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Controversies in long-term management of reflux disease
BaillieÁre's Clinical Gastroenterology Vol. 14, No. 5, pp. 811±826, 2000
doi:10.1053/bega.2000.0126, available online at http://www.idealibrary.com on
9 Controversies in long-term management of re¯ux disease John Dent
BA, MB, BChir, MRCP, FRACP, PhD, FRCP(UK)
Professor Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, Adelaide SA 5000, Australia
There are signi®cant controversies about the long-term therapy of re¯ux disease that arise primarily from a lack of data on the risks of the disease and its therapies over the relevant time scale of several decades. Currently, there are no appropriately structured direct comparisons between the two current major treatment options of tailored long-term acid suppression and laparoscopic anti-re¯ux surgery. Critical review of the available literature does not support the assertion that anti-re¯ux surgery has a superior risk/bene®t pro®le when compared to long-term proton pump inhibitor (PPI) therapy, since non-controlled data indicate that although both therapies are relatively safe, morbidity and mortality rates are lowest with PPI therapy, whilst ecacy is comparable. The clinical signi®cance of the re¯ux that continues to occur after both anti-re¯ux surgery and during PPI therapy is uncertain, but probably overestimated. As pathological duodenogastro-oesophageal re¯ux aects only a small minority of re¯ux disease patients, issues arising from it should not be regarded as mainstream in¯uences on the choice of long-term therapy. Notwithstanding, this type of re¯ux is substantially reduced by both PPI therapy and anti-re¯ux surgery. The choice between laparoscopic surgery and long-term tailored acid suppression should be determined primarily by assessment of operative risk, the quality of surgery available to the patient and by patient preference, after balanced explanation of the risks and bene®ts of each option. Given that the cost of PPI therapy is likely to drop substantially in the next few years, drug cost should not be a major pressure for the choice of anti-re¯ux surgery. Key words: gastro-oesophageal re¯ux disease; surgery; medical therapy; Barrett's oesophagus; oesophageal adenocarcinoma.
INTRODUCTION Other chapters in this volume have demonstrated the extent to which patients with re¯ux disease have gained during the last decade from substantial developments and re®nements of the management of this common disease. Better recognition of the chronic nature of re¯ux disease has been especially important, and maintenance of remission has been a major focus for the developments of both medical and surgical therapy. Evaluations of therapeutic developments have focused predominantly on outcomes for the ®rst 12 months of maintenance therapy, with few studies addressing the many important questions about the best approaches to management of re¯ux disease over a time span of decades. Even fewer of these studies have used rigorous 1521±6918/00/050811+16 $35.00/00
c 2000 Harcourt Publishers Ltd. *
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methodology and, in particular, appropriately chosen and observed control groups. For treatment or observation periods beyond 10 years, data of any form at all are especially scanty. As a result, discussion about the ecacy, risks and bene®ts of particular options for the very long-term management of re¯ux disease has been highly extrapolative; in some instances, strong views on the relative merits of surgery and medical therapy have been based on individual clinical experience or anecdotes, or studies in animal models. Such extrapolation is bound to excite controversy; this chapter reviews these areas. ISSUES RELEVANT TO EFFICACY What are the desirable outcomes of long-term therapy? In the case of symptoms, there is little controversy, since there appears to be agreement that therapy should at least control symptoms to the point at which they no longer impair quality of life.1,2 Formal studies of quality of life in re¯ux disease show that when heartburn episodes are reduced to two or fewer per week, there is unlikely to be impairment of health-related quality of life due to these.1,3 It is also important that therapy does not introduce its own symptoms; this is mainly an issue with anti-re¯ux surgery4 which is dealt with below. Desirable end points for the management of re¯ux oesophagitis are much more controversial. In the case of the many patients with troublesome re¯ux-induced symptoms who have no endoscopic oesophagitis, the limited data available indicate that over a time span of up to 15 years, progression to clear-cut endoscopic oesophagitis occurs rarely, if at all.1,2,5 Therefore, the treatment strategy should not be in¯uenced by the theoretical ability of particular treatments to prevent the development of oesophagitis over time. For patients with de®nite endoscopic re¯ux oesophagitis, de®ned as mucosal breaks according to the Los Angeles Classi®cation system (erosion or ulceration)6, a recent workshop1 distinguished between the risks of mild to moderate oesophagitis, de®ned as grades A and B, and the more severe grades C and D, in which mucosal breaks are continuous between the tops of two or more of the radial oesophageal folds. There appears to be agreement that Los Angeles grade C and D oesophagitis carries a substantial risk of complications, and so needs vigorous continuous treatment.1,2 In the case of Los Angeles grade A and B oesophagitis, half of the experts supported, and the other half disagreed with, the proposition that there was minimal risk from this severity of oesophagitis.1 This author sits somewhere between these extremes, doubting that Los Angeles grade A oesophagitis carries any substantial risk and so is probably an acceptable therapeutic outcome, but believing that grade B could well have signi®cant risks. These dierences of opinion re¯ect the lack of data on the very long-term risks of oesophagitis, especially the milder grades, and on the frequency of progression of Los Angeles grades A and B oesophagitis to grades C and D. Some proponents of the bene®ts of surgery place strong emphasis on `normalization' of oesophageal acid exposure, or even on abolition of re¯ux of all types, but these measures of outcome are of unproven additional value over and above control of symptoms and oesophagitis. How representative are the published data for outcomes in routine practice? This is a substantial issue in the case of anti-re¯ux surgery, especially via the laparoscopic route.7 Consistent success with this type of surgery requires considerable
Controversies in long-term management 813
% patients re-operated
20
10
0
15
610
1120
2140
4160
61+
Number in surgeons experience Figure 1. Re-operation rates for laparoscopic anti-re¯ux surgery according to the experience of the surgeon. This measure is considered a useful indicator of surgeon experience and skill. (Data from Watson, Baigrie and Jamieson8, with permission.) Data are from 11 surgeons who performed a total of 280 operations.
expertise.4 Outcomes have been shown to be operator-dependent, and even within a unit that has a special focus on methods of anti-re¯ux surgery, as shown in Figure 1, major outcomes are in¯uenced by the experience of the surgeon.4,8 Publications that report on the outcomes of anti-re¯ux surgery have come from surgical groups with a special interest in this surgery; such groups are likely to achieve better results overall than individual surgeons whose practice is not as highly focused on this particular type of surgery. Even amongst distinguished surgical units and groupings, there is quite a spectrum of results of laparoscopic anti-re¯ux surgery, with some units reporting excellent results4, while others report rather less good results compared to open surgery.9,10 The advent of the laparoscopic technique has led to a large increase in the number of patients having anti-re¯ux surgery, and it appears that most of this surgery is being done outside the environment of specialized units. The outcomes of antire¯ux surgery done in this setting are essentially not known. It is probably appropriate to believe that they are unlikely to emulate the data published from surgical groups with a special interest in anti-re¯ux surgery. In the case of medical therapy, no special skills are needed to deliver this care, so the results reported in the literature1,2,11 should be reasonably representative, though undoubtedly modi®ed by the lower levels of compliance with medication seen in routine practice compared to clinical trials. Non-compliance with therapy is, of course, not an issue for anti-re¯ux surgery. In the majority of re¯ux disease patients though, the major aim of therapy is merely control of symptoms, and there are now rigorous data which show that intermittent courses 12, or symptom-driven (`on-demand') use of proton pump inhibitors (PPI)13 is an eective option for endoscopy-negative re¯ux disease patients or patients with Los Angeles grades A and B oesophagitis. Furthermore, there is a good, though not perfect relationship between symptom relapse and relapse of oesophagitis14, which will tend to prompt the forgetful patient to use medication when it is really needed. On this basis, the published results of medical therapy are probably more representative of what can be achieved in routine practice than the results obtained with anti-re¯ux surgery outside specialized surgical units.
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How should the ecacies of medical therapy and anti-re¯ux surgery be compared? It may seem obvious that randomized, controlled, within-study comparisons are required, given the many pitfalls of making conclusions across dierent studies and unrandomized patient cohorts. The problem is that such studies are very dicult to carry out, so there are very few of them.15 Despite this dicult reality, the unsoundness of making comparisons of outcomes between dierent studies of medical and surgical therapy must be recognized. Unfortunately though, the lack of rigorous comparisons has led enthusiasts for either medical or surgical therapy to draw conclusions about comparative ecacies from their own, inevitably skewed, clinical experiences as well as from across studies. No single type of practitioner sees a truly representative sample of patients with re¯ux disease. The specialist surgeon sees mainly patients dissatis®ed with some aspect of non-surgical management, whilst surgically treated patients are usually only seen by a gastroenterologist when their outcomes are suboptimal. Discussion of the relative merits of medical and surgical therapy should also be con®ned to the best available options. Thus, reference to studies performed in previous therapeutic eras that compare anti-re¯ux surgery with lifestyle measures1,16, H2-receptor antagonist therapy17, or data from studies of PPI therapy that have ignored the use of the provision for increase of dosage in the event of incomplete response15 are not appropriate, since they do not re¯ect the current state of the art. How stable is the eective dose of PPI over time with very long-term maintenance therapy? Claims have been made, based apparently on clinical experience, that PPI dosage commonly needs to be increased over time during maintenance therapy. This view is not supported by the best evidence available, which comes from a structured followup of 230 patients treated continuously with omeprazole on a compassionate use programme for up to 11.2 years, with a median treatment duration of 6.5 years.18 These patients, who were deemed unsuitable for surgery, had severe re¯ux oesophagitis that was resistant to H2-receptor antagonists. Those whose oesophagitis healed with 40 mg daily were entered into the maintenance programme. Once patients had been calibrated to a minimum eective maintenance dose during the ®rst year of therapy, symptom assessment and yearly endoscopy showed that at least half of the patients were maintained successfully on omeprazole 20 mg. As shown in Figure 2, this pattern was maintained throughout the study, with very few patients requiring increase of omeprazole dose. CONTROVERSIAL ISSUES RELATED TO POSSIBLE ADVERSE EFFECTS OF LONG-TERM TREATMENT Mortality attributable to the disease and its therapies This issue of treatment-related mortality is a signi®cant one, given the very low overall mortality attributable to the disease itself in the total patient group with re¯ux disease. The small minority of patients with peptic stricture is exposed to the risk of death as a result of complications from perforation secondary to stricture dilatation.19 In the majority of patients, healing of oesophagitis by surgery or PPI therapy prevents
Controversies in long-term management 815
80 mg (or more) 2% 60 mg 10 %
@ 2 years
@ 5 years 27 %
@ 8 years
61 %
20 mg
40 mg 211 patients
157 patients
63 patients
Figure 2. Omeprazole dose over time required for prevention of relapse of oesophagitis in patients with previously severe re¯ux oesophagitis that was refractory to H2 receptor antagonist therapy. Patient numbers decreased primarily because of death due to causes unrelated to re¯ux disease. (Data from Klinkenberg-Knol et al.18)
recurrence of stricture20,21, and so controls this risk. Oesophageal adenocarcinoma is a major focus of attention at present as a source of re¯ux disease-related mortality (see Chapter 12). There has been a large proportional increase in the number of deaths due to oesophageal adenocarcinoma, but given the high prevalence of re¯ux disease, this remains a relatively small risk of having re¯ux disease, even if all cases of oesophageal adenocarcinoma are considered to be secondary to re¯ux-induced oesophageal columnar metaplasia. For example, a landmark study evaluated the epidemiology of oesophageal and gastric cardia adenocarcinoma by gathering and assessing all cases occurring in Sweden over a period of 25 months, during which 530 cases were recorded in a total population of around 10 million.22 Cisapride By contrast to the long-standing debate about the safety of acid suppression (see below), mortality that could be attributed to prokinetic therapy with cisapride has only become an issue very recently. In patients with pre-existing cardiac conduction defects, cisapride is now known to in¯uence cardiac conduction at the peak serum levels sometimes encountered with normal dosing.23 Furthermore even in patients without cardiac disease, when cisapride is taken with drugs that are also metabolized by its cytochrome P450 3A4 metabolic system, peak serum levels of this drug are reached that can produce life-threatening cardiac arrhythmias. Evidence that cisapride could be implicated in some sudden cardiac deaths has led the US Food and Drug Administration (FDA) to impose major restrictions on the use of cisapride and placement of a black-box warning on the packaging of cisapride which starts as follows `Serious cardiac arrhythmias, including ventricular tachycardia, ventricular ®brillation, torsades de pointes, and QT prolongation have been reported in patients taking Propulsid (cisapride)'. The warning also states that patients with cardiac disease may experience serious cardiac side eects during cisapride therapy, even when serum levels are not in¯uenced by drug±drug interactions. Unfortunately with the recognition of this signi®cant safety issue, it now appears inappropriate to use cisapride for the treatment of re¯ux disease except under unusual circumstances.
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Acid suppressant agents H2-receptor antagonists (H2RA) and PPIs have proved to be extremely safe and well tolerated drugs for both short-term and maintenance therapy. This experience extends beyond 15 years for H2RAs and beyond 10 years for PPIs.18 Discussion of the risks of using these agents long term has centred around the possibility that acid suppression could cause excess mortality indirectly, by increasing the risk of gastric malignancy. This is a legitimate concern, since these agents substantially alter the gastric luminal environment and mucosal structure and function. The development of gastric carcinoid tumours in rats during life-long massive dosing of both omeprazole and ranitidine24 emphasizes the need for continuing evaluation of the safety of acid suppressant agents, especially PPIs, during very long-term, continuous treatment. Data are needed for 30 or more years before the risks of acid suppression can be fully weighed against those of alternative therapies. The politics of the safety of long-term acid suppression with PPIs continue to be polarized, with divergent interpretations of data that are potentially relevant to long-term safety and morbidity. Concerns about these issues have been revisited in a recent commentary25, which has excited a critical response in which it is judged that any risks remain theoretical.26 The longest duration follow-up data that exist for continuous PPI therapy comes from the 230 patients with severe re¯ux oesophagitis who were treated with omeprazole for up to 11.2 years (median follow-up 6.5 years) on a compassionate use basis.18 No deaths were attributable directly or indirectly to this therapy, despite the frailty of many of the patients. Monitoring of gastric mucosal histology did not reveal any changes that could be interpreted as indicating that these patients were at any increased risk for the development of gastric, or any other, malignancy as a result of therapy. For the time span for which data are available, it appears that acid suppression itself carries minimal, if any, risk of treatment-related death. Anti-re¯ux surgery The risk of death from anti-re¯ux surgery is minimized by good patient selection, modern anaesthetic and surgical techniques, and high-quality post-operative care. Despite these enhancements, the nature of the intervention means that mortality cannot be eliminated. Estimates of the mortality from anti-re¯ux surgery are dicult to obtain, other than by pooling of reports in the literature, in order to obtain a large enough sample. Such a pooling for reports on open anti-re¯ux surgery published in the literature between 1980 and 1993 revealed four deaths within 30 days of surgery in 1152 patients, giving a crude mortality of 0.35% (R. McCloy and L. Lundell, pers. comm.) Of these four deaths, three were de®nitely related to the surgery. Five deaths attributable to laparoscopic anti-re¯ux surgery have been reported in the literature.4 Repeat anti-re¯ux surgery occurs suciently frequently that it should also be factored into the mortality equation. It is not only a double dose of risk for that particular patient, but the mortality of re-do anti-re¯ux surgery appears to be higher than that of the ®rst operation. How much of an issue are dysphagia and ¯atulence with anti-re¯ux surgery? This topic has been reviewed by Watson and de Beaux4 for laparoscopic surgery and in Chapter 8 of this volume. Controversy has arisen in part because it has not been realized that dysphagia and ¯atulence can be problems in re¯ux disease patients who
Controversies in long-term management 817
have not had anti-re¯ux surgery.17 The key messages though, are that anti-re¯ux surgery has the potential to produce disabling dysphagia and ¯atulence, and that the risk for this is dependent on details of the operative technique. This is more of a risk with laparoscopic than open surgery, at least in some hands.4 A very recent comparison from the Netherlands of the outcomes of open and laparoscopic Nissen fundoplication emphasizes this point.10 After laparoscopic Nissen fundoplication, seven out of 57 patients had persistent dysphagia 3 months after surgery, which was severe enough to require intervention. By comparison, none of the 46 patients having open Nissen fundoplication had dysphagia of this severity. This substantial dierence led to discontinuation of the trial on ethical grounds. This experience indicates how much the occurrence of dysphagia depends on the surgeon's technique. The outcomes of the Netherlands study should not be generalized to all laparoscopic anti-re¯ux surgery, since other comparisons between laparoscopic and open anti-re¯ux surgery have not shown major problems with dysphagia after laparoscopic anti-re¯ux surgery.4 The risk of dysphagia can probably be virtually eliminated by choice of surgeon, but it is also likely that at least in some hands, the choice of operation type may reduce the risk of persistently troublesome post-operative dysphagia, since partial and shorter complete fundoplications have been variably reported to be associated with fewer problems with dysphagia and bloating4 (see Chapter 8, this volume).
How does long-term PPI therapy compare with anti-re¯ux surgery for prevention of oesophagitis relapse? To date, only one study has addressed this question formally by randomizing 270 patients to either open anti-re¯ux surgery or current state-of-the-art medical therapy, in the form of omeprazole, with provision for dose increase to 40 mg daily in the event of failure of 20 mg daily.15 At the 3 year follow-up, anti-re¯ux surgery and omeprazole 20±40 mg (depending on the individual patient's response), were of equal ecacy for maintenance of oesophagitis healing and control of symptoms.27 The results for up to 5 years of follow-up are reported to show superiority in favour of anti-re¯ux surgery, but these data are not yet fully available.28 The results from the international omeprazole compassionate use programme provide useful but uncontrolled data on the ability of daily omeprazole to prevent relapse of oesophagitis in a highly selected population of problem patients for periods of up to 11 years.18 This structured observation of these 230 patients (in 38 of whom anti-re¯ux surgery had failed) included yearly endoscopy and extensive safety assessments. During follow-up on maintenance therapy, the overall average relapse rate was once every 9.4 patient years, including the ®rst year of maintenance therapy during which time the required maintenance dose was being determined after the initial healing dose of 40 mg had been reduced to 20 mg. After this phase of management was completed, the need to increase the dose of omeprazole was rare, and the mean omeprazole dose which kept oesophagitis healed and symptoms well controlled for the entire patient group was 29 mg daily per patient (Figure 2). When relapse of oesophagitis occurred, this was endoscopically mild in nearly three-quarters of instances and always responded to continuing omeprazole, rarely at increased dosage. The objective and well-structured observations summarized above are at odds with commentary that states that long-term omeprazole loses its eectiveness over time, with exposure of patients to substantial risk from smouldering, severe oesophagitis.29
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What is the role of duodenogastro-oesophageal re¯ux in the development of Barrett's oesophagus and oesophageal adenocarcinoma? This is an especially complex and controversial area, compounded by measurement diculties and inadequate understanding of the clinically relevant impacts on the oesophageal mucosa of the re¯uxate that contains duodenal enzymes and bile constituents. The global hypothesis of those who consider that anti-re¯ux surgery is a safer, more eective option for long-term management than PPIs, is that surgery is superior for both prevention of the development of Barrett's oesophagus and of oesophageal adenocarcinoma when Barrett's oesophagus is present, because re¯ux is prevented.30 Duodenogastro-oesophageal re¯ux (DGOR) is an important factor in this debate. The issues can be stepped through by addressing a series of focused questions. Duodenogastro-oesophageal re¯ux ± a factor that contributes to development of Barrett's oesophagus? The data available that bear on this question are reviewed in Chapter 3. First, it should be recognized that the Bilitec, the currently available method used to monitor for DGOR, has substantial inaccuracies that could disable the accurate dissection of the role of DGOR in Barrett's oesophagus, even though it is a major advance on previous methods available for measurement of DGOR.31 The available data show an association of high levels of DGOR with complicated (deep ulcer, stricture) Barrett's oesophagus, but this relationship is less convincing for individuals with uncomplicated Barrett's.32 Furthermore, very high levels of acid gastro-oesophageal re¯ux are closely associated with abnormal DGOR, so it is impossible to separate out the relative contributions of these two types of re¯ux to the pathogenesis of Barrett's oesophagus in the untreated patient. It can be concluded that currently available data on DGOR are insucient to clearly answer whether this contributes to the development of Barrett's oesophagus. Is duodenogastro-oesophageal re¯ux implicated in the development of Barrett's associated adenocarcinoma? The answer to this question is frequently taken as `yes', but the data that support this view are mostly indirect and limited in scope. Components of duodenal juice can potentiate acid/peptic damage to the oesophageal mucosa, but this does not mean that this injury determines progression to Barrett's cancer. Studies of Barrett's epithelium biopsies in organ culture suggest that full control of acid re¯ux episodes may be important in reducing the stimulation of processes in the mucosa that could favour the development of adenocarcinoma33 (see Chapter 12). There are no such data for DGOR. This question of the role of DGOR in Barrett's cancer has been addressed more directly by Stein et al34 by the performance of Bilitec monitoring in Barrett's patients with and without early adenocarcinoma or high-grade dysplasia (Figure 3). Monitoring was also done in a substantial group of patients with re¯ux oesophagitis, but no Barrett's oesophagus, patients with endoscopy-negative re¯ux disease, and normal subjects. Abnormal levels of bilirubin re¯ux were demonstrated in 11 out of 14 (78.6%) of the adenocarcinoma/high-grade dysplasia patients compared to 18 out of 33 (54.5%) of the Barrett's oesophagus patients without adenocarcinoma or high-grade dysplasia.
Controversies in long-term management 819
Electronic permission to reproduce this ®gure was not granted
Figure 3. Bilirubin re¯ux, into the oesophagus over 24 hours, used as an index of duodenogastrooesophageal re¯ux in dierent re¯ux disease patient groups and normal subjects. Data were obtained by Bilitech1 monitoring. (Reprinted from Stein et al34, with permission.) GORD, gastro-oesophageal re¯ux disease; HGD, high grade dysplasia.
Substantially less DGOR was seen in the other groups. These data are inconclusive as to the role of DGOR in cancer promotion. It is unlikely that there will ever be a de®nitive answer to the question of whether DGOR is a major driver for the development of Barrett's cancer, given the practical diculties of studying this. How important are issues relating to duodenogastro-oesophageal re¯ux in the full spectrum of re¯ux disease patients? Commentary about the importance of stopping pathological DGOR by the performance of anti-re¯ux surgery30 implies that this type of re¯ux is highly prevalent amongst re¯ux disease patients, or that patients are at risk for the development of pathological DGOR over time. This is a misleading message. Review of the endoscopic ®ndings in the full spectrum of re¯ux disease patients who present in primary care shows that about 60% of these have no oesophageal mucosal breaks, and a further 30% or so have only relatively mild re¯ux oesophagitis (Los Angeles grades A and B).1,2,35 These patients have been shown to have low levels of DGOR34 (Figure 3). Severe oesophagitis is usually only present in less than 10% of patients, and only a minority of these has Barrett's oesophagus with presumably associated pathological DGOR. Thus, issues relating to DGOR apply to a small subgroup of patients with gastro-oesophageal re¯ux disease (GORD). It has been implied that progression of the severity of re¯ux disease is to be expected over a relatively short time scale, and so should have an in¯uence on choice of therapy.29 There is no evidence to support this. Longitudinal follow-up of re¯ux disease patients has shown no change in endoscopic status over a time span of 10 to 15 years.1,5 These data need to be interpreted in the light of circumstantial evidence that points to the distinct possibility that re¯ux disease may progress in severity over a time span of several decades.
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Given the pattern of endoscopic ®ndings in re¯ux disease patients35, if DGOR is really an independent factor in the pathogenesis of Barrett's cancer, it is only of practical importance in a small minority of patients. Discussion of possible special management needs of this patient group should not be generalized to all patients with re¯ux disease. What are the risks and bene®ts of the patterns of re¯ux that occur during PPI therapy? PPIs achieve their substantial therapeutic eects by major reduction of the aggressiveness of gastric juice, through elevation of gastric pH to a level that makes gastric pepsin minimally active. The reduction of gastric secretion produced by PPIs appears also to have bene®cial eects on the volume and patterning of gastro-oesophageal re¯ux episodes, independent of their eects on pH. Advocates of anti-re¯ux surgery argue that the gastro-oesophageal re¯ux that occurs during long-term PPI therapy still carries a signi®cant risk for patients, a risk that is removed by anti-re¯ux surgery because this stops all re¯ux. This argument is open to question, not only from the point of view of whether patterns of re¯ux that occur during PPI therapy are harmful, but also from the point of view of the impacts of anti-re¯ux surgery on the patterns of re¯ux. Beyond 6 years, in at least 10±15% of patients, anti-re¯ux surgery no longer controls re¯ux to the level that prevents oesophagitis or symptoms.36 Also, in many of those patients in whom anti-re¯ux surgery achieves these desired end points, some gastro-oesophageal re¯ux does occur9,37, especially when surgical techniques are used that are designed to minimize the risk of persistent and troublesome post-operative dysphagia. The aggressiveness of the gastric juice that reaches the oesophagus in these patients is not moderated by any therapy. Thus, in a substantial minority of patients treated with anti-re¯ux surgery, there is a continuing, albeit reduced level of oesophageal mucosal insult. The occurrence of this re¯ux after surgery has not been adequately acknowledged and its clinical signi®cance not weighed adequately against the modi®ed patterning and composition of re¯ux that occurs during PPI therapy (see below). Do pathological levels of DGOR persist during PPI therapy? Arguments about the putative dangers of DGOR during PPI therapy appear to hinge on the assumption that DGOR will not be in¯uenced by this therapy. This is incorrect, as can be seen in Figure 4. These data show that DGOR is substantially reduced during PPI therapy, usually to within the normal range.38 This eect has been ascribed to reduction of gastric volume. How harmful is the acid re¯ux that occurs during PPI therapy? The proposition that the re¯ux that occurs during PPI therapy carries risk for patients needs more critical review than has occurred in the past. If PPI therapy does not result in healing of oesophagitis, it is reasonable to assume that there could be a risk for the development of Barrett's oesophagus. Such failure is, however, the exception with PPI therapy, even in the small minority of patients with Los Angeles grades C and D oesophagitis.11,18 This failure is associated with persistent symptoms in the majority of patients, and can usually be overcome by the use of increased dose PPI, preferably given twice daily.18
Percentage time oesophageal absorption > 0.14
Controversies in long-term management 821
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
Off omeprazole
On omeprazole
Figure 4. Reduction of duodenogastro-oesophageal re¯ux, measured as light absorbence bilirubin with Bilitech1 monitoring by omeprazole therapy in patients with Barrett's oesophagus. (Reprinted from Marshall et al38, with permission.)
Measures of dierentiation and proliferation in Barrett's mucosa are possible indicators of the risk for development of high-grade dysplasia or adenocarcinoma in Barrett's oesophagus. These measures have been assessed in oesophageal mucosal biopsies maintained in organ culture, which were obtained from Barrett's oesophagus patients.33 Completeness of long-term control of acid re¯ux achieved in each individual with lansoprazole therapy was correlated with measures of dierentiation and proliferation. Proliferation was found to be lower, and dierentiation higher, in patients in whom acid re¯ux was completely controlled, compared to biopsies from those in whom there was some persistent acid re¯ux. This ®nding gives some support to the assertion that the risk of development of Barrett's cancer may be reduced by a greater eect on re¯ux patterns than is required for healing of oesophagitis, or relief of symptoms. It was initially hoped that successful anti-re¯ux surgery or intensive PPI therapy could result in replacement of all oesophageal columnar metaplasia, with attendant abolition, or at least substantial reduction in the risk for adenocarcinoma. It is now clear that neither of these treatments alone can achieve this, although some regression has been shown to occur in some patients with both therapies. Given that oesophageal columnar metaplasia persists, it is important to know whether eective abolition of acid re¯ux could impact favourably on the risk for Barrett's cancer in both medically and surgically treated patients. Barrett's cancers have occurred after both apparently
822 J. Dent
successful anti-re¯ux surgery39 and healing of oesophagitis with proton pump inhibitor therapy18,40, but available data are insucient to judge whether these treatments reduce the risk of cancer. Once Barrett's oesophagus patients with high-grade dysplasia or adenocarcinoma have been recognized by initial screening and excluded from a surveillance cohort, the rate of development of high grade dysplasia or adenocarcinoma is low (see Chapter 12), so that very large studies are needed to address the question as to whether any form of therapy reduces the risk for the development of adenocarcinoma. Accordingly, the ®nding that only one of the 84 patients in the omeprazole compassionate treatment programme who had Barrett's oesophagus developed oesophageal adenocarcinoma over a median follow-up period of 6.5 years can only be considered an interesting morsel of information.18 Similarly, the literature on the impacts of anti-re¯ux surgery on the risk for oesophageal adenocarcinoma is also inconclusive, quite divergent conclusions being reached in dierent studies which contain insucient numbers of patients to have any authority.41±43 Possibly, large scale multicentre research studies may give a more clear indication of whether any form of anti-re¯ux therapy reduces the risk for development of Barrett's cancer. The likelihood of such studies succeeding in their aim is small, since ablation of the metaplastic Barrett's epithelium is now being done so widely.
How much of an issue is DGOR during PPI therapy? There are no data that allow any well informed judgement on whether DGOR plays any role in determining the risk for Barrett's cancer during PPI therapy. However, given the clear demonstration that PPI therapy greatly reduces DGOR38, this appears to be much less of an issue than has been claimed.30
Is there a clinically relevant eect of long-term acid suppression on Helicobacter pylori gastritis? This question excited considerable controversy when it was reported that omeprazole therapy caused an accelerated progression of H. pylori infection-related corpus gastritis over a period of several years.44 This study received much attention because it was suggested that such accelerated progression of gastritis could place these patients at a signi®cantly increased risk of gastric cancer. This conclusion, and the data that led to it have been strongly challenged. The most important point of criticism was that the comparator H. pylori-positive patient group not being treated with omeprazole (because they had had successful anti-re¯ux surgery) was not derived as a result of prospective randomization, and diered in several important characteristics from the omeprazole-treated patients. A recent report with more appropriate controls found no signi®cant eect of omeprazole on gastritis progression45, although the interpretation of this study has also been challenged. The clinician need not feel that this controversy poses major diculties. H. pylori infection can be easily eradicated if there is any concern about this possible eect, the clinical signi®cance of which is uncertain. In the meanwhile, the complex arguments about the clinical signi®cance and technical adequacies of the studies that address this issue will continue until sucient data are available to provide rigorous scienti®c clari®cation on this issue.
Controversies in long-term management 823
CONSIDERATIONS OF COST AND PATIENT-SPECIFIC FACTORS Given the high prevalence and chronicity of re¯ux disease, the cost of management is important. This should be evaluated over a time span of decades, rather than for one to several years. Practicalities such as the evolution of management strategies1,2 and the changing costs of treatments over time are very dicult to predict accurately and incorporate into cost models that cover decades. Currently the role of endoscopy for routine management, is being re-evaluated1,2, on the basis that the cost of this investigation is relatively high and the gains from it for the monitoring of management that have formed the basis of past studies have driven management costs by probably inappropriately frequent use of endoscopy.46 Also, the inevitable downward creep of drug costs over time has not been adequately taken into account. Competition in the market place and expiry of patents has reduced the cost of H2RAs to a fraction of their initial price. The same thing is now happening with PPIs. Such changes in drug costs over time have not been considered adequately in discussions of the relative costs of long-term medical therapy and of anti-re¯ux surgery. It is logical for evaluations of the cost of management to include all costs, but this has rarely been the case. Society bears the total cost, which will include time lost from work but, for instance, health care providers will usually only be concerned about those costs that they must bear. Even if the strategies that are being costed are optimal, the direct costs of medical care and its complications are not always fully assessed, let alone the indirect costs. For instance, the cost of failed anti-re¯ux surgery must be taken into account over a time scale that spans at least 5 and preferably 10 years. Furthermore, the costs of managing complications of anti-re¯ux surgery and both the medical and societal cost of the rare instance of mortality related to anti-re¯ux surgery must be included. It is evident that comparisons of the costs of dierent management options for the long-term management of re¯ux disease are complex, and include components that can vary substantially by location and time. Consequently, any statements about the relative costs of dierent options need to be evaluated very critically.
How much should the cost of therapy determine choice? There is, of course, no ready answer to this question. Given that very eective medical and surgical therapy is now available, the ®rst principle should be that patients should have access to more expensive therapies, if lower cost options such as lifestyle measures or H2RAs fail. This is frequently not the case, especially when payers consider only drug cost, rather than the full cost of re¯ux disease including those costs borne by the patient.
Patient characteristics relevant to choice of therapy Whilst all patients seek eective therapy, the choice between medical and surgical therapy will be in¯uenced by several major factors, which are listed in Table 1, according to whether they favour surgical or medical therapy. Controversial factors that have been addressed in earlier sections of this chapter, which have been used to argue in favour of surgery without adequate scienti®c support are listed as unproved. In this author's opinion, it is inappropriate to include these factors as relevant to the
824 J. Dent Table 1. Established and controversial criteria and bene®ts for the choice of surgery or medical therapy in re¯ux disease. Established criteria and bene®ts of greatest relevance to the choice between anti-re¯ux surgery and long-term medical management
Controversial or unproven bene®ts that might favour surgical or medical management
In favour of anti-re¯ux In favour of medical surgery therapy
In favour of anti-re¯ux In favour of medical surgery therapy
Younger patients without co-morbidities
Durability of laparoscopic antire¯ux surgery over decades
Older patients with signi®cant comorbidities
Patient aversion to longterm medication use Patient acceptance of long-term medication High quality surgery use Patient preference for Superior safety for at other reasons least 10 years Lower risk for enteric infections
Unknown quality of surgery Patient preference for other reasons
Impact on risk for Barrett's oesophagus Impact on risk for adenocarcinoma in Barrett's oesophagus Long-term cost favourable
Safety of acid suppression over decades Impact on risk for Barrett's oesophagus Impact on risk for adenocarcinoma in Barrett's oesophagus Long-term cost favourable
information that patients need to take into account in order to make a fully informed choice between medical and surgical therapy. BALANCE OF RISKS AND BENEFITS FOR DIFFERENT THERAPIES This chapter has endeavoured to review the information that is relevant to making a balanced risk/bene®t assessment of options for the long-term treatment of re¯ux disease. On the basis of existing data, long-term treatment with acid suppression has a signi®cantly superior safety pro®le compared to anti-re¯ux surgery. The claimed superiority of anti-re¯ux surgery for the management of Barrett's oesophagus and its associated risk for development of oesophageal adenocarcinoma is speculative. Furthermore the scienti®c basis on which the claim is made is based on questionable assumptions and so is considered unconvincing. Importantly, the arguments about these claimed bene®ts of surgery have been generalized inappropriately to the majority of patients with re¯ux disease. The major bene®t of anti-re¯ux surgery is that when it is performed by experts, it has a very high chance of providing enduring control of re¯ux disease, without the inconvenience of reliance on the regular use of medication. This is a bene®t that is very much in the eye of the beholder. The question of whether surgical or medical therapy has the bene®t of superior cost-eectiveness is controversial, even for current, let alone future costs. This balance will be greatly in¯uenced in the near future by substantial reductions in the cost of PPI therapy, and the minimization of drug costs by the use of symptom-driven dosing with a PPI, which appears to be an appropriate and eective option in about three-quarters of the re¯ux disease patients who present for management of re¯ux-induced symptoms in primary care.12,13,35
Controversies in long-term management 825
REFERENCES * 1. Dent J, Brun J, Fendrick AM et al. An evidence-based appraisal of re¯ux disease management ± The Genval Workshop Report. Gut 1999; 44 (supplement 2): S1±S16. 2. Galmiche JP, Jian R, Chassany O et al. French±Belgian Consensus Conference on Adult GastroOesophageal Re¯ux Disease `Diagnosis and Treatment': report of a meeting held in Paris, France, on 21±22 January 1999. European Journal of Gastroenterology and Hepatology 2000; 12: 129±137. 3. Revicki DA, Wood M, Maton PN & Sorensen S. The impact of gastroesophageal re¯ux disease on healthrelated quality of life. American Journal of Medicine 1998; 104(3): 252±258. 4. Perdikis G, Hinder RA, Lund RJ, Raiser F & Katada N. Laparoscopic Nissen fundoplication: where do we stand? Surgical Laparoscopy and Endoscopy 1997; 7: 17±24. 5. Isolauri J, Luostarinen M, Isolauri E et al. Natural course of gastroesophageal re¯ux disease: 17±22 year follow-up of 60 patients. American Journal of Gastroenterology 1997; 92: 37±41. 6. Lundell L, Dent J, Bennett JR et al. Endoscopic assessment of oesophagitis ± clinical and functional correlates and further validation of the Los Angeles classi®cation. Gut 1999; 45: 172±180. * 7. Kahrilas PJ. Laparoscopic antire¯ux surgery: silver bullet or the emperor's new clothes? American Journal of Gastroenterology 1999; 94: 1721±1723. 8. Watson DI, Baigrie RJ & Jamieson GG. A learning curve for laparoscopic fundoplication. Annals of Surgery 1996; 224: 198±203. 9. Rantanen TK, Salo JA, Salminen JT & Kellokumpu IH. Functional outcome after laparoscopic or open Nissen fundoplication. Archives of Surgery 1999; 134: 240±244. 10. Bais JE, Bartelsman JFWM, Bonjer HJ et al. Laparoscopic or conventional Nissen fundoplication for gastro-oesophageal re¯ux disease: randomised clinical trial. Lancet 2000; 1355: 170±174. 11. Chiba N, De Gara CJ, Wilkinson JM et al. Speed of healing and symptom relief in grade II to IV gastroesophageal re¯ux disease: a meta-analysis. Gastroenterology 1997; 112: 1798±1810. 12. Bardhan KD, MuÈller-Lissner S, Bigard MA et al. Symptomatic gastro-oesophageal re¯ux disease: double blind and controlled study of intermittent treatment with omeprazole or ranitidine. British Medical Journal 1999; 318: 502±507. 13. Lind T, Havelund T, Lundell L et al. On demand therapy with omeprazole for the long-term management of patients with heartburn without oesophagitis ± a placebo-controlled randomized trial. Alimentary Pharmacology and Therapeutics 1999; 13: 907±914. 14. Carlsson R, Galmiche J-P, Dent J et al. Prognostic factors in¯uencing relapse of oesophagitis during maintenance therapy with antisecretory drugs: a meta-analysis of long-term omeprazole trials. Alimentary Pharmacology and Therapeutics 1997; 11: 473±482. 15. Lundell L, DalenbaÈck J, Hattlebakk J et al. Nordic GORD-study Group. Outcome of open antire¯ux surgery as assessed in a Nordic multicenter, prospective clinical trial. European Journal of Surgery 1998; 164: 751±757. 16. Behar J, Sheahan DG, Biancani P et al. Medical and surgical management of re¯ux esophagitis: a 38month report of a prospective clinical trial. New England Journal of Medicine 1975; 239: 263±268. 17. Spechler SJ and The Department of Veterans Aairs Gastroesophageal Re¯ux Disease Study Group. Comparison of medical and surgical therapy for complicated gastroesophageal re¯ux disease in veterans. New England Journal of Medicine 1992; 326: 786±792. *18. Klinkenberg-Knol EC, Nelis F, Dent J et al. Long-term omeprazole treatment in resistant gastroesophageal re¯ux disease: ecacy, safety and in¯uence on gastric mucosa. Gastroenterology 2000; 118: 661±669. 19. Tytgat GNJ. Dilation therapy of benign esophageal stenoses. World Journal of Surgery 1989; 13: 142±148. 20. Smith PM, Kerr GD, Cockel R et al. A comparison of omeprazole and ranitidine in the prevention of recurrence of benign esophageal stricture. Gastroenterology 1994; 107: 1312±1318. 21. Spivak H, Farrell TM, Trus T et al. Laparoscopic fundoplication for dysphagia and peptic esophageal strictures. Journal of Gastrointestinal Surgery 1998; 2: 555±560. 22. Lagergren J, Bergstrom R, Lindgren A & Nyren O. Symptomatic gastroesophageal re¯ux as a risk factor for esophageal adenocarcinoma. New England Journal of Medicine 1999; 340: 825±831. 23. Sekkarie MA. Torsades de pointes in two chronic renal failure patients treated with cisapride and clarithromycin. American Journal of Kidney Diseases 1997; 30: 437±439. 24. Freston JW. Omeprazole, hypergastrinemia, and gastric carcinoid tumours. Annals of Internal Medicine 1994; 121: 232±233. 25. Waldum HL & Brenna E. Personal review: is profound acid inhibition safe? Alimentary Pharmacology and Therapeutics 2000; 14: 15±22. 26. Yeomans ND & Dent J. Personal review: alarmism or legitimate concerns about long-term suppression of gastric acid secretion? Alimentary Pharmacology and Therapeutics 2000; 14: 267±271.
826 J. Dent 27. Lundell L, Dalenback J, Hattlebakk J et al. Omeprazole or antire¯ux surgery in the long term management of gastroesophageal re¯ux disease: results of a multicentre, randomised clinical trial [abstract]. Gastroenterology 1998; 114: A207. 28. Lundell L, Miettinen P, Myrvold H et al. A randomised comparison between omeprazole and open antire¯ux surgery in the management of chronic gastroesophageal re¯ux disease. Report on ®ve year follow up [abstract]. Gut 1999; 45 (supplement V): A40. 29. Oberg S, Clark GWB & DeMeester TR. Barrett's esophagus. Update of pathophysiology and management. Hepato-Gastroenterology 1998; 45: 1348±1356. 30. DeMeester SR. Management of Barrett's esophagus free of dysplasia. Seminars in Thoracic and Cardiovascular Surgery 1997; 9: 279±284. 31. Vaezi MF, Lacamera RG & Richter JE. Validation studies of Bilitec 2000: an ambulatory duodenogastric re¯ux monitoring system. American Journal of Physiology 1994; 267: G1050±G1057. 32. Liron R, Parrilla R, Martinez de Haro LF et al. Quanti®cation of duodenogastric re¯ux in Barrett's esophagus. American Journal of Gastroenterology 1997; 92: 32±35. 33. Ouatu-Lascar R, Fitzgerald RC & Triada®lopoulos G. Dierentiation and proliferation in Barrett's esophagus and the eects of acid suppression. Gastroenterology 1999; 117: 327±335. *34. Stein HJ, Kauer WKH, Feussner H & Siewert JR. Bile re¯ux in benign and malignant Barrett's esophagus: eect of medical acid suppression and Nissen fundoplication. Journal of Gastrointestinal Surgery 1998; 2: 333±341. 35. Jones RH, Hungin APS, Phillips J et al. Gastro-oesophageal re¯ux disease in primary care in Europe: clinical presentation and endoscopic ®ndings. European Journal of General Practice 1995; 1: 149±154. 36. Luostarinen M. Nissen fundoplication for re¯ux esophagitis; long-term clinical and endoscopic results in 109 of 127 consecutive patients. Annals of Surgery 1993; 217: 329±337. 37. Peters JH, DeMeester TR, Crookes P et al. The treatment of gastroesophageal re¯ux disease with laparoscopic Nissen fundoplication. Annals of Surgery 1998; 228: 40±50. 38. Marshall REK, Anggiansah A, Manifold DK et al. Eect of omeprazole 20 mg twice daily on duodenogastric and gastro-oesophageal bile re¯ux in Barrett's oesophagus. Gut 1998; 43: 603±606. 39. McDonald ML, Trastek VF, Allen MS et al. Barrett's esophagus: does an antire¯ux procedure reduce the need for endoscopic surveillance? Journal of Thoracic and Cardiovascular Surgery 1996; 111: 1135±1140. 40. Triada®lopoulos G. Proton pump inhibitors for Barrett's oesophagus. Gut 2000; 46: 144±146. *41. Csendes A, Braghetto I, Burdiles P et al. Long-term results of classic antire¯ux surgery in 152 patients with Barrett's esophagus: clinical, radiologic, endoscopic, manometric, and acid re¯ux test analysis before and late after operation. Surgery 1998; 123: 645±657. 42. Williamson WA, Ellis FH Jr, Gibb SP et al. Eect of antire¯ux operation on Barrett's mucosa. Annals of Thoracic Surgery 1990; 49: 537±542. 43. Pearson FG, Cooper JD, Patterson GA et al. Peptic ulcer in acquired columnar-lined esophagus: results of surgical treatment. Annals of Thoracic Surgery 1987; 43: 241±244. 44. Kuipers EJ, Lundell L, Klinkenberg-Knol E et al. Atrophic gastritis and Helicobacter pylori infection in patients with re¯ux esophagitis treated with omeprazole or fundoplication. New England Journal of Medicine 1996; 334: 1018±1022. 45. Lundell L, Miettinen P, Myrvold HE et al. Lack of eect of acid suppression therapy on gastric atrophy. Gastroenterology 1999; 117: 319±326. 46. Hillman AL, Bloom BS, Fendrick AM et al. Cost and quality eects of alternative treatments for persistent gastroesophageal re¯ux disease. Archives of Internal Medicine 1992; 152: 1467±1472.
doi:10.1053/bega.2000.0126, available online at http://www.idealibrary.com on
9 Controversies in long-term management of re¯ux disease John Dent
BA, MB, BChir, MRCP, FRACP, PhD, FRCP(UK)
Professor Department of Gastroenterology, Hepatology and General Medicine, Royal Adelaide Hospital, Adelaide SA 5000, Australia
There are signi®cant controversies about the long-term therapy of re¯ux disease that arise primarily from a lack of data on the risks of the disease and its therapies over the relevant time scale of several decades. Currently, there are no appropriately structured direct comparisons between the two current major treatment options of tailored long-term acid suppression and laparoscopic anti-re¯ux surgery. Critical review of the available literature does not support the assertion that anti-re¯ux surgery has a superior risk/bene®t pro®le when compared to long-term proton pump inhibitor (PPI) therapy, since non-controlled data indicate that although both therapies are relatively safe, morbidity and mortality rates are lowest with PPI therapy, whilst ecacy is comparable. The clinical signi®cance of the re¯ux that continues to occur after both anti-re¯ux surgery and during PPI therapy is uncertain, but probably overestimated. As pathological duodenogastro-oesophageal re¯ux aects only a small minority of re¯ux disease patients, issues arising from it should not be regarded as mainstream in¯uences on the choice of long-term therapy. Notwithstanding, this type of re¯ux is substantially reduced by both PPI therapy and anti-re¯ux surgery. The choice between laparoscopic surgery and long-term tailored acid suppression should be determined primarily by assessment of operative risk, the quality of surgery available to the patient and by patient preference, after balanced explanation of the risks and bene®ts of each option. Given that the cost of PPI therapy is likely to drop substantially in the next few years, drug cost should not be a major pressure for the choice of anti-re¯ux surgery. Key words: gastro-oesophageal re¯ux disease; surgery; medical therapy; Barrett's oesophagus; oesophageal adenocarcinoma.
INTRODUCTION Other chapters in this volume have demonstrated the extent to which patients with re¯ux disease have gained during the last decade from substantial developments and re®nements of the management of this common disease. Better recognition of the chronic nature of re¯ux disease has been especially important, and maintenance of remission has been a major focus for the developments of both medical and surgical therapy. Evaluations of therapeutic developments have focused predominantly on outcomes for the ®rst 12 months of maintenance therapy, with few studies addressing the many important questions about the best approaches to management of re¯ux disease over a time span of decades. Even fewer of these studies have used rigorous 1521±6918/00/050811+16 $35.00/00
c 2000 Harcourt Publishers Ltd. *
812 J. Dent
methodology and, in particular, appropriately chosen and observed control groups. For treatment or observation periods beyond 10 years, data of any form at all are especially scanty. As a result, discussion about the ecacy, risks and bene®ts of particular options for the very long-term management of re¯ux disease has been highly extrapolative; in some instances, strong views on the relative merits of surgery and medical therapy have been based on individual clinical experience or anecdotes, or studies in animal models. Such extrapolation is bound to excite controversy; this chapter reviews these areas. ISSUES RELEVANT TO EFFICACY What are the desirable outcomes of long-term therapy? In the case of symptoms, there is little controversy, since there appears to be agreement that therapy should at least control symptoms to the point at which they no longer impair quality of life.1,2 Formal studies of quality of life in re¯ux disease show that when heartburn episodes are reduced to two or fewer per week, there is unlikely to be impairment of health-related quality of life due to these.1,3 It is also important that therapy does not introduce its own symptoms; this is mainly an issue with anti-re¯ux surgery4 which is dealt with below. Desirable end points for the management of re¯ux oesophagitis are much more controversial. In the case of the many patients with troublesome re¯ux-induced symptoms who have no endoscopic oesophagitis, the limited data available indicate that over a time span of up to 15 years, progression to clear-cut endoscopic oesophagitis occurs rarely, if at all.1,2,5 Therefore, the treatment strategy should not be in¯uenced by the theoretical ability of particular treatments to prevent the development of oesophagitis over time. For patients with de®nite endoscopic re¯ux oesophagitis, de®ned as mucosal breaks according to the Los Angeles Classi®cation system (erosion or ulceration)6, a recent workshop1 distinguished between the risks of mild to moderate oesophagitis, de®ned as grades A and B, and the more severe grades C and D, in which mucosal breaks are continuous between the tops of two or more of the radial oesophageal folds. There appears to be agreement that Los Angeles grade C and D oesophagitis carries a substantial risk of complications, and so needs vigorous continuous treatment.1,2 In the case of Los Angeles grade A and B oesophagitis, half of the experts supported, and the other half disagreed with, the proposition that there was minimal risk from this severity of oesophagitis.1 This author sits somewhere between these extremes, doubting that Los Angeles grade A oesophagitis carries any substantial risk and so is probably an acceptable therapeutic outcome, but believing that grade B could well have signi®cant risks. These dierences of opinion re¯ect the lack of data on the very long-term risks of oesophagitis, especially the milder grades, and on the frequency of progression of Los Angeles grades A and B oesophagitis to grades C and D. Some proponents of the bene®ts of surgery place strong emphasis on `normalization' of oesophageal acid exposure, or even on abolition of re¯ux of all types, but these measures of outcome are of unproven additional value over and above control of symptoms and oesophagitis. How representative are the published data for outcomes in routine practice? This is a substantial issue in the case of anti-re¯ux surgery, especially via the laparoscopic route.7 Consistent success with this type of surgery requires considerable
Controversies in long-term management 813
% patients re-operated
20
10
0
15
610
1120
2140
4160
61+
Number in surgeons experience Figure 1. Re-operation rates for laparoscopic anti-re¯ux surgery according to the experience of the surgeon. This measure is considered a useful indicator of surgeon experience and skill. (Data from Watson, Baigrie and Jamieson8, with permission.) Data are from 11 surgeons who performed a total of 280 operations.
expertise.4 Outcomes have been shown to be operator-dependent, and even within a unit that has a special focus on methods of anti-re¯ux surgery, as shown in Figure 1, major outcomes are in¯uenced by the experience of the surgeon.4,8 Publications that report on the outcomes of anti-re¯ux surgery have come from surgical groups with a special interest in this surgery; such groups are likely to achieve better results overall than individual surgeons whose practice is not as highly focused on this particular type of surgery. Even amongst distinguished surgical units and groupings, there is quite a spectrum of results of laparoscopic anti-re¯ux surgery, with some units reporting excellent results4, while others report rather less good results compared to open surgery.9,10 The advent of the laparoscopic technique has led to a large increase in the number of patients having anti-re¯ux surgery, and it appears that most of this surgery is being done outside the environment of specialized units. The outcomes of antire¯ux surgery done in this setting are essentially not known. It is probably appropriate to believe that they are unlikely to emulate the data published from surgical groups with a special interest in anti-re¯ux surgery. In the case of medical therapy, no special skills are needed to deliver this care, so the results reported in the literature1,2,11 should be reasonably representative, though undoubtedly modi®ed by the lower levels of compliance with medication seen in routine practice compared to clinical trials. Non-compliance with therapy is, of course, not an issue for anti-re¯ux surgery. In the majority of re¯ux disease patients though, the major aim of therapy is merely control of symptoms, and there are now rigorous data which show that intermittent courses 12, or symptom-driven (`on-demand') use of proton pump inhibitors (PPI)13 is an eective option for endoscopy-negative re¯ux disease patients or patients with Los Angeles grades A and B oesophagitis. Furthermore, there is a good, though not perfect relationship between symptom relapse and relapse of oesophagitis14, which will tend to prompt the forgetful patient to use medication when it is really needed. On this basis, the published results of medical therapy are probably more representative of what can be achieved in routine practice than the results obtained with anti-re¯ux surgery outside specialized surgical units.
814 J. Dent
How should the ecacies of medical therapy and anti-re¯ux surgery be compared? It may seem obvious that randomized, controlled, within-study comparisons are required, given the many pitfalls of making conclusions across dierent studies and unrandomized patient cohorts. The problem is that such studies are very dicult to carry out, so there are very few of them.15 Despite this dicult reality, the unsoundness of making comparisons of outcomes between dierent studies of medical and surgical therapy must be recognized. Unfortunately though, the lack of rigorous comparisons has led enthusiasts for either medical or surgical therapy to draw conclusions about comparative ecacies from their own, inevitably skewed, clinical experiences as well as from across studies. No single type of practitioner sees a truly representative sample of patients with re¯ux disease. The specialist surgeon sees mainly patients dissatis®ed with some aspect of non-surgical management, whilst surgically treated patients are usually only seen by a gastroenterologist when their outcomes are suboptimal. Discussion of the relative merits of medical and surgical therapy should also be con®ned to the best available options. Thus, reference to studies performed in previous therapeutic eras that compare anti-re¯ux surgery with lifestyle measures1,16, H2-receptor antagonist therapy17, or data from studies of PPI therapy that have ignored the use of the provision for increase of dosage in the event of incomplete response15 are not appropriate, since they do not re¯ect the current state of the art. How stable is the eective dose of PPI over time with very long-term maintenance therapy? Claims have been made, based apparently on clinical experience, that PPI dosage commonly needs to be increased over time during maintenance therapy. This view is not supported by the best evidence available, which comes from a structured followup of 230 patients treated continuously with omeprazole on a compassionate use programme for up to 11.2 years, with a median treatment duration of 6.5 years.18 These patients, who were deemed unsuitable for surgery, had severe re¯ux oesophagitis that was resistant to H2-receptor antagonists. Those whose oesophagitis healed with 40 mg daily were entered into the maintenance programme. Once patients had been calibrated to a minimum eective maintenance dose during the ®rst year of therapy, symptom assessment and yearly endoscopy showed that at least half of the patients were maintained successfully on omeprazole 20 mg. As shown in Figure 2, this pattern was maintained throughout the study, with very few patients requiring increase of omeprazole dose. CONTROVERSIAL ISSUES RELATED TO POSSIBLE ADVERSE EFFECTS OF LONG-TERM TREATMENT Mortality attributable to the disease and its therapies This issue of treatment-related mortality is a signi®cant one, given the very low overall mortality attributable to the disease itself in the total patient group with re¯ux disease. The small minority of patients with peptic stricture is exposed to the risk of death as a result of complications from perforation secondary to stricture dilatation.19 In the majority of patients, healing of oesophagitis by surgery or PPI therapy prevents
Controversies in long-term management 815
80 mg (or more) 2% 60 mg 10 %
@ 2 years
@ 5 years 27 %
@ 8 years
61 %
20 mg
40 mg 211 patients
157 patients
63 patients
Figure 2. Omeprazole dose over time required for prevention of relapse of oesophagitis in patients with previously severe re¯ux oesophagitis that was refractory to H2 receptor antagonist therapy. Patient numbers decreased primarily because of death due to causes unrelated to re¯ux disease. (Data from Klinkenberg-Knol et al.18)
recurrence of stricture20,21, and so controls this risk. Oesophageal adenocarcinoma is a major focus of attention at present as a source of re¯ux disease-related mortality (see Chapter 12). There has been a large proportional increase in the number of deaths due to oesophageal adenocarcinoma, but given the high prevalence of re¯ux disease, this remains a relatively small risk of having re¯ux disease, even if all cases of oesophageal adenocarcinoma are considered to be secondary to re¯ux-induced oesophageal columnar metaplasia. For example, a landmark study evaluated the epidemiology of oesophageal and gastric cardia adenocarcinoma by gathering and assessing all cases occurring in Sweden over a period of 25 months, during which 530 cases were recorded in a total population of around 10 million.22 Cisapride By contrast to the long-standing debate about the safety of acid suppression (see below), mortality that could be attributed to prokinetic therapy with cisapride has only become an issue very recently. In patients with pre-existing cardiac conduction defects, cisapride is now known to in¯uence cardiac conduction at the peak serum levels sometimes encountered with normal dosing.23 Furthermore even in patients without cardiac disease, when cisapride is taken with drugs that are also metabolized by its cytochrome P450 3A4 metabolic system, peak serum levels of this drug are reached that can produce life-threatening cardiac arrhythmias. Evidence that cisapride could be implicated in some sudden cardiac deaths has led the US Food and Drug Administration (FDA) to impose major restrictions on the use of cisapride and placement of a black-box warning on the packaging of cisapride which starts as follows `Serious cardiac arrhythmias, including ventricular tachycardia, ventricular ®brillation, torsades de pointes, and QT prolongation have been reported in patients taking Propulsid (cisapride)'. The warning also states that patients with cardiac disease may experience serious cardiac side eects during cisapride therapy, even when serum levels are not in¯uenced by drug±drug interactions. Unfortunately with the recognition of this signi®cant safety issue, it now appears inappropriate to use cisapride for the treatment of re¯ux disease except under unusual circumstances.
816 J. Dent
Acid suppressant agents H2-receptor antagonists (H2RA) and PPIs have proved to be extremely safe and well tolerated drugs for both short-term and maintenance therapy. This experience extends beyond 15 years for H2RAs and beyond 10 years for PPIs.18 Discussion of the risks of using these agents long term has centred around the possibility that acid suppression could cause excess mortality indirectly, by increasing the risk of gastric malignancy. This is a legitimate concern, since these agents substantially alter the gastric luminal environment and mucosal structure and function. The development of gastric carcinoid tumours in rats during life-long massive dosing of both omeprazole and ranitidine24 emphasizes the need for continuing evaluation of the safety of acid suppressant agents, especially PPIs, during very long-term, continuous treatment. Data are needed for 30 or more years before the risks of acid suppression can be fully weighed against those of alternative therapies. The politics of the safety of long-term acid suppression with PPIs continue to be polarized, with divergent interpretations of data that are potentially relevant to long-term safety and morbidity. Concerns about these issues have been revisited in a recent commentary25, which has excited a critical response in which it is judged that any risks remain theoretical.26 The longest duration follow-up data that exist for continuous PPI therapy comes from the 230 patients with severe re¯ux oesophagitis who were treated with omeprazole for up to 11.2 years (median follow-up 6.5 years) on a compassionate use basis.18 No deaths were attributable directly or indirectly to this therapy, despite the frailty of many of the patients. Monitoring of gastric mucosal histology did not reveal any changes that could be interpreted as indicating that these patients were at any increased risk for the development of gastric, or any other, malignancy as a result of therapy. For the time span for which data are available, it appears that acid suppression itself carries minimal, if any, risk of treatment-related death. Anti-re¯ux surgery The risk of death from anti-re¯ux surgery is minimized by good patient selection, modern anaesthetic and surgical techniques, and high-quality post-operative care. Despite these enhancements, the nature of the intervention means that mortality cannot be eliminated. Estimates of the mortality from anti-re¯ux surgery are dicult to obtain, other than by pooling of reports in the literature, in order to obtain a large enough sample. Such a pooling for reports on open anti-re¯ux surgery published in the literature between 1980 and 1993 revealed four deaths within 30 days of surgery in 1152 patients, giving a crude mortality of 0.35% (R. McCloy and L. Lundell, pers. comm.) Of these four deaths, three were de®nitely related to the surgery. Five deaths attributable to laparoscopic anti-re¯ux surgery have been reported in the literature.4 Repeat anti-re¯ux surgery occurs suciently frequently that it should also be factored into the mortality equation. It is not only a double dose of risk for that particular patient, but the mortality of re-do anti-re¯ux surgery appears to be higher than that of the ®rst operation. How much of an issue are dysphagia and ¯atulence with anti-re¯ux surgery? This topic has been reviewed by Watson and de Beaux4 for laparoscopic surgery and in Chapter 8 of this volume. Controversy has arisen in part because it has not been realized that dysphagia and ¯atulence can be problems in re¯ux disease patients who
Controversies in long-term management 817
have not had anti-re¯ux surgery.17 The key messages though, are that anti-re¯ux surgery has the potential to produce disabling dysphagia and ¯atulence, and that the risk for this is dependent on details of the operative technique. This is more of a risk with laparoscopic than open surgery, at least in some hands.4 A very recent comparison from the Netherlands of the outcomes of open and laparoscopic Nissen fundoplication emphasizes this point.10 After laparoscopic Nissen fundoplication, seven out of 57 patients had persistent dysphagia 3 months after surgery, which was severe enough to require intervention. By comparison, none of the 46 patients having open Nissen fundoplication had dysphagia of this severity. This substantial dierence led to discontinuation of the trial on ethical grounds. This experience indicates how much the occurrence of dysphagia depends on the surgeon's technique. The outcomes of the Netherlands study should not be generalized to all laparoscopic anti-re¯ux surgery, since other comparisons between laparoscopic and open anti-re¯ux surgery have not shown major problems with dysphagia after laparoscopic anti-re¯ux surgery.4 The risk of dysphagia can probably be virtually eliminated by choice of surgeon, but it is also likely that at least in some hands, the choice of operation type may reduce the risk of persistently troublesome post-operative dysphagia, since partial and shorter complete fundoplications have been variably reported to be associated with fewer problems with dysphagia and bloating4 (see Chapter 8, this volume).
How does long-term PPI therapy compare with anti-re¯ux surgery for prevention of oesophagitis relapse? To date, only one study has addressed this question formally by randomizing 270 patients to either open anti-re¯ux surgery or current state-of-the-art medical therapy, in the form of omeprazole, with provision for dose increase to 40 mg daily in the event of failure of 20 mg daily.15 At the 3 year follow-up, anti-re¯ux surgery and omeprazole 20±40 mg (depending on the individual patient's response), were of equal ecacy for maintenance of oesophagitis healing and control of symptoms.27 The results for up to 5 years of follow-up are reported to show superiority in favour of anti-re¯ux surgery, but these data are not yet fully available.28 The results from the international omeprazole compassionate use programme provide useful but uncontrolled data on the ability of daily omeprazole to prevent relapse of oesophagitis in a highly selected population of problem patients for periods of up to 11 years.18 This structured observation of these 230 patients (in 38 of whom anti-re¯ux surgery had failed) included yearly endoscopy and extensive safety assessments. During follow-up on maintenance therapy, the overall average relapse rate was once every 9.4 patient years, including the ®rst year of maintenance therapy during which time the required maintenance dose was being determined after the initial healing dose of 40 mg had been reduced to 20 mg. After this phase of management was completed, the need to increase the dose of omeprazole was rare, and the mean omeprazole dose which kept oesophagitis healed and symptoms well controlled for the entire patient group was 29 mg daily per patient (Figure 2). When relapse of oesophagitis occurred, this was endoscopically mild in nearly three-quarters of instances and always responded to continuing omeprazole, rarely at increased dosage. The objective and well-structured observations summarized above are at odds with commentary that states that long-term omeprazole loses its eectiveness over time, with exposure of patients to substantial risk from smouldering, severe oesophagitis.29
818 J. Dent
What is the role of duodenogastro-oesophageal re¯ux in the development of Barrett's oesophagus and oesophageal adenocarcinoma? This is an especially complex and controversial area, compounded by measurement diculties and inadequate understanding of the clinically relevant impacts on the oesophageal mucosa of the re¯uxate that contains duodenal enzymes and bile constituents. The global hypothesis of those who consider that anti-re¯ux surgery is a safer, more eective option for long-term management than PPIs, is that surgery is superior for both prevention of the development of Barrett's oesophagus and of oesophageal adenocarcinoma when Barrett's oesophagus is present, because re¯ux is prevented.30 Duodenogastro-oesophageal re¯ux (DGOR) is an important factor in this debate. The issues can be stepped through by addressing a series of focused questions. Duodenogastro-oesophageal re¯ux ± a factor that contributes to development of Barrett's oesophagus? The data available that bear on this question are reviewed in Chapter 3. First, it should be recognized that the Bilitec, the currently available method used to monitor for DGOR, has substantial inaccuracies that could disable the accurate dissection of the role of DGOR in Barrett's oesophagus, even though it is a major advance on previous methods available for measurement of DGOR.31 The available data show an association of high levels of DGOR with complicated (deep ulcer, stricture) Barrett's oesophagus, but this relationship is less convincing for individuals with uncomplicated Barrett's.32 Furthermore, very high levels of acid gastro-oesophageal re¯ux are closely associated with abnormal DGOR, so it is impossible to separate out the relative contributions of these two types of re¯ux to the pathogenesis of Barrett's oesophagus in the untreated patient. It can be concluded that currently available data on DGOR are insucient to clearly answer whether this contributes to the development of Barrett's oesophagus. Is duodenogastro-oesophageal re¯ux implicated in the development of Barrett's associated adenocarcinoma? The answer to this question is frequently taken as `yes', but the data that support this view are mostly indirect and limited in scope. Components of duodenal juice can potentiate acid/peptic damage to the oesophageal mucosa, but this does not mean that this injury determines progression to Barrett's cancer. Studies of Barrett's epithelium biopsies in organ culture suggest that full control of acid re¯ux episodes may be important in reducing the stimulation of processes in the mucosa that could favour the development of adenocarcinoma33 (see Chapter 12). There are no such data for DGOR. This question of the role of DGOR in Barrett's cancer has been addressed more directly by Stein et al34 by the performance of Bilitec monitoring in Barrett's patients with and without early adenocarcinoma or high-grade dysplasia (Figure 3). Monitoring was also done in a substantial group of patients with re¯ux oesophagitis, but no Barrett's oesophagus, patients with endoscopy-negative re¯ux disease, and normal subjects. Abnormal levels of bilirubin re¯ux were demonstrated in 11 out of 14 (78.6%) of the adenocarcinoma/high-grade dysplasia patients compared to 18 out of 33 (54.5%) of the Barrett's oesophagus patients without adenocarcinoma or high-grade dysplasia.
Controversies in long-term management 819
Electronic permission to reproduce this ®gure was not granted
Figure 3. Bilirubin re¯ux, into the oesophagus over 24 hours, used as an index of duodenogastrooesophageal re¯ux in dierent re¯ux disease patient groups and normal subjects. Data were obtained by Bilitech1 monitoring. (Reprinted from Stein et al34, with permission.) GORD, gastro-oesophageal re¯ux disease; HGD, high grade dysplasia.
Substantially less DGOR was seen in the other groups. These data are inconclusive as to the role of DGOR in cancer promotion. It is unlikely that there will ever be a de®nitive answer to the question of whether DGOR is a major driver for the development of Barrett's cancer, given the practical diculties of studying this. How important are issues relating to duodenogastro-oesophageal re¯ux in the full spectrum of re¯ux disease patients? Commentary about the importance of stopping pathological DGOR by the performance of anti-re¯ux surgery30 implies that this type of re¯ux is highly prevalent amongst re¯ux disease patients, or that patients are at risk for the development of pathological DGOR over time. This is a misleading message. Review of the endoscopic ®ndings in the full spectrum of re¯ux disease patients who present in primary care shows that about 60% of these have no oesophageal mucosal breaks, and a further 30% or so have only relatively mild re¯ux oesophagitis (Los Angeles grades A and B).1,2,35 These patients have been shown to have low levels of DGOR34 (Figure 3). Severe oesophagitis is usually only present in less than 10% of patients, and only a minority of these has Barrett's oesophagus with presumably associated pathological DGOR. Thus, issues relating to DGOR apply to a small subgroup of patients with gastro-oesophageal re¯ux disease (GORD). It has been implied that progression of the severity of re¯ux disease is to be expected over a relatively short time scale, and so should have an in¯uence on choice of therapy.29 There is no evidence to support this. Longitudinal follow-up of re¯ux disease patients has shown no change in endoscopic status over a time span of 10 to 15 years.1,5 These data need to be interpreted in the light of circumstantial evidence that points to the distinct possibility that re¯ux disease may progress in severity over a time span of several decades.
820 J. Dent
Given the pattern of endoscopic ®ndings in re¯ux disease patients35, if DGOR is really an independent factor in the pathogenesis of Barrett's cancer, it is only of practical importance in a small minority of patients. Discussion of possible special management needs of this patient group should not be generalized to all patients with re¯ux disease. What are the risks and bene®ts of the patterns of re¯ux that occur during PPI therapy? PPIs achieve their substantial therapeutic eects by major reduction of the aggressiveness of gastric juice, through elevation of gastric pH to a level that makes gastric pepsin minimally active. The reduction of gastric secretion produced by PPIs appears also to have bene®cial eects on the volume and patterning of gastro-oesophageal re¯ux episodes, independent of their eects on pH. Advocates of anti-re¯ux surgery argue that the gastro-oesophageal re¯ux that occurs during long-term PPI therapy still carries a signi®cant risk for patients, a risk that is removed by anti-re¯ux surgery because this stops all re¯ux. This argument is open to question, not only from the point of view of whether patterns of re¯ux that occur during PPI therapy are harmful, but also from the point of view of the impacts of anti-re¯ux surgery on the patterns of re¯ux. Beyond 6 years, in at least 10±15% of patients, anti-re¯ux surgery no longer controls re¯ux to the level that prevents oesophagitis or symptoms.36 Also, in many of those patients in whom anti-re¯ux surgery achieves these desired end points, some gastro-oesophageal re¯ux does occur9,37, especially when surgical techniques are used that are designed to minimize the risk of persistent and troublesome post-operative dysphagia. The aggressiveness of the gastric juice that reaches the oesophagus in these patients is not moderated by any therapy. Thus, in a substantial minority of patients treated with anti-re¯ux surgery, there is a continuing, albeit reduced level of oesophageal mucosal insult. The occurrence of this re¯ux after surgery has not been adequately acknowledged and its clinical signi®cance not weighed adequately against the modi®ed patterning and composition of re¯ux that occurs during PPI therapy (see below). Do pathological levels of DGOR persist during PPI therapy? Arguments about the putative dangers of DGOR during PPI therapy appear to hinge on the assumption that DGOR will not be in¯uenced by this therapy. This is incorrect, as can be seen in Figure 4. These data show that DGOR is substantially reduced during PPI therapy, usually to within the normal range.38 This eect has been ascribed to reduction of gastric volume. How harmful is the acid re¯ux that occurs during PPI therapy? The proposition that the re¯ux that occurs during PPI therapy carries risk for patients needs more critical review than has occurred in the past. If PPI therapy does not result in healing of oesophagitis, it is reasonable to assume that there could be a risk for the development of Barrett's oesophagus. Such failure is, however, the exception with PPI therapy, even in the small minority of patients with Los Angeles grades C and D oesophagitis.11,18 This failure is associated with persistent symptoms in the majority of patients, and can usually be overcome by the use of increased dose PPI, preferably given twice daily.18
Percentage time oesophageal absorption > 0.14
Controversies in long-term management 821
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
Off omeprazole
On omeprazole
Figure 4. Reduction of duodenogastro-oesophageal re¯ux, measured as light absorbence bilirubin with Bilitech1 monitoring by omeprazole therapy in patients with Barrett's oesophagus. (Reprinted from Marshall et al38, with permission.)
Measures of dierentiation and proliferation in Barrett's mucosa are possible indicators of the risk for development of high-grade dysplasia or adenocarcinoma in Barrett's oesophagus. These measures have been assessed in oesophageal mucosal biopsies maintained in organ culture, which were obtained from Barrett's oesophagus patients.33 Completeness of long-term control of acid re¯ux achieved in each individual with lansoprazole therapy was correlated with measures of dierentiation and proliferation. Proliferation was found to be lower, and dierentiation higher, in patients in whom acid re¯ux was completely controlled, compared to biopsies from those in whom there was some persistent acid re¯ux. This ®nding gives some support to the assertion that the risk of development of Barrett's cancer may be reduced by a greater eect on re¯ux patterns than is required for healing of oesophagitis, or relief of symptoms. It was initially hoped that successful anti-re¯ux surgery or intensive PPI therapy could result in replacement of all oesophageal columnar metaplasia, with attendant abolition, or at least substantial reduction in the risk for adenocarcinoma. It is now clear that neither of these treatments alone can achieve this, although some regression has been shown to occur in some patients with both therapies. Given that oesophageal columnar metaplasia persists, it is important to know whether eective abolition of acid re¯ux could impact favourably on the risk for Barrett's cancer in both medically and surgically treated patients. Barrett's cancers have occurred after both apparently
822 J. Dent
successful anti-re¯ux surgery39 and healing of oesophagitis with proton pump inhibitor therapy18,40, but available data are insucient to judge whether these treatments reduce the risk of cancer. Once Barrett's oesophagus patients with high-grade dysplasia or adenocarcinoma have been recognized by initial screening and excluded from a surveillance cohort, the rate of development of high grade dysplasia or adenocarcinoma is low (see Chapter 12), so that very large studies are needed to address the question as to whether any form of therapy reduces the risk for the development of adenocarcinoma. Accordingly, the ®nding that only one of the 84 patients in the omeprazole compassionate treatment programme who had Barrett's oesophagus developed oesophageal adenocarcinoma over a median follow-up period of 6.5 years can only be considered an interesting morsel of information.18 Similarly, the literature on the impacts of anti-re¯ux surgery on the risk for oesophageal adenocarcinoma is also inconclusive, quite divergent conclusions being reached in dierent studies which contain insucient numbers of patients to have any authority.41±43 Possibly, large scale multicentre research studies may give a more clear indication of whether any form of anti-re¯ux therapy reduces the risk for development of Barrett's cancer. The likelihood of such studies succeeding in their aim is small, since ablation of the metaplastic Barrett's epithelium is now being done so widely.
How much of an issue is DGOR during PPI therapy? There are no data that allow any well informed judgement on whether DGOR plays any role in determining the risk for Barrett's cancer during PPI therapy. However, given the clear demonstration that PPI therapy greatly reduces DGOR38, this appears to be much less of an issue than has been claimed.30
Is there a clinically relevant eect of long-term acid suppression on Helicobacter pylori gastritis? This question excited considerable controversy when it was reported that omeprazole therapy caused an accelerated progression of H. pylori infection-related corpus gastritis over a period of several years.44 This study received much attention because it was suggested that such accelerated progression of gastritis could place these patients at a signi®cantly increased risk of gastric cancer. This conclusion, and the data that led to it have been strongly challenged. The most important point of criticism was that the comparator H. pylori-positive patient group not being treated with omeprazole (because they had had successful anti-re¯ux surgery) was not derived as a result of prospective randomization, and diered in several important characteristics from the omeprazole-treated patients. A recent report with more appropriate controls found no signi®cant eect of omeprazole on gastritis progression45, although the interpretation of this study has also been challenged. The clinician need not feel that this controversy poses major diculties. H. pylori infection can be easily eradicated if there is any concern about this possible eect, the clinical signi®cance of which is uncertain. In the meanwhile, the complex arguments about the clinical signi®cance and technical adequacies of the studies that address this issue will continue until sucient data are available to provide rigorous scienti®c clari®cation on this issue.
Controversies in long-term management 823
CONSIDERATIONS OF COST AND PATIENT-SPECIFIC FACTORS Given the high prevalence and chronicity of re¯ux disease, the cost of management is important. This should be evaluated over a time span of decades, rather than for one to several years. Practicalities such as the evolution of management strategies1,2 and the changing costs of treatments over time are very dicult to predict accurately and incorporate into cost models that cover decades. Currently the role of endoscopy for routine management, is being re-evaluated1,2, on the basis that the cost of this investigation is relatively high and the gains from it for the monitoring of management that have formed the basis of past studies have driven management costs by probably inappropriately frequent use of endoscopy.46 Also, the inevitable downward creep of drug costs over time has not been adequately taken into account. Competition in the market place and expiry of patents has reduced the cost of H2RAs to a fraction of their initial price. The same thing is now happening with PPIs. Such changes in drug costs over time have not been considered adequately in discussions of the relative costs of long-term medical therapy and of anti-re¯ux surgery. It is logical for evaluations of the cost of management to include all costs, but this has rarely been the case. Society bears the total cost, which will include time lost from work but, for instance, health care providers will usually only be concerned about those costs that they must bear. Even if the strategies that are being costed are optimal, the direct costs of medical care and its complications are not always fully assessed, let alone the indirect costs. For instance, the cost of failed anti-re¯ux surgery must be taken into account over a time scale that spans at least 5 and preferably 10 years. Furthermore, the costs of managing complications of anti-re¯ux surgery and both the medical and societal cost of the rare instance of mortality related to anti-re¯ux surgery must be included. It is evident that comparisons of the costs of dierent management options for the long-term management of re¯ux disease are complex, and include components that can vary substantially by location and time. Consequently, any statements about the relative costs of dierent options need to be evaluated very critically.
How much should the cost of therapy determine choice? There is, of course, no ready answer to this question. Given that very eective medical and surgical therapy is now available, the ®rst principle should be that patients should have access to more expensive therapies, if lower cost options such as lifestyle measures or H2RAs fail. This is frequently not the case, especially when payers consider only drug cost, rather than the full cost of re¯ux disease including those costs borne by the patient.
Patient characteristics relevant to choice of therapy Whilst all patients seek eective therapy, the choice between medical and surgical therapy will be in¯uenced by several major factors, which are listed in Table 1, according to whether they favour surgical or medical therapy. Controversial factors that have been addressed in earlier sections of this chapter, which have been used to argue in favour of surgery without adequate scienti®c support are listed as unproved. In this author's opinion, it is inappropriate to include these factors as relevant to the
824 J. Dent Table 1. Established and controversial criteria and bene®ts for the choice of surgery or medical therapy in re¯ux disease. Established criteria and bene®ts of greatest relevance to the choice between anti-re¯ux surgery and long-term medical management
Controversial or unproven bene®ts that might favour surgical or medical management
In favour of anti-re¯ux In favour of medical surgery therapy
In favour of anti-re¯ux In favour of medical surgery therapy
Younger patients without co-morbidities
Durability of laparoscopic antire¯ux surgery over decades
Older patients with signi®cant comorbidities
Patient aversion to longterm medication use Patient acceptance of long-term medication High quality surgery use Patient preference for Superior safety for at other reasons least 10 years Lower risk for enteric infections
Unknown quality of surgery Patient preference for other reasons
Impact on risk for Barrett's oesophagus Impact on risk for adenocarcinoma in Barrett's oesophagus Long-term cost favourable
Safety of acid suppression over decades Impact on risk for Barrett's oesophagus Impact on risk for adenocarcinoma in Barrett's oesophagus Long-term cost favourable
information that patients need to take into account in order to make a fully informed choice between medical and surgical therapy. BALANCE OF RISKS AND BENEFITS FOR DIFFERENT THERAPIES This chapter has endeavoured to review the information that is relevant to making a balanced risk/bene®t assessment of options for the long-term treatment of re¯ux disease. On the basis of existing data, long-term treatment with acid suppression has a signi®cantly superior safety pro®le compared to anti-re¯ux surgery. The claimed superiority of anti-re¯ux surgery for the management of Barrett's oesophagus and its associated risk for development of oesophageal adenocarcinoma is speculative. Furthermore the scienti®c basis on which the claim is made is based on questionable assumptions and so is considered unconvincing. Importantly, the arguments about these claimed bene®ts of surgery have been generalized inappropriately to the majority of patients with re¯ux disease. The major bene®t of anti-re¯ux surgery is that when it is performed by experts, it has a very high chance of providing enduring control of re¯ux disease, without the inconvenience of reliance on the regular use of medication. This is a bene®t that is very much in the eye of the beholder. The question of whether surgical or medical therapy has the bene®t of superior cost-eectiveness is controversial, even for current, let alone future costs. This balance will be greatly in¯uenced in the near future by substantial reductions in the cost of PPI therapy, and the minimization of drug costs by the use of symptom-driven dosing with a PPI, which appears to be an appropriate and eective option in about three-quarters of the re¯ux disease patients who present for management of re¯ux-induced symptoms in primary care.12,13,35
Controversies in long-term management 825
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