Chapter 1Introduction

Gastro-oesophageal reflux disease

The lower oesophagus, at its junction with the stomach, normally acts as a sphincter to prevent the contents of the stomach flowing back up the oesophagus. When the sphincter does not work adequately, the acid stomach contents leak, or ‘reflux’, into the oesophagus. The commonest symptom that this causes is heartburn, a burning sensation in the chest or throat. GORD has been defined through an international consensus process as ‘a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications’; in this consensus, symptoms were considered ‘troublesome’ ‘if they adversely affected a patient's well-being’.⁶

Symptoms caused by gastro-oesophageal reflux are common: between 20% and 30% of a ‘Western’ adult population experience heartburn and/or reflux intermittently.^7–9

Treatment of GORD includes both medical and surgical management, the options depending on the severity of symptoms. The majority of people with reflux have only mild symptoms and require little, if any, medication. The simplest is self-administered antacids with advice to alter lifestyle factors such as dietary modification, smoking cessation and weight reduction. A minority have severe symptoms and develop overt complications, despite full medical therapy, and require surgical intervention. Among the remainder, control of symptoms requires regular or continuous acid-suppression therapy using either histamine receptor antagonists (H₂RAs) or proton pump inhibitors (PPIs); initial high-dose therapy may be followed by maintenance treatment using these drugs either intermittently or continuously at a reduced dose sufficient to suppress symptoms. It is from this intermediate group of patients with significant disease requiring maintenance medical treatment that most of the treatment costs for the health service arise.

Laparoscopic fundoplication

Interest in surgery as an alternative to long-term medical therapy for GORD has been considerable since the introduction of the minimal access laparoscopic approach in the early 1990s.¹⁰ Randomised trials conducted comparing laparoscopic with open surgery showed similar improvement in symptoms but with clear benefits of the laparoscopic approach in terms of recovery and fewer postsurgical complications.11 As a consequence, surgery was suggested as an alternative to long-term maintenance medical treatment with anti-reflux drugs.

The operative method, whether using an open or a laparoscopic approach, involves performing a fundoplication by wrapping the fundus of the stomach around the lower oesophagus to create a high-pressure zone, thus reducing gastro-oesophageal reflux. The wrap created can be either complete (360°) or partial. Many operative variants have been described. The commonest operation is a 1-cm complete wrap fashioned over a large bougie, the so-called ‘short-floppy Nissen’.^12,13 There has been debate about the use of a partial rather than a total fundoplication. The partial approach has a number of potential advantages (such as fewer postoperative complications) but several controlled studies have shown broad equivalence between the two approaches;¹⁴ for the purpose of this study they were therefore regarded as equivalent. Although fundoplication is reported to produce resolution of reflux symptoms in upwards of 90% of patients, like all surgery it carries risks and can have side effects. There is also uncertainty about the durability of benefit and frequency and severity of side effects following surgical therapy. Long-term follow-up to 12 years after open reflux surgery suggested attenuated but continuing better control of reflux symptoms; however, other symptoms such as difficulties swallowing (dysphagia), rectal flatulence and inability to belch or vomit were more common in surgical patients.¹⁵ An important objective of this study was to determine if the long-term pattern of symptoms following laparoscopic surgery was similar.

Medical management

Proton pump inhibitors, sometimes supplemented with prokinetics or alginates, are the most effective medical treatment for moderate to severe GORD. Once started on PPIs, the majority of patients with significant GORD remain on long-term treatment.¹⁶ It is estimated that around 1% or more of the UK adult population are prescribed PPI maintenance therapy.^17–19 The cost to the NHS of medical management of GORD is considerable. In England alone, the cost of PPIs is estimated to be £220M per year.²⁰ Of this budget, most of this prescribing occurs within the primary care setting.^21,22

Although PPIs are generally considered safe, there is increasing acknowledgement of their possible adverse effects.^23,24 Gastric acid suppression predisposes to enteric infections and the sustained hypergastrinaemia resulting from PPI use causes rebound acid hypersecretion and the development of acid-related symptoms if the drug is stopped. Acute severe hypomagnesaemia has been recognised relatively recently as a rare adverse reaction to PPIs; the mechanism underlying it is not known. The clinical significance of impaired vitamin B₁₂ and iron absorption due to PPIs is uncertain; there is also controversy about the risk of fractures and pneumonia and about the occurrence and significance of gastric mucosal atrophy and intestinal metaplasia, which have been seen in Helicobacter pylori-positive patients taking PPIs. Drug–drug interactions have also been a cause for concern,²⁵ although unequivocal evidence of their occurrence does not in itself establish clinical significance.

For the purpose of this study, medical therapy was taken to mean long-term therapy with PPIs (or H₂RAs if intolerant to PPIs).

Rationale for the study design

The original study design was based on the belief that decisions about the management of GORD should be made using unbiased, statistically precise comparisons of alternative policies. At study entry all patients fulfilled three criteria: they were on long-term acid suppression with PPIs; they had symptoms that were thought to be adequately controlled; and they were suitable in terms of fitness and comorbidity for either surgical or continuing medical treatment for their GORD. At the time that the study was planned, the consensus opinion of clinicians was that these three criteria identified GORD patients for whom surgical and continuing medical treatment could be considered equally acceptable treatment options and that, consequently, the comparison should be undertaken in patients meeting these criteria.

The most likely sources of bias were in the ways in which the groups being compared were selected; how their outcomes were assessed; and how the management was actually delivered. This is the basis for using a pragmatic randomised controlled trial (RCT) design. Random allocation protected against selection bias. Confining the trial to those with no clear treatment preference limits biased patient-centred assessment of outcome, and pragmatic comparison of alternative policies [with intention-to-treat (ITT) analysis] avoids bias introduced by individual cases of non-compliance. This approach had limitations, however, and for this reason we chose to incorporate two parallel, non-randomised preference groups.

Including those with a clear preference for one policy or the other allows broader extrapolation and generalisability. Study of this group may give insights into the reasons for preference and hence give pointers to patient choices after the study.²⁶ Furthermore, preference may influence outcome and, if so, this may also help when making treatment decisions.^26,27 A third reason for the parallel, non-randomised preference groups²⁸ was that the addition of data from the preference groups may reduce imprecision around the estimates from the randomised comparison and this may be particularly useful for rare events, such as complications that can be confidently ascribed to one or other treatment. (The limitation is that the preference groups are not derived by random allocation, and hence the comparisons are exposed to the biases of non-randomised studies.)

Reliable comparisons within and between randomised and preference groups require valid measurement of treatment outcome. Although there were a number of quality-of-life (QoL) tools available, none was sufficiently specific to assess the spectrum of gastrointestinal symptoms associated with the treatment of GORD, particularly those due to surgery. For this reason we developed and validated a new outcome measure (the REFLUX questionnaire). We have continued to use this as the primary outcome measure in the longer-term follow-up reported here. Details of the REFLUX questionnaire and its derivation have been described elsewhere.^1,4

Gastro-oesophageal reflux disease and its management represent a very significant call on NHS resources. Although clinical effectiveness, acceptability and safety will be important determinants of future policy, the issues of cost and resource use may be over-riding. This is the reason for the economic evaluation component of this study. Policy should be guided by both assessment of the relative cost-effectiveness of alternative policies and assessment of the impact that possible policy changes would have for the NHS and for patients with GORD.

The cost of laparoscopic fundoplication appears to be equivalent to the cost of 2–3 years of maintenance treatment with PPIs, although it is acknowledged that the costs of PPIs are falling.²⁹ The costs of surgery are related largely to two factors: the incidence of complications/length of hospital stay and the number of patients requiring long-term medical interventions after surgery.

We addressed cost-effectiveness in our report of the first phase of the REFLUX trial.¹ We reported both a within-trial cost-effectiveness analysis based on the results up to 12 months after surgery and an extended cost-effectiveness model that explored a number of scenarios beyond 12 months. The within-trial analysis related the extra mean costs associated with the surgical policy to the estimated increase in mean quality-adjusted life-years (QALYs) associated with surgery up to that time. The incremental cost-effectiveness ratio (ICER) was around £19,000 when the ITT analysis was used. Taking into account the uncertainties around the estimates of both costs and utilities, it was calculated that the chance that the surgical policy would be cost-effective at a threshold of £20,000 per QALY was 46%. This indicated considerable uncertainty at thresholds that are currently commonly applied to costs per QALY. The limitations of the within-trial analysis were discussed in detail in the earlier report, in particular that it ignored costs and benefits that accrued after 1 year.

The economic model was designed to address the limitations of the within-trial analysis. It explored a range of scenarios of varying lifetime benefits and costs, and analyses gave a wide range of incremental costs per QALY of £1000–44,000, again indicative of wide uncertainty. The factors contributing most to this uncertainty were the projected health-related quality-of-life (HRQoL) parameters and the long-term uptake of medication following surgery.

Thus, although data available up to a time equivalent to 1 year after surgery provided promising evidence that surgical management might well be cost-effective, there was too much uncertainty, especially about longer-term costs and benefits, to provide clear guidance for decision-makers. This was the justification for the longer-term follow-up to 5 years reported here.