a Private Practice, Lüneburg, Germany, b Department of Gastroenterology, Kaunas Received 30 September 2004 Accepted 21 April 2005

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1 Original article 935 Pantoprazole 20 mg on demand is effective in the long-term management of patients with mild gastro-oesophageal reflux disease Suleiman Kaspari a, Limas Kupcinskas b, Hartmut Heinze c and Peter Berghöfer c A total of 536 patients with endoscopically confirmed GORD grade 0/I were included in this multicentre study. In the acute phase, patients were treated with pantoprazole 20 mg o.d. for 4 weeks to obtain symptom relief. Symptomfree patients were included in the subsequent long-term phase, and were randomly treated on demand with either pantoprazole 20 mg or placebo for 6 months (antacids as rescue medication). After the 4 weeks acute phase, 439 symptom-free patients entered the long-term phase. The perceived average daily symptom load remained significantly lower during the 6-month on-demand treatment with pantoprazole 20 mg as compared to placebo. Both the rates for unwillingness to continue and number of additional antacids taken were also significantly lower with pantoprazole 20 mg than with placebo. Hence, on-demand treatment with pantoprazole 20 mg is safe and effective in maintaining control of the symptoms heartburn, acid regurgitation and pain on swallowing symptoms in patients with GORD grade 0/I with superiority to placebo. Eur J Gastroenterol Hepatol 17: c 2005 Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2005, 17: Keywords: drug administration schedule, follow-up studies, gastrooesophageal reflux/drug therapy, heartburn, long-term care, treatment outcome a Private Practice, Lüneburg, Germany, b Department of Gastroenterology, Kaunas Medical University, Lithuania and c Department of Gastroenterology, ALTANA Pharma AG, Konstanz, Germany. Sponsorship: This work was supported by ALTANA Pharma AG, Konstanz, Germany. Correspondence to Dr Peter Berghöfer, Department of Gastroenterology, ALTANA Pharma AG, Byk-Gulden-Strasse 2, Konstanz, Germany. Tel: + 49 (0) ; fax: + 49 (0) ; peter.berghoefer@altanapharma.com Received 30 September 2004 Accepted 21 April 2005 Introduction The majority of patients ( > 70%) with gastro-oesophageal reflux disease (GORD) experience symptomatic relapse within 6 months after cessation of short-term acid-suppressive therapy, regardless of the baseline endoscopic status [1]. It is hence a chronic disease requiring subsequent long-term management [2]. By now, maintenance therapy with proton pump inhibitors (PPIs) has been widely recommended in erosive GORD [3], offering the possibility of maintaining mucosal healing and symptom relief with adjusted minimal drug doses. Several long-term studies with pantoprazole up to 3 years demonstrated maintained healing of erosive oesophagitis and sustained symptom relief [4 9]. However, little is known about the long-term treatment, prognosis and natural history of non-erosive or mild erosive GORD, although 50 75% of patients presenting to physicians belong to this common population. Today, only a few studies have been published that have investigated maintenance treatment of symptoms in non-erosive or mild erosive GORD using PPI as maintenance therapy [10]. This is due to the increasing support for alternative treatment strategies that are triggered by a symptom relapse event, such as intermittent therapy (i.e., blocks of treatment of fixed X c 2005 Lippincott Williams & Wilkins duration, typically 2 4 weeks) or on-demand therapy (i.e., one dose on recurring symptoms, continued until symptom relief) with acid suppressant drugs. Several publications have reported on on-demand therapy with omeprazole [11,12], esomeprazole [13 16], and, recently, lansoprazole [17 19] and rabeprazole [20,21]. The results from these studies suggest on-demand therapy to be an effective, well-tolerated and most cost-effective medical regimen for endoscopy-negative and mild GORD. The data for on-demand use of pantoprazole are still limited. A small pilot study from Germany found ondemand therapy with pantoprazole 20 mg effective in patients with non-erosive or mild erosive GORD [22]. Hence, the aim of the study was to determine the efficacy and safety of on-demand treatment with pantoprazole 20 mg compared to placebo in maintaining control of the symptoms heartburn, acid regurgitation and pain on swallowing over a 6-month period, after preceding symptom relief, in patients with non-erosive GORD and reflux oesophagitis grade I in a larger clinical setting. It was our intention to evaluate the efficacy by means of a new approach. Thus, we used the perceived average daily symptom load as primary efficacy variable, based on data from patients diaries. We suppose that this variable is an alternative pragmatic outcome to the time to study

2 936 European Journal of Gastroenterology & Hepatology 2005, Vol 17 No 9 discontinuation or unwillingness to continue recommended by others [23], better reflecting the clinically relevant question of symptom control over a long-term treatment in GORD patients. Methods Design, conduct and ethical considerations This multicentre, bi-national study was performed in two phases involving 40 centres in Germany and five in Lithuania. The first acute phase was conducted as an open symptom-relief study. Patients (aged years) who had endoscopically confirmed non-erosive GORD or reflux oesophagitis grade I according to Savary Miller classification (modified by Siewert) and who suffered from frequent episodes of at least one of three typical GORD symptoms (heartburn, acid regurgitation, pain on swallowing) during the last 3 months were eligible for inclusion [24,25]. At least one of the three symptoms had to be of at least moderate intensity during the last 3 days before start as assessed by the investigator. In this acute phase 20 mg pantoprazole o.d. was administered for 4 weeks. For the evaluation of symptoms a patient diary was handed over in which patients had to record the typical symptoms and their intake of study medication on a daily basis. Further, the investigator questioned the patient as to the typical and additional symptoms (epigastric pain, abdominal pain, retrosternal feeling of tightness) at each visit. Those patients who were free from GORD-associated symptoms (heartburn, acid regurgitation, pain on swallowing) during the last 3 days before end of treatment, and who suffered from additional symptoms of, at most, mild intensity after this time, were included in the subsequent long-term phase. This phase was performed as a randomized, double-blind, placebo-controlled parallel-group comparison with on-demand treatment for 6 months in which patients received pantoprazole 20 mg or placebo. Patients were also provided with antacid tablets containing 800 mg magaldrate per tablet as rescue medication in case of insufficient symptom control. Patients were instructed to take one tablet of pantoprazole/placebo per day if any GORD symptoms occur. Only in the case that symptoms had not sufficiently improved within 2 h after intake, patients were allowed to take antacids. The consumption of antacids had to be documented by the patients in the diary as well. A total of four visits were scheduled during the whole study, i.e., the initial visit at study start where the endoscopy was performed, followed by three follow-up visits 4, 16 and 28 weeks after study start. For both phases, the following exclusion criteria applied: any other gastrointestinal diseases such as endoscopically confirmed GORD stages II to IV (according to Savary Miller classification), acute peptic ulcer and/or ulcer complications, known history of Zollinger Ellison syndrome, pyloric stenosis, ulcer complications, gastric surgery (except appendectomy, cholecystectomy and polypectomy), and severe diseases of other body systems. During the whole study no Helicobacter pylori eradication therapy, no systemic glucocorticosteroids or non-steroidal antiinflammatory drugs, including COX-2 inhibitors, and no supportive medication for the treatment of gastrointestinal complaints was allowed, except magaldrate during the long-term phase. Intake of acetylsalicylic acid up to a daily dose of 150 mg was allowed. The study was conducted according to Good Clinical Practice (GCP) and the Declaration of Helsinki. Independent local ethics committees in the respective countries approved the protocol. All patients gave their written informed consent prior to their participation. Symptom assessment by patient diary (long-term phase) The presence and intensity of the three typical GORDassociated symptoms heartburn, acid regurgitation and pain on swallowing was assessed on a daily basis by the patient and documented as either none, mild, moderate or severe and scored as 0 3 accordingly. Additionally, the intake of the on-demand study medication by crossing yes/no had to be documented in this diary and antacid consumption by filling in the number of tablets taken. A sum score was calculated based on the intensity of each symptom. Since patients were allowed to take antacids during the long-term phase, which have a suppressing effect on symptoms, the amount of antacids taken was to be considered in the score. For this calculation, the number of tablets taken was transferred to the same symptom scale from 0 to 3 (0 = tablets, 1 = one tablet, 2 = two tablets, 3 = three or more than three tablets per day). Further, since the score only reflects the symptom load on a single point in time, the overall sum score of symptoms over the individual study time (area under curve) was calculated and normalized to the duration of individual study time, yielding the patient s average symptom load per day. Finally, the primary variable of the study was calculated as a product of a patient s average symptom load and the relative frequency of days with intake of study medication. The resulting primary efficacy variable complies with the perceived average daily symptom load, ranging from 0 (i.e., no symptom load) to 24 (i.e., every day severe symptoms, despite intake of study medication and more than three tablets of antacids). Safety At every follow-up visit or whenever the patient returned unscheduled, patients were asked about adverse events and their corresponding intensity. Causal relationship to

3 Pantoprazole on demand for long-term management of GORD Kaspari et al. 937 the intake of the study medication was assessed by the investigator as not related, unlikely to be related, likely to be related, or definitely related. Statistical analysis The aim of this study was to determine the effect of ondemand therapy on the symptom load within a long-term observation period. Hence, the primary variable of this study perceived average daily symptom load was related to the second and long-term phase of this study. This score was compared one-sided between the two treatment groups using the Wilcoxon rank sum test on a level of a = Consistent with this test, the point estimate of the difference between treatments was determined according to Hodges Lehman and the onesided 95% confidence interval (CI) according to Moses. Statistical significance was concluded if the 95% CI excluded a value of 0. Secondary criteria were symptom relief rates and its 95% binomial confidence limits after 4 weeks of treatment with pantoprazole 20 mg (acute phase). Relief was defined as freedom from GORD-associated symptoms (heartburn, acid regurgitation, pain on swallowing) for the last 3 days before assessment. Further, secondary criteria were number of study medication taken, number of magaldrate tablets, and on-demand tablet intake behaviour. Additionally, the number of patients unwilling to continue the therapy and the corresponding reasons for it was analysed using the Kaplan Meier analysis. A statistically significant difference was concluded if the value 0 was not within the 90% CI of the estimated difference between the groups after 6 months. Analogously to the primary variable, secondary variables were analysed descriptively and compared one-sided by Wilcoxon rank sum test. Dichotomous parameters were compared by Fisher s exact two-tailed test and ordinal variables by the Wilcoxon rank sum test. Populations The intention-to-treat (ITT) and the per-protocol populations were defined separately for the acute and the long-term phase. For the acute phase, the ITT population comprised all patients for whom it could not be excluded that they took the study medication at least once. For the long-term phase, the ITT population was defined as those patients who entered the long-term phase after the acute phase and were free from typical GORD symptoms. The per-protocol analysis excluded protocol violators. Results Study populations A total of 536 patients were enrolled for this study (Fig. 1). In the acute phase, the main reasons for protocol violation were poor compliance, intake of concomitant medication that was not permitted, or too late or too early appearance for the first follow-up visit. Those patients classified as drop-outs withdrew prematurely because of an adverse event (n = 7) and/or due to lack of efficacy (n =2). In the subsequent long-term phase enrolling 439 patients (ITT), the main reasons for protocol violations were patients lost to follow-up, intake of concomitant medication that was not permitted, or missing entries on more than 4 consecutive days in the diary. The patients classified as drop-outs withdrew prematurely due to lack of efficacy (pantoprazole 20 mg: n =7, placebo: n = 25) and because of an adverse event (n = 1 in the pantoprazole 20 mg group). Baseline characteristics of patients Baseline characteristics of patients included in the ITT population of the long-term phase are shown in Table 1. Between the two treatment groups no substantial differences were found. Results were similar for perprotocol analysis (not shown). Efficacy Acute phase (4 weeks) After 4 weeks of treatment with pantoprazole 20 mg o.d. symptom relief rates were 83.2% and 86.0% in the ITT and per-protocol population, respectively, i.e., patients were free from heartburn, acid regurgitation and pain on swallowing during the last 3 days prior to the end of the acute phase, including additional symptoms of, at most, mild intensity. When considering freedom from heartburn, acid regurgitation and pain on swallowing only, relief rates increased to 83.6% (ITT) and 86.4% (perprotocol). Accordingly, the mean sum score of all six symptoms (heartburn, acid regurgitation, pain on swallowing, epigastric pain, abdominal pain and retrosternal feeling of fullness) decreased from 7.7 at baseline to 0.8 after 4 weeks. Long-term phase (6 months) Perceived average daily symptom load The effect of the ondemand therapy as assessed by the perceived average daily symptom load of heartburn, acid regurgitation and pain on swallowing is summarized in Figure 2. A comparison of the mean values of the primary variable yielded a statistically significant difference between the pantoprazole 20 mg and the placebo on-demand group, with P = for the ITT and P = for the perprotocol population. Thus, on-demand therapy with pantoprazole 20 mg reveals a significantly lower GORD symptom load compared to placebo over a 6 months ondemand treatment period. Tablet intake The number of tablets taken during the long-term phase was additionally analysed. Descriptive statistics were calculated for the absolute numbers of taken tablets over the whole observation period as well as for the relative numbers of tablets taken per day with

4 938 European Journal of Gastroenterology & Hepatology 2005, Vol 17 No 9 Fig. 1 Acute phase Screened patients n = 536 Long-term phase Intention-to-treat (acute phase) n = 536 Not healed according to leading symptoms n = 97 Randomization Intention-to-treat (long-term phase) n = 439 n Panto = 213 n Placebo = 226 Protocol violators n = 50 Per-protocol (acute phase) n = 486 (8 drop-outs) Per-protocol (long-term phase) n = 357 n Panto = 175 (8 drop-outs) n Placebo = 182 (25 drop-outs) Protocol violators n = 82 n Panto = 38 n Placebo = 44 Disposition of patients. Table 1 Baseline characteristics of patients (intention-to-treat) in the long-term phase (n = 439) Characteristic Treatment group Pantoprazole n = 213 Placebo n = 226 Demography Mean age ± SD 50.7 ± 13.7 years 51.0 ± 14.5 years Men/women (n) 98/115 98/128 Mean weight ± SD 75.3 ± 13.8 kg 78.2 ± 13.1 kg Mean height ± SD ± 9.0 cm ± 9.5 cm Mean body mass index ± sd 26.2 ± 3.8 kg/m ± 4.1 kg/m 2 Medical history GORD grade 0 (n) 49 (23.0%) 56 (24.8%) GORD grade I (n) 164 (77.0%) 170 (75.2%) regard of the individual duration of the long-term phase (Table 2). No statistically significant differences between the treatment groups with respect to study medication intake, both absolute and relative, could be observed. On the contrary, the antacid consumption in the placebo group was significantly higher than in the pantoprazole 20 mg group, both for absolute and relative intake data (Table 2). Results were similar for per-protocol analysis (not shown). Time of treatment Furthermore, the time of treatment and the duration of episodes (i.e., periods with successive o.d. tablet intake) were analysed (Table 2). The absolute number of episodes with medication intake was significantly higher in the verum than in the placebo group, while the duration of treatment intervals was significantly lower in the placebo group. The overall duration of treatment was significantly longer in the pantoprazole 20 mg than in the placebo group as assessed by diary. Results were similar for per-protocol analysis (not shown). Unwillingness to continue The reasons for unwillingness to continue were analysed and compared between the two treatment groups (Table 2). The rate of premature discontinuation due to insufficient symptom control (heartburn, acid regurgitation and pain on swallowing), unsatisfactory treatment or any reason was significantly lower in the pantoprazole 20 mg than in the placebo group. Results were similar for per-protocol analysis (not shown). Adverse events During the acute phase a total of 95 adverse events were reported in 71 patients (13%), most of which were either unrelated (62%) or unlikely related to study medication as assessed by the investigators. The continuous treatment with pantoprazole 20 mg was well tolerated.

5 Pantoprazole on demand for long-term management of GORD Kaspari et al. 939 During the long-term phase adverse events were experienced by 76 patients (36%) of the pantoprazole 20 mg group and 69 patients (31%) of the placebo-group. The majority of the events were classified as unrelated to the study medication (92% in the pantoprazole, 93% in the placebo group). There was no apparent relevant difference in the safety profile between verum and placebo during the long-term phase. For the entire study period a total of 21 serious adverse event symptoms were Fig. 2 Perceived average daily symptom load Pantoprazole 20 mg Placebo P < ITT < 0.05 Perceived average daily symptom load (ITT, n = 439; per-protocol, n = 357). The 95% confidence intervals and point estimates are shown in the table below. Population Point estimate 95% Confidence interval Intention to treat 0.16 [ 0.34; 0.01] * Per-protocol 0.26 [ 0.47; 0.08] * * Statistically significant if the 95% confidence interval excluded a value of 0. PP 2.3 observed in 17 out of 536 patients (3%). All serious adverse events were considered to be unrelated to the study medication. Discussion This study was designed to compare the efficacy and safety of on-demand therapy with pantoprazole 20 mg versus placebo after preceding relief from the symptoms heartburn, acid regurgitation and pain on swallowing. We used, as a new approach, the perceived average daily symptom load as primary efficacy variable, using the three above-mentioned symptoms which were self-assessed by the patient in a diary. This variable comprises several components, i.e., the assessed symptom score of GORD symptoms, the individual intake of study medication, and the individual study duration of each patient. Notably, the determination of symptom scores that are only related to relief of specific symptoms might be misleading in the case that patients could reduce symptoms by taking various amounts of any rescue medication. Hence, the intake of antacids can be regarded as a measure for suppressed (otherwise present) symptoms. And consequently, the number of antacids taken or suppressed symptoms was considered as a fourth dimension in addition to the three experienced symptoms heartburn, acid regurgitation and pain on swallowing. Thus, the perceived average daily symptom load is an overall sum score, reflecting the experienced and the suppressed symptoms, considering the individual study time as well as the individual intake of study medication. This scientific approach has not been examined in the literature so far. It is a pragmatic and well suited alternative to the time to study discontinuation or unwillingness to continue which has been previously recommended [23], since it directly and continuously Table 2 Summary of secondary efficacy parameters (ITT population, long-term phase) Parameter Pantoprazole, 20 mg, mean (n) Placebo, mean (n) Statistical analysis: P value Tablet intake Study medication Total number 51.9 (201) 49.2 (212) > 0.05 Average number/day 0.34 (201) 0.35 (212) > 0.05 Antacid Total number 48.3 (189) 66.6 (209) * Average number/day 0.34 (189) 0.53 (209) * Time of treatment Number of episodes 16.4 (201) 12.6 (214) * Mean duration of episodes (days) 9.8 (201) 11.3 (214) * Time of treatment (days) (201) (214) * Estimated discontinuation rate (%) Estimated discontinuation rate (%) Difference (%) [90% CI] Unwillingness to continue Insufficient control of symptoms ** [ 11.1; 3.3] *** Unsatisfactory treatment [ 12.0; 3.9] *** Any reason [ 13.8; 4.5] *** * Statistically significant. ** Heartburn, acid regurgitation, pain on swallowing. *** Statistically significant (concluded if the value 0 was not within the 90% CI of the estimated difference).

6 940 European Journal of Gastroenterology & Hepatology 2005, Vol 17 No 9 reflects the clinically relevant question of symptom control. Moreover, unwillingness to continue measures only one point in time in a subgroup of patients (those who discontinued), and refusal to discontinue is not necessarily connected with the most effective treatment. In the present study, the clinical and statistical superiority to placebo was demonstrated by a significantly lower perceived average daily symptom load with pantoprazole 20 mg compared to placebo. The absolute values of the perceived average daily symptom load, surprisingly, range on a low level in both groups. This can be explained by the strict inclusion conditions for entering the long-term phase, since all patients had to be free from heartburn, acid regurgitation and pain on swallowing and not only from heartburn which is mostly the condition in other on-demand studies [11,13,14]. The main outcome of this study was further supported by the evaluation of antacid intake which was significantly higher in the placebo (0.53 tablets/day) than in the pantoprazole 20 mg (0.34 tablets/day) group. This is in accordance with studies reported by Lind and co-workers [11] and Talley and colleagues [13,14] who have found comparable results, even though the antacid consumption was in general higher than in the present study. However, the different efficacy of treatments did not influence the average intake of study medication (pantoprazole 0.34, placebo 0.35 tablets per day). Again, these findings are in accordance with the results of other studies showing a similar average drug intake of approx. 0.3 with esomeprazole, 0.4 with omeprazole, and 0.4 with lansoprazole each similarly high to the amount of placebo taken [11,13,14,18]. The mean time of treatment, i.e., the time until last intake of medication, was longer in the pantoprazole 20 mg (140.8 days) than in the placebo group (124.6 days). Further, the number of episodes was higher in the pantoprazole 20 mg (16.4) than in the placebo group (12.6). This seems to be a discrepancy to the other findings of the trial, but it shows that patients discontinued the study earlier if they felt unsatisfactorily treated or experienced symptoms, which was particularly the case in the placebo group. Overall, 18.6% of patients discontinued the on-demand treatment in the placebo compared to 9.9% of the pantoprazole 20 mg. Only 2.9% of patients in the pantoprazole 20 mg group (vs. 10.1% in the placebo group) were unwilling to continue the study due to inadequate control of symptoms, i.e., the great majority of patients ( > 90%) were willing to continue the pantoprazole treatment. The rate for unwillingness to continue due to unsatisfactory treatment as well as due to any reason was also significantly lower in the pantoprazole group compared to placebo. Other studies found similar results with continuation rates of 70 83% with omeprazole 10 mg and 20 mg [11]. With esomeprazole 20 mg 86 93% of patients, with esomeprazole 40 mg 89% of patients, with lansoprazole 15 mg 81 85% of patients, and with rabeprazole 10 mg > 94% were willing to continue on-demand therapy for 6 months [13,14,16,18 21]. In the placebo groups these rates were significantly lower (with reported rates of < 58% in all studies). The high proportion of patients who were willing to continue the placebo treatment found in this study may be explained by the high rescue medication intake that was allowed to be taken (up to 800 mg magaldrate per tablet) as well as by the use of patient diaries which was previously shown to significantly enhance the patient compliance in clinical trials [26]. Conclusion The symptom-driven on-demand treatment with pantoprazole 20 mg is a well tolerated and effective strategy for long-term treatment of recurrent symptoms in patients suffering from non-erosive GORD or reflux oesophagitis grade I. It offers a management approach with the potential of being more cost-effective compared to continuous maintenance treatment. Acknowledgements We thank IFE Institute for Research and Development, Witten, Germany, for monitoring at the study sites, data collection, source data verification and statistical analysis. Conflict of interest None declared. Authors contributions SK and LK were clinical investigators in this study. They further provided substantial contribution to acquisition and interpretation of data. HH and PB provided substantial contribution to concept and design of the study and analysis of the data. 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