Introduction

Top Abstract Introduction Patients and methods Results Discussion References

Maintenance treatment with proton pump inhibitors is the most widely recommended form of treatment for the long term management of gastro-oesophageal reflux disease. Yet in day to day clinical practice treatment is commonly given in short courses, as and when symptoms demandthat is, intermittent treatmentparticularly for patients perceived to have mild or only moderately troublesome disease. Even when maintenance treatment is prescribed patients often take their drugs intermittently.¹

In contrast with maintenance treatment, which has been extensively investigated in clinical trials,^2-14 the strategy of intermittent treatment has not been formally assessed. We therefore assessed intermittent treatment as a strategy to manage patients with symptomatic gastro-oesophageal reflux disease over a 12 month period.

We also assessed control of symptoms after the first 2 weeks of treatment and studied the natural course of uncomplicated gastro-oesophageal reflux disease over the 12 month period.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

Design of trial
Our aim was to reflect common clinical practice. We therefore used both histamine H₂ receptor antagonists and proton pump inhibitors. Their doses were increased if symptoms were not controlled at the lower one. Patients received maintenance treatment if intermittent treatment at the higher doses failed.

Patients
Patients were recruited into the study either after hospital consultation or directly by their general practitioners. Patients with moderate (discomfort sufficient to cause interference with usual activities) or severe (leading to inability to perform normal activities) heartburn for more than 2 days in each of the previous 2 weeks and with normal endoscopy results or with mucosal breaks in the oesophagus (Los Angeles classification, grades A to C¹⁵) were included in the study (see table 1). Heartburn was defined as epigastric or substernal burning with ororadiation related to meals, straining, or posture. Those with the most severe erosive changes (grade D) were excluded. All antisecretory treatment not to be used in the study was stopped 2 weeks before entry to the study. Helicobacter pylori infection was detected with the rapid urease test.

Initial treatment
The patients were allocated to treatment according to a computer generated randomisation list. At each centre patients were allocated to the next available treatment number and received 2 weeks of double blind, double dummy treatment with ranitidine 150 mg twice daily, omeprazole 10 mg daily, or omeprazole 20 mg daily. After 2 weeks patients who had had no symptoms over the previous 7 days entered a follow up period (see below) for up to 12 months from randomisation. Those with symptoms had the omeprazole 10 mg or ranitidine dose doubled for a further 2 weeks, whereas those on omeprazole 20 mg continued on this dose. After 4 weeks patients who had no or only mild symptoms also entered the follow up period. A compound antacid preparation (Maalox) was provided for the control of reflux symptoms during the study.

Follow up period: intermittent treatment strategy
Patients received no further treatment until moderate or severe symptoms of heartburn recurred for at least 2 days in each of the previous 2 weeks or if more than three antacid tablets were needed per day to control symptoms, whereupon patients returned to the clinic for assessment of symptoms. Confirmation that the patient was experiencing moderate or severe symptoms triggered repeat treatment for 2 or 4 weeks with the dose initially found to control symptoms, and the cycle was repeated for subsequent relapses. Patients were reviewed routinely at 3, 6, 9, and 12 months or whenever the need for repeat treatment arose.

Open maintenance treatment
When intermittent treatment failed maintenance treatment with omeprazole 20 mg daily was given until 12 months after randomisation.

Statistical analysis
There were two approaches to the analyses: firstly, an intention to treat approach, which included those patients correctly randomised and treated and for whom there were follow up data on efficacy (n=677) and, secondly, an analysis of those 526 patients for whom final outcome was knownthat is, they reached an end point while still on intermittent treatment. Formal statistical comparison between the groups was possible only when the patients were still being treated as randomisedthat is, for the proportion of patients without symptoms after the initial 2 week treatment period and the proportions of patients reaching an end point on intermittent treatment who had no adjustment of dose during the initial treatment period. Elsewhere descriptive statistics have been used.

View larger version (42K): [in this window] [in a new window]   Fig 1.   Calculation of total time off treatment

Other details
The presentation of results meets the criteria of the CONSORT statement.¹⁶ This study was approved by the ethics committees of the participating centres and each patient gave written informed consent.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

The study involved 56 centres in the United Kingdom, Republic of Ireland, Germany, France, Spain, and Italy. The first patient entered the study in March 1994, and recruitment lasted for 1 year. Patients were followed up for 1 year, and the last patient completed the study in March 1996. A total of 704 patients were enrolled; about 10% were taking H₂ receptor antagonists or proton pump inhibitors before entry to the study. Twenty seven patients were excluded (six did not return for reassessment; 21 did not fulfil the inclusion criteria). The 677 remaining patients had data valid for the intention to treat analysis. Over half (54%) of the patients had been recruited after hospital consultation and the remainder directly by their general practitioners. The patients in the three treatment groups were well matched for all baseline characteristics (table 1).

Broad outcome of intermittent treatment
Three hundred and eighteen (47%) patients completed this study while they were still receiving intermittent treatment. One hundred and sixty one (24%) continued in the study on maintenance treatment, and 197 (29%) discontinued the study at some stage mainly because of unwillingness to continue (21), adverse events (51), and loss to follow up (58). Other patients discontinued for various reasons that were unrelated to treatment or symptoms of heartburn. No patient completed the study prematurely because of exhaustion of their drug supply. There were no differences with respect to these outcomes between the three initially randomised groups.

Intermittent treatment: outcome measures
Total time off treatment The median number of days off treatment for all 677 patients was 142 days and for the 526 patients who reached a treatment related end point was 281 days. Thus half the patients did not require treatment for at least 6 months in total over the 1 year period. Eighty six patients failed to respond to initial treatment and another 55 were lost to follow up in this phase, representing all patients who had no days off treatment. Five more patients relapsed within 7 days after completing initial treatment but did not respond to 4 weeks' further treatment; these are included in the 0 days off treatment column in figure 2. In contrast most patients had no relapse (217; 32%) or only one (163; 24%) or two (81; 12%) relapses. These patients generally had more than 280 days off treatment (fig 2). A similar pattern was seen for the 526 patients who reached a treatment related end point.

View larger version (19K): [in this window] [in a new window]   Fig 2.   Distribution of total number of days off treatment for 677 patients (all patients treated analysis)

View larger version (16K): [in this window] [in a new window]   Fig 3.   Time to failure of intermittent treatment in 677 patients (all patients treated analysis)

Treatment comparison
Omeprazole was significantly superior to ranitidine in outcome at week 2; the proportions without symptoms were 55% on omeprazole 20 mg, 40% on omeprazole 10 mg, and 26% on ranitidine (P<0.001; ² test). The outcome was similar in patients with and without oesophageal mucosal breaks at baseline.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Intermittent treatment: its rationale and outcome
The naturally relapsing nature of symptoms of gastro-oesophageal reflux is not altered by current management regimens. Patients with severe erosive or frequently relapsing disease require long term daily treatment.¹⁷ Most patients, however, have less severe disease and so may not require maintenance treatment. All of the patients in our study had a history of symptoms of reflux and, at entry, one third had a normal mucosa and 60% had mild erosive disease (grades A or B). Thus, they seemed suitable candidates for intermittent treatment. In fact, our study showed that intermittent treatment was effective for about half of such patients and drug treatment was unnecessary for much of the year. Relapses were, in general, infrequent and control of symptoms was achieved rapidly with a short course of repeat treatment. Omeprazole 20 mg was the most effective treatment for initial control of symptoms and might be expected to control symptoms in subsequent relapses.

Factors which influence outcome
In the attempt to target intermittent treatment, knowledge of factors which may indicate a good outcome is important. Others have shown that in patients who receive placebo after healing and control of symptoms only higher grades of oesophagitis and regurgitation before treatment clearly increase the risk of relapse. Older patients and smokers have a slightly increased risk of relapse.¹⁸

Differences in outcome between the treatment groups
Over 1 year we could find no difference between the groups, as randomised, in terms of overall outcome of intermittent treatmentfor example, in time to treatment failure or number of relapses. This is to be expected for two reasons. Firstly, an effective dose was determined for each patient by titration. As this dose was then used in all subsequent relapses a broadly similar response was to be expected across the treatment groups. Secondly, treatment with antisecretory drugs will only temporarily interrupt the natural history of gastro-oesophageal reflux disease.²⁰

Patients who do not respond to intermittent treatment
Two groups of patients who did not respond to intermittent treatment require special mention: those with initial treatment failure and those who failed subsequently. Despite initial dose titration, 13% (86/677) of patients remained symptomatic. As mentioned earlier, it was assumed that patients would respond in a similar manner to repeat treatment with the optimal dose, but 23% (121/526) ultimately failed to do so, suggesting that with time symptoms become less responsive in a proportion of patients. This has not been shown before to our knowledge, perhaps because the design of earlier studies precluded sequential observations on repeated relapses. It may also reflect the changing natural history of the disease in this subgroup of patients.

Cost effectiveness
A comment on cost effectiveness of treatment is appropriate. A recent report compared the costs of intermittent versus maintenance treatments. When the outcome was acceptable to the patient intermittent treatment was likely to be more cost effective than maintenance treatment.²² Our study included a parallel cost effectiveness analysis within intermittent treatment. The preliminary results indicate that starting intermittent treatment with omeprazole 20 mg is more cost effective than a dose titration approach with either omeprazole 10 mg or ranitidine 150 mg twice daily.²³

Practical application
Our findings encourage us to recommend intermittent treatment for the long term management of patients with heartburn and with normal results on endoscopy or with mild erosive disease. Starting treatment with omeprazole 20 mg minimises the need for subsequent adjustments of dose. The strategy of intermittent treatment is suitable for about half the patients. Those who respond quickly to initial treatment are more likely to have a better outcome. Conversely, those who take longer to respond to treatment or who relapse quickly when treatment stops are likely to require maintenance treatment. Such a strategy allows better targeting of intermittent and maintenance treatments and is applicable to general practice, where most patients are seen.

	Acknowledgments

The members of the European Study Group were as follows. France: Dr Abensur, Pont a Mousson; Dr Begue, Hayange; Professor Bigard, Dr Hudziak, Dr P Dieterling, Dr Pitoy, Dr Simon, Dr Protte, Nancy; Dr Courrier, Metz; Dr G Dalstein, Thionville; Dr R Fiorucci, Longwy; Dr Geoffroy, Epernay; Dr Goldfain, Dreux; Dr J Granguillaume, Belfort; Dr Jouin, Saint Avold; Dr J I Kolopp, Metz; Dr Laugros, Dr Seng, Freyming Merlebach; Dr Lirzin, Dr Salas, Troyes; Dr Pasqual, Dr Dahlab, Troyes; Dr Rotenberg, Dreux; Dr D Schmitz, Forbach; Dr Zahm, Hagondange; Professor Zeitoun, Reims. Germany: Dr G Buttner, Dr Ch von Wolff, Dr W Dubel, Dr E Gozdowsky, Dr H Hartmann, Dr U Kernchen, Dr J Machens, Dr B Marowski, Dr V Olivier, Dr H U Rehs, Dr A Ryschka, Dr K Scholze, Dr P Semier, Dr Med K Uhlig, Dr R Wach, Berlin. Republic of Ireland: Dr J P Crowe, Dr P W N Keeling, Professor D G Weir, Dublin. Italy: Dr A Andriulli, Rotondo (FG); Professor P Bianchi, Professor G Bianchi Porro, Milan; Dr E Colombo, Garbagnate (M1); Professor M Curzio, Varese; Professor G Mazzacca, Napoli; Dr G Minoli, Como. Spain: Dr D Abascal, Sevilla; Dr L Martin, Cadiz; Dr G Mino, Cordoba; Dr Julio Ponce, Valencia; Dr L Rodrigo, Oviedo; Professor Dr Diaz Rubio, Madrid. United Kingdom: Dr K D Bardhan, Rotherham; Dr R Cockel, Birmingham; Dr A Cowie, Bath; Dr T K Daneshmend, Exeter; Dr N Gough, Bradford-on-Avon; Dr K Gruffydd-Jones, Wiltshire; Dr J Hampton, Dr J Playfair, Bath; Dr J Hosie, Dr M G B Scott, Glasgow; Dr A P S Hungin, Stockton on Tees; Dr S Rowlands, Trowbridge; Dr S Wilkinson, Plymouth.

Contributors: KDB developed the concept of intermittent treatment (based on an earlier similar approach for the treatment of duodenal ulcer). SM-L, MAB, GBP, KRWG, RAP, and KDB designed the study through its various stages to the final protocol. In this they were helped by their team members and colleagues at Astra. JP, JH, MS, and DW also conducted the study with the help of colleagues in various centres. CF (and colleagues) and KRWG conducted the study, a major undertaking, and CF arranged the various investigators' meetings, large and small, when many different aspects of the study were discussed by several of the above contributors and other colleagues. RAP carried out the statistical analysis and produced the report. The paper went through several drafts and was written by KDB, SM-L, MAB, GBP, KRWG, RAP. KDB stands as guarantor.

Funding: Astra Clinical Research Unit, Edinburgh.

Competing interests: MAB has acted as consultant to Astra (manufacturers of Losec (omeprazole)) and Glaxo-Wellcome Laboratories (manufacturers of Zantac (ranitidine)). RAP is employed by Astra as a biostatistician and holds shares in the company.

	References

Top Abstract Introduction Patients and methods Results Discussion References

1. Hungin APS, Rubin GP, O'Flanagan H. How regularly do patients on long term PPIs take their therapy? Gastroenterology 1997; 112: A19.
2. Staerk Laursen L, Havelund T, Bondesen S, Hansen J, Sanchez G, Sebelin E, et al. Omeprazole in the long term treatment of gastro-oesophageal reflux disease. A double-blind randomised dose finding study. Scand J Gastroenterol 1995; 30: 839-846[Medline].
3. Zeitoun P, Isal JP, Barbier P. Comparison of two dosage regimens of omeprazole10mg once daily and 20mg weekendsas prophylaxis against recurrence of reflux oesophagitis. Hepatogastroenterol 1989; 36: 279-280.
4. Dent J, Yeomans ND, Mackinnon M, Reed W, Narielvala FM, Hetzel DJ, et al. Omeprazole v ranitidine for prevention of relapse in reflux oesophagitis. A controlled double-blind trial of their efficacy and safety. Gut 1995; 35: 590-598[Abstract/Free Full Text].
5. Vigneri S, Termini R, Leandro G, Badalamenti S, Panatalena M, Savarino V, et al. A comparison of five maintenance therapies for reflux oesophagitis. N Engl J Med 1995; 333: 1106-1110[Abstract/Free Full Text].
6. Bate CM, Booth SM, Crowe JP, Mountford RA, Keeling PWN, Hepworth-Jones B. Omeprazole 10mg or 20mg once daily in the prevention of recurrence of reflux oesophagitis. Gut 1995; 36: 492-498[Abstract/Free Full Text].
7. Hallerbäck B, Unge P, Carling L, Edwin B, Glise H, Havu N, et al. Omeprazole or ranitidine in longterm treatment of reflux oesophagitis. Gastroenterology 1994; 107: 1305-1311[Medline].
8. Bardhan KD, Cherian P, Vaishnavi A, Jones RB, Thompson M, Morris P, et al. Erosive oesophagitis: outcome of repeated long term treatment with low dose omeprazole 10mg or placebo. Gut 1998; 43: 458-464[Abstract/Free Full Text].
9. Robinson MJ, Lanza F, Avner F, Haber M. Effective maintenance treatment of reflux oesophagitis with low dose lansoprazole. Ann Intern Med 1996; 124: 859-867[Abstract/Free Full Text].
10. Gough AL, Long RG, Cooper BT, Fosters CF, Garrett AD, Langworthy CH. Lansoprazole vs ranitidine in the maintenance treatment of reflux oesophagitis. Aliment Pharmacol Ther 1996; 10: 529-539[Medline].
11. Hatlebakk JG, Berstad A. Lansoprazole 15 and 30mg daily in longterm treatment of erosive reflux oesophagitis. Gastroenterology 1995; 108: A111.
12. Poynard T, Staub JL, Lemerez M, Deltenre M, Rekacevica C, Sallerin V. Efficacy and safety of lansoprazole 15mg OAD or 30mg OAD as one year maintenance treatment for erosive reflux oesophagitis, a randomised trial. Gastroenterology 1995; 108: A195.
13. Baldi F, Bardhan KD, Borman BC, Brullet E, Dent J, Galmiche JP, et al. Lansoprazole maintains healing in patients with reflux oesophagitis. Gastroenterology 1996; 110: A55.
14. Sontag S. Rolling review; gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1993; 7: 293-312[Medline].
15. Armstrong D, Bennett JR, Blum AL, Dent J, de Dombal FT, Galmiche J-P, et al. The endoscopic assessment of oesophagitis: a progress report on observer agreement. Gastroenterology 1996; 111: 85-92[Medline].
16. Altman DG. Better reporting of randomised controlled trials: the CONSORT statement. BMJ 1996; 313: 570-571[Free Full Text].
17. Lambert R. Review article. Current practice and future perspectives in the management of gastroesophageal reflux disease. Aliment Pharmacol Ther 1997; 11: 651-662[Medline].
18. Carlsson R, Galmiche J-P, Dent J, Lundell L, Frison L. Prognostic factors influencing relapse of oesophagitis during maintenance therapy with antisecretory drugs: a meta-analysis of long-term omeprazole trials. Aliment Pharmacol Ther 1997; 11: 473-482[Medline].
19. Tytgat GNJ, Blum AL, Verlinden M. Prognostic factors for relapse and maintenance treatment with cisapride in gastro-oesophageal reflux disease. Aliment Pharmacol Ther 1995; 9: 271-280[Medline].
20. Sandmark S, Carlsson R, Fausa O, Lundell L. Omeprazole or ranitidine in the treatment of reflux oesophagitis: results of a double-blind, randomised, Scandinavian multicenter study. Scand J Gastroenterol 1988; 23: 625-632[Medline].
21. Lind T, Havelund T, Carlsson R, Eriksson G, Glise H, Junghard O, et al. The effect of omeprazole (OME) 20mg and 10mg daily on heartburn in patients with endoscopy negative reflux disease (ENRD) treated on an on-demand basis. Gastroenterology 1996; 100: A178.
22. Harris RA, Kupperman M, Richter JE. Prevention of recurrences of erosive reflux oesophagitis: a cost-effectiveness analysis of maintenance proton pump inhibition. Am J Med 1997; 102: 78-88[Medline].
23. Bardhan KD, Müller-Lissner S, Bigard MA, Bianchi-Porro G, Ponce J, Hosie J, et al. Cost-effectiveness (C-E) of omeprazole (OM) and ranitidine (RAN) in intermittent treatment (IT) of symptomatic gastroesophageal reflux disease (GERD). Gut 1997; 41(suppl 3): A203.