Effect of Cisapride on Relapse of Reflux Oesophagitis, Healed with an Antisecretory Drug
Scand J Gastroenterol Downloaded from informahealthcare.com by UB Heidelberg on 11/16/14 For personal use only.
G. N . J . TYTGAT, 0. J . ANKER HANSEN, L. CARLING, G . H. de GROOT. H. GELDOF, H. GLISE, P. EFSKIND, L. ELSBORG, A. L. KARVONEN, B. OHLIN, 0 . H. SOLHAUG, B. VEKMEERSCH & OTHER SCANEDCIS TRIALISTS* Dept. o f Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands; Dept. of Gastroenterology, Lakar Hospital, Motala, Sweden; Dept. of Gastroenterology, Bollnas Hospital, Bollnas. Sweden; Dept. of Internal Medicine, Red Cross Hospital, Beverwijk/Heemskeerk, The Netherlands; Dept. of Gastroenterology, Bergweg Hospital, Rotterdam, The Netherlands; Dept. of Gastroenterology, Central Hospital, Vanersborg, Sweden; Dept. of Gastroenterology, 0stfold Hospital, Fredrikstad, Norway; Dept. of Gastroenterology, Hillersd Hospital, Hillered, Denmark; Dept. of Gastroenterology, University Central Hospital, Tamperc, Finland; Dept. of Gastroenterology, Central Hospital, Karlskrona, Sweden; Dept. of Gastroenterology, Hedmark Central Hospital, Elverum, Norway: and Dept. of Gastroenterology, Academic Hospital, Ghent, Belgium Tytgat GNJ, Anker Hansen OJ, Carling L, de Groot GH, Geldof H, Glise H, Efskind P, Elsborg L, Karvonen AL, Ohlin B, Solhaug OH, Vermeersch B, Other Scanedcis Trialists. Effect of cisapride on relapse of reflux oesophagitis, healed with an antisecretory drug. Scand J Gastroenterol 1992, 27, 175-183 Maintenance treatment with cisapride was evaluated in 298 patients in whom reflux oesophagitis had been healed with antisecretory drugs. Initially, 34% of the patients had grade-I oesophagitis, 33% had grade 11, and 33% had grade 111. The paticnts were treated with 20 mg cisapride twice daily or placebo for 6 months or until endoscopic relapse was shown if this occurred earlier. Survival analysis showed that cisapride significantly prolonged the time to endoscopic relapse in grade-I patients (P = 0.02). The intergroup difference in symptomatic relapse in all patients was also significant ( P = 0.010). ’The effect of cisapride was less clearcut in grade 11 or 111, and/or in patients healed with omeprazole. Factors associated with early relapse were placebo therapy, prior omeprazole therapy, duration of pre-trial symptomatic period, and initial endoscopic severity grade. Adverse experiences were limited; diarrhoea was reported by 9% of the cisapride patients.
Key words: Acid suppression; cisapride: maintenance treatment; omeprazole; reflux oesophagitis; relapse Prof. G. N . J . Tytgat, Dept. of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 A Z Amsterdam, The Netherlands
Drug therapy of reflux oesophagitis is aimed at neutralizing or suppressing gastric acid (H2-receptor antagonists, omeprazole). protecting the damaged mucosal tissue (sucralfate), and/or improving upper gastrointestinal motility, in particular lower oesophageal sphincter pressure, oesophageal clearance, and gastric emptying (prokinetic agents) (1). The latter group of drugs has not received much attention in this condition, probably owing to a lack of efficacy (2). The effect of cisapride in the treatment of oesophagitis has
been the subject of several trials ( 2 , 3 ) .Cisapride was shown to be superior to placebo (4,5) and comparable with cimetidine and ranitidine in producing endoscopically shown mucosal healing ( 6 8 ) . In one placebo-controlled trial in the USA, healing rates during treatment with cisapride were lower than those reported in Europe (9). In two placebocontrolled trials, 20 mg cisapride daily also prevented relapse of oesophagitis (10, 11). In these trials, in which patients had had mainly grade-I or -11 oesophagitis before the healing
* Other Scanedcis trialists: Belgium: F. Barbier and A. Elewaut, Dept. of Gastroenterology, Academic Hospital, Ghent; Denmark: E. Krag, Dept. of Gastroenterology, Hvidovre Hospital, Hvidovre; Finland: M. Farkkila and T. Miettiner, Dept. of Medicine, University of Helsinki, Helsinki; Norway: A . Rosseland, Dept. of Gastroenterology, Akerhus Central Hospital, Nordbyhagen, and S. Wetterhus, Dept. of Gastroenterology, Kongsvinger Hospital, Kongsvinger; Sweden: B. Bergmann, Dept. of Gastroenterology, Ludvika Hospital, Ludvika; T. Hallgren, Dept. of Gastroenterology, Kungalv Hospital, Kungalv; R . Jansson, Dept. of Gastroenterology, Boras Hospital, Boras; I. Kagevi, Dept. of Gastroenterology, Karn Hospital, Skiivde; B. Person, Dept. of
Gastroenterology, Hudiksvall Hospital, Hudiksvall; and P. Unge, Dept. of Gastroenterology, Sandviken Hospital, Sandviken; and The Netherlands: W. Dekker, Dept. of Gastroenterology, St. Elisabeth’s of Groote Hospital, Haarlem; L. C. J . B. Engels, Dept. of Internal Medicine, Hospital ‘De Goddelijke Voorzienigheid’, Sittard; J . H. Goedhard, Dept. of Internal Medicine, St. Jozef Hospital, Kerkrade; R. Groenendijk, Dept. of Internal Medicine, Holy Hospital, Vlaardingen; J . J . Nicolai, Dept. of Gastroenterology, Leyenburg Hospital, Den Haag; M. Schrijver, Dept. of Internal Medicine, Bronovo Hospital, ’s Gravenhage; and J . Van Spreeuwel, Dept. of Gastroenterology, Eindhoven Catharina Hospital, Eindhoven.
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treatment. relapse rates were 20% with cisapride and 39%~ including vagotomy or fundoplication (excluding cholccystectomy, appendectomy, or repair o f inguinal hernia), with placebo at 6 months of treatment (11) and 33% with cisapride and 51% with placebo at 12 months of treatment inflammatory bowel disease, advanced renal, cardiac, hepatic, or pulmonary disease, malignancy, and expected (10). poor conipliance were excluded. Oesophageal columnar The aim of thc present trial was to investigate further the metaplasia, with or without previous ulceration, was not a effect of maintenance therapy with o r a l cisnpride on the recurrence of reflux symptoms and oesophagitis. The trial reason for exclusion. Each patient gave written informed consent before entry in the trial. Approval was obtained design was specifically geared to evaluating the influence of the initial gradc of oesophagitis on relapsc. In addition, the from the ethical committccs of the participating centres. At selection, patients were stratified in accordance with potential prognostic significance of other patient-, disease-. and therapy-related variables was investigated. Cisapride the initial grade o f severity of oesophagitis (grades I , 11, was compared with placebo in patients in whom prior healing 111) into three categories. Each participating centre had to include an equal number of patients in the three categories. of oesophagitis was obtained with antisecretory agents. The chosen dose o f ciaapride, 20mg twicc daily, which is the The medication was randoniizett in accordance with a conidose used for healing of oesophagitis ( 4 7 ) , was double the puter-generated list based on this stratification. In a doubleblind fashion, patients were assigned to 20 rng cisapride twice one used in previous maintenance trials (10. 11 ) in view of the expected high number of patients with severe. rather daily or matching placebo. Thc dr-ug was to b c taken IS30 niin before breakfast arid before dinner. The treatment recalcitrant reflux oesophagitis. lasted for up to 6 months. Use of concomitant medication affccting the motility of MATERIALS AND METHODS the upper gastrointestinal tract (cholinergics, antrcholinergics, antiemetics, and other prokinetics), sucrnlfate, H2Pntienl .veliwion rind trial design receptor antagonists (1l2RA), omcprazole. and prostaAdult ambulatory patients were entered i n the trial after endoscopic evidence of healing of oesophagitis with an anti- glandin analogues was prohibited. Minor tranquillizers, lowsecretory agent had been obtained within I week before dose 11,-antihistaininics, and adrcnergic and adrcnolytic inclusion in the trial. Patients with oesophageal stenosis, drugs were allowed and registered on the casc record forms. concurrent gastric or duodenal ulcer, gastrointestinal surgery Patients were explicitly asked not to take antacids. At each
Table I. Base-line characteristics of patients
--___
Cisapride No. of patients (malc/lcmalc) Severity of ocsophagitis; no. of patients ('% ) 0.1) with regard to all patient characteristics at base line. At the start of the trial concurrent disorders and corresponding medications were present in one-third of all patients. Hypertension was the most frequent concomitant condition, being present in 9% of the patients. There were no differences in base-line characteristics between the groups except that the use of hypoglycaemics for diabetes was more common in the placebo group.
Table 11. Mean relative score* for the three reflux symptoms separately and combined Symptom ~~
Group
Start of maintenance
Cisapride Placebo Cisapride Placebo Cisapride Placebo Cisapride Placebo
13 10 9 11 10 10 11 10
End pointt
~
Heartburn Regurgitation Epigastric pain Reflux$
33 ( P = 0.11) 41
2" (' = 0'03) 29 21 ( p = 0.49) 26 25 ('= o'037) 32
* Score expressed as percentage of the maximum score, being the sum of the scores for frequency, severity, and day/night occurrence. t In parentheses, cisapride versus placebo. $ Reflux score: sum of the scores for the three symptoms.
179
Endoscopy Overall, no control endoscopy was performed in 14 patients of the placebo group and in 8 of the cisapride group because they were lost to follow-up or had discontinued the treatment, for different reasons; no endoscopy was performed in only 5 (3%) of the 170 patients who had symptoms suggestive of relapse. The time to endoscopically proven recurrence of oesophagitis in each of the three grades, as estimated by survival analysis, is shown in Fig. 1. The divergence between the cisapride and placebo groups was significant ( P = 0.02) for grade I but not for grade TI or 111. The time to endoscopic relapse in the first quartile of the cisapride and placebo patients was 87 days and 47 days for grade I; in this stratum the median time to relapse could not be calculated in cisapride patients since less than 50% of the patients relapsed. For the other two grades the median time to relapse was longer in the cisapride than in the placebo group (180 days versus 126 days for grade I1 and 180 days versus 125 days for grade 111).
Symptoms
Symptoms suggestive of relapse recurred earlier ( P = 0.010) in the placebo group than in the cisapride group (Fig. 2). At 6 months the estimated overall recurrence rates I 111) were 55% for cisapride and 79% for (grades I placebo. The median time to recurrence was 168 days and 93 days, respectively. Table 11 shows the relative reflux scores at the start and the end of treatment. At the end point not only patients with symptom recurrence were taken into account but also patients who were still in remission and who were likely to have a minimal contribution to the symptom severity in the group. Yet, at this time, there was a difference between the two groups with regard to severity score ( P = 0.048), frequency score ( P = 0.041), time (day/night) of symptoms ( P = 0.048), average duration of reflux episodes ( P = 0.027), and total score ( P = 0.031) for regurgitation. For heartburn there was a tendency towards a lower total score ( P = 0.11) at end point in the cisapride group. This difference should be seen in the light of the tendency ( P = 0.097) towards more severe heartburn in the cisapride group at the start (heartburn was absent in 88 cisapride versus 105 placebo patients). Moreover, at end point the number of patients with mild and occasional heartburn, occurring for only a few minutes during either the day or the night, was significantly higher in the cisapride group (34 of 146 versus 12 of 149; P < 0.0001). For epigastric pain the overall difference in total score was not significant, but, again, more cisapride patients had this symptom at the start, and at end point significantly more cisapride patients (21 of 146 versus 10 of 149; p = 0.037) had the lowest possible score. The relative total reflux score, expressed as a percentage of the maximal possible score, was similar in the two groups at the start of
+ +
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G . N . J . Tytgat er al.
the maintenance trial but was different at the end of the maintenance trial ( P = 0.037). The global occurrence of other associated symptoms was similar in the two groups. Belching, postprandial fullness, or early satiety and epigastric bloating prevailed, being reported by about one-quarter of the patients. Anorexia, vomiting, and nocturnal coughing or wheezing were limited and hardly changed. At end point, slightly more placebo patients reported belching (36%; versus 25% with cisapride) and postprandial fullness (24%) versus 17%). Dysphagia, oesophageal pain on swallowing. and nausea were noted in twice as many patients (about 20%') ;it end point a s tit the start in both the placebo and the cisapride group. This change was due to worsening of the condition in relnpsers. Examination of the response of associated symptoms in relapsers versus non-relapscrs in 'untreated' (placebo) patients disclosed that hardly any change was noted in nonrelnpsers, and, if anything, symptoms further irnprcwed in timc. whereas in relapsers some symptoms did not substantially recur (postprandial fullness, epigastric hloating). and some clearly worsened (belching. from 27% at the start to 42%) of paticiits at end point; nausea. from 9%. t o 21 7%;
placebo
I
200
1
0
30
- - - -- - .
.
1
'
60
1
90
.
1
120
.
1
150
.
1
180
days
orneprazole H2 -RA
Fig. 3. Endoscopic relapse (percentage of patients in remission) in patients hcaled with omeprazole or with an H2-rcccptor antagonist and maintained with cisapride or placebo. "Intergruup difference, logrank test.
dysphagia, from 6% to 26%; pain on swallowing, from 6% to 20%). At the start of the maintenance trial the VAS scores were comparable in the cisapride and placebo group; mean scores for general well-being we.e 76 and 77, respectively. and for reflux symptoms 19 and 21. As compared with placebo, cisapride tended to limit (68 versus 63 for placebo; P = 0.15) the decline in general well-being. Deterioration or reappearance of reflux symptoms was significantly prevented by cisapride (mean score at end point, 36 versus 46 f o r placebo; P = 0.014).
Relationship betweeri syrrrptorns rind lesions The association between symptoms suggestive of relapse and the endoscopic presence of abnormalities was determined on the basis of all cases in which both assessments were made. In 8 2 % of all cases (cisapride + placebo) in which suggestivc symptoms were present, mucosal lesions were also present. In 93% of all cases in which suggestive symptoms were absent, lesions were also absent. Looking at this relationship from the endoscopic perspective gave a similar result: in 77% of all endoscopic relapses, recurrence of symptoms was seen a s well, and in 95% of itll cases in which no endoscopic relapse was noted, no symptoms were reported cither. These symptom-lesion relationships were similar in the cisapride and placebo group. Prognostic factors Apart from the treatment (longer remission with cisapride than with placebo; P = 0.036), the factors that possibly influenced relapse were, in the order of their importance: total duration of the symptomatic period during the most recent episode of oesophagitis (the shorter this duration, the longer the remission: P < 0.00 I ) , healing treatment with orneprazole (associated with earlier relapse; P
Scand J Gastroenterol Downloaded from informahealthcare.com by UB Heidelberg on 11/16/14 For personal use only.
G. N . J . TYTGAT, 0. J . ANKER HANSEN, L. CARLING, G . H. de GROOT. H. GELDOF, H. GLISE, P. EFSKIND, L. ELSBORG, A. L. KARVONEN, B. OHLIN, 0 . H. SOLHAUG, B. VEKMEERSCH & OTHER SCANEDCIS TRIALISTS* Dept. o f Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands; Dept. of Gastroenterology, Lakar Hospital, Motala, Sweden; Dept. of Gastroenterology, Bollnas Hospital, Bollnas. Sweden; Dept. of Internal Medicine, Red Cross Hospital, Beverwijk/Heemskeerk, The Netherlands; Dept. of Gastroenterology, Bergweg Hospital, Rotterdam, The Netherlands; Dept. of Gastroenterology, Central Hospital, Vanersborg, Sweden; Dept. of Gastroenterology, 0stfold Hospital, Fredrikstad, Norway; Dept. of Gastroenterology, Hillersd Hospital, Hillered, Denmark; Dept. of Gastroenterology, University Central Hospital, Tamperc, Finland; Dept. of Gastroenterology, Central Hospital, Karlskrona, Sweden; Dept. of Gastroenterology, Hedmark Central Hospital, Elverum, Norway: and Dept. of Gastroenterology, Academic Hospital, Ghent, Belgium Tytgat GNJ, Anker Hansen OJ, Carling L, de Groot GH, Geldof H, Glise H, Efskind P, Elsborg L, Karvonen AL, Ohlin B, Solhaug OH, Vermeersch B, Other Scanedcis Trialists. Effect of cisapride on relapse of reflux oesophagitis, healed with an antisecretory drug. Scand J Gastroenterol 1992, 27, 175-183 Maintenance treatment with cisapride was evaluated in 298 patients in whom reflux oesophagitis had been healed with antisecretory drugs. Initially, 34% of the patients had grade-I oesophagitis, 33% had grade 11, and 33% had grade 111. The paticnts were treated with 20 mg cisapride twice daily or placebo for 6 months or until endoscopic relapse was shown if this occurred earlier. Survival analysis showed that cisapride significantly prolonged the time to endoscopic relapse in grade-I patients (P = 0.02). The intergroup difference in symptomatic relapse in all patients was also significant ( P = 0.010). ’The effect of cisapride was less clearcut in grade 11 or 111, and/or in patients healed with omeprazole. Factors associated with early relapse were placebo therapy, prior omeprazole therapy, duration of pre-trial symptomatic period, and initial endoscopic severity grade. Adverse experiences were limited; diarrhoea was reported by 9% of the cisapride patients.
Key words: Acid suppression; cisapride: maintenance treatment; omeprazole; reflux oesophagitis; relapse Prof. G. N . J . Tytgat, Dept. of Gastroenterology and Hepatology, Academic Medical Centre, Meibergdreef 9, 1105 A Z Amsterdam, The Netherlands
Drug therapy of reflux oesophagitis is aimed at neutralizing or suppressing gastric acid (H2-receptor antagonists, omeprazole). protecting the damaged mucosal tissue (sucralfate), and/or improving upper gastrointestinal motility, in particular lower oesophageal sphincter pressure, oesophageal clearance, and gastric emptying (prokinetic agents) (1). The latter group of drugs has not received much attention in this condition, probably owing to a lack of efficacy (2). The effect of cisapride in the treatment of oesophagitis has
been the subject of several trials ( 2 , 3 ) .Cisapride was shown to be superior to placebo (4,5) and comparable with cimetidine and ranitidine in producing endoscopically shown mucosal healing ( 6 8 ) . In one placebo-controlled trial in the USA, healing rates during treatment with cisapride were lower than those reported in Europe (9). In two placebocontrolled trials, 20 mg cisapride daily also prevented relapse of oesophagitis (10, 11). In these trials, in which patients had had mainly grade-I or -11 oesophagitis before the healing
* Other Scanedcis trialists: Belgium: F. Barbier and A. Elewaut, Dept. of Gastroenterology, Academic Hospital, Ghent; Denmark: E. Krag, Dept. of Gastroenterology, Hvidovre Hospital, Hvidovre; Finland: M. Farkkila and T. Miettiner, Dept. of Medicine, University of Helsinki, Helsinki; Norway: A . Rosseland, Dept. of Gastroenterology, Akerhus Central Hospital, Nordbyhagen, and S. Wetterhus, Dept. of Gastroenterology, Kongsvinger Hospital, Kongsvinger; Sweden: B. Bergmann, Dept. of Gastroenterology, Ludvika Hospital, Ludvika; T. Hallgren, Dept. of Gastroenterology, Kungalv Hospital, Kungalv; R . Jansson, Dept. of Gastroenterology, Boras Hospital, Boras; I. Kagevi, Dept. of Gastroenterology, Karn Hospital, Skiivde; B. Person, Dept. of
Gastroenterology, Hudiksvall Hospital, Hudiksvall; and P. Unge, Dept. of Gastroenterology, Sandviken Hospital, Sandviken; and The Netherlands: W. Dekker, Dept. of Gastroenterology, St. Elisabeth’s of Groote Hospital, Haarlem; L. C. J . B. Engels, Dept. of Internal Medicine, Hospital ‘De Goddelijke Voorzienigheid’, Sittard; J . H. Goedhard, Dept. of Internal Medicine, St. Jozef Hospital, Kerkrade; R. Groenendijk, Dept. of Internal Medicine, Holy Hospital, Vlaardingen; J . J . Nicolai, Dept. of Gastroenterology, Leyenburg Hospital, Den Haag; M. Schrijver, Dept. of Internal Medicine, Bronovo Hospital, ’s Gravenhage; and J . Van Spreeuwel, Dept. of Gastroenterology, Eindhoven Catharina Hospital, Eindhoven.
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G . N . J . Tyigat et a1
treatment. relapse rates were 20% with cisapride and 39%~ including vagotomy or fundoplication (excluding cholccystectomy, appendectomy, or repair o f inguinal hernia), with placebo at 6 months of treatment (11) and 33% with cisapride and 51% with placebo at 12 months of treatment inflammatory bowel disease, advanced renal, cardiac, hepatic, or pulmonary disease, malignancy, and expected (10). poor conipliance were excluded. Oesophageal columnar The aim of thc present trial was to investigate further the metaplasia, with or without previous ulceration, was not a effect of maintenance therapy with o r a l cisnpride on the recurrence of reflux symptoms and oesophagitis. The trial reason for exclusion. Each patient gave written informed consent before entry in the trial. Approval was obtained design was specifically geared to evaluating the influence of the initial gradc of oesophagitis on relapsc. In addition, the from the ethical committccs of the participating centres. At selection, patients were stratified in accordance with potential prognostic significance of other patient-, disease-. and therapy-related variables was investigated. Cisapride the initial grade o f severity of oesophagitis (grades I , 11, was compared with placebo in patients in whom prior healing 111) into three categories. Each participating centre had to include an equal number of patients in the three categories. of oesophagitis was obtained with antisecretory agents. The chosen dose o f ciaapride, 20mg twicc daily, which is the The medication was randoniizett in accordance with a conidose used for healing of oesophagitis ( 4 7 ) , was double the puter-generated list based on this stratification. In a doubleblind fashion, patients were assigned to 20 rng cisapride twice one used in previous maintenance trials (10. 11 ) in view of the expected high number of patients with severe. rather daily or matching placebo. Thc dr-ug was to b c taken IS30 niin before breakfast arid before dinner. The treatment recalcitrant reflux oesophagitis. lasted for up to 6 months. Use of concomitant medication affccting the motility of MATERIALS AND METHODS the upper gastrointestinal tract (cholinergics, antrcholinergics, antiemetics, and other prokinetics), sucrnlfate, H2Pntienl .veliwion rind trial design receptor antagonists (1l2RA), omcprazole. and prostaAdult ambulatory patients were entered i n the trial after endoscopic evidence of healing of oesophagitis with an anti- glandin analogues was prohibited. Minor tranquillizers, lowsecretory agent had been obtained within I week before dose 11,-antihistaininics, and adrcnergic and adrcnolytic inclusion in the trial. Patients with oesophageal stenosis, drugs were allowed and registered on the casc record forms. concurrent gastric or duodenal ulcer, gastrointestinal surgery Patients were explicitly asked not to take antacids. At each
Table I. Base-line characteristics of patients
--___
Cisapride No. of patients (malc/lcmalc) Severity of ocsophagitis; no. of patients ('% ) 0.1) with regard to all patient characteristics at base line. At the start of the trial concurrent disorders and corresponding medications were present in one-third of all patients. Hypertension was the most frequent concomitant condition, being present in 9% of the patients. There were no differences in base-line characteristics between the groups except that the use of hypoglycaemics for diabetes was more common in the placebo group.
Table 11. Mean relative score* for the three reflux symptoms separately and combined Symptom ~~
Group
Start of maintenance
Cisapride Placebo Cisapride Placebo Cisapride Placebo Cisapride Placebo
13 10 9 11 10 10 11 10
End pointt
~
Heartburn Regurgitation Epigastric pain Reflux$
33 ( P = 0.11) 41
2" (' = 0'03) 29 21 ( p = 0.49) 26 25 ('= o'037) 32
* Score expressed as percentage of the maximum score, being the sum of the scores for frequency, severity, and day/night occurrence. t In parentheses, cisapride versus placebo. $ Reflux score: sum of the scores for the three symptoms.
179
Endoscopy Overall, no control endoscopy was performed in 14 patients of the placebo group and in 8 of the cisapride group because they were lost to follow-up or had discontinued the treatment, for different reasons; no endoscopy was performed in only 5 (3%) of the 170 patients who had symptoms suggestive of relapse. The time to endoscopically proven recurrence of oesophagitis in each of the three grades, as estimated by survival analysis, is shown in Fig. 1. The divergence between the cisapride and placebo groups was significant ( P = 0.02) for grade I but not for grade TI or 111. The time to endoscopic relapse in the first quartile of the cisapride and placebo patients was 87 days and 47 days for grade I; in this stratum the median time to relapse could not be calculated in cisapride patients since less than 50% of the patients relapsed. For the other two grades the median time to relapse was longer in the cisapride than in the placebo group (180 days versus 126 days for grade I1 and 180 days versus 125 days for grade 111).
Symptoms
Symptoms suggestive of relapse recurred earlier ( P = 0.010) in the placebo group than in the cisapride group (Fig. 2). At 6 months the estimated overall recurrence rates I 111) were 55% for cisapride and 79% for (grades I placebo. The median time to recurrence was 168 days and 93 days, respectively. Table 11 shows the relative reflux scores at the start and the end of treatment. At the end point not only patients with symptom recurrence were taken into account but also patients who were still in remission and who were likely to have a minimal contribution to the symptom severity in the group. Yet, at this time, there was a difference between the two groups with regard to severity score ( P = 0.048), frequency score ( P = 0.041), time (day/night) of symptoms ( P = 0.048), average duration of reflux episodes ( P = 0.027), and total score ( P = 0.031) for regurgitation. For heartburn there was a tendency towards a lower total score ( P = 0.11) at end point in the cisapride group. This difference should be seen in the light of the tendency ( P = 0.097) towards more severe heartburn in the cisapride group at the start (heartburn was absent in 88 cisapride versus 105 placebo patients). Moreover, at end point the number of patients with mild and occasional heartburn, occurring for only a few minutes during either the day or the night, was significantly higher in the cisapride group (34 of 146 versus 12 of 149; P < 0.0001). For epigastric pain the overall difference in total score was not significant, but, again, more cisapride patients had this symptom at the start, and at end point significantly more cisapride patients (21 of 146 versus 10 of 149; p = 0.037) had the lowest possible score. The relative total reflux score, expressed as a percentage of the maximal possible score, was similar in the two groups at the start of
+ +
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G . N . J . Tytgat er al.
the maintenance trial but was different at the end of the maintenance trial ( P = 0.037). The global occurrence of other associated symptoms was similar in the two groups. Belching, postprandial fullness, or early satiety and epigastric bloating prevailed, being reported by about one-quarter of the patients. Anorexia, vomiting, and nocturnal coughing or wheezing were limited and hardly changed. At end point, slightly more placebo patients reported belching (36%; versus 25% with cisapride) and postprandial fullness (24%) versus 17%). Dysphagia, oesophageal pain on swallowing. and nausea were noted in twice as many patients (about 20%') ;it end point a s tit the start in both the placebo and the cisapride group. This change was due to worsening of the condition in relnpsers. Examination of the response of associated symptoms in relapsers versus non-relapscrs in 'untreated' (placebo) patients disclosed that hardly any change was noted in nonrelnpsers, and, if anything, symptoms further irnprcwed in timc. whereas in relapsers some symptoms did not substantially recur (postprandial fullness, epigastric hloating). and some clearly worsened (belching. from 27% at the start to 42%) of paticiits at end point; nausea. from 9%. t o 21 7%;
placebo
I
200
1
0
30
- - - -- - .
.
1
'
60
1
90
.
1
120
.
1
150
.
1
180
days
orneprazole H2 -RA
Fig. 3. Endoscopic relapse (percentage of patients in remission) in patients hcaled with omeprazole or with an H2-rcccptor antagonist and maintained with cisapride or placebo. "Intergruup difference, logrank test.
dysphagia, from 6% to 26%; pain on swallowing, from 6% to 20%). At the start of the maintenance trial the VAS scores were comparable in the cisapride and placebo group; mean scores for general well-being we.e 76 and 77, respectively. and for reflux symptoms 19 and 21. As compared with placebo, cisapride tended to limit (68 versus 63 for placebo; P = 0.15) the decline in general well-being. Deterioration or reappearance of reflux symptoms was significantly prevented by cisapride (mean score at end point, 36 versus 46 f o r placebo; P = 0.014).
Relationship betweeri syrrrptorns rind lesions The association between symptoms suggestive of relapse and the endoscopic presence of abnormalities was determined on the basis of all cases in which both assessments were made. In 8 2 % of all cases (cisapride + placebo) in which suggestivc symptoms were present, mucosal lesions were also present. In 93% of all cases in which suggestive symptoms were absent, lesions were also absent. Looking at this relationship from the endoscopic perspective gave a similar result: in 77% of all endoscopic relapses, recurrence of symptoms was seen a s well, and in 95% of itll cases in which no endoscopic relapse was noted, no symptoms were reported cither. These symptom-lesion relationships were similar in the cisapride and placebo group. Prognostic factors Apart from the treatment (longer remission with cisapride than with placebo; P = 0.036), the factors that possibly influenced relapse were, in the order of their importance: total duration of the symptomatic period during the most recent episode of oesophagitis (the shorter this duration, the longer the remission: P < 0.00 I ) , healing treatment with orneprazole (associated with earlier relapse; P
