Reflux disease management strategy: initial therapy
2003; Wiley; Volume: 17; Issue: s1 Linguagem: Inglês
10.1046/j.1365-2036.17.s1.9_1.x
ISSN1365-2036
Autores Tópico(s)Eosinophilic Esophagitis
ResumoProf. 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. 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. Prof. Tytgat : The majority of the audience has chosen to begin with proton pump inhibitor therapy, rather than opting for a step-up approach. 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. 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 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 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. 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. 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. 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. 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. This patient is only 40 years old, so the risk of oesophageal or gastric cancer is a priori very low. 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. 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. The postmarketing surveillance of proton pump inhibitors has been very reassuring. 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. 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. 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? 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. 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. 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. 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. 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. 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. Prof. Tytgat : The audience is very divided on this. Professor Talley, what is the current view on 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. 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 Prof. Vakil : The clinical relevance of acid rebound is in a small group of patients who take
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