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Does an increased dosage of an H2RA have an obvious effect on healing of esophagitis and relief of symptoms?
J.G. Mills (London), R.H. Murdoch (Glaxo Research Triangle Park, North Carolina)
Ranitidine given 150 mg twice daily, or even as a single 300 mg dose at bedtime is an effective treatment for most patients with reflux esophagitis [1,2]. Nevertheless, a proportion of patients fail to respond. There is some evidence to suggest that patients whose esophagitis does not heal show little or no reduction in acid reflux time [3,4],
Reduction in esophageal acid contact time - a dose response
Ranitidine 150 mg b.d. is associated with a significant reduction in total reflux time. However, this dosage regimen is less effective in controlling daytime than nocturnal acid reflux and does not normalize acid contact time (ACT) in all patients (i.e., reduction of acid contact time (ACT) to <4.0%).
Increasing the dose of ranitidine, but more importantly the frequency of dosing, is associated with a further reduction in acid contact time (ACT) [5-7]. A dose-response relationship is most clearly demonstrated by the study of Jansen et al. [5]. The patients studied all had severe erosive esophagitis which had not responded to treatment with 150 mg b.d. However, larger and more frequent doses (up to 4 and 6 times 300 mg) reduced acid contact time (ACT) to within the normal range. A dose-response relationship has been confirmed in studies with other H2-receptor antagonists. A comparison of famotidine 40 mg nocte, 40 mg b.d. or 20 mg b.d. showed that twice daily administration was significantly more effective than the once daily regimen [8].
Healing of esophagitis - endoscopic assessment
Comparison of the efficacy a ranitidine 300 mg once daily, given after the evening meal or at bedtime, with a twice daily regimen, showed a numerical advantage for ranitidine 300 mg b.d. - cumulative healing of 77% compared to 68% by week 12 - but this difference was not statistically significant [9].
The effects of a higher dose, ranitidine 300 mg q.d.s., were compared with the most usually recommended dosage regimen, 150 mg b.d., in 138 patients with moderate to severe reflux esophagitis, Savary-Miller grades II and III [10]. Data from 122 patients were available for analysis at 4 weeks and from 117 patients at 8 weeks. The results of endoscopic examination are shown in Table 1.
There was a highly significant difference between the two treatment groups. Grade II esophagitis was more likely to have healed than grade III esophagitis after 4 or 8 weeks, irrespective of treatment given. However, the benefit of treatment with the higher dose was most marked in patients with more severe disease.
This study confirmed the benefit of higher dose regimens but did not show whether the benefit is due to the higher dose or shorter dosing interval. Two trials were therefore designed to evaluate the efficacy of ranitidine 150 mg and 300 mg, each given 4 times daily for up to 12 weeks, in a large number of patients with endoscopically confirmed erosive esophagitis [11,12]. In both studies patients with erosive esophagitis, defined as Hetzel grades II-IV, were screened for baseline symptomatology for 7 days and then allocated to one of the three treatment groups. Healing was defined as a normal appearance on endoscopy or erythema only. In each study endoscopically documented healing at 4, 8 and 12 weeks was significantly higher for both ranitidine treatment groups than for placebo. Since the studies were identical with respect to the inclusion criteria, procedures and definition of endoscopic appearance, the results have been combined in Fig. 1 [13].
A total of 670 patients were enrolled in the two studies. After 4 weeks treatment healing of esophagitis was recorded for 48% of patients treated with ranitidine compared to 22% of placebo (p < 0.001). Cumulative healing after 12 weeks was 58, 84 and 82% for placebo, ranitidine 150 mg q.d.s. and 300 mg q.d.s., respectively. There was no difference between the two ranitidine dosage regimens. The benefit of
Table 1..
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Esophagitis grade at pretrial
visit
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ap <0.01; hp < 0.0001 x2 test.
Figure 1. .Healing of reflux esophagitis (*p < 0.001 vs. placebo).
ranitidine was evident in patients with grade II esophagitis and those with more severe disease (grades III and IV).
Symptom relief
After 4 weeks of treatment 46% of patients receiving ranitidine 150 mg b.d. and 67% of those receiving ranitidine 300 mg q.d.s. were completely symptom free [10]. The run-in period incorporated into the design of studies comparing ranitidine 150 mg q.d.s., ranitidine 300 mg q.d.s. and placebo allowed more detailed analysis of the time course of symptom relief. In both studies there was a significant difference in the frequency of heartburn between ranitidine and placebo groups within 24 h of starting treatment (Table 2).
Differences in the frequency and severity of daytime and night-time heartburn were sustained throughout the treatment period.
Conclusions
Increasing doses of ranitidine are associated with an increasing pharmacological response (suppression of intragastric acidity and reduction in esophageal acid contact
Table 2. .Mean (SEM) heartburn episodes/day
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Time relative to start of treatment
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ap < 0.001 vs. placebo.
time). Frequency of dosing is probably more important than an increase in unit dose. Clinical studies provide evidence that higher daily doses are associated with greater healing of esophagitis and rapid relief of symptoms. The best results are achieved with ranitidine 150 mg q.d.s.; a further increase in dose provides no additional benefit.
In this paper we have used ranitidine as an example, but the same general conclusion may be expected from appropriate dosage regimens of other H2-receptor antagonists.
References
1. Halvorsen L, Lee FI, Wesdorp ICE, Johnson NJ, Mills JG, Wood JR. Acute treatment of reflux oesophagitis: a multi-centre study to compare 150 mg ranitidine twice daily with 300 mg ranitidine at bedtime Aliment Pharmacol Ther 1989;3: 171-181.
2. Dammann HG. Treatment of gastroesophageal reflux disease with ranitidine. In: Scarpignato C (ed) Frontiers in Gastrointestinal Research. Basel: Karger, 1992:20:208-230.
3. Robertson DAF, Aldersley MA, Shepherd H, Lloyd RS, Smith CL. H2-antagonists in the treatment of reflux oesophagitis: can physiological studies predict the response. Gut 1987;28:946-949.
4. Collen MJ, Lewis JH, Benjamin SB. Gastric acid hypersecretion in refractory gastroesophageal reflux disease. Gastroenterology 1990;98:654-661.
5. Jansen JBM, Baak LC, Lamers CBHW. Are increasing doses of ranitidine helpful in reducing acid exposure of the esophagus in reflux esophagitis? Proc Dutch Soc Gastroenterol, Oct 1988.
6. Barlow A, Watson A, Attwood S, Dixon JS, Johnson NJ. A double-blind crossover comparison of the effects of ranitidine 300 mg q.d.s., 150 mg b.d. and placebo on intragastric acidity and intraoesophageal pH. Gullet 1992;2:63-69.
7. Russell J, Orr WC, King JF, Finn AL. The effects of high doses of ranitidine on oesophageal reflux and symptom severity. Am J Gastroenterol 1988;83:A32.
8. Orr WC, Robinson MG, Humphries TJ, Antonello J, Cagliola A. Dose-response effect of famotidine on patterns of gastroesophageal reflux. Aliment Pharmacol Ther 1988:2:229-235.
9. Johnson NJ, Laws S, Mills JG, Wood JR. Effect of three ranitidine dosage regimens in the treatment of reflux oesophagitis:
results of a multicentre trial. Eur J Gastroenterol Hepatol 1991:3:769-774. 10. Johnson NJ, Boyd EJS, Mills JG, Wood JR. Acute treatment of reflux oesophagitis: a multicentre trial to compare 150 mg
ranitidine b.d. with 300 mg ranitidine q.d.s. Aliment Pharmacol Ther 1989;3:259-266 11. Roufail W, Belsito A, Robinson M, Barish C, Rubin A and Glaxo Erosive Esophagitis Study Group. Ranitidine for erosive
esophagitis: a double-blind, placebo-controlled study. Aliment Pharmacol Ther 1992:6:597-607.
12. Euler AR, Murdock RH, Wilson TH, Silver MT, Parker SE, Powers L. Ranitidine is effective therapy for erosive esophagitis. Am J Gastroenterol 1993:88:520-524.
13. Euler AR, Murdock RH, Wilson TH, Silver MT, Parker SE. Raniudine 150 mg and 300 mg four times a day are equally effective for healing erosive esophagitis and relieving heartburn. Hepatogastroenterology 1991; Abstract of the European Digestive Disease Week: A150.
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