Omeprazole and Ranitidine in Duodenal Ulcer Healing Analysis of Comparative Clinical Trials
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
C. J. J . MULDER & D. L. SCHIPPER Dept. of Hepatogastroenterology, Rijnstate Hospital, Arnhem, The Netherlands Mulder CJJ, Schipper DL. Omeprazole and ranitidine in duodenal ulcer healing. Analysis of comparative clinical trials. Scand J Gastroenterol 1990, 2S(suppl 178), 62-66 Ten double-blind randomized studies with omeprazole versus ranitidine in duodenal ulcer healing have been published. The total number of patients in the trials amounted to 2225. To detect treatment differences. a meta-analysis was performed. After 2 and 4 weeks of treatment results have been evaluated. After 2 weeks of treatment omeprazole produced higher healing rates than ranitidine in nine studies. However, at 4 weeks numerical differences in favour of omeprazole were found in nine studies. Relief of ulcer symptoms occurred more rapidly with omeprazole than ranitidine. No major clinical or biochemical side effects were recorded. However, no data are available about maintenance therapy in double-blind randomized studies comparing both drugs or about rebleeding rates in bleeding duodenal ulcer treatment. Key words: Duodenal ulcer; meta-analysis; multicentre trials; omeprazole; ranitidine Chris J. J . Mulder, M. D . , Depr. of Heparogasrroenrerology, Rijnstare Hospiral-GZ, P . 0. Box Y555. 6800 TA Arnheim, The Netherlands
Omeprazole, a substituted benzimidazole, is a potent inhibitor of H+.K+-ATPase,the end-point in the acid secretion process (1). In several studies treatment with omeprazole has healed duodenal ulcers in almost all patients (2, 3). Furthermore, omeprazole is effective in healing reflux oesophagitis ( 4 6 ) and in patients with the ZollingerEllison syndrome (7). It has been shown to be effective in the treatment of peptic ulcer and reflux oesophagitis resistant to H2-receptor antagonists (2, 5, 6, 8). Until a few years ago it was difficult to foresee any agent challenging the dominance of Hz-blockers such as ranitidine and cimetidine during this century. Ranitidine seems to fulfil the criteria of clinical need and efficacy (9-13). We have examined the data from trials comparing the effects of omeprazole and ranitidine on the rate of duodenal ulcer healing and the proportion of symptom-free patients. We here subject these to meta-analysis in an attempt to assess the differences, if any, between omeprazole and ranitidine.
Studies comparing the two drugs in long-term treatment are not available. Studies comparing both drugs in acute (bleeding) duodenal ulcers and comparing rebleeding rates after an initial stop of the bleeding after sclerotherapy are not yet available. METHODS The aim of the analysis was to compare healing rates of omeprazole in the recommended dose of 20mg in the morning with the recommended doses of ranitidine-that is, 150mg twice daily and 300 mg at bedtime in the short-term treatment of duodenal ulcer. A search of the published literature identified 10 such trials (1424). Basic clinical trial information was necessary to ensure comparability of groups, and the following criteria were used to identify clinical trials that might be suitable for pooling. The publication had to contain statements on randomization, doubleblindness, information on patient demography, and the use of endoscopy for diagnosis and
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
Omeprazole and Ranitidine in DU Healing
assessment of duodenal ulcer healing. Unhealed ulcers had to be treated for at least 4 weeks, with endoscopy at 2 and 4 weeks. The number of patients together with the number and/or percentage of patients healed was also required. The Mantel-Haenszel chi-square test for comparison of proportions from independent samples was used for evaluation of overall results (25). There were other trials comparing omeprazole with ranitidine. Some were reported only as abstract, and no further data are available. In most of these trials patients had duodenal ulcers that were resistant to previous therapy with H2receptor antagonists. For that reason we excluded these studies from our study. However, for individual therapeutic considerations these studies are very interesting (2. 8). RESULTS Nine of the 10 studies on 20mg omeprazole in the morning versus 150mg ranitidine twice daily or
63
300mg at bedtime exhibited greater healing rates after 2 weeks of treatment for the omeprazole group, and 7 of the studies showed a statistically significant advantage for omeprazole at the 5% significance level. The overall difference was 16.5 percentage points based on a healing rate of 69.3% for omeprazole and 52.8% for ranitidine (p < 0.0001). At 4 weeks the healing rates were 92.8% and 83.1%, respectively, with a difference of 9.7 percentage points (p < 0.0001). Three trials compared 20 mg omeprazole in the morning with 300 mg ranitidine at bedtime (14, 15. 17). Seven trials compared 20mg omeprazole in the morning with 150mg ranitidine twice daily (16, 1&22, 24). Omeprazole demonstrated significantly higher healing rates than 150mg ranitidine twice daily and 300mg ranitidine at bedtime both at day 15 and at day 29 (Table 1-111). The difference in proportions of patients without symptoms 2 weeks after start of treatment was about 14% favouring omeprazole (71.1% versus 57.60/0; p < 0.001).
Table I. Details of the 10 trials comparing omeprazole and ranitidine ~~
~~
Endoscopic healing, YO Reference
Trial no.
Design*
Treatment groups
No.
2 weeks
4 weeks
114 115 126 122 83 87 84 69 66 146 160 91 90
75 46 79 61 77 86 63 65 39 72 59 63 65
64 64
66
97 83 91 80 95 96 93 97 81 96 92 91 96 97 85 97 loo 82 82 63 94 88
~~
Chelvam (14)
A
McFarland (15)
B
Hui (16)
C
Marks (17)
D
Classen (IS)
E
Mulder (19)
F
Barbara (20)
G
Bardhan (21)
H
Deventer (22)
I
Lind (23)
J
R , DB. MC Omeprazole. 20 mg in the morning Ranitidine. 300 mgat bedtime R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 300 mg at bedtime Omeprazole, l0mgin the morning R.DB Omeprazole, 20 mg in the morning Ranitidine, 150 mg twice daily Omeprazole, 20 mg in the morning R,DB Ranitidine, 300mgat bedtime R , D B . M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B . M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mg in the morning Omeprazole, 40mg in the morning Ranitidine, 150mgtwice daily R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mgin the morning Ranitidine, 150 mg twice daily
R := randomized; D B = double-blind: MC = multicentre
34 36 35 151 158 167 163
53 83 83 53 42 34 69 54
C. J. J. Mulder & D. L. Schipper
64
Table 11. Percentage difference and power for studies included in meta-analysis results after 2 weeks of treatment: 20 mg omeprazole in the morning versus ranitidine, 150 mg twice daily or 300 mg at bedtime
Trial no.
Healed after 2 weeks, YO Omeprazole
~~
~
A
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
Ranitidine
76 79 86 65 72 63 66 83 42 69
B C D E F G H I J
46 61 63 39 59 65 53 53 34 54
95% Confidence interval andp values for chi-square test and Fisher exact test Difference (0-R), %
+30
+ 18 +23 +26 + 13 -2 + 12 +30 +8 + 15
DISCUSSION In this review of duodenal ulcer treatment we studied the results of omeprazole and ranitidine after 2 and 4 weeks' of treatment. Significant differences in 7 of 10 studies is a convincing result. The rapidity and efficacy of healing in favour of omeprazole correlate to some extent, however, with the antisecretory effectiveness (26), and this probably explains the differences in the results. Our Dutch study with unexpected data was the reason for the analysis (19). Ranitidine has proved to be a safe and highly effective drug in acute and continuous treatment of peptic ulcer disease. Data about its efficacy and
Difference
Chi-square
Fisher
lu-42 7-29 1&36 17-48 2-23
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
C. J. J . MULDER & D. L. SCHIPPER Dept. of Hepatogastroenterology, Rijnstate Hospital, Arnhem, The Netherlands Mulder CJJ, Schipper DL. Omeprazole and ranitidine in duodenal ulcer healing. Analysis of comparative clinical trials. Scand J Gastroenterol 1990, 2S(suppl 178), 62-66 Ten double-blind randomized studies with omeprazole versus ranitidine in duodenal ulcer healing have been published. The total number of patients in the trials amounted to 2225. To detect treatment differences. a meta-analysis was performed. After 2 and 4 weeks of treatment results have been evaluated. After 2 weeks of treatment omeprazole produced higher healing rates than ranitidine in nine studies. However, at 4 weeks numerical differences in favour of omeprazole were found in nine studies. Relief of ulcer symptoms occurred more rapidly with omeprazole than ranitidine. No major clinical or biochemical side effects were recorded. However, no data are available about maintenance therapy in double-blind randomized studies comparing both drugs or about rebleeding rates in bleeding duodenal ulcer treatment. Key words: Duodenal ulcer; meta-analysis; multicentre trials; omeprazole; ranitidine Chris J. J . Mulder, M. D . , Depr. of Heparogasrroenrerology, Rijnstare Hospiral-GZ, P . 0. Box Y555. 6800 TA Arnheim, The Netherlands
Omeprazole, a substituted benzimidazole, is a potent inhibitor of H+.K+-ATPase,the end-point in the acid secretion process (1). In several studies treatment with omeprazole has healed duodenal ulcers in almost all patients (2, 3). Furthermore, omeprazole is effective in healing reflux oesophagitis ( 4 6 ) and in patients with the ZollingerEllison syndrome (7). It has been shown to be effective in the treatment of peptic ulcer and reflux oesophagitis resistant to H2-receptor antagonists (2, 5, 6, 8). Until a few years ago it was difficult to foresee any agent challenging the dominance of Hz-blockers such as ranitidine and cimetidine during this century. Ranitidine seems to fulfil the criteria of clinical need and efficacy (9-13). We have examined the data from trials comparing the effects of omeprazole and ranitidine on the rate of duodenal ulcer healing and the proportion of symptom-free patients. We here subject these to meta-analysis in an attempt to assess the differences, if any, between omeprazole and ranitidine.
Studies comparing the two drugs in long-term treatment are not available. Studies comparing both drugs in acute (bleeding) duodenal ulcers and comparing rebleeding rates after an initial stop of the bleeding after sclerotherapy are not yet available. METHODS The aim of the analysis was to compare healing rates of omeprazole in the recommended dose of 20mg in the morning with the recommended doses of ranitidine-that is, 150mg twice daily and 300 mg at bedtime in the short-term treatment of duodenal ulcer. A search of the published literature identified 10 such trials (1424). Basic clinical trial information was necessary to ensure comparability of groups, and the following criteria were used to identify clinical trials that might be suitable for pooling. The publication had to contain statements on randomization, doubleblindness, information on patient demography, and the use of endoscopy for diagnosis and
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
Omeprazole and Ranitidine in DU Healing
assessment of duodenal ulcer healing. Unhealed ulcers had to be treated for at least 4 weeks, with endoscopy at 2 and 4 weeks. The number of patients together with the number and/or percentage of patients healed was also required. The Mantel-Haenszel chi-square test for comparison of proportions from independent samples was used for evaluation of overall results (25). There were other trials comparing omeprazole with ranitidine. Some were reported only as abstract, and no further data are available. In most of these trials patients had duodenal ulcers that were resistant to previous therapy with H2receptor antagonists. For that reason we excluded these studies from our study. However, for individual therapeutic considerations these studies are very interesting (2. 8). RESULTS Nine of the 10 studies on 20mg omeprazole in the morning versus 150mg ranitidine twice daily or
63
300mg at bedtime exhibited greater healing rates after 2 weeks of treatment for the omeprazole group, and 7 of the studies showed a statistically significant advantage for omeprazole at the 5% significance level. The overall difference was 16.5 percentage points based on a healing rate of 69.3% for omeprazole and 52.8% for ranitidine (p < 0.0001). At 4 weeks the healing rates were 92.8% and 83.1%, respectively, with a difference of 9.7 percentage points (p < 0.0001). Three trials compared 20 mg omeprazole in the morning with 300 mg ranitidine at bedtime (14, 15. 17). Seven trials compared 20mg omeprazole in the morning with 150mg ranitidine twice daily (16, 1&22, 24). Omeprazole demonstrated significantly higher healing rates than 150mg ranitidine twice daily and 300mg ranitidine at bedtime both at day 15 and at day 29 (Table 1-111). The difference in proportions of patients without symptoms 2 weeks after start of treatment was about 14% favouring omeprazole (71.1% versus 57.60/0; p < 0.001).
Table I. Details of the 10 trials comparing omeprazole and ranitidine ~~
~~
Endoscopic healing, YO Reference
Trial no.
Design*
Treatment groups
No.
2 weeks
4 weeks
114 115 126 122 83 87 84 69 66 146 160 91 90
75 46 79 61 77 86 63 65 39 72 59 63 65
64 64
66
97 83 91 80 95 96 93 97 81 96 92 91 96 97 85 97 loo 82 82 63 94 88
~~
Chelvam (14)
A
McFarland (15)
B
Hui (16)
C
Marks (17)
D
Classen (IS)
E
Mulder (19)
F
Barbara (20)
G
Bardhan (21)
H
Deventer (22)
I
Lind (23)
J
R , DB. MC Omeprazole. 20 mg in the morning Ranitidine. 300 mgat bedtime R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 300 mg at bedtime Omeprazole, l0mgin the morning R.DB Omeprazole, 20 mg in the morning Ranitidine, 150 mg twice daily Omeprazole, 20 mg in the morning R,DB Ranitidine, 300mgat bedtime R , D B . M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B . M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mg in the morning Omeprazole, 40mg in the morning Ranitidine, 150mgtwice daily R , D B , M C Omeprazole, 20 mg in the morning Ranitidine, 150mg twice daily R , D B , M C Omeprazole, 20 mgin the morning Ranitidine, 150 mg twice daily
R := randomized; D B = double-blind: MC = multicentre
34 36 35 151 158 167 163
53 83 83 53 42 34 69 54
C. J. J. Mulder & D. L. Schipper
64
Table 11. Percentage difference and power for studies included in meta-analysis results after 2 weeks of treatment: 20 mg omeprazole in the morning versus ranitidine, 150 mg twice daily or 300 mg at bedtime
Trial no.
Healed after 2 weeks, YO Omeprazole
~~
~
A
Scand J Gastroenterol Downloaded from informahealthcare.com by Universitaetsbibliothek Dortmund on 10/17/14 For personal use only.
Ranitidine
76 79 86 65 72 63 66 83 42 69
B C D E F G H I J
46 61 63 39 59 65 53 53 34 54
95% Confidence interval andp values for chi-square test and Fisher exact test Difference (0-R), %
+30
+ 18 +23 +26 + 13 -2 + 12 +30 +8 + 15
DISCUSSION In this review of duodenal ulcer treatment we studied the results of omeprazole and ranitidine after 2 and 4 weeks' of treatment. Significant differences in 7 of 10 studies is a convincing result. The rapidity and efficacy of healing in favour of omeprazole correlate to some extent, however, with the antisecretory effectiveness (26), and this probably explains the differences in the results. Our Dutch study with unexpected data was the reason for the analysis (19). Ranitidine has proved to be a safe and highly effective drug in acute and continuous treatment of peptic ulcer disease. Data about its efficacy and
Difference
Chi-square
Fisher
lu-42 7-29 1&36 17-48 2-23
