A Controlled Clinical Trial of Cholestyramine in the Treatment of Gastric Ulcer

Vol. 61, No.6

GASTROENTEROLOGY

Copyright ©197 1 by The Willia ms & Wilkins Co.

Printed in U.S.A.

A CONTROLLED CLINICAL TRIAL OF CHOLESTYRAMINE IN THE TREATMENT OF GASTRIC ULCER R. B, BLACK, F.R.A.C.S., J . RHODES, M.D., G. T. DAVIES, F.F.R., H. GRAVELLE, F.F.R. , AND P. SWEETNAM Welsh National S chool of Medicine and the M edical Research Council Department of Epidemiology, Cardiff Royal Infirmary, Cardiff, Wales

Cholestyramine, an exchange resin which binds bile acids has been used for the treatment of gastric ulcer in a double blind controlled clinical trial. Four grams of the compound were given three times daily with food, for 1 or 2 months, and change in the ulcer size was followed radiologically. Thirty-five patients completed the trial. We were unable to show conclusively that cholestyramine was effective in healing gastric ulcer, although there was a small advantage in favor of the treated group. Patients given cholestyramine had fewer symptoms, required fewer antacid tablets, and had a greater mean reduction in ulcer size, but none of these differences was statistically significant. Since the cause of gastric ulcer is unknown, treatment is empirical. Bed rest, carbenoxolone, and cessation of smoking have been shown to accelerate healing of the ulcer. ,_ 3 It has been suggested that delay in gastric emptying 4 and reflux of bile into the stomach 5 • 6 may play a part in the etiology of gastric ulcer. Bile is often present in the stomach in gastric ulcer, 5 • 7 • 8 and produces a gastritis 9 which may predispose to ulceration. In an attempt to examine the significance of bile reflux in gastric ulcer, we have given patients cholestyramine in a controlled trial, and followed the rate at which healing occurred. Cholestyramine is a basic anionic exchange resin which binds bile salts 10 and might therefore reduce

damage to the mucosa and accelerate healing of the ulcer.

Methods Subjects. Thirty-seven patients, 16 male and 21 female, were admitted to the trial after a benign gastric ulcer had been demonstrated radiologically. In all patients the area of the ulcer in profile, as demonstrated by X-ray, was greater than 10 sq mm. None of the patients had had previous gastric surgery. None had a duodenal ulcer or had received analgesic therapy. All patients had a full physical examination and many were examined by gastroscopy. Samples of gastric juice were taken from 29 patients while fasting and after a standard liquid meal consisting of 500 ml of water, 22 g of com oil, and 56 g of dextrose . The concentration of bile acids in these samples was measured by a method which involved the enzyme hydroxy steroid dehydrogenase•; the maximal concentration after the meal is referred to in the results. Trial design . Patients were allocated to a treatment or placebo group by a series of numbers held in the pharmacy department. Neither the patient nor medical staff were aware of which treatment was given. All except 8 patients were treated entirely at home; these 8 patients, 4 from each group, spent between 2

Received May 3, 1971. Accepted July 16, 1971. Address requests for reprints to: Dr. John Rhodes, Welsh National School of Medicine, Cardiff Royal Infirmary, Newport Road, Cardiff, CF2 1SZ, Wales. The authors gratefully acknowledge help from members of the gastroenterology department of the Mayo Clinic who assisted us with preliminary plans. Physicians and surgeons of the United Cardiff Hospitals kindly referred patients. Mead-Johnson supplied the cholestyramine and Bayer and Company supplied the Actal. 821

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BLACK ET AL.

and 28 (mean 9) days in the hospital before returning home. If the drug were to potentiate healing, a clinically significant effect would be to produce a reduction in the mean ulcer size which was 20% greater in the treated compared with the placebo group. For example, a mean reduction in ulcer size of 70% in the cholestyramine patients compared with 50% in the placebo group. The size of the trial was sufficient to give a statistically valid result if such a difference were present. The size of the ulcer was reassessed by X-ray after 4 weeks and if still present, a further 4weeks treatment was given before the final radiological assessment. At these barium meal examinations the ulcer was demonstrated in a projection similar to that used in the first examination, so that measurements would be comparable. Patients were asked to complete a diary card 11 during the trial, to record the severity of pain and occurrence of vomiting. At the end of each month they were asked to describe their symptoms as excellent, good, fair, bad, or terrible; these statements were given a score of 1 to 5 respectively. They were also questioned about the occurrence of side effects. Treatment. Cholestyramine or lactose powder was given in packets, each of which contained a single dose of 4 g (Questran, Mead-Johnson and Co., Evansville, Ind.). Three doses of the powder were taken each day with meals. Antacid tablets [Actal (sodium polyhydroxaluminum monocarbonate hexitol complex, Winthrop Laboratories, Surbiton, Surrey, England)] were taken for relief of discomfort, and the number used each month was recorded. Patients were advised to reduce their tobacco and alcohol consumption and to avoid aspirin preparations and any food which they had found to precipitate indigestion. Assessment of results. (1) Radiographs from each examination were chosen to show the ulcer profile in a similar projection. The outline of the ulcer was traced and the area measured with a planimeter. (2) Four assessments of symptoms were noted. These were the diary card record of pain each day (scored 0 to 3), pain at night (0 or 1), and vomiting (0 or 1) . At the end of each month a general assessment of the patient was made; this was scored 1 to 5 as described above. (3) The number of antacid tablets used each month was also used to assess the response to treatment. Results were analyzed using Student's t-test on the basic data or on transformations of the basic data and the standard x• test.

Vol . 61, No.6

Results Two patients were withdrawn during the trial because of failure to attend the clinic or to take treatment regularly. Results from the remaining 35 patients were analyzed. Comparability of groups. Patients in the cholestyramine and placebo group were similar with respect to the number of each sex, the patients' age, ulcer size, past history of day pain, night pain, vomiting, and the duration of symptoms (table 1). There was no difference in the maximal concentration of bile acids in gastric juice from the two groups (table 1) and a similar number of patients had had previous complications. Effect of treatment. (1) Ulcer size. The size of each ulcer at the beginning of the trial and after 1 and 2 months is in figure 1. Changes which occurred during treatment are in table 2. Mter 2 months the number of patients with a healed ulcer was similar in the two groups. However, the mean percentage reduction in ulcer size was slightly greater for the cholestyramine than for the placebo group. (2) Symptoms. There was no statistical difference in the symptoms of the two groups (table 3). In calculating the day pain scores for both months it has been assumed that symptoms did not occur in the 2nd month in those patients with a healed ulcer at the end of the 1st month. Both day pain and night pain occurred more frequently in the placebo group. Vomiting occurred more frequently in the cholestyramine group but this group was more satisfied with their condition on the monthly assessment score. However, none of these differences was statistically significant. (3) The consumption of antacid was greater in the placebo group than the cholestyramine group but the difference was not statistically significant. Side effects. The occurrence of loss of appetite, nausea, and constipation was similar in the two groups; the percentage of patients who complained at any time of these side effects was approximately 20, 38, and 20% respectively. Factors associated with complete healing.

TABLE

1. A comparison of patients in the cholestyramine and placebo groups, on admission to the trial Cholestvramine group (N ~ 18)"

Details of patients

53 6.4 4.4 117

Age, in years . Total duration of symptoms, in years . Recent duration of symptoms, in months . Initial ulcer size, in square millimeters . No. of male/female patients .. No. of patients with history of day pain . No. of patients with history of night pain No. of patients with history of vomiting . No. of patients with maximal bile acid concentrations• of <1 1- < 2 ;;> 2

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CHOLESTYRAMINE TREATMENT OF GASTRIC ULCER

December 1971

8/ 10 18 13 12

mM

7

mM

5 3

mM .

(12) (5 .6) (4.3) (88)

Placebo group (N ~ 17)•

54 7. 1 2.9 145

(11)

(5 .3) (2.8) (87)

8/9 17 10 10 9 2

3

Mean and standard deviation (standard deviations are in parentheses). • Bile acid concentrations not available for 3 patients in each group. There was no statistical difference between the two groups. a

PLACEBO N:17

300

200

E E

..li' . ·;;;

.:

Ql

a;

... 5

100

0

1

months

0

1

months

FIG. 1. Size of the ulcer profile, measured in square millimeters for patients in both groups, before treatment and after 1 and 2 months of treatment.

The total and recent duration of symptoms were marginally longer in those who had healed than in those who had not; the mean initial bile acid concentration was also higher in those who had healed. The mean initial ulcer size in those who healed completely was 107 sq mm and for those who did not heal 149 sq mm. None of these differences was statistically significant. Discussion If bile damage to the gastric mucosa is important in gastric ulcer, cholestyramine may be of some value in treatment. Although the patients treated with cholestyramine had a greater reduction in the size of the ulcer, had less pain, and used fewer antacid tablets than patients in the placebo group, the differences were not significant . The difference in the mean reduction in ulcer size was about lO rr. Such a small advantage, even if substantiated by a larger trial, would be of little clinical value and for this reason the trial has not been continued. Our results suggest that the percentage change in ulcer size in the 1st month is similar to that in the 2nd month; the mean reduction in ulcer size was approximately exponential. This effect has also been noted by others. 12 In the trial we have been unable to show

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Vol. 61, No . 6

BLACK ET AL. TABLE

2. Change in ulcer size after treatment No. of patients with ulcer Mean reduction in ulcer size

Reduction in size

Group

Time

Healed

50- 99Sf

Less than soc;-

c;

After 1 month

Cholestyramine (N = 18) Placebo (N = 17)

2 3

9 7

7 7

55 46

After 2 months

Cholestyramine (N = 17a) Placebo (N = 17)

7 8

8 4

2 5

81 69

a One patient in the cholestyramine group had no result at the end of the 2nd month. (Differences between the two groups were not statistically significant.)

TABLE

3. Effect of treatm ent on symptoms during the 1st m onth and both months in the

cholestyramine and placebo groups Both months"

1st month"

Characteristic

Total day pain score .. . ... No. of Acta! tablets used . ' .. . . General monthly assessment No. of patients with night pain• Ever Never ..... No. of patients with vomiting• Ever ..... .. . . . . . . . ... Never . . . . .

Cholestyramine (N ~ 18)

18 . 2 35 .3 2. 1

(15) (40) (1)

Placebo (N

24 . 6 37 .3 2.4

~

17)

(14) (26) (1)

Cholestvram ine (N,;, 18)

29 . 4 57.4 3. 6

(30) (78) (2)

Placebo (N

~

40 67 . 9 4. 1

(27) (61) (2)

9 9

13 3

10 8

13 3

8 10

6 10

9 9

7 9

16)

a Mean values of characteristic (standard deviations are in parentheses). • "Ever" and "never" refer to the number of patients who ever or never complained of the symptom during the period of treatment. None of the differences was statistically significant.

conclusively that cholestyramine is effective in healing gastric ulcer. This may be because the cholestyramine was ineffective or the trial too small. If the hypothesis is correct, that reflux of bile is important in the etiology of gastric ulcer, then the small effect of cholestyramine may be due to the short period it would remain in the stomach, leaving the mucosa exposed to bile at other times. One could speculate that it may have been more effective to give the drug in smaller doses more frequently, although this would have been difficult with the resin in its present form. Cholestyramine would also increase the ratio of trihydroxy to dihydroxy bile acids, 13 which could increase the damaging effect of bile on the mucosa. 14, 1s Further attempts to establish the rele-

vance of bile reflux in gastric ulcer may be directed toward prevention of the reflux with compounds which will correct the underlying motility disturbance. REFERENCES 1. Doll R, Pygott F : Factors influencing the rate of

healing of gastric ulcer: admission to hospital, phenobarbitone, and ascorbic acid. Lancet 1: 171- 175, 1952 2. Doll R, Hill ID, Hutton C, et a! : Clinical trial of a triterpenoid liquorice compound in gastric and duodenal ulcer. Lancet 2:793- 796, 1962 3. Doll R, Jones FA, Pygott F: Effect of smoking on the production and maintenance of gastric and duodenal ulcers. Lancet 1:657-662 4. Dragstedt LR: A concept of the etiology of gastric and duodenal ulcers. Gastroenterology 30:208220, 1956

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CHOLESTYRAMINE TREATMENT OF GASTRIC ULCER

5. Du Plessis DJ : Pathogenesis of gastric ulceration. Lancet 1:974-978, 1965 6. Capper WM: Factors in the pathogenesis of gastric ulcer. Ann Roy Coli Surg Eng 1:21-34, 1967 7. Rhodes J, Barnardo DE, Phillips SF, et al: Increased reflux of bile into the stomach in patients with gastric ulcer. Gastroenterology 57:241-252, 1969 8. Black RB, Roberts G, Rhodes J: The effect of healing on bile reflux in gastric ulcer. Gut 12:552558, 1971 9. Lawson HH : Effect of duodenal contents on the gastric mucosa under experimental conditions. Lancet 1:469-472, 1964 10. Hofmann AF, Small DM : Detergent properties of bile salts: correlation with physiological function. Ann Rev Med 18:333-376, 1967 11. Kaye MD, Rhodes J , Beck P, et al: A controlled

12.

13.

14.

15.

825

trial of glycopyrronium and !-hyoscyamine in the long term treatment of duodenal ulcer. Gut 11 : 559-566, 1970 Zimmon DRS, Guy R, Tesler MA : The healing rate of gastric ulcer in man. Implications for evaluation of therapy. Fourth World Congress of Gastroenterology, Copenhagen, July, 1970 van der Linden W, Nayama F: Change of bile composition in man after administration of cholestyrarnine (a gallstone dissolving agent in hamsters). Acta Chir Scand 135:433-438, 1969 van Geertruyden J , Wissocq P, Dejardin N, et al: Action des constituants biliaires sur Ia secretion gastrique. Etude chez le rat a pylore ligature. C R Soc Bioi (Paris) 154:414-417, 1960 Ivey KJ, den Besten L, Clifton JA: Effect of bile salts on ionic movement across the human gastric mucosa. Gastroenterology 59:683-690, 1970