecting patients for cholecystectomy, compared with standard of care.

Added value of this study

Our randomised, controlled, non-inferiority trial (SECURE) in patients with abdominal pain and ultrasound-proven gallstones or sludge compared usual care with a restrictive strategy for selecting patients for cholecystectomy. The restrictive strategy was based on the Rome criteria of biliary colic. The findings showed that the primary outcome of pain reduction was suboptimal with both usual care and the restrictive strategy (non-inferiority of the restrictive strategy not shown). However, the restrictive strategy was associated with a reduction in cholecystectomies by 7·7% compared with usual care.

Implications of all the available evidence

The SECURE trial illustrates that current surgical treatment of patients with gallstones and abdominal symptoms is far from optimal, and is not improved by implementing a more restrictive selection for cholecystectomy. It is important to realise that most international guidelines on management of cholelithiasis include the Rome criteria as part of the diagnostic selection process for cholecystectomy. These findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms.

International guidelines advise laparoscopic cholecystectomy to treat symptomatic cholecystolithiasis,6, 7, 8 resulting in 700 000 cholecystectomies in the USA per year,3 at estimated costs of US$9·9 billion.9 However, a systematic review10 and multiple prospective cohort studies11, 12, 13 indicate that 10–41% of patients continue to have persistent abdominal pain despite cholecystectomy. As well as affecting their quality of life, these patients generate a substantial burden for health-care systems, including in economical terms.13, 14

The indication for cholecystectomy in uncomplicated symptomatic cholecystolithiasis varies globally.15 There is no consensus on the best criteria to select patients for elective surgery, resulting in preference-sensitive care16 and large variations in cholecystectomy practices among and within countries.17, 18, 19, 20 This variation emphasises the need for a better diagnostic strategy to select patients with uncomplicated symptomatic cholecystolithiasis for successful cholecystectomy.21, 22 A standardised strategy with stepwise selection for cholecystectomy based on the presence of true biliary symptoms might assist in reducing the number of ineffective cholecystectomies. To this end, we designed a randomised nationwide clinical trial in the Netherlands comparing the effectiveness of a restrictive standardised strategy with usual care to select patients for cholecystectomy. We hypothesised that the restrictive strategy arm would be non-inferior to usual care in the number of patients being pain-free at 12 months' follow-up at a lower proportion of cholecystectomies.

Section snippets

Study design and participants

The trial protocol, including study procedures and randomisation23 and the statistical analysis plan24 have been published before. Briefly, in this multicentre, randomised, parallel-arm, non-inferiority study (SECURE), patients were enrolled from 24 academic and non-academic hospitals in the Netherlands. The institutional review board of the Academic Medical Center (Amsterdam, Netherlands) approved the study protocol. The local ethical committees and boards of directors of all participating

Results

Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for ITT analysis: 537 allocated to usual care and 530 to the restrictive strategy (figure 2). 525 (98%) of 537 patients allocated to usual care and 383 (72%) of 530 patients allocated to the restrictive strategy were treated per protocol (figure 2).

The baseline characteristics of patients in the usual care and the restrictive strategy groups were similar (table 1). Patients in the restrictive strategy group reported more severe

Discussion

This trial showed suboptimal pain reduction in patients with gallstones and abdominal pain following both usual care and a restrictive strategy for selection for cholecystectomy. Even after cholecystectomy, 37% of patients in both groups continued to have abdominal pain. However, the restrictive strategy was associated with fewer cholecystectomies at 12 months follow-up. Presence of biliary colics before cholecystectomy was associated with better pain relief after cholecystectomy compared with

Data sharing

The study protocol and statistical analysis plan are published online. To access de-identified participant data, contact Philip de Reuver ([email protected]); access criteria will be defined after receipt of a research proposal.

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