Gut 1995; 36: 492-498

Omeprazole 10 mg or 20 mg once daily in theprevention of recurrence of reflux oesophagitis

C M Bate, S N Booth, J P Crowe, R A Mountford, P W N Keeling, B Hepworth-Jones,M D Taylor, P D I Richardson, and the Solo Investigator Group

AbstractThis study determined the optimal main-tenance dose of omeprazole in refluxoesophagitis. One hundred and ninetythree patients rendered asymptomaticand healed after four or eight weeksomeprazole were randomised doubleblind to 10 mg omeprazole once daily(n=60 evaluable), 20 mg omeprazole oncedaily (n=68), or placebo (n=62) for oneyear or until symptomatic relapse. Eachomeprazole regimen was superior toplacebo in preventing both symptomaticrelapse (life table analysis, p<0001) andendoscopically verified relapse (p<0.001).At 12 months, the life table endoscopicremission rates (proportions of patientswithout grade -2 oesophagitis) were: 50%(95% confidence intervals 34 to 66%) with10 mg omeprazole once daily, 74% (62 to86%) with 20 mg omeprazole once daily,and 14% (2 to 26%) with placebo. At12 months, the life table symptomaticremission rates (proportions of patientsasymptomatic or with mild symptoms)were: 77% (64 to 89%) with 10 mg omepra-zole once daily, 83% (73 to 93%) with 20mg omeprazole once daily, and 34% (16 to52%) with placebo. Both 10 mg and 20 mgomeprazole once daily were effectivein prolonging the remission of refluxoesophagitis: 10 mg may be appropriateto start longterm treatment, thoughthe existence of a dose response relationmeans that 20 mg once daily may beeffective in patients for whom 10 mg oncedaily is suboptimal.(Gut 1995; 36: 492-498)

Keywords: omeprazole, reflux oesophagitis.

Omeprazole (Losec, Astra Pharmaceuticals)20 mg once daily is effective in the longtermtreatment of reflux oesophagitis and superiorto the H2 receptor antagonist ranitidine(150 mg twice daily) in this regard.1 2Treatment should normally represent theminimum drug exposure, however, whichproduces the greatest benefit in the greatestproportion of patients.3 Thus, there are soundreasons for evaluating 10 mg omeprazole oncedaily in the prevention of relapse of refluxoesophagitis in comparison with the standarddose. Preliminary, short term (six month) trialshave been conducted with the 10 mg regimen,which suggest that it may be effective asprophylaxis against the recurrence of refluxoesophagitis, although the assessment of

efficacy was based solely on (disparate)endoscopic criteria.4 5

This study assessed whether 10 mg omepra-zole once daily would be effective in thelongterm (one year) treatment of refluxoesophagitis, in comparison with 20 mgomeprazole once daily and placebo, basedon both endoscopic and symptomaticrecurrences.

Methods

STUDY DESIGNOne hundred and ninety three of 200 patientsboth healed of reflux oesophagitis andrendered asymptomatic from 313 patients whoreceived either omeprazole 20 mg once dailyfor four to eight weeks, or 20 mg once daily forfour weeks followed by 40 mg once daily forthe second four weeks,6 were randomised toreceive double blind either 10 mg omeprazoleonce daily or 20 mg omeprazole once daily ormatched placebo for up to one year. The studydrugs were presented as hard gelatin capsuleswith an opaque body, containing eitheromeprazole 20 mg, omeprazole 10 mg, orplacebo (lactose) as enteric coated granules,with each 'treatment' being of identicalappearance. Endoscopy was performed afterthree months, and on completion, or in theevent of symptomatic relapse (for definitionsee below). It was considered prudent to assesswhether each patient remained healed ofoesophagitis after three months, as relapse mayoccur comparatively early during longtermtreatment, and 12 weeks has been quoted as amedian time to relapse.7

At clinic visits every three months, patients'symptoms (overall assessment, heartburn,regurgitation, dysphagia) were recorded on afour point scale (0=none, 1= mild, 2=moder-ate, 3= severe); the presence or absence ofodynophagia, and possible adverse eventswere elicited in response to a standard openquestion. Interim (unscheduled) visits wereavailable to any patient experiencing trouble-some symptoms. Patients also completed dailydiary cards for the first three months of thestudy to record the severity of symptoms byday and by night, and the number of tablets ofalginate-antacid relief medication (Gaviscon:Reckitt & Colman; 500 mg alginic acid, 25 mgmagnesium trisilicate, 100 mg dried alu-minium hydroxide gel, 170 mg sodium bicar-bonate. Neutralising capacity: 3.7 mmol H+per tablet) taken by day and by night. Theprimary end point for the diary card data wasthe absence of symptoms by day and by night.

Royal Albert EdwardInfirmary, WiganC M Bate

KidderminsterGeneral Hospital,KidderminsterS N Booth

Mater MisericordiaeHospital, Dublin,IrelandJ P Crowe

Bristol RoyalInfirmary, BristolR A Mountford

StJames' Hospital,Dublin, IrelandP W N Keeling

Clinical ResearchDepartment, AstraPharmaceuticalsLimited, KingsLangleyB Hepworth-JonesM D TaylorP D I Richardson

Correspondence to:Dr C M Bate, Royal AlbertEdward Infirmary, WiganWN1 2NN.

Accepted for publication15 July 1994

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Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis

Endoscopic relapse was defined as therecurrence of grade 2-4 oesophagitis (forgrading see Table II). The finding of grade 2-4oesophagitis on endoscopy associated witheither mild or no symptoms was consideredas an asymptomatic relapse. Symptomaticrelapse was defined as the recurrence ofgastro-oesophageal reflux disease symptoms,graded as moderate or severe.

PATIENTSEntry criteria for the healing trial precedingthis study have been reported elsewhere,6 themain inclusion criteria being: age 18-80 years,minimum of three months' history ofsymptoms of gastro-oesophageal reflux dis-ease, and grade 2-4 reflux oesophagitis on

endoscopy (for grading see Table II); the mainexclusion criteria were: oesophageal varices or

stricture, upper gastrointestinal bleeding,peptic ulcer, and past upper gastrointestinalsurgery or vagotomy.At entry to this maintenance study each

patient had to have been rendered healed(grade 0 on endoscopy) and symptom free(grade 0 on patient's overall assessment) aftertheir initial treatment with omeprazole. In thisstudy, patients were withdrawn in the event of(a) the recurrence of symptoms, graded as

moderate or severe, and which would in theinvestigator's opinion have warranted a furtherhealing course of omeprazole; (b) erosiveoesophagitis (grade 2-4) at the three monthendoscopy.

All patients gave written informed consentto participate in the study, which was approvedby the ethics committee at each institution.

recent episode of reflux oesophagitis;endoscopic grade of oesophagitis or overallsymptom grading at entry into the precedinghealing trial, healing treatment (omeprazole20/20 mg or 20/40 mg) and duration required(four or eight weeks) to attain presentendoscopic and symptomatic remission; age;

sex; concurrent smoking or alcohol consump-

tion; previous H2 receptor antagonist use;

and treatment (10 mg omeprazole, 20 mg

omeprazole or placebo).Plots of diary card assessments were derived

from the percentage of patients reporting no

daytime or night time symptoms. These dataare presented cumulatively as the average

number of such days per patient; and a

comparison made between groups using a x2test.

Values are presented as mean (SD).

ResultsOne hundred and ninety three patients were

randomised to receive 10 mg omeprazole once

daily (n=61), 20 mg omeprazole once daily(n=69), or placebo (n=63). Three patients(one omeprazole 10 mg, one omeprazole20 mg, one placebo) were lost to follow up. Inthe absence of any data on efficacy, thesepatients were excluded from the analyses.There were no significant differences betweenthe groups at randomisation into the studywith regard to demographic characteristics,history of oesophagitis, and endoscopicfindings immediately before the most recenthealing treatment (Tables I and II).

ASSESSMENTS AT CLINIC VISITS

STATISTICAL ANALYSES

In the primary analysis, the endoscopic remis-sion rates after 12 months with omeprazole10 mg once daily and placebo were compared,giving at least 99% power at the 5% signifi-cance value to detect the observed differencebetween groups of 36% (50% v 14%, respec-tively).

Endoscopic and symptomatic remissionrates with 95% confidence intervals were

determined using life table analyses. Inaddition to the full 12 month analyses, it wasconsidered important to highlight the analysesfor the first three months, as the design of thetrial up to then wholly reflected routine clinicalpractice and patients' continuous (daily)assessments of symptoms were available fromdiary cards.An additional comparison of remission rates

(all patients treated approach, with denomina-tors of 60, 10 mg omeprazole; 68, 20 mgomeprazole; 62, placebo; unless otherwisestated) was carried out (X2 tests), although it isrecognised that this analysis may underestimate the true proportions of patients inremission, it permits comparison to be madewith some earlier trials.A logit analysis was conducted to identify

possible factors predictive of a reduced risk ofrelapse: covariates were duration of most

Endoscopic relapse: one to three monthsAt three months, the life table endoscopicremission rates (proportions of patients

TABLE I Patients' characteristics at randomisation

Omeprazole Omeprazole10 mg 20 mg Placebo

Demographic featuresPatients (n)Sex (M:F)Age (y)Weight (kg)

Height (cm)

6044:1653 (15)78 (13)

170 (11)(n= 59)

Smokers (%) 25Drinkers (%) 67Oesophagitis historyYears since 'oesophagitis'

first diagnosed 1-2 (2.6)(n=52)

6848:2053 (14)76 (14)(n=67)171 (9)(n= 67)2271

6248:1453 (14)80 (11)(n=61)172 (8)

1986

17 (43) 12 (23)(n=55) (n=56)

Symptom historyAssessment immediately before most recent healing treatment

Heartburn (%) 98 94 95Regurgitation (/) 77 72 71Dysphagia (%) 37 35 32Odynophagia (/) 25 27 29

Healing regimen for most recent episode*Om 20 (%) 73 59 60Om 20/20 mg(%) 8 13 16Om 20/40 mg (/) 18 28 24

Data are shown as numbers or proportions of patients in eachcategory or as mean (SD). *Patients received 20 mgomeprazole once daily for four weeks. Those not both healedand symptom free after four weeks received either 20 mgomeprazole once daily (OM 20/20 mg) or 40 mg omeprazoleonce daily (OM 20/40 mg) for a further four weeks (weeks5-8).

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TABLE II Findings at endoscopic examinationimmediately before the most recent healing treatment

Omeprazole Omeprazole10 mg 20 mg Placebo

Patients (n) with each grade of oesophagitisGrade 0 0 0 0Grade 1 0 0 0Grade 2 (%/o) 43 (72) 44 (65) 42 (68)Grade 3 (%/o) 14 (23) 22 (32) 15 (24)Grade 4 (%) 3 (5) 2 (3) 5 (8)

Linear extent of 4-5 (2-3) 4-7 (2-1) 4-4 (2.2)oesophagitis (cm) (n=67)

Stricture passable with anadult endoscope (%/o) 4/60 (7) 8/68 (12) 4/62 (7)

Endoscopic evidence ofBarrett's oesophagus (%) 5/60 (8) 1/68 (2) 5/62 (8)

Data are shown as numbers of patients in each category, oras mean (SD). Endoscopic grades were defined as follows:Grade 0 - normal mucosa. Grade 1 - no macroscopicerosions visible; erythema or diffusely red mucosa; oedemacausing accentuated folds. Grade 2 - isolated round or linearerosions extending from the squamocolumnar junctionupwards in relation to the folds, but not involving the entirecircumference. Grade 3 - confluent erosions involving theentire circumference. Grade 4 - frank benign ulcer. Barrett'soesophagus was defined as the presence of columnar linedepithelium extending more than 3 cm above the proximalmargin of the gastric folds (gastro-oesophageal junction) andaround the entire circumference.

without grade -2 oesophagitis, Fig 1) were:79% (95% CI 69 to 90%/o) (68% on an allpatients treated basis) with omeprazole 10 mgonce daily, 89% (81 to 97%) (76%) with20 mg omeprazole once daily, and with placebo41% (28 to 53%) (23%; 10 mg group NS v20 mg group, each p< 0001 v placebo, Fig 2).At the three month clinic visit, fewer

patients receiving the 10 or 20 mg regimenswere classified as having an asymptomaticendoscopic relapse than those receivingplacebo (eight of 47 (17%) of those in sympto-matic remission in the 10 mg group, seven of58 (12%) 20 mg group, NS between groups,each p<0001 v 18 of 30 (60%) placebo).Of the 'asymptomatic' relapses, six of eightreceiving 10 mg omeprazole, four of seven

---- Omeprazole 20 mg od - Omeprazole 10 mg od -- Placebo(NS v 10 mg regimen, (p < 0.001 v placebo)p < 0-001 v placebo)

1l

l

L1.I.l

21

2 3 4 5 6 7 8 9 10 1 1 12 13

receiving 20 mg omeprazole, and 12 of 18receiving placebo were associated with therecurrence of mild symptoms.

Endoscopic relapse: one to 12 monthsAt 12 months, the life table endoscopicremission rates (Fig 1) were: 50% (95%/o CI 34to 66%) (50/o on an all patients treated basis)with omeprazole 10 mg once daily, 74% (62 to86%) (68%) with 20 mg omeprazole oncedaily, and with placebo 14% (2 to 26%) (10%;10 mg group NS v 20 mg group, eachp<0'0001 v placebo, Fig 2).At the one year clinic visit, the proportions

without troublesome symptoms but relapsingendoscopically were again similar in theomeprazole treated groups, although astatistical comparison against placebo was notpossible given the small number of patients insymptomatic remission in the placebo group(five of 28 ( 18%) of those 'asymptomatic' inthe 10 mg group, three of 39 (8%) 20 mggroup, NS between groups, three of five (60%)placebo). Of the 'asymptomatic' relapses, twoof five receiving 10 mg omeprazole, one ofthree receiving 20 mg omeprazole, and one ofthree receiving placebo were associated withthe recurrence of mild symptoms.

Symptomatic relapse: one to three monthsAt three months, the life table symptomaticremission rates (proportions of patientsasymptomatic or with mild symptoms, Fig 3)were: 91% (95% CI 84 to 99%) (78% on an allpatients treated basis) with omeprazole 10 mgonce daily, 94% (88 to 100%) (85%) with20 mg omeprazole once daily, and withplacebo 63% (55 to 76%) (48%; 10 mg groupNS v 20 mg group, each p<0001 v placebo,Fig 4).

Symptomatic relapse: one to 12 monthsAt 12 months, the life table symptomaticremission rates (Fig 3) were: 77% (95% CI 64to 89%) (78% on an all patients treated basis)with omeprazole 10 mg once daily, 83% (73 to93%) (82%) with 20 mg omeprazole oncedaily, and with placebo 34% (16 to 52%)(45%; 10 mg group NS v 20 mg group, eachp<0000 1 v placebo, Fig 4).

Logit analysisThe most influential factors for a reducedlikelihood of endoscopic relapse were:treatment (20 mg omeprazole> 10 mg omepra-zole>placebo; p<0 0001), and treatmentduration required to attain present endoscopicand symptomatic remission (four or eightweeks; p<0 0 1); with the highest probability ofsustained remission being associated withlongterm 20 mg omeprazole once daily, andwith remission being attained after four weeksrather than eight weeks treatment of the indexepisode of reflux oesophagitis.The factors most predictive of a reduced

risk of symptomatic relapse were: treatment

C0

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1._

MonthFigure 1: Endoscopic relapse: 1 to 12 months (presentation extended to day 385 to includedata from temporal outliers for the endoscopy scheduled at 12 months). OD=once daily.

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Omeprazole 10 mg or 20 mg once daily in the prevention of recurrence of reflux oesophagitis

70 r

60K

50s

40 F-

30 F-

201-

10 -

LI] Grade 0

M Grade 1M Grade 2M Grade 3M Grade 4

n1

0 6iMonth -2 to-1 3 12 -2 to -1 3 12 -2 to-1 3 12

Omeprazole Omeprazole Placebo10 mg 20 mg

Figure 2: Endoscopic grades at entry to the preceding healing trial (- 2 to -1 months),then after 3 months and 12 months maintenance treatment; NS between 10 mg and 20 mggroups after 3 and 12 months, each p<0 0001 v placebo.

(20 mg omeprazole> 10 mg omeprazole>placebo, p<0-0001), and overall symptomgrading at entry into the preceding healingtrial (p<005); with the highest probability ofsustained remission being associated withlongterm 20 mg omeprazole once daily, andwith the presence of mild symptoms at presen-tation for the preceding episode of refluxoesophagitis.

'Survival' time in studyThe interval from randomisation to eitherwithdrawal of treatment or study completionwas longer in the omeprazole treated groupsthan the placebo group (247 days, 10 mggroup; 263 days, 20 mg group; NS betweengroups, each p<0 001 v 113 days placebo).

Symptoms recorded by the physicianAt three months 35 (58% on an all patientstreated basis (67% of those for whom data areavailable)) with 10 mg once daily, 47 (69%(78%)) with 20 mg once daily, and 17 (27%(42%)) with placebo were completely asymp-tomatic (NS between 10 mg and 20 mggroups, each p<0 001 v placebo).The proportions of patients reported as

asymptomatic on completion of the study were32 (53% (56%)) receiving 10 mg once daily,46 (68% (71%)) receiving 20 mg once daily,and 14 (23% (24%)) receiving placebo (NSbetween 10 mg and 20 mg groups, eachp<0001 v placebo). Table III shows theproportions of patients without specificsymptoms after three months treatment and oncompletion.

Diary card assessments: one to three monthsPatients receiving either dose of omeprazolehad more days free of symptoms thanthose receiving placebo (Fig 5): cumulatively,by three months on average each patientexperienced 63 such days in the 10 mg group,and 65 days in the 20 mg group, comparedwith 45 days with placebo (NS between 10 mgand 20 mg regimens, each p<00 1 v placebo).With regard to the gain in symptom free days,this represents on average during the initialthree months an additional 18 or 20 dayswithout any symptoms for each patient receiv-ing omeprazole 10 mg once daily or 20 mgonce daily, respectively, in comparison withplacebo. Conversely, the probability ofpatients in the 10 mg and 20 mg groupsexperiencing a symptomatic day was 54%(100X(84-63)/84-45) and 49% (100X(84-65)/84-45), respectively, of that for patientsreceiving placebo.

Tolerability---- Omeprazole 20 mg od - Omeprazole 10 mg od -- Placebo A total of 91 adverse events was reported during

(NS v 10 mg regimen, (p < 0.001 v placebo) the study, 33 from 19 of 61 patients receivingp < 0.001 v placebo) omeprazole 10 mg once daily, 42 from 25 of 69

patients receiving omeprazole 20 mg once daily,100 and 16 from 13 of 63 patients receiving placebo.

so L+' ---- Te largest number of adverse events was gas-90 -----------

trointestinal (13, 10 mg omeprazole; 12, 20 mgomeprazole; nine, placebo), for example, diar-rhoea, vomiting; then in order of diminishing

70 'L frequency: circulatory (10, 10 mg omeprazole;L four, 20 mg omeprazole; none, placebo), for

60 11 example, angina pectoris; musculoskeletal (two,10 mg omeprazole; four, 20 mg omeprazole;

50 _ I three, placebo), for example, pain in the joints.

40 -- In general, the nature and incidence ofadverse events were comparable across the

30 treatment groups. With regard to circulatoryadverse events, these were reported by six

20 - patients receiving 10 mg omeprazole (10adverse events/one treatment withdrawal) by

10 - three receiving 20 mg omeprazole (4/0), and

o l I I I I|| Ii by none receiving placebo. This represents a0 1 2 3 4 5 6 7 8 9 10 11 12 13 subgroup of elderly trial patients, as the mean

Month (SD) age of these nine patients was 69 (4)ure 3: Symptomatic relapse: 1 to 12 months (presentation extended to day 385 to years (compared with 53 (14) years forude datum from temporal outlierfor the visit scheduled at 12months). the whole study patient population). Most

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Fig.inch

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70

60

50 [-

c

0c

CL

40

30

20

10

o0Month -2 to -1 3 12 -2 to -1 3 12 -2 to -1 3 12

Omeprazole Omeprazole Placebo10 mg 20 mg

Figure 4: Symptom grades at entry to the preceding healing trial (-2 to -1 months), thenafter 3 months and 12 months maintenance treatment; NS between 10 mg and 20 mggroups after 3 and 12 months, each p<0 001 v placebo.

(eight of 14) of the reports were of anginapectoris, and all but one of these were asso-

ciated with previous (pre-trial) cardiovasculardysfunction, for example, myocardial infarc-tion, hypertension, angina. The remainingreports were of peripheral oedema (n=4, threeof which were associated with previouscardiovascular dysfunction), cerebrovasculardisorder, and syncope. No relation betweenthe dose of omeprazole and the incidence ofcirculatory adverse events was apparent,although no such events were seen in patientswho received placebo. As regards outcome,nine of the adverse events resolved withcontinued omeprazole treatment; there beingno reports of any of the remainder resolvingupon withdrawal of treatment.

Seven adverse events were classified as

serious according to the protocol definition, asfollows: adverse events requiring hospitalisa-tion (four, 10 mg omeprazole; one, 20 mgomeprazole; one, placebo), malignancy(one, omeprazole 20 mg: abdominal pain ofsufficient severity to require treatment with-drawal, leading to a subsequent diagnosis ofpancreatic carcinoma; patient died 53 daysafter withdrawal of treatment); none was

TABLE III Relief ofspecific symptoms recorded by physicians at clinic visits

Omeprazole Omeprazole10 mg 20 mg Placebo

HeartburnMonth 3 (%) 40 (67 (77))t 51 (75 (85))t 18 (29 (44))Completion (O/o) 34 (57 (61))t 50 (74 (77))4 13 (21 (22))

RegurgitationMonth 3 (%) 43 (72 (83))* 56 (82 (93))4 26 (42 (63))Completion (%) 39 (65 (70))4 55 (81 (85))4 18 (29 (32))

DysphagiaMonth 3 (/) 48 (80 (94)) 59 (87 (100)* 38 (61 (95))Completion (%) 52 (87 (95)) 64 (94 (98)) 50 (81 (86))

OdynophagiaMonth 3 (%) 52 (87 (100))* 59 (87 (98))* 40 (65 (98))Completion (%) 54 (90 (96)) 60 (88 (92)) 49 (79 (84))

*p<O-Ol, tp<0-001, 4p<00001 v placebo; NS between 10 mg and 20 mg groups in eachassessment. Data are shown as number of patients without the symptom. Proportions are givenin parentheses on the following basis: (all patients treated (of these for whom data areavailable)).

attributed by the investigators as having acausal relation with the trial medication.Patients were withdrawn from treatment forthe following reasons: adverse events, (two,10 mg omeprazole; four, 20 mg omeprazole;three, placebo), non-compliance (1 1, 10, and9, respectively), relapse (19, 14, 45).

DiscussionThe aims for longterm treatment of refluxoesophagitis are: firstly, to provide completeand sustained symptom relief; and secondly, toensure prolonged symptomatic and endo-scopic remission. For each of these analysesthe rates of success were similar in patientsreceiving omeprazole at a dose of 10 mg oncedaily or 20 mg once daily, each regimen beingsuperior to placebo.Omeprazole 20 mg once daily was associ-

ated with a one year endoscopic remissionrate of 74%, which is similar to previouslypublished figures for this regimen (89%l;50%2). Though in statistical terms (in thesurvival analyses) the two omeprazoleregimens were deemed to be of comparableefficacy in preventing both symptomatic andendoscopically verified relapse, there wasconsistent numerical superiority for thehigher dose in each of the analyses; a trendindicative of a clinically relevant distinctionbetween treatments. Whereas the 10 mgdose may be appropriate to start longtermtreatment, the existence of a dose responserelation means that a daily dose of20 mg may be effective in patients for whom10 mg is suboptimal.The clinical effectiveness of omeprazole at

a dose of 10 mg in this study would seem tosurpass that anticipated, based on clinicalpharmacology studies.8-10 We believe that thistype of 'discrepancy' can be explained by thefact that many of the early studies used healthyvolunteers rather than patients or involvedsmall numbers of subjects, or both.8 9 Recentwork considers such points, and has shownthat the acid suppression achieved with 10 mgomeprazole is sufficient to produce healing inmost duodenal ulcer patients.10 None the less,it seems inadvisable to extrapolate from onecondition (active duodenal ulcer disease) toanother (healed reflux oesophagitis) and fromdata on clinical pharmacology to those onclinical effectiveness, in seeking to predictpatients' responsiveness to 10 mg omeprazole.

It is appropriate that clinical trials aredirected at clinical end points appertaining tothe 'usual' assessment of patients within thehealthcare system. Initial assessments ofrelapse and decisions about clinical inter-ventions in gastro-oesophageal reflux disease,are made routinely on a symptomatic basis, apractice wholly reflected by the first threemonths treatment within this trial. Anendoscopy was scheduled after three months,as it was deemed prudent to assess whetherpatients remained healed of oesophagitis, adecision supported by the finding that almostone third of patients randomised to placebo,although without troublesome symptoms,

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* Omeprazole 20 mg od 0 Omeprazole 10 mg od A Placebo(NS v 10 mg regimen, (p < 0.01 v placebo)p < 0.01 v placebo)

65-

60

55-

> 50

.4545

E 40-0.35-

E3o3

> 25

7s 20

E15-

10

5

00 21 42 63 84

DayFigure 5: Cumulative number of days (of 24 hours each) free ofsymptoms per patientreceiving 10 mg omeprazole once daily, 20 mg omeprazole once daily, or placebo; based ondiary card data.

were found to have erosive oesophagitis. Incontrast, this was true for only some 13% and10% of patients receiving either 10 mg or20 mg omeprazole, respectively, illustratingthat the continued absence of troublesomesymptoms is a reliable indicator of sustainedendoscopic healing in patients given omepra-zole. These findings support the findings ofprevious work, showing a positive correlationbetween symptom improvement and endo-scopic healing in most patients treated withomeprazole."1 Hence, patients receivingomeprazole are considered unlikely to requireendoscopy to detect their relapse, which is animportant consideration given the present highdemands being placed upon finite endoscopyservices, and one which could have financialattractions for a healthcare purchaser.'2The recurrence of even mild symptoms can

be indicative of endoscopic relapse, and suchpatients may require longterm continuoustreatment. Moreover, truly asymptomaticrelapse was rare in this study. Although ahigher proportion of patients receiving placebothan receiving either dose of omeprazole wereregarded as treatment failures after threemonths and were therefore lost to follow up,the overall analysis after 12 months was consis-tent with that over the first three months oftreatment.Some may argue that longterm symptom

relief alone is an adequate goal, butwith ineffective treatment there remains thesuspicion of an unacceptably high number of(unpredictable) endoscopic relapses, whichcould ultimately be associated with complica-tions including the possible development ofoesophageal stricture or columnar metaplasia,or both."1 In clinical trials omeprazole hasbeen shown to be effective not only in pre-venting the recurrence of oesophagitis but

also in oesophageal stricture prophylaxis'3and in inducing regression of columnarmucosa in Barrett's oesophagus,14 hence itsuse in the long term may reduce the incidenceof gastro-oesophageal reflux disease associatedcomplications.

Omeprazole treatment was shown, throughthe analysis of possible prognostic factors, tobe associated with a reduced likelihood ofrelapse, in agreement with the results of the lifetable analyses. The finding of longer 'survival'times in the study of patients receiving eachomeprazole regimen, more than twice theduration seen with placebo, is a compositeindicator of the therapeutic advantage foromeprazole and its good tolerability.

This study reflects the maintenance treat-ment of patients with signs and symptoms ofoesophagitis at initial presentation. Having aplacebo control group offers an insight into thenatural history of this chronic recurrent condi-tion. Most patients receiving placebo relapsedwithin three months of attaining remission,pointing to the need for effective longtermtreatment in reflux oesophagitis. A less highlyselected population than that included in thistrial would contain patients with typical refluxsymptoms but without oesophagitis. While it isnot as yet possible to predict which of theseendoscopy 'negative' patients, subsequent tosatisfactory initial treatment, will require nofurther treatment, or intermittent therapy;some will require longterm continuous treat-ment. In this trial, symptomatic relapse wasinsensitive to the initial grade of oesophagitis,whereas there was a positive correlationbetween the likelihood of relapse and symptomseverity immediately before acute treatment.Thus, one possible inference would be thatpatients with troublesome symptoms of gastro-oesophageal disease but no unequivocalendoscopic evidence of oesophagitis, are at riskof relapse and hence are candidates for longterm treatment.

In conclusion, omeprazole at half thestandard healing dose for reflux oesophagitis iseffective in long term disease treatment, by pro-longing remission. Omeprazole 10 mg oncedaily may be used when starting maintenancetreatment. Patients with an apparent clinicalneed for optimal treatment may have need forthe higher dose, including those slow to attainremission or prone to troublesome symptoms orwith a history of complication, or the few whoare inadequately controlled with 10 mg.

The following physicians also contributed to the study: P BMcIntyre, Queen Elizabeth II Hospital, Welwyn Garden City;R J McFarland, Ulster Hospital, Belfast; J R B Green, CityGeneral Hospital, Stoke on Trent; R P H Thompson, StThomas' Hospital, London; J D R Rose, Ballochmyle Hospital,Ayrshire; G Bevan, Edgware General Hospital, Edgware; T KDaneshmend, Royal Devon and Exeter Hospital, Exeter; JCalam, Hammersmith Hospital, London; T O'Gorman,Regional Hospital, Galway; D N Clarke, Stirling RoyalInfirmary, Stirling; D R Shreeve, North Manchester GeneralHospital, Manchester; K F Schiller, St Peter's District GeneralHospital, Chertsey; N Krasner, Walton Hospital, Liverpool; DN Foster, Birch Hill Hospital, Rochdale; P M Smith,Llandough Hospital, Penarth; M C Bateson, The GeneralHospital, Bishop Auckland. Emma Beresford analysed thestudy and Sarah Hewett prepared the manuscript.

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