Aliment. Pharmacol. Therap. (1991) 5, 227-243.

ADONIS

0269281391000244

Ranitidine in the treatment of duodenal ulcer disease : relationship between antisecretory effect and ulcer healing rate

R. L. McISAAC, J. S. DIXON, J. G. MILLS & J. R. W O O D Division of Gastroenferology, Glaxo Group Research Ltd, Greenford, Middlesex, UK Accepted for publication 18 February 1991

SUMMARY

The relationship between drug-induced suppression of intragastric acidity and the rate of duodenal ulcer healing was examined using data for a single drug, ranitidine, from 156 clinical trials involving 16362 patients together with data on acid suppression from 37 studies of intragastric acidity in 630 subjects. In these studies ranitidine was given in doses ranging from 150 mg to 1200 mg per day administered in 9 different dosage regimens. The overall percentage of patients whose duodenal ulcers healed at 2 and 4 weeks on the different regimens was highly correlated with the percentage suppression of 24-hour intragastric acidity induced by different regimens. Thus the therapeutic benefit of a given ranitidine dosage regimen in healing duodenal ulcers relates directly to its antisecretory effect. INTRODUCTION The rate of healing of duodenal ulcers during antisecretory therapy is related to the degree of suppression of intragastric acidity. Jones et al.' applied linear regression analysis to data from 17 dosage regimens involving 7 antisecretory agents and Correspondence to: Dr J. R. Wood, Division of Gastroenterology, Glaxo Group Research Ltd, Greenford Road, Greenford UB6 OHE, Middlesex, UK. 22 7

16-2

228

R. L. McISAAC ef al.

found a significant linear correlation between ulcer healing at 4 weeks and the suppression of 24-h intragastric acidity. In an extension of this study using a threedimensional model incorporating the duration of suppression, pH threshold and ulcer healing, Burget ef al.’ showed that the ulcer healing achieved at 4 weeks was maximal when intragastric pH was kept at or above 3 for at least 16 h a day. Suppression of acidity to a greater degree produced little additional benefit. Ranitidine has been extensively studied using various dosage regimens, and the aim of the present study was to evaluate the available data to determine the relationship between suppression of acidity and ulcer healing for a single drug. METHODS Overall duodenal ulcer healing rates for ranitidine-treated patients were derived from the literature (searches conducted on Medline, Glaxoline and Datastar) and in-house unpublished data from Glaxo Group Research Ltd. Three inclusion criteria were used for clinical trial data to be eligible : (a) trials had to evaluate a specified ranitidine dosage regimen and use endoscopy for evaluation of ulcer healing ; (b) there had to be information available concerning the number of patients treated and the proportion healed at two and/or four weeks. In those trials where both intention to treat and per protocol analyses were available, the latter was used; (c) data had to be available on suppression of intragastric acidity for the dosage regimen studied. Overall average healing rates for each ranitidine dosage regimen were calculated by adding the number of patients with healed ulcers in each study and the number treated in each study at two and four weeks. The percentage healed at each time point was calculated from the totals. This provided a weighted average since the larger studies contributed more to the totals than the smaller studies. Ninety-five per cent confidence intervals (CI) were also determined. Data on suppression of intragastric acidity were also obtained from literature sources and from unpublished studies. The studies assessed 24-h intragastric pH or acidity in healthy subjects or patients with duodenal ulcer disease using one of three different techniques : continuous pH-monitoring, telemetry or intermittent aspiration of gastric contents. Studies were included if a value for percentage suppression of 24-h acidity or time pH 2 3.0 was given. If individual subject data were available from the authors or from unpublished reports, then these were used to calculate values for percentage suppression of 24-h acidity compared with the control results, using the area under the hydrogen ion concentration-time curve (AUC) as follows : AUC placebo - AUC active x 100 = % suppression. AUC placebo

RANITIDINE: A C I D SUPPRESSION A N D ULCER HEALING RATE 229 The number of hours/day that the pH was 2 3.0 was estimated from the percentage of total time that pH was 3 3.0. For each study a median value was calculated for each of these two parameters. For each dosage regimen an arithmetic mean of the results from all studies was used to represent the overall percentage suppression of 24-h intragastric acidity and number of hours that the pH was 2 3.0. The relationship between these variables and ulcer healing was determined using Spearman rank correlation.

RESULTS Duodenal ulcer healing rates from nine different ranitidine dosage regimens were available for 16362 patients from 156 clinical trials (151 of which are published, References 3-153). Overall duodenal ulcer healing rates ( 95 'YO CI) after two and four weeks treatment are listed in Tables 1 and 2, respectively, together with the number of patients and the number of clinical trials for each regimen. Table 1. Combined duodenal ulcer healing rates at two weeks for the different ranitidine dosage regimens

Ranitidine dosage regimen ~

300 mg 300 mg 300 mg 600 mg 300 mg 300 mg 150 mg 150 mg 300 mg

Ulcer healing (%)

95% CI

No. patients

68.2 5 7.6 57.1 50.6 55.4 50.9 47.8

59.5-76.9 45.7-69.5 53.340.9 43.3-5 7.9 52.5-58.2 48.7-53.1 45.6-5 0.0

110 66 648 178 1142 2036 1896

-

-

No. trials

-~

q.d.s. t.d.s. b.d. post-evening meal post-evening meal nocte b.d. nocte mane

24.7-56.3

40.5

37

1 1

6 1 6 23 24 1

Table 2. Combined duodenal ulcer healing rates at four weeks for the different ranitidine dosage regimens

Ranitidine dosage regimen

Ulcer healing

(YO)

95% CI

No. patients

No. trials

.___

300 mg 300 mg 300 mg 600 mg 300 mg 300 mg 150 mg 150 mg 300 mg

q.d.s. t.d.s. b.d. post-evening meal post-evening meal node b.d. nocte mane

92.4 95.5 91.9 90.3 85.5 81.5 78.8 72.4 67.6

87.3-97.5 90.5-100 89.8-94.0 85.9-94.7 83.5-87.5 80.5-82.5 77.9-79.7 63.8-80.2 58.6-76.6

105 66 630 176 1185 6376 7603 116 105

1 1

6 1

6 57 108 2 3

230

R. L. McISAAC ef al.

Twenty-four hour intragastric acidity profiles were reported for 630 subjects in 37 studies (30 of which are published, References 154-183) with 75 active treatment arms. In 14 of the 37 studies individual subject data were not available and percentage suppression of acidity was accepted as reported in the publication. Continuous pH monitoring was used in 14 studies, telemetry in 3 studies and intermittent aspiration of gastric contents in 20 studies. The mean degree of acid suppression over 24 h and the mean time that pH 2 3.0 over the same period are given in Figures I and 2. Figure 1 shows the percentage suppression of 24-h intragastric acidity resulting from the different dosage regimens in duodenal ulcer patients and healthy subjects. Substantial interstudy variability in the degree of acid suppression was seen for each dosage regimen. The spread of results was such that little difference could be detected between data from healthy subjects and from duodenal ulcer patients, but the average degree of suppression showed an increase with increase in total daily dose. A similar pattern of variability and relationship was found when the results were expressed in terms of numbers of hours per day that the pH was 3 3.0 (Figure 2). There was a significant correlation between the mean percentage suppression of 24-h acidity and overall healing rates at two and four weeks (Figure 3). Similarly there was a significant correlation when the number of hours that pH was 3 3.0

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Figure 1.Suppression of 24-h intragastric acidity for nine dosage regimens of ranitidine in duodenal ulcer patients (w) and healthy subjects (0). Each point represents the average result from one 24-h monitoring period from one study.

RANITIDINE: A C I D SUPPRESSION A N D ULCER HEALING RATE 231 -~ -

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Figure 3. Association between suppression of 24-h intragastric acidity during dosing with ranitidine and the two- and four-week healing rates of duodenal ulcers during treatment with the same ranitidine regimen: healing at two weeks; r, = 0.90 ( P < 0.01); healing at four weeks; r, = 0.95

( P < 0.01).

R. L. McISAAC et al.

232

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Figure 4. Association between the number of hours over a 24-h period spent above pH 3 3.0 during dosing with ranitidine and the two- and four-week healing of duodenal ulcers during treatment with the same ranitidine regimen: healing at two weeks; r, = 0.90 ( P < 0.01); healing at four weeks; r, = 0.88 ( P < 0.01).

was substituted for percentage acid suppression (Figure 4), the rank order of healing rates being similar to the rank order of the antisecretory potency for the different dosage regimens. There is a decrease of acid suppression during continued treatment with Hireceptor a n t a g 0 n i ~ t s . IIn ~ ~the present analysis the largest amount of data came from investigation of 300 mg ranitidine daily (29 studies in 346 individuals, excluding morning dosing). The duration of ranitidine treatment varied from one to 28 days, with the largest number of subjects being studied on Day 1of treatment. The average percentage suppression of acidity was 59% (range 26-73) on Day 1 (23 studies), 55 YO (45-66) by Day 3 (6 studies), 5 4 % (41-74) on Day 7 (5 studies), 5 2 % (37-64) on Day 14 (3 studies) and 5 0 % (42-57) on Day 28 (6 studies) of treatment. Due to the relative lack of data on the percentage acid suppression from Day 3 to Day 28 and because the largest difference occurred by Day 3 these data have been combined to give an average of 52%. Similarly data for the highest dosage regimen, 300 mg ranitidine q.d.s. showed acid suppression of 86% (5 studies, range 82-88%) after treatment for 1 day, 74% by day 6 (5 studies, range 70-82%) and 90% by day 28 (1 study). The relationship between suppression of acidity, comparing the data for Day 1with the combined acid suppression for Days

RANITIDINE: ACID S U P P R E S S I O N A N D ULCER HEALING RATE 233 100

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Figure 5. Relation between suppression of 24-h intragastric acidity with either no ranitidine pretreatment (m, dashed line), or with ranitidine dosing from 3 to 28 days (0, solid line), and ulcer healing rates at 2 and 4 weeks of suppression with ranitidine.

3 to 28, of dosing with ranitidine, and ulcer healing at weeks 2 and 4 are shown in Figure 5.

DISCUSSION There is clear evidence that drugs which inhibit gastric secretion can enhance the rate of healing of duodenal ulcer when compared with that of placebo. Metaanalyses of ulcer healing rates and suppression of intragastric acidity have shown that the rate at which a given drug regimen can induce ulcer healing over a fourweek course of therapy is directly related to the extent to which it can inhibit 24-h intragastric acidity.'. Such meta-analyses have used data from a variety of drugs acting through different pharmacological mechanisms and provide no information on such a relationship for incremental doses of an individual therapeutic agent. As a result of the extensive worldwide literature for ranitidine, sufficient information has accrued to enable this relationship to be determined for a single drug. The nine dosage regimens for which data were available represented a wide range of inhibitory profiles and healing rates. The analysis has shown an increasing and essentially linear relationship between the average percentage suppression of intragastric acidity during dosing with ranitidine and the overall ulcer healing rate for both 2 and 4 weeks of therapy. Suppression of 24-h intragastric acidity ranged from an average of 31 % during dosing with 300 mg ranitidine mane to 80 % during dosing with 300 mg ranitidine q.d.s. The standard recommended doses of ranitidine, 150 mg b.d. or 300 mg nocte were comparable, both in terms of suppression of 24-h acidity and ulcer healing.

234

R. L. M c I S A A C et a/.

When results from three studies in small numbers of patients are combined they suggest that ulcer healing for 300 mg ranitidine mane is less than that for 300 mg ranitidine nocte,23r67’92 though the individual studies are clearly subject to type I1 errors. In the present study, the suppression of 24-h acidity caused by 300 mg ranitidine mane is also less than that seen for the standard 300 mg nocte regimen. Trials which have examined early evening dosing suggest that there may be a small benefit both in ulcer healing and suppression of acidity when 300 mg ranitidine is given immediately after the evening meal rather than at bedtime. The analysis also indicates that increasing the dose of ranitidine to 600 mg as a single evening dose provided minimal incremental benefit both in terms of acid suppression and ulcer healing, possibly because suppression of nocturnal acidity is already greater than 90% when 300 mg ranitidine nocte or 300 mg post-evening meal is given.170However, dividing the higher dose to 300 mg twice daily increased the rate of ulcer healing compared with that achieved by the standard 300 mg nocte regimen. Increasing the dose to ranitidine 300 mg q.d.s. accelerated healing further at 2 weeks but not at 4 weeks. Burget et a/.’ suggested that another criterion for effective control of acidity and hence ulcer healing was the time over which intragastric pH was maintained above 3.0. This view was supported by the results in the present investigation where ulcer healing at both 2 and 4 weeks was significantly correlated with the number of hours at or above pH 3.0. Recent studies have shown a small decrease of antisecretory effect with l8O, 183 This tolerance has been continued dosing of an H,-receptor antagoni~t.’~~’ shown to occur in normal subjects in several studies, but the one study in patients with duodenal ulcer disease suggests that tolerance may not occur in patients.’” Two-thirds of the available intragastric acid suppression data available for the present analyses was obtained from normal subjects, and hence tolerance was certainly a feature of these results and may have contributed to the variability in the data. The increase in the variability of the observed response and possible distortion of the data introduced by tolerance were not considered in previous analyses of the relationship between pharmacological effect and ulcer healing. However, as illustrated in Figure 5, the relationship between intragastric acid suppression and ulcer healing rate is not influenced significantly by the tolerance phenomenon. In conclusion, decreasing intragastric acidity is clearly an important mechanism in the healing of duodenal ulcer during treatment with ranitidine, and a doseresponse relationship is evident over the dose range from 150 mg to 1200 mg daily.

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RANITIDINE: A C I D SUPPRESSION A N D ULCER HEALING RATE

3

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