Gut 1994; 35:8-14

PAPERS

Predictive factors of the long term outcome in gastro-oesophageal reflux disease: six year follow up of 107patients

Elbio Kuster, Emilio Ros, Victor Toledo-Pimentel, Amadeo Pujol, JosepM Bordas,Luis Grande, Cristobal Pera

GastroenterologyService, Endoscopy Unitand Motility Laboratory,Department of Surgery,Hospital Clinic iProvincial, Barcelona,SpainE KusterE RosV Toledo-PimentelA PujolJ M BordasL GrandeC PeraCorrespondence to:Dr Emilio Ros,Gastroenterology Service,Hospital Clinic i Provincial,C Villarroel, 170 08036Barcelona, Spain.Accepted for publication26 May 1993

AbstractThere is little information concerning thelong term outcome of patients with gastro-oesophageal reflux disease (GORD). Thus 109patients with reflux symptoms (33 with erosiveoesophagitis) with a diagnosis of GORD afterclinical evaluation and oesophageal testingwere studied. AU patients were treated with astepwise approach: (a) lifestyle changes weresuggested aimed at reducing reflux andantacids and the prokinetic agent domperidonewere prescribed; (b) H2 blockers were addedafter two months when symptoms persisted;(c) anti-reflux surgery was indicated whenthere was no response to (b). Treatment wasadjusted to maintain clinical remission duringfollow up. Long term treatment need wasdefined as minor when conservative measuressufficed for proper control, and as major ifdaily H2 blockers or surgery were required.The results showed that one third of thepatients each had initial therapeutic need (a),(b), and (c). Of 103 patients available for followup at three years and 89 at six years, respectivetherapeutic needs were minor in 52% and 55%and major in 48% and 45%. Eighty per cent ofpatients in (a), 67% in (b), and 17% in (c)required only conservative measures at sixyears. A decreasing lower oesophagealsphincter pressure (p<0-001), radiologicalreflux (p=0028), and erosive oesophagitis(p=0-031), but not initial clinical scores, wereindependent predictors of major therapeuticneed as shown by multivariate analysis. Thelong term outcome of GORD is better thanpreviously perceived.(Gut 1994; 35: 8-14)

Gastro-oesophageal reflux disease (GORD) is acommon ailment. A cross sectional survey ofpresumably healthy people in the United Stateshas found that 10% experience heartburn dailyand up to 40% have it at least once a month.'Indeed, most otherwise healthy heavy con-sumers of antacids have reflux disease.2

Gastro-esophageal reflux disease is a chronicdisease that requires long term management innearly all patients. The conventional medicaltreatment begins with modifications of lifestylethat are aimed at reducing the reflux of gastric

contents into the oesophagus, such as dietary,alcohol, drug, and tobacco restriction, and eleva-tion of the bedhead; such measures, togetherwith appropriate antacid use, are usually effec-tive for patients with clinically mild GORD,whereas patients with more frequent or severereflux symptoms often require some form of acidsuppressive medication with or without additionof gastric prokinetic agents.3 Antireflux surgeryis a good alternative treatment for patients whodo not respond well to medical treatment.4About one third ofthe patients with heartburn

who seek medical care have endoscopic evidenceof oesophagitis,' and therapeutic studies ofGORD have been limited primarily to short termobservations of the effects of single drugs in thissubset of patients, with little or no emphasis onmodifications of lifestyle.6 Recent clinical trialsin patients with oesophagitis suggest that mostpatients relapse quickly when treatment is inter-rupted after healing7-'0; however, a bias towardmore severe cases to enter such trials cannot bediscounted. There is little information about thelong term clinical course of patients with pepticoesophagitis after diagnosis," and even less onpatients with GORD but no oesophagitis.The present study was carried out in a con-

secutive series ofoutpatients referred to a gastro-enterology clinic who sought medical carebecause of reflux symptoms and had confirmedGORD, with and without oesophagitis. Thepatients were submitted initially to a stepwisetherapeutic regimen until clinical remission andwere subsequently given maintenance treatmentsufficient for them to feel satisfied. They werethen followed up for up to six years. Our aimswere to devise a rational therapeutic approach toGORD and to assess the existence of predictivefactors of the long term outcome. The informa-tion gathered in the study provides a comprehen-sive evaluation of the efficacy of prolongedtreatment in GORD.

Patients and methods

PATIENTSOne hundred and thirty two consecutive out-patients who had reflux symptoms (heartburn,or acid regurgitation, or both) as their maincomplaint were prospectively evaluated during a

8

Predictivefactors ofthe long term outcome in gastro-oesophageal reflux disease: sixyearfollow up of107 patients

five year period (December 1979 to January1985) at a university affiliated gastroenterologyclinic that receives referrals from communitypractitioners and specialists. Patients were

accepted if they had had no treatment with H2blockers for at least two months. There were 67women and 65 men, with a mean age of 48(range, 19-79) years. The main duration ofsymptoms was 11 (range, 1-50) years. Patientswith peptic ulcer, prior gastric or oesophagealsurgery, or any medical condition that couldcause or aggravate reflux (scleroderma,alcoholism) were excluded from the study.

STUDY PROTOCOLAt the initial evaluation a composite clinicalscore was constructed for each patient that tookinto account the frequency and severity of heart-burn, regurgitation, and dysphagia. Otherclinical features such as non-cardiac chest painand respiratory symptoms were also considered.All patients were offered diagnostic testingwith barium swallow, fibreoptic endoscopy withpinch oesophageal biopsies, oesophagealmotility studies, and either standard acid refluxtest without HC1 loading (during the first fouryears of patient acquisition) or 24 hour oesopha-geal pH monitoring (during the last year).

THERAPEUTIC APPROACHAfter baseline examination, the patients weregiven detailed dietary, alcohol, smoking, drug,and postural advice.'2 '4 Besides efforts at modi-fication of lifestyle, all patients were treated withsingle doses of an oral prokinetic drug (10 mgdomperidone) before meals in addition to 15 mlof a liquid antacid preparation (aluminiumhydroxide/magnesium hydroxide mixture withan in vitro neutralising capacity of 4 0 mmol H+/ml) six times a day, one hour, and three hoursafter meals, for at least two months. Specificinstructions were given to regularly take theprescribed doses ofantacid even in the absence ofsymptoms and to use additional antacid asneeded for symptom relief. After two months,patients with unimproved symptoms weretreated additionally with standard doses of H2receptor blockers (cimetidine (1-2 g/day) or

ranitidine (300 mg/day) in divided doses) foranother two months, with treatment extendedfor up to six months when symptoms were

unremitting. After this period, and when no

major clinical changes were noted, anti-refluxsurgery was indicated. When patients respondedto pharmacological treatment, the drugs were

progressively tapered to minimal effectivemaintenance doses while follow up was con-tinued. Conversely, drug treatment was scaledup when symptomatic relapses occurred. Thepatient's own assessment of satisfaction or dis-satisfaction was the main determinant of treat-ment modifications.

During follow up the patients were evaluatedclinically at regular intervals of one to sixmonths, depending on the clinical state. At eachvisit symptoms, compliance with conservativetreatment, and the consumption of medicationswere assessed; advice on dietary, posture, and

other lifestyle changes was reinforced whennecessary. Endoscopies were performed everysix months in patients with erosive oesophagitisand at least once in those with non-erosiveGORD.

MethodsThe scoring system for heartburn, regurgitation,and dysphagia was established from 0 points (nosymptoms) to 5 points (daily, severe, disablingsymptoms). The maximum clinical score wasthus 15 points. Endoscopic oesophagitis wasgraded as follows: 0, none; I, erythema; II, non-confluent erosions; III, confluent erosions orcircumferential shallow ulcerations; IV, deepulcer or stricture. Endoscopic pinch biopsieswere obtained at least 3 cm above the cardia andevaluated histologically according to standardcriteria.Manometry to determine mean basal lower

oesophageal sphincter pressure (LOSP) andperistaltic response to wet swallows were per-formed as described.'5 A standard acid refluxtest'6 without HC1 loading was carried out atthe end of the oesophageal motility study. InJanuary 1984 this test was substituted by station-ary 24 hour oesophageal pH monitoring, whichwas performed and interpreted as previouslyreported.'7The diagnosis of GORD was based on a

positive result in at least two of the followingtests: spontaneous reflux ofbarium during radio-logical studies, erosions or ulcerations of theoesophageal mucosa at endoscopy, microscopicoesophagitis on endoscopic biopsy specimens,LOSP s,7 mm Hg (mean -2 SD of our motilitylaboratory controls),'5 pH <4 during a standardacid reflux test or abnormal reflux by 24 h pHmonitoring.

Because all patients completing the long termstudy had a follow up of at least six years,outcomes were evaluated at three and six yearsafter entry. Six possible outcomes were defined:(1) no symptoms or occasional symptoms requir-ing antacids; (2) sustained remission with fre-quent consumption of antacids with or withoutdomperidone alone; (3) seasonal symptomsrequiring full courses of treatment with eitherantacids or H2 blockers, with interveningperiods as in outcomes 1 or 2; (4) sustainedremission with daily maintenance doses of H2blockers; (5) need of uninterrupted treatmentwith full dose H2 blockers; (6) anti-reflux pro-cedure performed. To simplify the expression ofresults, outcomes 1 to 3 were grouped together as'minor therapeutic need' (patients were comfort-able most of the time utilising simple, inexpen-

TABLE I Results ofdiagnostic studies in 109 patients withreflux symptoms

Study Diagnosis No (0)

Barium swallow Radiological reflux 40 (37)Endoscopy Erosive oesophagitis 33 (30)Oesophageal biopsy Microscopic oesophagitis 97 (89)Motility studies LOSP <7 mm Hg 46 (42)SART* (n=89) Positive acid reflux 25 (28)24 hour pH monitoring(n=20) Abnormal reflux 18 (90)

*Standard acid reflux test without HCI loading.

9

Kuster, Ros, Toledo-Pimentel, Pujol, Bordas, Grande, Pera

sive therapeutic measures), whereas thoselabelled 4 to 6 were pooled as 'major therapeuticneed' (patients required expensive pharmaco-logical measures, close medical supervision, orsurgery).

EXPRESSION OF RESULTS AND STATISTICALANALYSESAll quantitative data are expressed as means(SD). The unpaired Student's t test, the non-parametric test of Mann-Whitney, an analysis ofvariance (ANOVA), and the XI test with con-tinuity correction factor as needed were usedwhen appropriate to detect any differencesbetween groups. Statistical significance wasdefined at an a risk of5% (p<0O05). Multivariatestatistics following Cox's logistic regressionmodel'8 was used to detect variables with predic-tive value; therapeutic need at three years wasthe dependent variable and all variables withpredictive value by univariate analysis wereincluded as independent variables. The statisti-cal processing of the data for the multivariateanalysis was performed with BMDP software.'9

Results

FINDINGS AT INITIAL EVALUATIONOf the 132 patients initially evaluated, 23 wereexcluded for various reasons - namely, gastro-duodenal ulcer found at barium studies or endo-scopy (11), refusal to undergo one or more of therequired procedures (seven), and negativeresults of oesophageal examinations (fivepatients). Thus 109 patients were finallyincluded in the study (56 women and 53 men; age50 (13), range 19-77 years).Twenty seven (25%) patients were cigarette

smokers and 35 (32%) were obese (body massindex >130). Heartburn was present in 106(97%), regurgitation in 90 (82%), and dysphagiain 42 (38%). Fifty nine (54%) patients hadnocturnal symptoms (heartburn or regurgitationawakening them from sleep) at least once a week.The mean clinical score was 6 4 (2 7) (range3-13). A history of relapsing chest pain withnegative cardiac studies was elicited from 21(19%) patients, whereas 37 (34%) gave a historyof bronchial asthma or chronic cough.

Table I gives the relevant results of oesopha-geal studies. The barium swallow revealed ahiatus hernia in 64 patients (60%). The endo-scopic grading ofoesophagitis was 0, 54 patients;I, 22 patients; II, 16 patients; III, six patients;

TABLE II Response to initial graded treatment in 107 patients with GORD in relation topresentingfeatures

Control with Control with Surgeryantacids HI blockers indicated(n=35) (n=37) (n=35)

Sex (F/M) 19/16 18/19 19/16Age (mean (SD) y) 50(13) 50(14) 50(13)Clinical score (mean (SD)) 6-2 (2 9) 59 (2-2) 7-1 (29)Radiological reflux (No (%)) 13 (37) 8 (22) 19 (54)*Erosive oesophagitis (No (%)) 5 (14) 12 (32) 16 (46)tLOSP (mean (SD) mm Hg) 12-3 (7 0) 111 (6 8) 7 0 (4 9)t

*p=0 009 v H2 blocker group; tp=0 004 v antacid group; tp=0-001 by analysis of variance.

and IV, 11 patients (stricture, seven patients;deep ulcer, four patients, one of whom hadBarrett's epithelium).Symptom severity was unrelated to either the

degree of endoscopic oesophagitis or to LOSP.On the other hand, 20 of 33 (61%) patients witherosive oesophagitis had a basal LOSP 67 mmHg whereas only 27 of 76 (36%) with non-erosiveGORD had abnormally low values (p0=0 15).

RESULTS OF INITIAL, GRADED TREATMENTTwo patients voluntarily withdrew before com-pleting the initial phase of medical treatment.Table II shows the response to treatment inrelation to the clinical score, the presence ofoesophagitis, and LOSP in the remaining 107patients. About two thirds of the patientsresponded well to medical treatment; nearly halfof them were well controlled with simple pro-kinetic plus antacid treatment, whereas the otherhalf required addition of H2 blockers. Age, sex,smoking, obesity, and other clinical variableswere unrelated to outcome. Whereas initialsymptom severity did not predict the response,patients refractory to treatment were more likelyto have both erosive oesophagitis and a lowerLOSP than those with a good response (TableII). Among the non-responders there were 16 of33 (49%) patients with erosive oesophagitis, 22 of45 (49%) with LOSP -7 mm Hg, and 12 of 19(63%) with both abnormalities.

OUTCOMES DURING FOLLOW UPThe follow up time for the 107 patients complet-ing the initial treatment phase is close to sevenyears (83 (30), range 6-136 months).

Withdrawals and deathsFour patients (three deaths) were lost to followup during the first three years, 12 additionalpatients withdrew from the study between thethird and sixth year, and two deaths occurredduring this period. All deaths were unrelated toGORD.

Side effects ofmedical treatmentRaising the head of the bed caused some prob-lems for 12 patients. Eight of them repeatedlyslipped off the end of the bed during the night;these difficulties were overcome by substitutingcotton or wool garments for the original silk ornylon ones. Four patients had impaired venouscirculation in the lower extremities and requiredan additional leg raising device for the night.Domperidone was universally well tolerated.Changes in bowel motions (either diarrhoea orconstipation) attributable to antacid use werereported by 11 patients; they were solved byjudicious substitution of equivalent aluminiumhydroxide or magnesium hydroxide prepara-tions for some of the doses of the originalmixture. A 79 year old woman with borderlineimpaired renal function developed reversible,high output renal failure four weeks after start-ing treatment with 1200mg cimetidine a day. Noside effects occurred with ranitidine.

10

Predictivefactors ofthe long term outcome in gastro-oesophageal reflux disease: sixyearfollow up of107 patients

TABLE III Clinical state of107 patients with GORD afterlong term follow up

At3years At 6yearsTreatment needs (No (%)) (No (%))

Well with conservative treatment:Symptom free or occasional AA 17 (16-5) 20 (22-5)Frequent use ofAA 21 (20 4) 15 (16-9)Seasonal AA or anti-H2 16 (15-5) 14 (15-7)

Continuous treatment required:Maintenance anti-H2 17 (16-5) 10 (11-2)Full/scaled up anti-H2 doses 9 (8.7)* 7 (7*9)tAntireflux surgery 23 (22 3) 23 (25 8)

Totalt 103 (96 3)§ 89 (83 2)§

*Four patients required ranitidine (600 mg/day) for propercontrol; tfour patients required omeprazole (20 mg/day) for goodcontrol; tnumber of patients available at each follow up period;Spercentage of patients completing the initial treatment protocol(n= 107); AA=antacids; anti-H2=histamine H2 blockers.

Anti-reflux surgeryAnti-reflux surgery was eventually carried out in23 of 35 (66%) patients not responding to initialmedical treatment, including 13 of 33 (39%)patients and 10 of 74 (14%) patients with andwithout oesophagitis, respectively. The reasonsfor not operating on the remaining 12 patientswith refractory GORD were patient's refusal(n= 10) and high surgical risk (n=2). A Nissenfundoplication was performed in 21 patients,whereas in the other two patients an antrectomyand Y de Roux procedure was selected as thesurgical technique of choice because of theexistence of a peptic stricture with shortenedoesophagus. All surgical repairs were performedwithin the first three years (14 (6), range 3-24months) after the initial evaluation.

Long term outcomeWhereas two thirds of the patients had initiallyrequired H2 blockers, 52% and 55% of thoseavailable for follow up at three and six years,respectively, fared well with a conservativeapproach (Table III). Anti-reflux surgeryresulted in long lasting remission ofreflux symp-toms in 22 of 23 patients who were operated onand who have been followed up for 72 (15), range54-1 16 months.

Table IV shows the treatment needs duringlong term follow up in relation to the outcome ofinitial, graded treatment. Nearly all patients whohad a good initial response to domperidone plusantacids were well controlled with conservativemeasures at three and six years, and the sameapplied to nearly two thirds of those who hadrequired H2 blockers at the outset.

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Relation oflower oesophageal sphincter pressure (LOSP) tothe endoscopic grading ofoesophagitis in 103 patients withgastro-oesophageal reflux disease divided into two groups withdifferent treatment requirements after afollow up ofthreeyears: open circles, well with conservative treatment; closedcircles, needing daily H2-blockers or anti-reflux surgery.

Long term treatment needs differed inpatients with or without oesophagitis at entry(Table V). It is worth noting that one third of thepatients with oesophagitis had a prolongedclinical remission with conservative measuresalone, whereas slightly more than one third ofthose with non-erosive GORD needed more

aggressive treatment for appropriate long termcontrol.

Oesophagitis was healed at follow up endo-scopy in the 13 patients operated on and in 10medically treated patients; minimal oesophagealerosions remained for periods of up to two yearsin seven other patients who were otherwise inclinical remission with maintenance treatment.Follow up endoscopies in patients who enteredthe study without erosive oesophagitis showednormal oesophageal mucosa in all but twopatients out of 73 available at three years and 63at six years.

Predictive factorsBecause patients with worse GORD underwentanti-reflux surgery early after entry and, exceptfor a single patient with surgical failure, theywere no longer under active treatment beyondthree years, the analysis of possible predictivefactors ofoutcome has been performed consider-ing the clinical state of the patients at the threeyear assessment.

TABLE IV Treatment requirementsfor symptom control ofpatients with GORD duringfollow up according to the response toinitial treatment

Treatment requirements

At3years At 6years

Response to initial treatment Antacids* Anti-H2t Operated Lost Antacids* Anti-H2ft Operatedt Lost

Antacids (n=35) 28 (85) 3 (9) 2 (6) 2 24 (80) 4 (13) 2 (7) 5H2 blockers (n=37) 23 (64) 11 (30) 2 (6) 1 20 (66 5) 8 (26-5) 2 (7) 7Refractory to treatment (n=35) 3 (9) 12 (35) 19 (56) 1 5 (17) 5 (17) 19 (66) 6Total (n= 107) 54 (53) 26 (25) 23 (22) 4 49 (55) 17 (19) 23 (26) 18

Data are expressed as No (%) of patients available for evaluation at each time period.*Symptom free with lifestyle modifications and either prn or frequent antacid consumption or with seasonal symptoms only.tRequiring uninterrupted treatment with H2 blockers at either maintenance or stepped up doses.tNo further patients underwent anti-reflux surgery after three years and none was lost from follow up.

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TABLE V Treatment requirements duringfollow up according to the presence or absence ofoesophagitis at the outset

Treatment requirements

At3years At6years

Erosive oesophagitis Antacids* Anti-H2f Operated Lost Antacids* Anti-H2t Operatedt Lost

Yes (n=33) 11(37) 7 (20) 13 (43) 3 9 (35) 4 (15) 13 (50) 4No (n=74) 44 (60) 19 (26) 10 (14) 1 40 (64) 13 (20) 10 (16) 11

Footnotes as for Table IV.

The relation of initial oesophagitis grade andbasal LOSP with three year therapeutic need foreach patient (Figure) shows that both oesopha-gitis and low LOSP are good predictors ofoutcome. Thus major treatment was required by19 of 30 patients with and 30 of 73 withoutoesophagitis (p=0 040), and by 28 of 45 patientswith LOSP s7mm Hg and 21 of 58 with normalLOSP (p=0 009). The comparison ofpresentingfeatures of patients with different treatmentrequirements at the three year evaluation (TableVI) also shows that oesophagitis and low LOSP,in addition to radiological reflux, were associatedwith major therapeutic need.By multivariate analysis, the following factors

were shown to be independent predictors ofvigorous treatment requirements: low LOSP(p<0-001), radiological reflux (p=0-028), anderosive oesophagitis (p=0-031). Respectivepositive predictive values, derived from data inTable V and the Figure, were 0-62, 0-63, and0-63.

DiscussionIn this study 107 consecutive outpatientswith documented GORD were prospectivelyevaluated with a clinical score, radiology, endo-scopy, and manometry. They were subsequentlymanaged with lifestyle changes plus a stepwisetherapeutic approach and followed up for up tosix years. Patient's satisfaction was the mainfactor that influenced treatment adjustments;thus the success of treatment (symptomaticremission) was determined by the patients ratherthan by their physicians. The results show that aconservative approach can provide long lastingremission in many patients and suggest that,once those with worse GORD are treated withanti-reflux surgery, the disease tends to run a

TABLE VI Presentingfeatures ofpatients with GORD in relation to treatment requirements atthreeyears

Continuousanti-H2 or

Conservative anti-refluxInitialfeatures treatment surgery p Value

Patients (No) 54 49Sex (M/F) 27/27 23/26Age (mean (SD) y) 48 (19) 52 (18)Smokers (No) 17 10Quit smoking (No (%)) 9 (53) 1 (10)Obese (No) 17 18Lost >5 kg (No (%)) 8 (47) 4 (22)Clinical score (mean (SD)) 6-1 (2 7) 6-7 (2-7)Hiatus hernia (No (%)) 31 (57) 30 (61)Radiological reflux (No (%)) 14 (26) 24 (49) 0-016Erosive oesophagitis (No (%)) 11 (20) 19 (39) 0-040LOSP (mean (SD) mm Hg) 12-0 (7-1) 7-7 (5 0) <0-001Stimultaneous peristaltic waves (No (%)) 6 (11) 10 (20)Distal peristaltic amplitude (mean (SD) mm Hg) 43-3 (15-6) 40-2 (13-2)Distal amplitude <25 mm Hg (No (%)) 7 (13) 6 (12)

benign course; they also indicate that oesopha-gitis, radiological reflux, and low LOSP areindependent predictors of more vigorous thera-peutic need during long term follow up.

Because admission into the study was based onsymptoms and not oesophagitis or abnormalprolonged pH monitoring, it could be arguedthat some patients were not true refluxers. Mostpatients with typical reflux symptoms can bediagnosed reliably, however, by history alone.20Furthermore, each patient was positive in at leasttwo of several highly specific tests for GORD.2'Most patients were studied before the wide-spread availability of 24 hour oesophageal pHmonitoring; in the few patients in whom it wasused, its positivity had a 90% correlation withsymptoms. This test, however, has not yet beenestablished as the gold standard for the diagnosisof GORD.22 24 Our patients had clinically severeGORD, as shown by the frequency of nocturnalreflux, respiratory symptoms, and non-cardiacchest pain, but only 30% had erosive oesopha-gitis and 10% had complications (strictures ordeep oesophageal ulcer); on the other hand,clinical scores were similar regardless ofoesophagitis grade. These findings underline thewell known discrepancy between symptomaticseverity and the endoscopic appearance ofoesophagitis in GORD.5Whereas the clinical, endoscopic, and mano-

metric scores of the patients who were refractoryto medical treatment implied severe GORD,anti-reflux surgery had excellent results in 22 of23 patients followed up for a mean of six yearsafter the procedure. It deserves mention thatthese overall good surgical results were obtainedby two surgeons (LG and CP) skilled in thetechnique of fundoplication. Reports on the longterm follow up of patients whose surgical repairwas performed by single surgical teams confirmthe long lasting good results of this anti-refluxprocedure.42526

Although neither the clinical severity ofGORDnor the presence of oesophagitis seem to berelated to increased rates of gastric acid secre-tion,27 28 it is clear now that profound acidsuppression, such as that provided by the drugomeprazole, is required for symptom control andhealing of oesophagitis in many patients.929Had our study not predated the availability ofomeprazole, some patients might not have beensubmitted to anti-reflux surgery because ofrefractory GORD.Due to the tendency of GORD to improve

during extended outpatient care (table IV), theinitial response to graded treatment was a goodpredictor of treatment needs during long termfollow up only for patients achieving sympto-matic remission with conservative treatment.

12

Predictivefactors ofthe long term outcome in gastro-oesophageal reflux disease: sixyearfollow up of107 patients 13

Thus 80% of those and 67% of patients initiallyrequiring H2 blockers had a lasting response tosimple modes of treatment, which was shared by17% of the patients who had been refractory toshort term medical management but did not haveanti-reflux surgery. The results challenge thepresumption that long term intensive treatmentis necessary for most patients with GORD.Other authors7-'0 have reported that patientswith oesophagitis relapse quickly when pharma-cological treatment is interrupted. Both selectionof more severe cases and the overlooking oflifestyle modifications in these studies7'-0 couldexplain the differences from our present series.At all times during prolonged patient care in

our study emphasis was placed on simplistic,traditional modes of treatment, such as dietmodification, elevation of the bedhead, tobacco,alcohol and drug restriction, and antacid use. Asrecently reviewed,30 these measures are based onsound physiological principles but are oftenneglected in this age of potent acid suppressivedrugs. In our study controllable changes, likestopping smoking and weight loss, occurredmore often in patients who did well on conserva-tive treatment (Table VI).

Little is known about factors influencingtherapeutic responses in GORD.729 We did notcarry out tests for alkaline reflux, which can beassociated with complications of oesophagitis orrefractoriness to medical treatment.3' Thelogistic regression analysis in our study showsthat a low basal LOSP, the detection of reflux bybarium meal, and the existence of oesophagealerosions as judged by endoscopy, independentlypredict the long term need for sustained pharma-cological acid suppression or anti-reflux surgeryin GORD. According to their positive predictivevalues, the presence of each one of these vari-ables would correctly predict the long termcourse in roughly two out ofevery three patients,thus their investigation should be clinically use-ful. The association of low LOSP with vigorouslong term treatment requirements is consistentwith available evidence." 21 27 3233 A potentialexplanation for the fact that radiological refluxhad prognostic value independently of LOSPcould be that, as well as a low basal LOSP,it reflected an increased rate of transientrelaxations of a normotensive lower oesopha-geal sphincter after the barium meal.4 Asexpected,729 another independent predictor ofneed for continuous treatment was the presenceof endoscopic oesophagitis at initial evaluation.Taken together, these results suggest thatrefractoriness to conservative treatment inGORD is due to the severity of the reflux itself.

For such a common disease as GORD, it issurprising how little is known about the longterm outcome of treated patients. Studies ofpatients with oesophagitis followed up forperiods of two to three years under continuoustreatment with antacids32 or H2 blockers with orwithout added metoclopramide" indicate that asignificant proportion of patients have frequentsymptomatic relapses when treatment is taperedoff. On the other hand, continuous treatment ofpatients with complicated GORD with a combi-nation of general anti-reflux measures, antacids,and standard doses of ranitidine is useful in

controlling symptoms for up to two years,although surgical treatment is more effective.35 Arecent study suggests that most patients withnon-erosive GORD treated with antacids, butnot advised on lifestyle changes, have persistingsymptoms after one year.36 Schindlbeck et al37have recently reported that less than a quarter ofpatients with conventional GORD treated con-servatively improve after three years; thesepatients, however, were not directly followed upby the authors after diagnosis, and no mention ismade of modifications in lifestyle.37 A differentpicture emerges from our study, which showsthat more than half of unselected patients withGORD do well with simple modes of treatmentfor up to six years. Consequently, the clinicalcourse of GORD under continuous medicalsurveillance seems to be more benign thanpreviously presumed.The clinical experience gained in this study

supports the notion that conservative treatmentshould be tried initially in patients with refluxsymptoms.32' 30 Many patients will be expectedto have a lasting response to this simple, low costapproach. In non-responding patients, radio-logical, endoscopic, and manometric findingshave predictive value for the long term outcomeand can help in the early selection of candidatesfor anti-reflux surgery or, alternatively, sus-tained pharmacological acid suppression.This work was supported in part by grants 85/1130 and 90/0505from FIS, Spanish Ministry of Health, a grant of the HospitalClinic i Provincial to Dr A Pujol, and the Fundaci6 Catalana perl'Estudi de les Malalties del Fetge i Gastroenterol6giques.

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2 Graham DY, Smith JL, Patterson DJ. Why do apparentlyhealthy people use antacid tablets? Amj Gastroenterol 1983;78: 257-60.

3 Castell DO. Overview of treatment of gastroesophageal refluxdisease. In: Casteli DO, Wu WC, Ott DJ, eds. Gastro-esophageal reflux disease: pathogenesis, diagnosis, therapy.Mount Kisco, NY: Futura, 1985: 211-20.

4 Dehn TCB. Surgery for uncomplicated gastrooesophagealreflux. Gut 1992; 33: 293-4.

5 Heading RC. Epidemiology of oesophageal reflux disease.Scandj Gastroenterol 1989; 24 (suppl 168): 33-7.

6 Koelz HR. Treatment of reflux esophagitis with H2-blockers,antacids and prokinetic drugs: an analysis of randomizedclinical trials. ScandJ Gastroenterol 1989; 24 (suppl 156): 25-36.

7 Koelz HR, Birchler R, Bretholz A, Bron B, Capitaine Y,Delmore G, et al. Healing and relapse of reflux oesophagitisduring treatment with ranitidine. Gastroenterology 1986; 91:1198-205.

8 Sandmark S, Carlsson R, Fausa 0, Lundell L. Omeprazole orranitidine in the treatment of reflux esophagitis. Results of adouble-blind, randomized, Scandinavian multicenter study.Scandj Gastroenterol 1988; 23: 625-32.

9 Glise H. Healing, relapse rates and prophylaxis of refluxesophagitis. ScandJ Gastroenterol 1989; 24 (suppl 156): 57-64.

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