Review article: management of mild and severe gastro-oesophageal reflux disease

Transcription

1 Aliment Pharmacol Ther 2003; 17 (Suppl. 2): Review article: management of mild and severe gastro-oesophageal reflux disease G. N. J. TYTGAT Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands SUMMARY Treatment of endosocopy-negative gastro-oesophageal reflux disease (s-gerd) should be directed towards rapid relief of symptoms and then maintenance of relief using minimum yet effective therapy. Responses to proton pump inhibitors are somewhat lower in s-gerd patients compared to GERD with overt erosive damage (e-gerd). The reasons for a lower response rate are not clear but may relate to the inclusion of patients who do not have reflux disease or patients with a lower oesophageal sensory threshold. Also poorly understood is the lower yield of complete heartburn relief when the number of associated dyspeptic symptoms is high. Some form of long-term therapy is needed in the majority of patients. ÔOn demandõ proton pump inhibitor therapy to control reflux symptoms is a new and attractive option. Time to study discontinuation due to insufficient control of heartburn, or any other reason resulting in unwillingness to continue with on-demand therapy, is a pragmatic outcome that is well suited to definition of the efficacy of on-demand therapy. The goals of treatment of e-gerd should be to relieve symptoms and to heal lesions. Symptom severity and much less endoscopic abnormalities drives the therapeutic choices. When symptoms are mild or intermittent and when oesophagitis is of limited degree, standard dose proton pump inhibitor is usually instituted. Fewer and fewer clinicians would still opt for an H2-receptor antagonist. If there is moderate or severe oesophagitis or if symptoms are particularly troublesome, then the patient should start with standard-dose proton pump inhibitor therapy once a day, but not uncommonly a b.d. dosage maybe necessary. Once the dose of the acid suppressant that relieves symptoms is found, this dose should be maintained for a period of 3 months. After this time, an attempt should be made to reduce the dose. If symptoms recur, then the patients should go back to the full-dose proton pump inhibitor and a plan should be formulated for long-term treatment. The long-term treatment options vary between ongoing acid and suppressant therapy, with occasional attempts to reduce the dose, or to go for Ôon demandõ therapy and (rarely) includes consideration for surgery or endoscopic anti-reflux therapy. INTRODUCTION The spectrum of gastro-oesophageal reflux disease (GERD) can be subdivided into: endoscopy-negative GERD (ENRD); nonerosive GERD (NERD); reflux oesophagitis (GERD); and GERD with oesophageal columnar metaplasia (Barrett). Other less commonly used terminology for the subcategories which span reflux disease are: symptomatic GERD with no overt endoscopic damage of Correspondence to: Prof. G. N. J. Tytgat, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, the Netherlands. g.n.tytgat@amc.uva.nl the squamous epithelium (s-gerd); GERD with overt erosive damage (e-gerd); and GERD with tissue metaplastic change (m-gerd). Increasingly a distinction is made between s-gerd and e-gerd regarding therapy, both for the initial healing phase and for maintenance, because there are some peculiar differences. More than half the GERD population belongs to the s-gerd category. Of the e-gerd category, roughly 60 70% belongs to Los Angeles Classification system (LA) grade A and B, some 15% to grade C, and 6% to grade D. There may well be distinct pathophysiological differences between s-gerd or NERD and e-gerd. 1, 2 52 Ó 2003 Copyright Blackwell Publishing Ltd

2 REVIEW: MANAGEMENT OF MILD AND SEVERE GERD 53 THERAPY OF s-gerd NERD Initial healing therapy Many patients with very intermittent reflux symptomatology, essentially heartburn, or with regularly recurring symptoms prior to formal medical consultation, self medicate with over-the-counter antacids, alginates or low dose H2-receptor antagonists (H2RA). 3 5 Medical consultion is usually sought once the symptoms become troublesome, frequently recurring and or respond insufficiently to self-medication (so-called patient dissatisfaction). Not uncommonly sleep disturbance is present. because of reflux when specifically asked for. In contrast to the past where traditionally a Ôstep-up approachõ was advised, currently a step-down approach is increasing accepted as the most cost-effective therapy, starting with a proton pump inhibitor once daily, preferably before breakfast, in the standard dose (esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 30 mg, rabeprazole 20 mg) 5a although some controversy persists. 6, 7 All trials comparing proton pump inhibitors with H2RAs have shown without exception superiority of proton pump inhibitors with respect to symptom relief, particularly with respect to heartburn and sleep disturbance. 8 Also, Richter et al. 9 compared lansoprazole to ranitidine in s-gerd and stressed the superiority of the proton pump inhibitor over the H2RA. Some peculiarities deserve further comment. The overall symptom relief in s-gerd, although superior to the symptom relieving capability of H2RAs, does not reach 100% but plateaus around 60% after a 4-weeks therapy. It would indeed appear that the antisecretory therapy is less effective in s-gerd compared to e-gerd. Venables et al. 10 reported that treatment with omeprazole 20 mg d relieved heartburn in 61% of the overall GERD population, of which two thirds had s-gerd, compared to 79% with e-gerd. Also Carlsson et al. 11 found that omeprazole was less effective in s-gerd and that s-gerd patients were less likely than e-gerd patients to experience complete resolution of symptoms. Similar findings were made by Galmiche et al. 12 Comparable figures were recently found for rabeprazole 10 or 20 mg d by Miner et al. 13 Satisfactory heartburn relief (no more than one episode of heartburn of moderate severity during the week) was obstained in 60% and 57% of patients receiving either 10 or 20 mg of rabeprazole at week 4, respectively. The results obtained with esomeprazole 40 mg d were in the same range. Moreover the likelihood of heartburn relief decreased even further as the number of dyspeptic symptoms increased. 14 Why proton pump inhibitorinduced heartburn relief in s-gerd is less effective remains unknown. Is it related to increased chemoreceptor sensitivity to acid as suggested by Johnston et al.? 15 or is it related to nonacid reflux? Maintenance therapy Almost no data are available regarding proton pump inhibitor or H2RAs as maintenance therapy in s-gerd. Yet a new concept of Ôon-demandÕ therapy was launched particularly for s-gerd patients. 16 Lind et al. 17 compared different doses of omeprazole with placebo on demand. Tally et al. compared different doses of esomeprazole with placebo on demand. 18 Both omeprazole and esomeprazole were effective and well tolerated in maintaining symptom control. INITIAL HEALING THERAPY IN e-gerd Several studies have shown that proton pump inhibitors are effective for promoting symptom relief and healing in patients with e-gerd. Only the recently published studies will be considered here. Although there may be differences with respect to the initial velocity of symptom relief between the various proton pump inhibitors, the end result is usually more or less indistinguishable. Complete heartburn relief in the Richter 19 and Kahrilas 20 studies was obtained in, respectively, 63 and 65% at 4 weeks when esomeprazole 40 mg d compared to 58 and 57% omeprazole 20 mg d. Castell et al. 21 compared esomeprazole 40 mg with lansoprazole 30 mg d and obtained complete heartburn relief in, respectively, 63 and 60% after 4 weeks in well over 5000 patients. Again healing data are somewhat higher compared to those for resolution of symptoms. The overall healing obtained with proton pump inhibitors obtained with omeprazole, lansoprazole and pantoprazole has been extensively discussed in the literature and was the subject of several meta-analyses. 22, 23 Dekkers et al. 24 compared rabeprazole 20 mg d with omeprazole 20 mg d for 8 weeks in 202 e-gerd patients and obtained equivalent healing rates. Also Delchier et al. l 25 compared rabeprazole 20 mg d or 10 mg b.d. with omeprazole 20 mg d in 310 e-gerd patients and obtained equivalent healing rates.

3 54 G. TYTGAT The healing rate in the Richter 19 and Kahrilas 20 studies with 40 mg esomeprezole compared to 20 mg omeprazole were, respectively, 82 and 69% and 76 and 65% after 4 weeks of therapy. When analysed according to the degree of initial LA severity, the superiority of esomeprazole became more obvious from LA grade A to D: the worse the damage of the squamous layer, the lesser the healing efficacy. The healing rates in the EAZEE study of Castell et al. 21 comparing esomeprazole 40 mg d vs. lansoprazole 30 mg d were, respectively, 93 vs. 87% at week 8. Again the differences in efficacy became more obvious as the severity of the reflux damage worsened. This superiority of esomeprazole over lansoprazole could not be confirmed in another American trial of Howden et al. 26 Here the healing rates were, respectively, 89 and 91% for esomeprazole 40 mg vs. lansoprazole 30 mg d at week 8. Whether this discrepancy relates to differences in the spectrum of severity of the patients involved in the studies or to major inequalities in the number of patients entered (over 5000 vs. 284) is not entirely clear. It is unfortunate that different severity grading schemes were used in both trials. In a large scale open ongoing study in Germany called the Pro-GERD study (Malfertheiner, personal communication)), involving over 5000 patients, it was found that the healing rates in patients with a segment of columnar metaplasia were substantially less compared to nonmetaplastic GERD. In all probability this reflects the more severe end of the spectrum of GERD with massive acid reflux also at night, during episodes of nocturnal acid breakthrough. 27 Presumably such patients would profit from b.d. proton pump inhibitor dosing to curtail this ongoing nocturnal acid exposure. Maintenance therapy in e-gerd Maintenance therapy of e-gerd is considered to be lifelong because the majority of the patients experience relapse within a year of treatment. Several studies have shown that proton pump inhibitors are highly effective in preventing relapse in patients with e-gerd 28, 29 as summarized in a forthcoming systemic review. 30 This was again confirmed in 31, 32 two mega-maintenance trials with esomeprazole. In the Vakil-study 32 88% of the patients remained relapse-free with esomeprazole 40 mg d at month 6 compared to 29% with placebo. The corresponding figures in the Johnson-study 33 were 94% vs. 29%. Lauritsen 34 compared esomeprazole 20 and lansoprazole 15 mg d as maintenance therapy in patients healed initially with esomeprazole 40 mg. At month 6, 83% remained relapse free in the esomeprazole arm compared to 74% in the lansoprazole arm. Again the difference between the two therapies became more obvious in patients with initial LA grade C, D. Baldi et al. 35 compared lansoprazole 15 mg d and 30 mg on alternate days over a 6-month period after initial healing with lansoprazole 30 mg d in 137 e-gerd patients. Relapse occurred in 12% and 19%, respectively. The daily administration seemed to have a better effect on symptomic recurrence. Lansoprazole 30 mg and omeprazole 20 mg were compared for Ôon-demandÕ treatment in 300 e-gerd patients during 6 months. 36 The patients were initially treated until symptom-free. The patients were instructed to take the medication only when reflux symptoms occurred. In order to document dosing patterns, the medication was dispensed in bottles supplied with a Medication Event Monitoring System, recording date and time the bottles were opened. There was no difference in the number of capsules consumed (0.73 lansoprazole vs omeprazole day). Both drugs were effective in controlling symptoms as fewer then 1 20 withdrew from the study due to symptoms. The patient s habit of regular intake of medication rather than the symptoms determined the frequency and interval of medication intake. The fact that Ôon-demandÕ therapy appears possible, also for patients with reflux oesophagitis would suggest that some of those patients could be weaned off all therapy in due course in parallel with improvement of the GERD provoking factors. 37 CONCLUSION Reflux is provoked by food intake. As a result, refluxinduced symptoms, most commonly heartburn, usually occur after food. These symptoms can occur many times a week, causing significant impairment of health-related quality of life. Of the 40 60% of reflux disease patients who have definite endoscopic oesophagitis, this is severe in 10 20% (grades C and D, Los Angeles Classification system). proton pump inhibitors have revolutionized the medical therapy of reflux disease because of their high success rate in this indication. All other available options for medical therapy are of substantially lower efficacy in both oesophagitis and endosocopy-negative reflux disease patients. Proton pump inhibitors are

4 REVIEW: MANAGEMENT OF MILD AND SEVERE GERD 55 believed to act primarily through elevation of the ph of gastric juice to a level that makes it much less injurious to the oesophagus, but reduction of gastric volume consequent on inhibition of acid secretion may also play a role in reducing the amount of reflux that occurs. In 40 60% of patients with troublesome heartburn, there is no endoscopic evidence of oesophagitis, defined as mucosal breaks. The severity and frequency of refluxinduced symptoms in these patients do not differ from those with oesophagitis. It is only recently that adequate clinical trials have been done in this very important reflux disease patient sub-group. Such trials have shown the same hierarchy of efficacy of therapies on heartburn as is seen in trials on patients with reflux oesophagitis. Heartburn is the hallmark symptom of reflux disease, and is by far the most common of the reflux-induced symptoms. It is the only suitable criterion for enrolment of endoscopy-negative reflux disease patients in clinical trials, as it is the only symptom that will select the great majority of patients with this problem. Given that heartburn is the major cause of disability in endoscopynegative reflux disease, it is also the most relevant outcome measure. Thresholds for frequency and severity of heartburn at entry have ensured that only patients with troublesome reflux disease are entered. Troublesome heartburn is objectively defined as heartburn that has been occurring for at least 6 months, which had been present on at least 4 of the 7 days prior to randomization. Treatment of reflux oesophagitis with proton pump inhibitors is not universally successful. Failure of proton pump inhibitor treatment is associated with either less elevation of intragastric ph or smaller reductions of oesophageal acid exposure. 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