Parts of this chapter are reproduced with permission from Ahmed et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Introduction
Gallstone disease (cholelithiasis) is one of the most common gastrointestinal disorders in industrialised societies. The prevalence of gallstones in the adult population is approximately 10–15%.2–6 Gallstones are more common in women and people over the age of 40 years.
Clinical surveys conducted in Europe, North and South America, and Asia indicate that prevalence rates for gallstone disease range from 5.9% to 25% and tend to increase with age.7–10 A clinical ultrasound survey conducted in the UK reported prevalence rates of 12% among men and 22% among women over 60 years of age.9 A multicentre population-based study conducted in Italy has reported an annual incidence of gallstone disease of 0.66% in men and 0.81% in women.11
In the UK and North America, the number of surgical procedures for gallstone disease increased steadily between the 1950s and 1990s, reflecting the rise in prevalence of identified gallstone disease and the use of cholecystectomy as the treatment of choice. Rates of surgical procedures stabilised in these countries towards the end of the twentieth century.6
The natural course of gallstones is benign, with most people being asymptomatic and with relatively low progression from asymptomatic disease to symptomatic disease.12 In an Italian population-based study, the overall frequency of symptom development in asymptomatic people was around 20% over a long follow-up period (mean 8.7 years).12 Similarly, a systematic review published in 2007 reported that the progression of asymptomatic to symptomatic disease ranged from 10% to 25% in studies that followed up patients after their initial diagnosis (up to 15 years of follow-up).13 The annual risk of developing symptoms has been estimated to be around 2–4%.12
Most people with symptomatic uncomplicated gallstone disease probably do not develop complications; the annual rates of developing gallstone-related complications (e.g. acute cholecystitis, acute pancreatitis, acute cholangitis obstructive jaundice) have been reported to be as low as 1–3%.14–16 The Italian Group for the Epidemiology and Prevention of Cholelithiasis study reported an annual incidence of complications of 0.7% for symptomatic patients.17
Mortality from gallstone disease is rare, with typically < 1% of people dying from gallstone-related causes.12,17,18
From a patient’s perspective, the defining symptom of gallstone disease is severe and lasting (i.e. > 30 minutes) abdominal pain.19,20 Commonly, general abdominal symptoms intensify over a period and become regular pain attacks (biliary colic) and may require medical attention.
A recent large prospective study conducted in the UK (8909 participants) has shown that 10.8% of people experienced complications 30 days after surgery.21 Furthermore, a proportion of people (up to 40%) may continue to experience pain and abdominal symptoms after surgery.22 In particular, persistent pain similar to that experienced preoperatively has been reported in about 20% of people after cholecystectomy23,24 and de novo pain has been reported in up to 14% of people.25
The term ‘postcholecystectomy syndrome’ is an umbrella term widely used to describe the range of symptoms that occur after cholecystectomy.26 The term ‘persistent postcholecystectomy symptoms’ has been suggested as a more accurate description of these symptoms.27 Symptoms include biliary and non-biliary abdominal pain, dyspepsia, heartburn, nausea, vomiting and jaundice. Persistent diarrhoea or constipation is often reported after cholecystectomy, and flatulence may arise de novo after surgery.25 There is no consistent pathophysiological explanation for persistent postcholecystectomy symptoms and, in about 5% of people, the reason for constant abdominal pain remains unknown.28,29
The rationale for the trial
Current clinical guidelines recommend expectant treatment for asymptomatic gallstones and hence laparoscopic cholecystectomy is considered for biliary pain or acute cholecystitis with radiological evidence of gallstones (i.e. symptomatic gallstones).30 As per most of the international guidelines, cholecystectomy is the default option for people with symptomatic gallstone disease,30 and one of the most common and, in terms of total costs, costly elective surgical procedures performed in the NHS in the UK. Some 74,373 cholecystectomies were performed in England in 2019 at an average cost of £3581 per procedure31 (61,584 of these following elective admissions).32 These figures indicate that although some patients are operated on in the acute hospital setting, many people with uncomplicated symptomatic gallstone disease are put on a waiting list and operated on electively after several months. Mean waiting time varies according to available resources; in the UK pre-COVID it has been reported to be around 12 months.33
Observation and relief of symptoms, delivered mainly in primary care, may be a valid therapeutic option in people presenting with uncomplicated disease, depending on their age, clinical presentation and evolution of symptoms over time. Symptom management includes the prescription of analgesics alongside dietary advice and, when necessary, anti-inflammatory drugs or antibiotics. Moreover, as symptoms of uncomplicated gallstones are usually not urgent, it may be reasonable to consider a conservative option first, which could save a considerable amount of NHS resources.
Early natural history studies, and more recent observational and population-based studies, have suggested that a proportion of people with symptomatic gallstone disease no longer experience biliary pain after the onset of symptoms.12,17,18,22,34 Larsen et al.22 found that 45% of symptomatic people on watchful waiting were relieved from symptoms during a 1-year observation period. Similarly, Festi et al. observed that 58% of people with initially mild symptoms, and 52% of those with more severe symptoms, did not experience further pain episodes during a follow-up period of 10 years, or an increase in disease severity over time.12 If about half of the people treated conservatively were likely to be symptom-free, up to 30,000 cholecystectomies per year could potentially be avoided with a likely saving for the NHS of around £68 million/year.
A National Institute of Health and Care Research (NIHR) Health Technology Assessment (HTA) found that, on average, cholecystectomy is more costly but more effective than observation/conservative treatment for symptomatic gallstones or cholecystitis.35 Nevertheless, half of the people treated conservatively were symptom-free and did not require surgery in the long term (14-year follow-up) indicating that there is probably a proportion of patients with uncomplicated symptomatic gallstone disease who could benefit from a conservative approach. The specific results were that participants randomised to observation/conservative treatment were significantly more likely to experience gallstone-related complications [risk ratio (RR) 6.69; 95% confidence interval (CI) 1.57 to 28.51; p = 0.01], in particular acute cholecystitis (RR 9.55; 95% CI 1.25 to 73.27; p = 0.03), but less likely to undergo surgery (RR 0.50; 95% CI 0.34 to 0.73; p = 0.0004) and experience surgery-related complications (RR 0.36; 95% CI 0.16 to 0.81; p = 0.01) than those randomised to receive surgery. Fifty-five per cent of people randomised to observation/conservative treatment did not require an operation during the 14-year follow-up period, and 12% of people randomised to cholecystectomy did not undergo the scheduled surgical operation. These results were subject to major uncertainties in the reported economic model. Even when cholecystectomy occurred after conservative management, a conservative management strategy had between 40% and 60% chance of being cost-effective for alternative values of willingness to pay for an additional quality-adjusted life-year (QALY).
Furthermore, results were strongly influenced by the proportion of individuals initially treated conservatively who subsequently required surgery. Due to the limited evidence available and the current lack of UK NHS data, the C-GALL Research Group highlighted the need for a well-designed trial assessing the effects and safety of observation/conservative treatment compared with cholecystectomy.
Aims and objectives
The primary aim of the study is to assess the clinical and cost-effectiveness of observation/conservative management with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in a secondary care setting.
The primary patient objective is to compare observation/conservative management with laparoscopic cholecystectomy in terms of participants’ quality of life (QoL) using the Short Form-36 items (SF-36) health survey bodily pain domain at up to 18 months after randomisation.
The primary economic objective is to assess the cost-effectiveness of observation/conservative management versus laparoscopic cholecystectomy in terms of the incremental cost per QALY.
The secondary objectives are to compare observation/conservative management with laparoscopic cholecystectomy in terms of condition-specific quality of life (CSQ); SF-36 domains (excluding bodily pain domain); complications; need for further treatment; persistent symptoms; healthcare resource use (HCRU); and costs. Secondary outcomes are assessed at 18 and 24 months after randomisation. The bodily pain domain of the SF-36 health survey will also be assessed up to 24 months after randomisation.
The null hypothesis being tested is that there is no difference between observation/conservative management and laparoscopic cholecystectomy. The alternative hypothesis is that laparoscopic cholecystectomy is superior.