Reflux disease management strategy: initial therapy

Authors

  • J. Dent,

  • G. Tytgat


Case history for votes 1–4

Prof. Talley : Our first case is a male, aged 40 years, who presents for the first time with heartburn and acid regurgitation. He has had these symptoms for 5 years and they are getting worse. He has no alarm features (he has not lost weight, is not vomiting, and has no dysphagia) and has been taking antacids, but these have proved inadequate.

Question 1: How would you manage this patient initially?

Commentary

Prof. Dent : The answer to this question is probably going to be influenced by whether you are practising in primary care or in a specialist setting. We have here a predominance of empiricists over endoscopists.

Prof. Hatlebakk : I would choose proton pump inhibitor therapy for this patient, and would probably start him on esomeprazole, 40 mg, because I want him to have rapid symptom relief. Partly, I want to reassure him that we know what he is suffering from, but there is also diagnostic value in this approach. I would not perform an endoscopy at this stage.

Prof. Tytgat : I would definitely perform an endoscopy. It is likely that this man will need an endoscopy sooner or later, so I would prefer to perform one at this stage and know exactly what I am dealing with.

Question 2: Assuming you decide to treat the patient empirically, what would be your main option?

Commentary

Prof. Tytgat : The majority of the audience has chosen to begin with proton pump inhibitor therapy, rather than opting for a step-up approach.

Step-up or proton pump inhibitor therapy?

Professor J. Hatlebakk

When we refer to step-up and step-down therapies, we are considering not only the initial choice of drug and whether the dosage should be varied up or down, but also changing from one class of drug to another. Thus, step-up therapy in this context means starting with an H2-receptor antagonist (H2RA) and then increasing the potency of therapy to a proton pump inhibitor in those patients who do not respond. Step-down therapy may mean starting with a 4–8-week course of proton pump inhibitor therapy, followed by a decrease in potency to an H2RA. The alternatives to these regimes are chronic H2RA or proton pump inhibitor therapy.

These strategies have so far been tested in only one study, which compared chronic proton pump inhibitor and H2RA therapy with step-up and step-down approaches in patients with gastro-oesophageal reflux disease (GERD). Figure 31 shows the median severity of heartburn over 20 weeks according to patient diary cards, with any change of medication taking place after 8 weeks. Patients treated chronically with the H2RA performed worst of all, followed by those who stepped down from a proton pump inhibitor to an H2RA, then those who stepped up from an H2RA to a proton pump inhibitor, with chronic proton pump inhibitor treatment proving the most effective. The difference between the step-up and step-down groups probably reflects the relative difference in duration of proton pump inhibitor and H2RA therapy in the two groups.

Figure 3.

Severity of heartburn over 20 weeks of therapy in 593 patients with gastro-oesophageal reflux disease when treated with either ranitidine, 150 mg twice daily; stepped-down from lansoprazole, 30 mg once daily, to ranitidine, 150 mg twice daily after 8 weeks; stepped-up from ranitidine, 150 mg twice daily, to lansoprazole, 30 mg once daily, after 8 weeks; or lansoprazole, 30 mg once daily. 1

When we compare the percentages of days and nights free of heartburn among the step-up and step-down groups, we find that the step-down patients perform best at the start, but after changing to the H2RA they perform worse than the step-up patients (Figure 4).1 I would therefore advocate the chronic proton pump inhibitor strategy in preference to step-down therapy because, although the two groups perform equally well during the first 8 weeks, symptom relief deteriorates significantly over the next 12 weeks among step-down patients (Figure 5).1

Figure 4.

Percentage of 24-h period with no episodes of heartburn in patients treated with ranitidine, 150 mg twice daily, for 8 weeks, then changing to lansoprazole, 30 mg once daily, for 12 weeks, or vice versa. Reprinted with permission from the American College of Gastroenterology, (American Journal of Gastroenterology, 2001; 96: 1704–10). 1

Figure 5.

Percentage of 24-h period with no episodes of heartburn in patients treated with lansoprazole, 30 mg once daily, for 20 weeks or with ranitidine, 150 mg twice daily, for 8 weeks, then changing to lansoprazole, 30 mg once daily, for 12 weeks. Reprinted with permission from the American College of Gastroenterology, (American Journal of Gastroenterology, 2001; 96: 1704–10). 1

Our strategy should be to deliver an effective initial therapy to gain rapid symptom relief, to reassure the patient and to save costs. Effective treatment should then be maintained at a level that normalizes quality of life, and the best way to achieve this is with chronic proton pump inhibitor therapy.

Discussion

Prof. Tytgat : There is something that I do not understand: if you have a patient with reflux disease, and you believe that we should look at the level of acid suppression that is necessary to control the disease, then does it make any difference whether you step up or step down to find the correct dose? Ultimately, you are going to find the level of symptom control that you want, so what are the arguments for stepping down?

Prof. Hatlebakk : The argument for stepping down is that you are aiming to reach the minimum dose that will control the patient's symptoms and maintain healing over time.

Prof. Tytgat : But does it matter in which direction you go?

Prof. Dent : Yes, it does matter. If you can achieve your aims quickly and easily with 2 weeks of proton pump inhibitor therapy, which is what it takes for most patients, then why choose different pathways that take much longer?

Prof. Tytgat : But do we really know that this approach is the most cost-effective?

Prof. Dent : There are studies that suggest this, but they depend on the model used and we need real-life measurements relating to management strategies and the costs associated with them.

Prof. Vakil : I think that stepping down makes sense if there is a cost saving. The idea here is to give a high level of initial therapy to be sure of eliminating the patient's symptoms. Stepping down eventually saves money because you use less of the drug.

Prof. Tytgat : Forgetting this patient for the moment, would you treat any patient with a proton pump inhibitor from the moment he/she enters the room?

Prof. Lauritsen : It would depend on the severity and frequency of the symptoms. If the complaint was only minimal, then I would probably recommend nothing except lifestyle changes initially. However, if the symptoms were impairing quality of life, the patient requires therapy.

Prof. Talley : Do lifestyle changes work? Professor Tytgat, you seem to be an advocate for these strategies, but do they actually do anything?

Prof. Tytgat : I do not see what is wrong in advising the patient to try and control factors that might help to control the disease. In some patients it does not work, but in others it does. However, if a patient has predominant nocturnal symptoms, for example, then I would certainly advise medication.

Question 3: What is the risk of harming the patient with empirical treatment without previous endoscopy?

Commentary

Prof. Dent : Remember that the question relates to endoscopy at this stage . Even if we do not use endoscopy at this stage, we may have a strategy to use it later on. Over two-thirds of the audience believe that we are not taking very much risk at all. I wonder whether anyone in the audience would like to argue for there being a moderate–high risk, as there was a significant minority who voted this way. Perhaps Professor Lauritsen would like to comment on this point first and then we will open the discussion to the floor.

Empirical therapy − what are the risks?

Professor K. Lauritsen

In assessing the risk of harming the patient, I am only going to consider the short term, and I am assuming that alarm symptoms, such as dysphagia or weight loss, are absent. The risks that could be important here are the development of oesophageal adenocarcinoma in association with Barrett's oesophagus, missing an important differential diagnosis, and incorrectly assessing the severity of the underlying pathology.

Risk of developing oesophageal adenocarcinoma in association with Barrett's oesophagus

This risk is so small in isolated individuals presenting in primary care with heartburn that it should not, in my opinion, be the primary determinant of whether endoscopy is performed. This is supported by the literature. However, the perspective of the patient on endoscopic surveillance may differ from that of a health care funding system, which must balance spending priorities. The Genval Workshop Report, an evidence-based appraisal of reflux disease management, recommends: ‘In patients without alarm symptoms who have not been endoscoped, prompt endoscopy is the best clinical strategy in those who have experienced reflux symptoms at least twice a week for at least 6 months.’ Although the evidence supporting this statement is weak, it was recognized that the patient group described had a troublesome, chronic problem that required long-term management.

Risk of missing a diagnosis of cancer

This patient is only 40 years old, so the risk of oesophageal or gastric cancer is a priori very low.

Risk of missing a diagnosis of peptic ulcer disease

This risk varies from country to country, and in Europe is probably not as great as in countries where there is a higher prevalence of Helicobacter pylori infection. Furthermore, although a substantial proportion of patients presenting with heartburn may have concomitant peptic ulcer disease, empirical therapy with a proton pump inhibitor is also a very good treatment for peptic ulcer disease. Delaying endoscopy will therefore only delay the permanent treatment of the underlying disorder and will not harm the patient.

Risk of missing a diagnosis of severe oesophagitis

The most severe types of oesophagitis – Los Angeles (LA) Grades C and D – would still be treated adequately with a full-dose proton pump inhibitor.

Risk associated with proton pump inhibitor treatment itself

The postmarketing surveillance of proton pump inhibitors has been very reassuring.

Conclusion

I am therefore in agreement with the audience that, in my opinion, the risk of harming the patient is minimal, although in theory it can never be regarded as nil.

Discussion

Comment from the audience : As an additional factor, you have not taken into account the risk of endoscopy itself, which is obviously a very low risk, but it must sometimes harm a patient.

Prof. Lauritsen : I cannot put a number on this.

Comment from the audience : I have a problem with just treating reflux symptoms. Once a patient is losing weight, the chances are that we have missed the boat in terms of a long-term cure, and I think it is the same with patients with dysphagia. There are now a number of younger patients presenting with oesophageal cancer – and so, in a way, I am redefining the point at which I would refer a patient for endoscopy.

Prof. Dent : Yes, we have different points of view in that, on the one hand, we are putting patients at risk, but on the other hand we do not have the resources to provide endoscopy for all.

Prof. Vakil : I think that you are right to be concerned about this. We have not said that we would never endoscope this patient, but the real issue is whether he is at risk at the moment . If we look at the data on young individuals who develop cancer, virtually all of them have an alarm symptom on first presentation. The few patients who do not have alarm symptoms tend to have advanced disease at the time of presentation, and it is debatable whether performing an endoscopy will benefit them in any way. We have seen this ourselves, and so have a couple of other groups in the Western world. So I do not think that we are doing much harm to this patient at this stage by waiting.

Comment from the audience : We are having problems getting endoscopies performed in our area. It is taking 6–9 months in the absence of alarm symptoms so, to a certain extent, we are having our hands forced anyway. We are being asked to do things that maybe we would not do under different circumstances.

Prof. Dent : Reality is important and you do have to think about costs.

Prof. Tytgat : Many patients with reflux disease are treated in the primary care setting. Without a proper diagnosis, you start with proton pump inhibitor therapy, and then the patient comes back year after year and is continued on proton pump inhibitor therapy. Is that a wise policy? Do you make a distinction between treatment in primary care and treatment at the specialist level?

Prof. Lauritsen : This is an interesting question. We do not know all the details of why patients consult and how they are referred to specialist care. I take your point that empirical therapy is OK in the short term. I see no major risk − it is not zero, but not a major risk. If a patient was referred to the hospital, however, we would institute the best management strategy without considering costs and would include an early endoscopy.

Question 4: Assuming that you decide to treat with esomeprazole, 40 mg once daily, for how long would you continue the treatment?

Commentary

Prof. Tytgat : This is what I would have voted for too, because this patient has long-standing disease. Professor Dent, what is your optimum initial treatment course?

Duration of initial therapy

Professor J. Dent

I would propose that an initial 2-week therapy course is worth considering, although this is based on limited data. The results of the Contest study, which I described earlier, showed that the major response of heartburn to esomeprazole, 40 mg once daily, in a representative group of primary care patients with and without oesophagitis occurred within 2 weeks.2 Similarly, if we look at the first 2 weeks of therapy in patients with reflux oesophagitis, this is when the great bulk of symptom response occurs (Figure 8).3, 4 So, as far as symptom response is concerned, 2 weeks of therapy seems to be a reasonable proposition.

Figure 8.

Within 2 weeks, the major response of heartburn to proton pump inhibitor therapy has already occurred. 3

Healing of oesophagitis is also a relevant issue and we have some very limited data on the outcomes of 2-week therapy. Two studies with lansoprazole in patients with oesophagitis show a healing rate of about 70% at 2 weeks.5, 6 Another study, which splits the response according to endoscopic grade,7 shows that, apart from the five patients with Savary–Miller Grade 1 disease, the healing rate is clearly related to the initial endoscopic grade, as might be expected (Figure 9). I think that most patients with LA Grades A or B oesophagitis would heal with 2 weeks of proton pump inhibitor therapy. Moreover, if we take the complete spectrum of endoscopic findings in patients with reflux disease, and assume a 65% healing rate after 2 weeks of therapy among those with oesophagitis, we would achieve healing of oesophagitis and relief of symptoms in well over three-quarters of patients with GERD in primary care practice.

Figure 9.

Summary of the available data on the proportion of patients with healing of oesophagitis after 2 weeks of proton pump inhibitor therapy. Though these data from three studies 5–7 are very limited, they indicated that healing of oesophagitis occurs in the majority of patients within 2 weeks. Reproduced with permission from Kluwer Academic Publishers (Dig Dis Sci 1995; 40: 590–7).

In summary, we have data that show satisfactory outcomes with 2 weeks of proton pump inhibitor therapy in most primary care patients. However, we do not know whether stopping therapy at this time results in a higher rate of relapse than when treatment is continued for a further 2 weeks. We know that in a significant minority of patients withdrawal of therapy is followed by a long period of freedom from the problem of reflux disease. The data we have make it appropriate, in my opinion, to test the 2-week initial treatment period, but at the moment I do not think we have enough evidence to endorse this as standard practice.

Discussion

Prof. Tytgat : I am intrigued by what happens to patients who do not become symptom-free after 2 weeks.

Prof. Dent : Quite a large proportion of patients who do not have resolution of heartburn do have a very major response in their heartburn. I think that using very exact clinical trial criteria to define success is a little bit misleading as to the overall success rate that you would achieve.

Prof. Tytgat : It occurs to me that we are only looking at part of the spectrum of reflux disease − those patients with heartburn as their predominant symptom − because this was a selection criterion for entry into the clinical trials. Can we apply the results of the studies that we have discussed to those with nonheartburn-predominant reflux symptoms?

Prof. Dent : I would estimate that about 80% of patients with reflux disease have heartburn as their predominant problem and that other symptoms that are less specific are therefore less important.

Prof. Tytgat : If you go for an empirical therapy, I think that you should aim to knock out the acid to determine whether the patient is really responding to acid suppression, so why not go for a higher dose? What is the best proton pump inhibitor dose for an empirical therapeutic trial?

Prof. Vakil : I agree with you that there are two ways to approach this. In the patient that we are discussing, the diagnosis is not in much clinical doubt, so there is no need to give a very high dose of therapy to abolish acid to prove the diagnosis. However, there are patients, for example those with chest pain, in whom the diagnosis is obscure. In these patients, I would go for a higher dose, and perhaps even double the dose, as a trial of therapy. This would assure me that we have knocked out the acid and then I would investigate further if the patient was no better.

Prof. Talley : I would treat this patient for 4 weeks based on the current data. The 2-week data are intriguing, but we do not have trials that directly address the issue of 2-week therapy, and until we have these I would be loath to recommend it broadly.

Prof. Lauritsen : A trial of therapy is useful, because it can identify a subset of maybe 20% of patients who will need no more drug therapy, and this is worthwhile in my opinion.

Prof. Hatlebakk : I would treat for 4 weeks, because I want as many patients to respond as possible. However, I would not schedule the patient to come back until he had been off medication for perhaps 4 weeks, because I think that it is also important to see what happens on stopping medication.

Question : Do you think that this patient, after 2 or 4 weeks of treatment, should always have the medication to take at home on demand? Or does he have to go to the doctor again to have another consultation and another prescription? This second consultation, and the time that the patient has to take off work to attend it, costs money. Is it cost-effective?

Prof. Vakil : I think that this is an interesting question. We are still dealing with a patient who has not been endoscoped. We have given him a trial of therapy and we are looking for a response. I think that I would have the patient back at some point to review what has happened with the therapy before establishing a long-term treatment approach.

Prof. Dent : I guess that it depends on how far you inform your patient of your strategy in advance. You have to have very specific set points at which you ask the patient to come back, particularly if you have not performed an endoscopy, as is the case here.

Comment from the audience : The distinction between primary care treatment and secondary care treatment is quite evident within the discussion here. If I referred every patient for endoscopy at first presentation, the hospital would be inundated.

Prof. Tytgat : The vast majority of patients are treated in primary care without endoscopy. They are often treated for many years, and 80% or more of prescriptions are refills, presumably mainly for heartburn. The question is whether this is the best policy for the patients. I do not think that we really know.

Question : Are there studies that compare esomeprazole, 40 mg once daily in the morning, with omeprazole, 80 mg?

Prof. Vakil : There are none to my knowledge, and I am not sure why one would want to do that. We have had a number of similar questions suggesting a comparison of esomeprazole, 40 mg, with lansoprazole, 60 mg, for example. There are two things that I want to say about this. The first thing is that increasing the dose does not necessarily give you a linear effect. You enter a plateau phase after the dose is increased beyond a certain point. The second thing is that we must consider cost in this equation. In the USA, lansoprazole, 30 mg, and esomeprazole, 40 mg, cost the same, but to perform a study comparing double doses would double the cost of one side of the arm and I do not think that this is a very meaningful comparison.

Question : How easy or difficult is it for our primary care colleagues to review patients on a regular basis so that they can tailor the treatment and ask for specialist investigation when necessary?

Prof. Dent : We do not have anyone from primary care on the faculty, which is an omission, but one of our primary care doctors in the audience is happy to respond.

Reply from the audience : I think that once we have established that this patient is not at major risk of developing a serious illness in the near future, it is easy to see him once a month or once every 3 months to check that he has not lost weight, he has not been sick, or his symptoms have not become worse after stopping the proton pump inhibitor. However, if the patient's symptoms have not settled down, I would definitely investigate further.

Question : General practitioners almost always deny patients with severe oesophagitis access to nonsteroidal anti-inflammatory drugs (NSAIDs) in the belief that they are bad for them. Are there any data in the literature to suggest that NSAIDs are contraindicated in patients with oesophagitis or Barrett's oesophagus?

Prof. Tytgat : We have only evidence of stomach damage, and not oesophageal damage.

Prof. Vakil : You could make a small argument that NSAIDs may be of benefit through cyclo-oxygenase (COX)-2 mechanisms, and we will touch upon this later.

Case history for votes 5–9

Prof. Talley: Our patient does well during the 4 weeks of initial treatment for his heartburn, but he suffers a symptomatic relapse within a few weeks of ceasing therapy. He has not previously been endoscoped.

Question 5: What would you do now?

Commentary

Prof. Dent : This is difficult, because we do not have any good strategic studies of management approaches. The vast majority of the audience feels that the patient should now have an endoscopy, but would not we expect this patient to relapse? It is not at all surprising, so why should it change our strategy of empirical therapy? I would argue that it is reasonable to try self-directed, on-demand therapy in this patient and, if that fails, then to perform an endoscopy.

Prof. Hatlebakk : I think that the relapse is just what we would expect and this confirms our symptomatic diagnosis. What I would do is reinstate proton pump inhibitor therapy for a further 4 weeks and then let the patient use the medication on demand, but ask him to get in touch with me if he has a relapse during on-demand therapy.

Prof. Dent : Where does endoscopy fit in your scheme?

Prof. Hatlebakk : I would endoscope the patient perhaps during the first year or so, but I would do it at a time when the oesophagitis is likely to have healed, because I think the only good reason to perform an endoscopy in this patient is to look for Barrett's oesophagus. This is much easier to do when the oesophagitis has healed.

Prof. Tytgat : I would perform an endoscopy, so that I know what is going on − what the disease is, how the anatomy looks, what severity it is, and so on. It would help me in planning what I should do.

Prof. Vakil : I disagree with that because I do not think that it helps you at all. You are going to give the same therapy no matter what you find. I think that when we stop initial therapy after 4 weeks, we should warn the patients that there is a 60–70% probability that the disease will relapse and tell them that if it does we will retreat them, and that after retreating them we will perform an endoscopy. Why do we endoscope after retreatment? There are good data to show that if you find Barrett's oesophagus and do a biopsy, you will not make the mistake of diagnosing dysplasia caused by inflammation. There are also some data to suggest that you can find Barrett's oesophagus more accurately if you do not look in the acutely inflamed mucosa. Therefore, I would treat this patient again and perform an endoscopy in 4–6 weeks because he has long-standing reflux disease.

Question : I am a little concerned about this obsession with Barrett's oesophagus. Firstly, a 40-year-old is less likely to have Barrett's oesophagus than someone who is older, and it would be a rare diagnosis in this age group. Secondly, we do not really know whether surveillance for Barrett's oesophagus is worthwhile, so why are we looking for it?

Prof. Vakil : I think that there are two points that we must remember. The first is the patient's point of view. We are telling him that he has a chronic disease, that he is going to have to take medication for the rest of his life, and that we are never going to take a look and see whether there is anything more sinister going on. That is like telling an antihypertensive that he has got hypertension today, he will have to take pills for the rest of his life, and we are never going to check his blood pressure again. It does not really make much sense to patients.

The second thing that we have shown, at least in American patients, is that patients have very strong anxieties about an underlying serious process when the symptoms are chronic, which are relieved by endoscopy. The relief caused by a negative endoscopy persists for at least 6 months, and we are looking further into this, so there could be something to be gained even by a negative endoscopy, which we should not forget.

Question 6: How large a contribution do you think acid rebound made to the relapse?

Commentary

Prof. Tytgat : The audience is very divided on this. Professor Talley, what is the current view on acid rebound?

Potential clinical importance of acid rebound

Professor N. Talley

We do not know much about the potential clinical importance of acid rebound.8–11 However, it is an important issue to consider, because if you believe that acid rebound is key, you might wish to avoid any kind of acid suppression and perhaps introduce patients to some other kind of therapy. So really the question is: ‘Does post-treatment high acid secretion occur with proton pump inhibitors or H2RAs and, if so, is it clinically relevant?’ There are very few studies that address this issue. Gillen et al. compared maximal acid output among H. pylori-negative and -positive individuals after 3 months of high-dose omeprazole therapy.10 In the H. pylori-positive group, there was no significant difference in maximal acid output preomeprazole and on Day 15 postomeprazole. By contrast, among H. pylori-negative patients, there was a significant increase in maximal acid output (Figure 12). Acid secretion in these individuals was stimulated by pentagastrin, which is arguably unphysiological, but there was nevertheless a difference between those with and those without H. pylori infection, although it did not apply to all individuals in the study. There was also a significant, but less convincing, elevation of basal acid output.

Figure 12.

Maximal acid output in H. pylori -negative and -positive patients before and 15 days after an 8-week course of omeprazole (40 mg daily). Figure from ‘Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status’ in Gastroenterology, Volume 116, 239–247, Copyright © 1999 by American Gastroenterological Association, reproduced with permission from W.B. Saunders, an imprint of Elsevier Science (USA). 10

Does short-term treatment with a high-dose proton pump inhibitor cause rebound symptoms? In one of the few studies available, 62 patients with endoscopy-negative reflux disease were randomized, double-blind, into two 5-day treatment periods with lansoprazole, 60 mg once daily, and two 5-day placebo periods, given in a random order with 9-day washout periods in between.12 No difference was found before and after proton pump inhibitor and placebo therapies in any of the reflux symptom scores that were applied. In other words, there was no symptomatic rebound. This crossover study was limited by small numbers, but it is still of interest.

Summarizing studies that are available, acid rebound can occur 7 days or so after ceasing 2–3 months of high-dose proton pump inhibitor treatment. Basal acid output is increased, but maximal acid output more consistently so (but after an unphysiological stimulus). Increased acid suppression may last for a prolonged period (up to 11 months reported in one uncontrolled study)11, though this phonemenon may not occur in H. pylori-positive patients. The mechanisms involved in acid rebound remain to be clarified and the relevance to symptom relapse is unclear.

Acid rebound has also been reported within 7–10 days of stopping treatment with an H2RA.8, 9 There are increases in postprandial and nocturnal acid secretion, the effect is lower with once-daily dosing, and it lasts for up to 10 days. It may be due to H2-receptor up-regulation, in which case it is probably reversible, but it certainly occurs in both H. pylori-positive and -negative patients.

To conclude, the limited studies that we have available indicate that acid rebound does occur. Its clinical relevance is unclear, although it may interfere with attempts to withdraw therapy. Certainly, it could be argued that you should use the lowest effective proton pump inhibitor dosage. Acid rebound is clearly not a relevant issue in patients with severe oesophagitis who require maintenance therapy, because you are not going to withdraw treatment. It is also probably not relevant in patients taking a proton pump inhibitor on demand, as the vast majority will take their medication for only a few days and then stop. Whether acid rebound is relevant in other patient groups is unclear.11

Discussion

Prof. Vakil : The clinical relevance of acid rebound is in a small group of patients who take intermittent therapy. If you take on-demand therapy for 1 or 2 days, it is not regarded as a big phenomenon. However, if you take acid-suppressant therapy for a protracted period and then stop, it could become a clinical factor. So, I think that there is a small group of patients in whom acid rebound may make a difference, but it is not a huge problem.

Prof. Hatlebakk : A few patients seem to report some sort of rebound phenomenon. I think that there is a psychological factor here too, because they have previously been symptom-free while taking medication. It is difficult to decide whether acid rebound really exists, and it has not been studied with intragastric pH measurement, which is the most logical way of studying this phenomenon in my opinion.

Prof. Vakil : One simple clinical way to deal with stopping therapy in this case is to ask the patient to go on to alternate-day treatment for a while, and then stop the medication. This way, you remove the daily therapy and so you take away the daily suppressive stimulus, but you still have enough acid suppression occurring for therapeutic effect. Then you can discontinue treatment completely after 2 weeks.

Prof. Dent : I think that such use of alternate-day therapy probably dignifies acid rebound as a cause of relapse with more weight than is justified from what we know at the moment. We know that reflux disease is a chronic remitting condition. We know that patients who, for instance, have not had effective surgery can suffer relapse of their oesophagitis and symptoms. The continuity of the pathophysiological factors that cause reflux disease is the most important factor that leads to relapse when you stop treatment.

Prof. Tytgat : Could the fact that it is often clinically difficult to switch from a proton pump inhibitor to an H 2 RA be due to acid rebound?

Prof. Lauritsen : No, I do not think so. This relates to the class effect of the drugs. There is a large therapeutic gain in favour of proton pump inhibitors in whatever trial we study in the literature, in both endoscopy-positive and -negative disease, and it is certainly nothing to do with acid rebound.

Prof. Tytgat : How can we ever know whether prior treatment leads to the earlier reactivation of symptoms? How can you design a study to check on that and compare it with the natural history?

Prof. Dent : If there was an effective nonacid-suppressive therapy for GERD, that might give you some means of making a comparison, but of course we do not have such a pharmacological therapy at the moment. Hopefully, we will have such a therapy in the future, and that will allow us to address this question. However, I agree with Professor Hatlebakk in that you will get a very good handle on this question if you perform 24-h pH-monitoring in a spectrum of patients.

Question : Is there any evidence on the pharmacokinetics of drug excretion after continued use, and could this affect the rebound phenomenon?

Prof. Dent : I do not think that we have any such data. We know that the relationship between dose and area under the curve is nonlinear when you go from esomeprazole, 20 mg, to esomeprazole, 40 mg, during therapy. However, once the proton pump inhibitor is withdrawn, I think that the effect only persists at a detectable level for 2 days, so I do not quite see how we can explain rebound on that basis.

Prof. Tytgat : There is certainly no evidence of true tachyphylaxis during therapy, as far as we know.

Question 7: You perform an endoscopy. What is the likelihood of you finding severe oesophagitis (LA Grades C or D)?

Commentary

Prof. Dent : Estimates of the likelihood of finding severe oesophagitis are variable, depending on where you are and which study you read, so its not too surprising if we get some variation in the response.

Prof. Hatlebakk : In one Norwegian study, we endoscoped 573 patients, all of whom had heartburn as the main complaint. In doing so, we found that about 6% had what is equivalent to LA Grades C and D oesophagitis, and only 1.2% had Barrett's oesophagus. So these more severe manifestations of reflux disease are really very uncommon in patients recruited in primary care.

Prof. Vakil : There are contrary data from the USA, and you saw some of them in the EAZEE trial. 13 For example, the prevalence of LA Grades C and D oesophagitis was higher than you found in Norway. Of course, you can argue that these were selected patients. However, a very interesting study was carried out in pharmacies, in which patients buying antacids on a regular basis for 3 months were asked to undergo an endoscopy. These patients had never seen a physician for their reflux disease: 18% were found to have Barrett's oesophagus, 42% had erosive oesophagitis, and several of them, I do not know the exact percentage, were found to have LA Grades C or D oesophagitis, so the distribution was quite different from that seen in the Norwegians.

Prof. Dent : I think that we just have to accept that the pattern of severity of reflux oesophagitis varies and is probably influenced in a large part by how patients are actually accessed for endoscopy.

Question 8: What is the likelihood of finding oesophageal columnar metaplasia ≥3 cm (Barrett's oesophagus)?

Commentary

Prof. Dent : With this question, you need to remember what the denominator is. If you are thinking about patients with oesophagitis only, then they are going to represent about 45–50% of the total patient population.

Prof. Talley : I guess I can comment in terms of population studies. There is a study in northern Sweden in which a random population has been endoscoped, and the prevalence of Barrett's oesophagus was found to be extremely low. Indeed, in the normal population it is not a major issue. Obviously, the apparent rate will be influenced by how many patients are referred for endoscopy, and secondary care is almost certainly different from primary care.

Prof. Dent : Professor Tytgat, what is gained by performing an endoscopy in our patient?

What is gained by performing an endoscopy in this patient?

Professor G. Tytgat

There are very few studies to help prove that endoscopic inflammation is of major importance in the overall management of the patient. We have to accept that therapy in reflux disease is essentially symptom-driven, particularly when symptoms are typical. However, there are many patients with symptomatology that is atypical: a percentage of patients with reflux disease have some minor form of dysphagia, for example, and these patients would certainly profit from having an endoscopy.

What are the indications for an endoscopy in the absence of alarm symptoms? Certainly, to detect columnar metaplasia as, in endoscopic series, the prevalence of Barrett's oesophagus is higher than 5%. Also, to stage the endoscopic severity of damage, because it certainly helps in estimating the prognosis, in reinforcing the therapy, and in deciding on the long-term follow-up strategy. If you see severe oesophagitis, then you definitely have a different view of that patient. In addition, you want to detect concomitant peptic ulcer disease, although admittedly this is disappearing very rapidly now that H. pylori is disappearing. Not so long ago, up to 30% of patients who had peptic ulcer disease had so-called secondary reflux disease, whereas now this applies to less than 5%. Moreover, endoscopy enables you to appreciate the global anatomy: the size of the hiatus hernia, the presence of other lesions that might interfere with sphincter function, and outlet obstruction for whatever reason.

As far as timing of the endoscopy is concerned, the patient should be off acid-suppressive therapy for grading the damage to the squamous epithelium and looking at the severity of oesophagitis. If you are looking for dysplastic change in columnar metaplasia, the endoscopy should be performed during acid-suppressive therapy, so that the picture is not confused by reactive inflammatory changes.

In general, about 55–60% of patients with reflux disease are so-called endoscopy-negative, and the rest are endoscopy-positive. Among those who are endoscopy-positive, the majority have LA Grades A and B oesophagitis, about 20% have Grade C and 5–6%, or sometimes 7%, have Grade D disease. So, no more than one-quarter of the total endoscopy-positive population has severe abnormalities. However, the chaos continues over the relevance of so-called ‘minor or equivocal lesions’, and this is only solvable by using modern technology, such as high-resolution endoscopy plus chromoscopy with Lugol's staining. A typical finding is shown in Figure 15, which shows tiny abnormalities of the squamocolumnar mucosal junction, with irregular Lugol's staining at that level together with minute triangular heads.

Figure 15.

Tiny abnormalities of the squamocolumnar mucosal junction, with irregular Lugol's staining at that level together with minute triangular heads.

Question 9: What would be your recommendation for further endoscopy if you found Barrett's oesophagus free of dysplasia/cancer?

Commentary

Prof. Tytgat : The majority of the audience has gone for 1–2-year surveillance intervals. Professor Vakil, is this a reasonable answer?

Surveillance intervals for patients with barrett's oesophagus

Professor N. Vakil

The issue of surveillance intervals for Barrett's oesophagus is really a two-part question. We have to think of the individual patient sitting in our office, but whenever we consider surveillance we are also talking about public policy and public health. By investing money to prevent a disease, we are taking dollars away from some other preventive strategy. We need to keep that social commentary in perspective. In addition, we must remember that there has been a strong referral and publication bias in reports of Barrett's oesophagus.

The American College of Gastroenterology guidelines, as they currently stand, recommend endoscopy and biopsy ‘every 2–3 years’. We deliberately said ‘2–3’ years, because we could not find any data that specifically said ‘2’ or ‘3’. We are currently looking at a proposed revision recommending that patients who have no dysplasia after two examinations should have repeat endoscopy every 4–5 years, but this has not passed the governing board yet.

Why do we have this controversy? The real problem lies with the data that are available in the literature. As I said before, there is a strong publication bias, which is reflected in the information provided in Table 1. This shows that the reported incidence of adenocarcinoma in patients with Barrett's oesophagus (most of these studies are restricted to long-segment Barrett's) ranges from a high of 1 in 52 cancers per patient-year to a low of 1 in 441. This wide variability is indicative of the very small number of cancers observed in these studies. We really do not know what the rate of developing cancer is in a given population.

Table 1.  Incidence of adenocarcinoma in patients with Barrett's oesophagus
StudyPatients (n)Cancers (n)Mean follow-up (years)Incidence (cancer/ patient years)
Hameeteman et al.365055.21/52
Ovaska et al.373236.71/55
Robertson et al.385642.91/56
Miros et al.398133.61/96
Williamson et al.4017653.01/99
Achkar and Carey416212.61/166
Spechler et al.4210523.31/175
van der Burgh et al.4316689.31/180
Drewitz et al.4417044.81/208
O'Connor et al.4513624.21/285
Cameron et al.4610428.51/441
Total1138   

What can we say today about the situation? Firstly, changes are being considered only in patients who have no dysplasia on biopsies, and not in patients who have mild or moderate dysplasia. Secondly, that a longer surveillance than the current 2–3 years is likely to be adopted, but we have no consensus yet on whether this will be after the first examination or after two negative examinations for dysplasia. This is an area of uncertainty at the present time.

Discussion

Prof. Tytgat : Can you explain to me, in simple terms, exactly what you mean by cost-effectiveness?

Prof. Vakil : Cost-effectiveness is quite simply the numerical evaluation of technology in terms of both its cost and its medical effectiveness. Normally, we look only at treatments according to how effective they are in therapeutic terms, but here we include the element of cost. We have divided the question up and compared the different strategies, and asked: ‘To get this extra effectiveness, or save lives by doing this, how much more money do I have to spend?’ The economists and public policy makers eventually make decisions and, of course, it is open to question and debate as to what the magic number should be in the end. But in public policy you have to spend money somewhere and you have to decide where you are going to spend it. If you can achieve a saving of quality-adjusted life by spending a modest amount of money, then it is worthwhile, but otherwise you might be better off spending your money teaching pregnant women not to smoke, for example.

Question : Prof. Lauritsen, how would you supervise a patient with Barrett's oesophagus in Denmark?

Prof. Lauritsen : We are nowhere near a national consensus on this, so the situation will depend on the individual case. For example, if we compare a 75-year-old alcoholic with a young man, such as our patient, then in the latter case surveillance will be more worthwhile? I think that many clinicians in my country will discuss the benefits and the costs in such a situation and then make a decision on an individual basis. It is not only the cost of endoscopy, but also the cost of the patient's time, and so on.

Comment from the audience : I would like to highlight your failure to state that most of the surveillance studies that you have quoted vary based on their geography. There is a high incidence of conversion from Barrett's oesophagus to adenocarcinoma in Europe, whereas there is a low incidence in the USA. Your arguments about economy and your models are correct. However, your audience, which is predominantly from Europe, needs to understand that, in the UK for example, we have adenocarcinoma rates that are three times higher than in the USA in our base population, and a conversion rate from Barrett's oesophagus to cancer of at least twice that in the USA. So, for our particular geographical location, we must consider the higher risks.

Prof. Vakil : Well, the advantage of the model and the way that I showed it is that, if in your area you have a high transition rate, you can follow the high transition path of the model. If you are in an area with a low transition rate, you can follow the low transition path. I must stress that there is a strong referral bias in all of the studies and I am not convinced yet that there is, in fact, such a high rate of transition, because the negative studies never get published. If you have two cancers in 20 patients your paper may be published, but if you have 25 patients with no cancer nobody wants to publish it.

Prof. Hatlebakk : In Norway, we endoscope and take biopsies every 2 years, and we do so for as long as the patient is fit for oesophagectomy. Of course, the age limit might be pushed upwards by introducing endoscopic techniques for therapy.

Comment from the audience : Economic models are only as good as the data you put into them, and apparently the data on Barrett's oesophagus are poor. However, I am concerned about this increase in the interval between endoscopies. Of the little evidence we do have, virtually all of it comes from yearly surveillance. Of the list you showed, maybe one or two studies were based on 2-year surveillance, the rest were 1-year surveillance studies, and none was a 5-year surveillance study. So to extrapolate beyond the limited data available is quite heroic, and you would have to regard the costs that you generate from them with care.

Prof. Tytgat : How do we ever solve the problem of whether surveillance is sensible, taking into account the cost, the patient problems, the anxiety that we create and all the other things?

Comment from the audience : Sadly, I think that with Barrett's oesophagus we never will. But it is a lesson for us in the future that when we think that we might do some good, rather than just doing it we should do controlled trials of some nature. You could still do that in Barrett's oesophagus. You could, for example, randomize people to 5-yearly surveillance and annual surveillance and see if there is any difference. That would be ethical and probably acceptable to the patient population, would answer some of the questions, and I think would be well worth doing.

Prof. Vakil : I do not agree with the comment that, as most of our data are based on annual endoscopies, we cannot extrapolate to 5-yearly intervals because we do not have studies that look at every 5 years. If you had an endoscopy every year, you could tell what you would find out if you performed an endoscopy after 5 years, because you would be able to accumulate the cases. In fact, if you look at the data in this way, you discover that after the first 2 years you rarely find anything at all in most of these patients. That is why it can be argued that two negative endoscopies should be followed by a longer time interval before further investigation.

Prof. Tytgat : Obviously, we lose a lot of time on patients who really do not need frequent follow-up. Will we ever find the true marker that tells us which patients really deserve surveillance?

Prof. Dent : I do not know. There are a lot of people who are studying oesophageal mucosae and looking for markers, but we do not have any at the moment. We do have epidemiology, however, which tells us which groups we should target our surveillance on most, because there are distinct differences in the rates at which adenocarcinoma develops in males and females, for instance, and also on the basis of age.

Prof. Tytgat : Is it the same problem as with gastric cancer, in which females are protected as long as oestrogens are higher, but as soon as they reach the menopause they start to catch up?

Prof. Dent : Data on adenocarcinoma according to gender, from my reading of the literature, show that there is a major preponderance of males regardless of age.

Comment from the audience : If you do agree on surveillance of patients with Barrett's oesophagus, I find that many patients are very ill-informed about what you are looking for and what will happen if you do find high-grade dysplasia. It is very important for patients to realize that, if we do find changes in the cells and high-grade dysplasia, they are going to have major surgery, which carries its own mortality.

Question 10: How would the demonstration of Barrett's oesophagus influence your use of proton pump inhibitor (assuming that the patient has no oesophagitis or the oesophagitis is healed and the patient is currently symptom free on proton pump inhibitor therapy)?

Commentary

Prof. Tytgat : The majority of the audience would remain with the same dose of proton pump inhibitor.

Value of intensive acid suppression in patients with barrett's oesophagus

Professor J. Dent

There are some provocative data on the value of acid suppression in patients with Barrett's oesophagus, although they do not necessarily tell us how we should act. Figure 18 shows data from a study in which the lansoprazole dose was titrated to control heartburn in 42 patients with Barrett's oesophagus.14 Oesophagitis was healed in all but one patient and, among those whose acid reflux was controlled, there was impressive control of both day- and night-time reflux. This was achieved with a wide range of lansoprazole dosages, indicating the great variability in responsiveness of individual patients to proton pump inhibitor therapy. However, in 16 patients, acid reflux was not controlled, either by day or by night, with the lansoprazole doses arrived at by this titration approach. Therefore, if symptom relief was chosen as the end-point for determining the dosage of proton pump inhibitor, a significant sub-group of patients would continue to have acid reflux, either by day or by night. Other studies indicate that, if you treat Barrett's oesophagus very aggressively with proton pump inhibitors to ablate acid exposure in the oesophagus, very little consistent regression is achieved. So we cannot really use therapy in this way to attempt to reduce the risk of development of adenocarcinoma.

Figure 18.

Summary of outcomes for control of acid reflux according to lansoprazole dose in patients with Barrett's oesophagus when control of heartburn was used to calibrate lansoprazole dosage. 14

A different question is: ‘Can ablation of acid reflux with intensified proton pump inhibitor therapy reduce the risk of development of adenocarcinoma in persistent metaplastic mucosa?’ In the study described above,14 biopsies were taken from the patients both before they started their acid-suppressive regime and subsequently. The percentage of patients in whom Barrett's mucosa biopsies were positive for proliferating cell nuclear antigen (PCNA) gave an indication of the degree of mucosal proliferation.

Assessment of the percentage of PCNA-positive cells among patients with adequate acid suppression and those with inadequate acid suppression provided a marker of the effect of major suppression of acid. The baseline values in the two groups were not significantly different for PCNA positivity. However, there was a major and highly significant drop in the PCNA positivity rate among patients with adequate acid suppression after 6 months, whilst there was no beneficial effect on PCNA positivity in patients with inadequate acid suppression (Figure 19). It is unclear whether this is telling us anything about the risk of development of adenocarcinoma, or is just indicating that the mucosa is being irritated.

Figure 19.

Proportions of proliferating cell nuclear antigen-positive cells present in biopsies from the Barrett's mucosa of patients prior to and after 6 months of acid-suppressant therapy, according to whether oesophageal acid exposure was controlled or not. 14 Control of oesophageal acid exposure was associated with a significant reduction in the proportion of proliferating cell nuclear antigen-positive cells at 6 months.

A subsequent study from the same group is also provocative, showing that there is a step-wise increase in COX-2 levels in the oesophageal mucosa as you go through the normal squamous mucosa, to Barrett's mucosa, to dysplastic mucosa, and to Barrett's adenocarcinoma (Figure 20).15 Is this just ‘guilt by association’ or is it telling us something about the value of trying to control acid reflux? Furthermore, organ culture and biopsies taken from these patients showed that pulsation of acid environment in the organ culture and the addition of bile acids intermittently led to induction of COX-2 in the mucosa.

Figure 20.

Cyclo-oxygenase-2 levels in mucosal biopsies from Barrett's oesophagus patients. 15 Figure from ‘Cyclooxygenase 2 expression in Barrett's oesophagus and adenocarcinoma: ex vivo induction by bile salts and acid exposure' in Gastroenterology, Volume 118, 487–496, Copyright © 2000 by American Gastroenterological Association, reproduced with permission from W.B. Saunders, an imprint of Elsevier Science (USA).

We are left with the question of whether high levels of COX-2 could be a driver in the development of adenocarcinoma and whether acid suppression could act favourably on this risk, independently healing oesophagitis by reducing the level of induction. This is exciting science, but it is far from the clinic, and in answer to this question I do not think that we have enough data to justify changing our clinical practice. I voted for recognition of Barrett's oesophagus not having any influence on how I use proton pump inhibitors. The logic for this is partly a matter of cost and benefit, and I believe that the benefit equation does not yet add up convincingly to support the added expenditure of twice-daily proton pump inhibitor therapy.

Discussion

Prof. Tytgat : If acid reflux is the mechanism that leads to columnar metaplasia and perhaps to dysplasia and so on, yet symptomology does not help in telling you that acid reflux is controlled, does this mean that you should use pH-monitoring to ensure that you are indeed controlling acid reflux in such patients?

Prof. Dent : No, I do not think that pH-monitoring should be used in this way. If you are sufficiently convinced by these as yet very limited data, which are also highly indirect, then probably you should just use high-dose proton pump inhibitor in all patients with Barrett's oesophagus. I suspect that this is a more practical approach than trying to titrate with pH.

Prof. Tytgat : And high dose would mean what?

Prof. Dent : Probably, esomeprazole, 40 mg twice daily. There are enough data to suggest that a study would be very well worth doing, but I do not think we should change our clinical practice on the basis of the data that I have just presented.

Prof. Tytgat : Suppose a patient with long-segment Barrett's oesophagus has no symptoms whatsoever and has no evidence of damage to the squamous layer, would you treat this patient just because he has a columnar segment?

Prof. Dent : Probably not. If there was oesophagitis, I would treat this and I would endoscope the patient to ensure that it was healed, because the data indicate that occurrence and progression of Barrett's are related to mucosal breaks.

Prof. Vakil : We do not really have enough evidence to give an evidence-based answer. I would not alter the proton pump inhibitor dose based on the current evidence, but I am troubled by these data. As far as the other question is concerned, I do have one patient with Barrett's oesophagus with no symptoms and no obvious evidence of oesophagitis who is taking proton pump inhibitor therapy. I talked to him about it and he elected to go on to this treatment, but we have no data at all to support its use.

Prof. Hatlebakk : I actually voted for an increase in medication to twice-daily dosing, which comes from my experience with omeprazole. We know that most patients with Barrett's oesophagus have nocturnal acid breakthrough and acid reflux during the early hours of the night. Twice-daily dosing may not be absolutely necessary with esomeprazole, but I would certainly give omeprazole twice daily.

Prof. Lauritsen : I am not convinced by the surrogate markers mentioned by Professor Dent. I think that we need more data to warrant costly twice-daily treatment.

Prof. Talley : I am more aggressive with my patients with Barrett's oesophagus. I like to give them twice-daily therapy, and I make sure that they are totally symptom free. This is not based on many data, but I do not monitor their pH − this is probably going too far at this stage. Twice-daily proton pump inhibitor is my standard approach for Barrett's oesophagus.

Prof. Dent : We always have problems in dealing with Barrett's oesophagus and what strategies we should be using. However, we need to keep this in perspective. Barrett's oesophagus is an issue in a sub-group of patients and we should not allow it to dominate our management strategies.

Question : Can you explain the different responses of reflux oesophagitis in patients with Barrett's oesophagus and those without Barrett's oesophagus, which was shown earlier in the pro-GERD study?

Prof. Tytgat : I think that we have a more severe diathesis in patients with Barrett's oesophagus. Everything points in the same direction and that is the reason why these patients have more nocturnal acid reflux as well. Indeed, if you truly want to cut down on acid secretion in patients with Barrett's oesophagus, in general you have to give a higher dose of proton pump inhibitor than for regular reflux patients.

Prof. Dent : I think that this is correct and that we should be aiming, in this group, to cover the full 24 h of acid exposure.

Prof. Tytgat : There is something that really bothers me. We have now had very adequate acid suppression for 15 years, and stricturing in reflux disease has largely disappeared from our endoscopy suites, whereas in the old days it was a daily occurrence. In contrast, columnar metaplasia and the other problems have not really disappeared. Why is there a discrepancy between these two phenomena in the same disease?

Prof. Dent : You are suggesting that there is a difference between the healing of oesophagitis and the development and progression of Barrett's oesophagus. In terms of fixing stricture that depends on fixing oesophagitis, but there are factors other than just healing oesophagitis that are involved in patients with Barrett's oesophagus. I think this is what you are driving at is not it?

Prof. Tytgat : Correct, but both phenomena are at the end of the spectrum of complications of the disease, and one does better than the other, which, if anything, gets worse. Why is that?

Prof. Dent : There is a background of an increase in oesophageal cancer, which plays a part.

Prof. Vakil : I think that there is an alternative hypothesis for this Barrett's vs. stricture question. You have presented data from culture studies in vitro , which show changes in PCNA, but let me propose another argument. Let us say that the stricture disease is related to acid, whereas once you get intestinal metaplasia acid does not play any role in determining whether there is progression from metaplasia. This would explain why you have this dichotomy and why, in all the studies on surgery and long-term proton pump inhibitor therapy, we can not show a reduction in the rate of oesophageal cancer, which is in fact rising. My argument for not increasing proton pump inhibitor therapy is that once you get metaplastic change other genetic factors determine whether you go on to develop cancer or not, and it is not related to acid any more.

Prof. Tytgat : You cannot say that. In the Stanford hypothesis, it is acid that enters the absorptive cells in the intercellular metaplastic mucosa and which is a major factor in giving a proliferative boost.

Prof. Vakil : That is only one study, and its a study in vitro .

Prof. Hatlebakk : I think that there is a continuous process, but we do not know whether acid or reflux, with all its different components, is also driving metaplasia towards neoplasia.

Question : Why is there an increase in oesophageal cancer? Is it due to treatment with proton pump inhibitors, or a fall in H. pylori infection rates, or something else?

Prof. Talley : Nobody knows why adenocarcinoma is rising. It could be due to the disappearance of H. pylori , and there are arguments for this. However, I think that it is because we are all getting fatter, which might lead to reflux, and there is real evidence to support this epidemiology. It could be that dietary issues are more important than anything else.

Reflux disease management strategy: continuous treatment

Case history for votes 11–12

Prof. Talley : Our second case, a female, was initially treated with pantoprazole, 40 mg, for heartburn. She also complained of nocturnal heartburn and described acid regurgitation as an acid taste in her mouth. Because she was failing on proton pump inhibitor therapy she was referred for endoscopy, which revealed LA Grade C oesophagitis.

Question 11: What would you do next?

Commentary

Prof. Dent : I think that the majority audience choice of esomeprazole, 40 mg once daily, is logical. From the data that we have, esomeprazole, 40 mg, is in effect an escalation over pantoprazole, 40 mg, and the pH data on this are very convincing. Unfortunately, however, we do not as yet have comparative clinical data. Nocturnal acid breakthrough is important in considering success or failure in the treatment of reflux disease.

Nocturnal acid breakthrough

Prof. N. Vakil

Nocturnal acid breakthrough has been defined as an intragastric pH of less than 4 for longer than 1 h in the overnight period. Figure 22 shows a typical intragastric pH curve when a single dose of proton pump inhibitor is taken in the morning before breakfast. Somewhere in the late evening, postdinner, there is a drop in pH in the stomach. This occurs with all the proton pump inhibitors available so far, and this phenomenon may be quite important.

Figure 22.

A typical intragastric pH curve.

I want to draw your attention to two things. Firstly, nocturnal acid breakthrough does not mean nocturnal heartburn; many of these patients do not have heartburn at all. Indeed, an analysis of the number of episodes of reflux symptoms per hour throughout the 24-h period in 105 patients with reflux disease showed that most suffered daytime, postprandial reflux, and there was a very small prevalence of night-time symptomatic reflux (Figure 23). Secondly, this pH phenomenon may be extremely important in both patients with Barrett's oesophagus and in those with extra-oesophageal disease. However, here I am confining my comments to the patient who has classical reflux disease and some night-time symptoms while on proton pump inhibitor therapy.

Figure 23.

An analysis of the number of episodes of reflux symptoms per hour throughout the 24-h period in 105 patients with reflux disease. Reprinted from Gullet, 1992; 2: 58–72, Johnsson L, Adlouni W, Johnsson F, Joelsson B ‘Timing of reflux symptoms and esophageal acid exposure, Copyright 1992, by permission Elsevier Science.

Information on symptoms of heartburn before and during proton pump inhibitor therapy can be obtained from daily diary cards filled in by nearly 5000 patients with reflux disease in the USA in two randomized, controlled trials of esomeprazole and omeprazole.3,4 Approximately half of the population reported night-time symptoms of heartburn before starting therapy, but 7 days after treatment the number had fallen to about 12–15%. By 28 days, the prevalence dropped to 5–7%, so night-time symptoms of heartburn were really quite uncommon in patients who were already on proton pump inhibitor therapy.

Now to the question of whether we should give these patients an additional H2RA at bedtime. What would this accomplish? Is it better to give a proton pump inhibitor in the morning, plus an H2RA at bedtime, or to double the dose of the proton pump inhibitor? We have no symptom data on this, but we do have intragastric pH measurements of the median time that pH was less than 4 in 20 healthy volunteers. In one group, omeprazole, 20 mg, was given twice daily, before breakfast and before dinner, whereas the second group took omeprazole, 20 mg, before breakfast and ranitidine, 150 mg, at bedtime. The results show that, in both the upright and recumbent positions, omeprazole, 20 mg twice daily, was significantly more effective at maintaining the pH in the stomach above 4 than the omeprazole plus ranitidine combination (Figure 24). This indicates that doubling the dose of proton pump inhibitor provides superior acid control compared with a combination of single doses of proton pump inhibitor and an H2RA.

Figure 24.

Omeprazole, 20 mg twice daily, was significantly more effective at maintaining the pH in the stomach above 4 than the omeprazole, 20 mg, plus ranitidine, 150 mg, combination. 34

What about the issue of long-term use of H2RAs in this particular patient who reports night-time symptoms of heartburn? Figure 25 shows the results of a crossover study to investigate what happens over time when you give a combination of a proton pump inhibitor and an H2RA. With a proton pump inhibitor given twice daily, the intragastric pH was below 4 for approximately 30% of the time. There was a significant drop in acid production when ranitidine was added at bedtime, but this was only true when the duration of therapy was less than 1 week. When the treatment was continued chronically, tachyphylaxis developed and, within 4 weeks, the additional effect of the H2RA was lost, resulting in a similar level of acid control as when the proton pump inhibitor was given alone twice daily.

Figure 25.

The results of a crossover study which investigated what happened over time when the combination of a proton pump inhibitor and H 2 -receptor antagonist was given. 35

We can summarize the following points about nocturnal acid breakthrough and heartburn:

  • ? recent studies show that a small proportion of patients on proton pump inhibitor therapy have nocturnal heartburn;
  • ? tachyphylaxis develops with continued use of H 2 RAs;
  • ? nocturnal acid breakthrough is a pH phenomenon and is not the same as nocturnal heartburn;
  • ? the role of nocturnal acid breakthrough in Barrett's oesophagus and extra-oesophageal disease needs to be clarified further as it may be very important.

Discussion

Question : Do you think that, when you give a proton pump inhibitor on demand, people will take it when they need it, which is before bedtime? What I saw in your figures was that there was a rise in pH level at night and in the middle of the day. When you take a proton pump inhibitor before bedtime it will work for 16 h.

Prof. Vakil : I am not sure that I follow your argument here. The main stimulus for evening acid secretion is dinner, and if you take a proton pump inhibitor after dinner in the postprandial phase you have delayed gastric emptying. By the time that the proton pump inhibitor gets into the duodenum and has been absorbed, most acid secretion has already taken place, so I am not sure that taking a proton pump inhibitor at bedtime is a good idea.

Question 12: The patient's heartburn is resolved on esomeprazole, 40 mg. After 8 weeks of therapy, what would you do?

Commentary

Prof. Tytgat : This is excellent, and is what I would have chosen too.

Esomeprazole, 20 mg, on-demand therapy and la grade

Professor J. Hatlebakk

My recommendation for this patient would be to step down to esomeprazole, 20 mg once daily, and then observe. Support for this approach comes from the large maintenance studies with esomeprazole conducted in the USA. Figure 2716 shows the results of a study by Professor Vakil and colleagues, showing a small numerical difference between esomeprazole, 40 mg, and esomeprazole, 20 mg, in maintaining healing of oesophagitis, but not one that is statistically significant. A second major study by Johnson et al.17 hardly showed a numerical difference between the two doses in maintenance therapy. Furthermore, neither study showed a difference in maintained healing between the various grades of oesophagitis according to the LA classification.

Figure 27.

Maintained healing of reflux oesophagitis over 6 months with esomeprazole, 20 mg once daily, compared with esomeprazole, 40 mg once daily, esomeprazole, 10 mg once daily, and placebo. The observed difference between the 40 mg and 20 mg groups was not statistically significant, whereas all doses of esomeprazole were significantly more effective than placebo. Reproduced with permission from Aliment Pharmacol Ther 2001; 15: 927–35. 16

One alternative, which is clearly inappropriate in this patient, but which could be considered for patients with less severe reflux disease, is to use on-demand therapy. This would mean starting the patient on esomeprazole, 20 or 40 mg once daily, for up to 4 weeks, and then instructing the patient to take medication only when needed to control symptoms. In the studies that have looked into this approach in patients with endoscopy-negative reflux disease, the end-point was time to discontinuation due to unwillingness to continue therapy. Over a period of 6 months, 85% of patients taking esomeprazole, 20 mg, were willing to continue, compared with just 48% with placebo.18 However, I stress that this approach is documented only in endoscopy-negative GERD, and is inappropriate for this patient.

In conclusion, esomeprazole, 20 mg once daily, is highly effective for the maintenance of healing and also for symptom relief in patients with healed reflux oesophagitis. This is irrespective of the baseline grade of oesophagitis. On-demand therapy is suitable only for endoscopy-negative GERD but, in the future, may prove useful in long-term management of patients with LA Grade A, and possibly Grade B, oesophagitis, but this requires further investigation.

Discussion

Prof. Tytgat : Concerning the patient, how long would you give maintenance therapy with esomeprazole, 20 mg? What would you tell the patient?

Prof. Hatlebakk : This is a chronic disease, I would give maintenance therapy indefinitely.

Prof. Tytgat : If she is asymptomatic, let us say for a year, would you try on-demand treatment in such a patient?

Prof. Hatlebakk : Not based on the evidence that we have today. We must remember that she has LA Grade C oesophagitis, which is uncommon. Only 5–6% of patients have severe oesophagitis and it has the potential to create complications over time.

Prof. Tytgat : Some patients very occasionally have heartburn during maintenance therapy, for which they take antacids. Do antacids taken together with esomeprazole interfere with its bioavailability?

Prof. Hatlebakk : This has not been shown with esomeprazole, but it has been shown with lansoprazole.

Prof. Lauritsen : I would strongly advise that this patient be continued on treatment with profound acid inhibition if the disease of origin is LA Grades C or D, because some studies in the literature indicate that the risk of stricture is increased in these patients.

Prof. Tytgat : This patient comes back with symptoms, but she has candidiasis of the oesophagus. What do you do? Do you stop the acid suppressant, or do you leave the candidiasis and continue the acid suppressant?

Prof. Dent : You have to continue the acid suppressant, because we know from the withdrawal of therapy in patients with LA Grade C oesophagitis that they relapse promptly to the same severity, so there is no logic in stopping therapy.

Prof. Vakil : I think that you are asking this question because ketoconazole is not absorbed if you are taking proton pump inhibitors. However, there are other treatment options for candidiasis.

Question 13: Year 2004: a patient sees one of your colleagues for a second opinion because of reports in the newspaper about reflux disease and cancer. He has found a fundic gland polyp. What would you recommend?

Commentary

Prof. Dent : Professor Talley appears unbothered by the presence of this fundic gland polyp, but there are quite a few people in the audience who have a different opinion. Professor Tytgat, what about this and other aspects of proton pump inhibitor safety?

Safety aspects of long-term treatment with proton pump inhibitors

Professor G. Tytgat

Fundic gland polyps are innocent changes of the mucosa (Figure 29). Their prevalence in patients on acid-suppressive therapy varies from 5% to 9%, but one major study from Germany indicates that the prevalence is similar in a control population.19 Fundic gland polyps do not require any surveillance and some of the lesions may even regress during therapy. Sometimes they are solitary, but a whole stomach may be covered with these fundic gland polyps and, if you look at these ectatic glandular structures, it is not uncommon to see parietal cells with some protrusions, which are also the consequence of long-term acid suppression.20

Figure 29.

Fundic gland polyps.

Long-term proton pump inhibitor therapy has proved to be remarkably safe, and the changes that do occur are seen mainly in H. pylori-infected stomachs. In my opinion, this is one of the many arguments in favour of eradication of the organism and bringing the mucosa back to normal before embarking on long-term therapy. A number of concerns about profound and prolonged acid suppression have been expressed, including associations with:

  • ? carcinoid formation;
  • ? cancer;
  • ? gastric bacterial overgrowth;
  • ? reduced fat absorption, mineral bioavailability and vitamin B 12 absorption;
  • ? stimulation of adenoma/carcinoma cell proliferation.

Carcinoid formation

There may be some increase in the number of enterochromaffin-like (ECL) cells in the corpus mucosa (ECL cell hyperplasia), but true carcinoids have not been described, except in the setting of Zollinger–Ellison syndrome or multiple endocrine neoplasia syndrome.

Cancer

The issue of cancer has already been dealt with earlier and is associated with H. pylori infection. Several recent studies have been unable to confirm any rapid increase in atrophy in H. pylori-positive stomachs. Certainly, there is no mucosal change in an H. pylori-negative stomach, even after 5–10 years of proton pump inhibitor therapy, there is no evidence of transition from atrophy to intestinal metaplasia, and no increase in gastric malignancy.21,22

Gastric bacterial overgrowth

There is bacterial overgrowth during proton pump inhibitor therapy, initially with the oral flora and later with the intestinal flora, but we are uncertain of the clinical relevance of this. In H. pylori-negative individuals, bacterial overgrowth has not led to changes in the mucosa. Furthermore, the risk of enteric infection is minor, although there are a couple of studies indicating that the risk is a little higher in patients taking acid suppressants than in those not taking these agents.23–28

Reduced fat absorption, mineral bioavailability and vitamin B12 absorption

Malabsorption of fat has not been observed. In a large Scandinavian study that compared surgically vs. medically treated patients, followed for at least 5 years, body weight remained exactly the same in the two patient populations.29 Similarly, mineral malabsorption does not occur, although some lowering of vitamin B12 levels after long-term proton pump inhibitor therapy has been reported, particularly in individuals who already had some atrophy to start with. However, in the Scandinavian study mentioned above, the changes in B12 levels in patients treated long-term were low and fell within the normal range, and there was no difference between medically and surgically treated patients. Certainly, pernicious anaemia has not been described.30

Stimulation of adenoma/carcinoma cell proliferation

Gastrin levels do rise slightly, particularly in individuals infected with H. pylori but also to some extent in noninfected individuals. There is no doubt that gastrin is a trophic factor for many cell types, but it is still not entirely clear to what extent this might affect adenocarcinoma or carcinoma formation − so far, there is no evidence that it does, but we have to remain vigilant.31,32

Surgery

In considering the issues associated with proton pump inhibitor safety, we should take a similar view of surgery, which is the alternative approach to therapy. Two recent long-term evaluations of laparoscopic anti-reflux surgery, followed for 5–10 years, quote a patient satisfaction rate of more than 90%. However, breakdown of all the data provides a slightly different picture (Table 2), with 4–10% of operations having a poor outcome, and 5–13% needing reoperation, when the results of reperformed surgery are fairly dismal. In addition, many patients still suffered from bloating, difficulty in belching, diarrhoea, recurrent heartburn and dysphagia. In addition, the need for dilatation was high (5–7%), and 11–14% of patients still required proton pump inhibitor therapy. Taking all these into account, it is difficult to come to a 90% successful outcome figure for surgery.

Table 2.  Long-term outcome laparoscopic anti-reflux surgery
 Lafullarde47Bammer48
n followed >5 years 171200
Satisfied (%)9690
Poor outcome (%)410
Need for re-operation (%)513
Bloating (%)2166
Impossibility of belching (%)High28
Diarrhoea (%)12
Recurrent heartburn (%)640 (27 mild)
Dysphagia (%)2820
Need for dilatation (%)75
Need for proton pump inhibitor (%)1411

Surgical treatment must be put into perspective, and it is our task to inform the patient as well as we can of the pros and the cons of both this and long-term acid-suppressive therapy. A number of novel endoscopic techniques are currently being evaluated to try to mimic the surgical results. However, I am rather pessimistic about the long-term outcome of these, because the phenomenon that ultimately led to reflux disease will remain the same. Sooner or later reflux will probably return.

Conclusion

Proton pump inhibitor therapy has shown remarkable long-term safety. Klinkenberg-Knol and colleagues have now followed a cohort of patients with severe GERD for over 1500 patient-years and have found no serious drug-related adverse events.49 As far as I am concerned, the chance of any future surprises is extremely remote.22

Discussion

Question : Should the treatment of reflux disease be focused on prevention of acid being in the wrong place rather than just trying to suppress it?

Prof. Dent : I think that this is a very good point. Perhaps I can answer by saying that we do not yet have drugs that are effective at this, but I am very pleased to say that AstraZeneca is working hard at developing such drugs and that progress is occurring in this area.

Question : Where does the problem of hiatus hernia fit in as a cause of reflux disease?

Prof. Tytgat : The vast majority of patients with reflux disease have hiatus hernia if you look carefully for it. It certainly interferes with sphincter function, and it may be even more important in transit. I think that the whole mechanism of transient lower oesophageal sphincter relaxations needs to be restudied with more sophisticated technology to discover the importance of the displacement of the internal component of the sphincter. There is no doubt that it is of major importance, but it is something that you accept that you cannot do anything about.

Question : Firstly, does bile reflux make Barrett's oesophagus worse? Secondly, should patients with fundic gland polyps in the stomach be referred for a colonoscopy to look for colonic polyps?

Prof. Lauritsen : I am not convinced that bile reflux in Barrett's oesophagus contributes to the problem, and I am not aware of any studies that give a clear message on this.

Prof. Dent : I think that I would differ slightly; there is increasing evidence of a fairly high prevalence of bile reflux in patients with Barrett's oesophagus, and there is one study that suggests that bile reflux is highest in patients who develop cancer. The problem, however, is the small number of patients.

Prof. Lauritsen : This does not prove any causal relationship, though.

Prof. Tytgat : All the recent animal experiments point in the same direction − that bile reflux is important. To me, the ultimate therapy of reflux disease will be a combination of acid suppression plus something that can pharmacologically prevent reflux events.

Prof. Dent : What about fundic polyps and colonoscopy?

Prof. Tytgat : It is true that some patients with fundic polyposis have fundic gland polyps and, interestingly, these can come and go, but this is not really good enough to support looking at the colon too.

Question : If you have a patient who has had an antral gastrectomy and has oesophagitis, how would you treat him?

Prof. Tytgat : You would initially treat a patient with partial gastrectomy in the usual way, but if there is a substantial biliary component it can be very difficult.

Prof. Talley : Sometimes, the bile-salt-sequestering agents help, but it is a clinically difficult situation.

Prof. Dent : The first thing to do is suppress the acid.

Prof. Talley : Yes − it would not be as effective as in the normal situation, but it can work.

Comment from the audience : The greatest risk for one of the patients described today was not his reflux disease but his cardiovascular risk from being overweight, so we must not forget to remind him of the benefits of a change of lifestyle. This is very worthwhile.

Question : Surely, the impact of therapy on quality of life in patients with reflux oesophagitis is ultimately the most important end-point in comparisons of esomeprazole and omeprazole?

Prof. Vakil : I agree that quality of life is a very important end-point from the patient's standpoint. There are good data to show that quality of life in reflux disease is related very strongly to symptomatology, and the disappearance of symptoms in a sustained manner translates into improvements in quality of life. I think that this has been established with the data that we've shown on sustained resolution of heartburn.

Question : Why define acid breakthrough based on intragastric pH when we are interested in the oesophageal pH and symptoms?

Prof. Vakil : There are two variables to consider − one is the pH in the stomach and the second, which none of us ever talks about, is the volume of acid in the stomach. You could have 2 mL of gastric contents with a very acidic pH, but there is nothing to reflux up into the oesophagus. Many studies are now being carried out with dual probes, looking at the oesophageal pH as well, but you are absolutely right that the nocturnal acid breakthrough question has not adequately addressed the oesophagus.

Question : What is the comparison between esomeprazole therapy and anti-reflux laparoscopic surgery in terms of long-term symptom relief and cost-effectiveness?

Prof. Dent : Essentially, there are no data as yet, but I guess these will be forthcoming in due course.

Prof. Tytgat : We have only the comparison between surgery and omeprazole. If you allow the dose of omeprazole to be adapted to the symptom pattern of the patient and then compare symptom profiles over 5 years of follow-up, the two arms are essentially indistinguishable with respect to symptom relief.

Question : Are there any data to suggest that the incidence of Barrett's oesophagus is high in patients who have had a gastrectomy? This would suggest that bile does play a role here, and is probably more direct than using bilirubin concentration monitoring (Bilitech).

Prof. Tytgat : There are no good data. The vast majority of patients with antrectomy do not have reflux disease, but the minority who do usually have rather severe disease. Although it is rare, patients can have Barrett's oesophagus after a total gastrectomy or an oesophagojejunostomy, but there is no doubt that the frequency depends on whether or not they have reflux disease.

Question : Can you monitor symptoms and, if the symptoms are responsive to therapy, does this mean that patients will not develop Barrett's oesophagus?

Prof. Hatlebakk : The symptomatic response to therapy usually means that either the oesophagitis heals or it decreases to LA Grades A or B, which is not likely to be complicated with Barrett's oesophagus.

Prof. Tytgat : Why is esomeprazole, 20 mg, preferred to esomeprazole, 40 mg, for on-demand therapy?

Prof. Lauritsen : The results achieved with 40 mg were very similar to those achieved with 20 mg in endoscopy-negative patients.

Question : Are there any data regarding bacterial overload during long-term therapy with esomeprazole, 20–40 mg, compared with placebo and other proton pump inhibitors?

Prof. Tytgat : All the proton pump inhibitors do the same thing. As soon as you raise the pH above 4, even with H 2 RAs, organisms can survive, regardless of which drug you use. Initially, it usually affects the oral flora, but gradually it can affect the colonic flora too.

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