SOMATOSTATIN IN TREATMENT OF HAEMATEMESIS AND MELAENA

130 SOMATOSTATIN IN TREATMENT OF HAEMATEMESIS AND MELAENA K. W. SOMERVILLE J. G. DAVIES C. J. HAWKEY

TABLE I-COMPARABILITY OF TREATMENT GROUPS

D. A. HENRY K. R. HINE M. J. S. LANGMAN

University Department of Therapeutics, Queen’s Medical Centre,

Nottingham 630 patients with haematemesis and melaena randomly allocated to treatment by a constant intravenous infusion of either somatostatin or an apparently identical placebo in a double-blind controlled trial. Rebleeding was less common in treated patients (70 episodes in 315 individuals compared with 89 episodes in 315 controls) but the difference was not significant. Operation rates were virtually identical (35 treated patients and 34 controls), while there were slightly more deaths in the treated group than in the controls (31 and 25, respectively). These results are in clear disagreement with those of other smaller series. Though it is not possible to be completely sure that treatment is not useful in some individuals, earlier claims of marked benefit seem unlikely to be justified.

Summary

were

Introduction THE mainstays of treatment of acute upper-gastrointestinal bleeding have been liberal blood transfusion and operations for cases in which recurrent bleeding is thought to pose unacceptable risks. Two forms of treatment which might, theoretically, be useful are antisecretory drugs, which might reduce the tendency to digest clot adhering to an ulcer base, and agents which reduce splanchnic blood flow. So far there have been no large-scale trials of the latter drugs, but there have been claims that histamine H2-receptor antagonists might benefit patients with haematemesis and melaena;1,2 the evidence is not entirely convincing, however.3 The hormone somatostatin has powerful gastric antisecretory properties and in non-cirrhotics it reduces splanchnic blood flow.4,s In several studies of small numbers of patients it apparently reduced the frequency of recurrent bleeding and the need for operation in patients admitted to hospital with haematemesis and melaena.6-12 We have carried out a large double-blind controlled study in unselected patients admitted to our hospitals with haematemesis and melaena.

J

R CHAPMAN AND OTHERS: REFERENCES

1. Atkinson K,

Biggs JC; Ralston M, Dodds AJ, Concannon AJ, Naidoo D Cyclosporin A nephrotoxicity in the first 100 days after allogeneic bone marrow transplantation: three distinct syndromes. Br J Haematol 1983, 54: 59-67 Myers BD, Ross J, Newton L, Luetscher J, Pelroth M. Cyclosporine-associated chronic nephropathy. N Engl J Med 1984; 311: 699-705. Powell-Jackson PR, Young B, Calne RY, Williams R. Nephrotoxicity of parenterally administered cyclosporine after orthotopic liver transplantation. Transplantation associated

2 3.

1983, 36: 505-08. 4 d’Ardenne AJ, Dunhill MS, Wood RFM, Thompson JF, Morris PJ. Cyclosporine treatment does not cause specific histological changes in human renal allografts. Transplant Proc (m press). 5 Varghese Z, Chan MK, Steele LV, Sweny P, Fernando ON, Moorhead JF. How to measure cyclosporin. Lancet 1984, i: 1407-08. 6. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one year follow up of a multicentre trial. Lancet 1983; n: 986-89. 7 Donatsch P, Albisch E, Homberger M, Traber R, Trapp M, Voges R. A radioimmunoassay to measure cyclosporin A in plasma and serum samples. J Immunoassay 1981; 53: 19-32 8. Cameron JS, Simmonds HA. Uric acid, gout and the kidney. J Clin Pathol 1981; 34: 1245-54.

SBP=systohc blood pressure; Hb = haemoglobin (on admission). *At endoscopy.

HR=heart

rate (on

admission);

Patients and Methods We used a similar method to that used in our study of tranexamic acid and- cimetidine.13 All patients admitted in emergency to Nottingham City and University Hospitals with a primary diagnosis of haematemesis and melaena were considered. Patients were included within 12 h of admission, regardless of age, unless bleeding was either trivial or so severe that immediate operation was necessary. We also excluded diabetic patients and those in whom coincident severe disorders made active management inappropriate. Approval was obtained from hospital ethics committees and informed consent was sought whenever possible.

Day-to-day management decisions were made by the admitting physicians and surgeons but upper-gastrointestinal endoscopy was carried out, usually within 24 h of admission, by members of a team of experienced endoscopists. Precoded treatment packs were provided which contained an initial intravenous bolus dose of 250 µg somatostatin or placebo, followed by a 72 h intravenous saline infusion providing 250 µg of somatostatin or placebo hourly. The apparently identical ampoules contained somatostatin or a placebo powder which was diluted immediately before infusion. No restrictions were placed on the use of other treatments except that physicians were asked not to prescribe cimetidine or ranitidine during the infusion period. Outcome was assessed by measuring the rates of rebleeding, operation, or death during that hospital admission in the two groups. Rebleeding was defined as fresh haematemesis or melaena after admission or as an unexplained drop of 2 g/dl or more in the haemoglobin level in any 24 h period after the first day. The trial was planned to run for 2 years during which we expected to randomise at least 600 patients. Primary comparisons were made between all randomised patients on an intention-to-treat basis whether or not treatment seemed, in retrospect, to be justified, thus mirroring what might happen in ordinary practice. Statistical analyses were based on the calculation of significance levels for fourfold tables with continuity correction and two-tailed tests of significance.14 Trial end-points were assessed before the code was broken. treatment

Results 779 patients were referred to the hospitals during the study - period (May, 1982, to April, 1984, for the City Hospital; December, 1982, to April, 1984, for the University Hospital) with a primary diagnosis of acute upper-gastrointestinal haemorrhage. 149 of these patients were excluded: bleeding was trivial in 50 and required emergency surgery in 4; 23 had diabetes mellitus; 6 had terminal non-alimentary disease; 6 had advanced malignant disease; 7 were unable to give consent and 5 refused; 1 died before randomisation; 1 was pregnant; and 46 apparently eligible patients were

131 TABLE II-RESULTS IN ALL PATIENTS

(INTENTION-TO-TREAT)

TABLE IV-OUTCOME IN ULCER AND NON-ULCER PATIENTS

*&khgr;2 =2.73, p=0. 10 t&khgr;2 =0.016, p=0-89. X2 =0.49, p=0.51.

inadvertently not included. The two treatment groups were generally comparable in age, sex, severity of blood loss, and the proportions with active bleeding and with gastric or duodenal ulcers (table I). Intention-to-treat analyses are shown in table II. Although there was evidence of rebleeding in fewer somatostatintreated than placebo-treated patients, the difference did not reach conventional levels of significance (p 0’ 1, two-tailed) and there was no parallel change in operation or death rates. The chances of death were, if anything, greater in the treated group, although the difference was not significant and the

&khgr;2=0.40, p=053. f=5.18,p=0-02.

=

confidence limits were wide. The fact that we included all

patients with substantial upper-gastrointestinal haemorrhage meant that some patients were included inappropriately. 96 patients were withdrawn from the trial without knowledge of the treatment received. In 41 (no deaths) there was no evidence of uppergastrointestinal bleeding; the bleeding was shown to have been from the large bowel in 6. 19 had other serious medical disorders which inhibited treatment of bleeding; 8 died, none of gastrointestinal bleeding. 7 were unable to tolerate the infusion (no deaths). 6 discharged themselves from hospital within 36 h of admission. 4 patients received both active drug and placebo owing to an administrative error. 8 patients had appropriate treatment which was withdrawn; in 2 cases the infusion was stopped prematurely after injection sclerotherapy for varices but in the remainder treatment was withdrawn for reasons other than those specified in the trial protocol (2 died). 1 patient was withdrawn because of a possible adverse reaction; immediately after receiving the bolus dose of somatostatin he complained of a generalised burning sensation and dyspnoea. This settled rapidly with reassurance and seemed to be a panic attack rather than a specific reaction to the drug. 10 patients were found to be

placebo group and (t= 2. 43, p<0. 02).

8 1 mmol/1 for the somatostatin group

Of the 10 deaths in withdrawn patients, 4 were in the placebo group and 6 the somatostatin group. Exclusion from consideration of patients withdrawn had little effect on the results. In the 534 patients who continued treatment, the rebleeding rate was slightly greater in the placebo group than in the somatostatin group, but operation and death rates were, if anything, rather greater in the somatostatin group (table III). None of these differences was statistically significant. Examination of transfusion requirements, deaths at each hospital, and deaths in association with continued bleeding or after operation showed nothing untoward. The timing of death was similar in both groups: there was no evidence of rebound mortality after the infusion finished. Rebleeding was commoner in placebo-treated than in somatostatin-treated patients with gastric and duodenal ulcers and with bleeding from other sites (table IV), a trend to be expected from the overall data. There were more deaths in the somatostatin than the placebo group of patients with TABLE

V-FREQUENCY OF DIAGNOSES

IN NON-ULCER PATIENTS

diabetic after admission and were therefore withdrawn from the study (no deaths); hyperglycaemia requiring intervention or trial withdrawal did not occur. The mean highest blood sugar of those continuing in the study was 7 - 3 mmol/1 for the TABLE III-OUTCOME IN PATIENTS WHO CONTINUED TREATMENT

TABLE VI-CAUSES OF DEATH IN PLACEBO-TREATED AND SOMATOSTATIN-TREATED PATIENTS

*Placebo: 1 each from postoperative complication and Somatostatm: 1 each from renal failure and stroke.

systemic embolus.

132

duodenal ulcers, but this trend

was counterbalanced by the in the higher placebo group with other causes of bleeding. However, the numbers in each subgroup are inevitably small and the confidence limits wide. The frequencies of non-ulcer diagnoses, and the numbers of deaths, were similar in the placebo and somatostatin groups (table v). The causes of death in each group are given in table vi. Apart from the 1 possible adverse reaction which led to treatment withdrawal, we noted no adverse effects of somatostatin. Haematological and biochemical safety tests were not done routinely, but during clinical care no test abnormalities were noted which were attributed to treatment.

death

rate

Discussion

Apart from individual case-reports there have been three controlled studies in which somatostatin treatment was found to improve the outcome in patients with acute uppergastrointestinal bleeding. One seems to have been the subject of five reports6-10 which apparently discuss the same group of patients. In 10 pairs of patients 1 was given somatostatin and 1 cimetidine; clinical benefit was greater in 7 of the 10 pairs in the somatostatin-treated patient and 3 pairs showed no difference. In Magnusson et al’s study" 95 patients received infusions of somatostatin or placebo for massive gastrointestinal bleeding. More operations were carried out in placebo recipients (14/49, 29%) than in somatostatin recipients (5/46, 11 %), but rebleeding, blood transfusion, and mortality rates did not differ between the two treatment groups. In Coraggio et al’s studyl2 three groups of 20 patients with haematemesis or melaena associated with antiinflammatory drug treatment were randomly allocated to treatment with somatostatin, ranitidine, or placebo. In contrast to Magnusson’s study, they found substantial differences between placebo and somatostatin. Only 1 of the somatostatin-treated

patients required operation, compared placebo-treated and 10 ranitidine-treated. Furthermore, haemorrhage, detected by gastric lavage, ceased within 12 h in all the remaining somatostatin-treated patients, but did not stop in any of the ranitidine or placebo recipients until at least 40 h. Clearly our results, from a much larger study, are not reconcilable with these previous findings. We set out to study at least 600 patients; with this number we calculated that there would be at least an 85% chance of detecting a 50% reduction in rebleeding or operation rates as significant (p<0. 05), and a 5007o chance of detecting a reduction in death rates from 1007o to 5%. Rebleeding, operation, and death rates were all rather lower than expected, increasing the possibility with

12

of type 11 error-a claim of no difference when one did exist. The reasons for the better than expected outcome are unclear. Wehave found a lower mortality rate in recipients of tranexamic acid than in placebo recipients; 13although tranexamic acid treatment was allowed in this study, few patients were given it, and hyposecretory treatments were withheld during the period of drug or placebo infusion. The overall death rate (9%) was only slightly lower than expected and was not so great as to prevent us detecting degrees of benefit claimed in earlier studies. Despite the size of our trial, however, the confidence limits round estimates of operation and death rates were quite large, and we cannot be completely sure that a true difference favouring the active remedy has not been missed, although the lack of trend in operation and death rates suggests that this is unlikely.

Our patients were well matched, and the slightly higher proportions of elderly patients and of patients with low haemoglobin levels in the somatostatin group were offset by higher proportions with active bleeding at endoscopy and or a visible vessel at endoscopy in the Inevitably some patients included in an early

with adherent clot

placebo

group.

trial will turn out to have disease which is inappropriately treated. It is important to consider separately the outcome in all patients who received treatment, to gauge whether inappropriate treatment poses any hazards, and whether benefit in patients appropriately treated is being concealed by inappropriate treatment of others. Analysis of outcome in patients who continued to receive treatment showed no evidence of such bias. The proportions of individuals with bleeding gastric or duodenal ulcers or with bleeding from other sites in the two treatment groups were similar. More deaths were observed in gastric-ulcer patients who received placebo and in duodenal-ulcer patients who received somatostatin, but this pattern probably represents random variation. Treatment was well tolerated and no adverse effects were attributed to it. Somatostatin recipients on average had higher blood sugar levels during treatment than placebo recipients, but the differences were small and no active intervention was required. Considerable practical difficulties were, however, encountered in ensuring that infusions were maintained continuously-this is essential in view of the shortlived effect of somatostatin once treatment has ceased. There was, however, no reason to believe that failures of response were attributable to consistent difficulties in maintaining treatment. We conclude that somatostatin treatment is unlikely to have any substantial effect on outcome in most patients with acute upper-gastrointestinal

treatment

bleeding. We thank Kabi Vitrum Ltd and Serono Ltd for supplies of somatostatin and

placebo, and for financial support, and medical, hospital pharmacy, and surgical colleagues for their cooperation. Correspondence should be addressed to M. J. S. L., Department of Therapeutics, C Floor, South Block, University Hospital, Nottingham NG7 2UH. REFERENCES 1. Hoate 2

AM, Bradby GVH, Hawkins CF, Kang JY, Dykes PW. Cimetidine in bleeding peptic ulcer Lancet 1979; ii: 671-73. Dawson J, Cockel R Ranitidine in acute upper gastrointestinal haemorrhage Br Med J

1982, 285: 476-77 3 Dronfield MW, Langman

MJS Acute gastrointestinal bleeding Appraisal of management In: Jewell DP, Shepherd HA, eds. Topics in gastroenterology II. Oxford Biackwell, 1983 13-25 4 Schrumpf E, Vatn MH, Hanssen KF, Myren J A small dose of somatostatin inhibits the pentagastrin-stimulated secretion of acid, pepsin and intrinsic factor in man Clin Endocrinol 1978, 8: 391-95 5. Sonnenberg A, West C Somatostatin reduces gastric mucosal blood flow in normal subjects but not in patients with cirrhosis ofthe liver Gut 1983, 24: 148-53. 6. Kayasseh L, Gyr K, Stalder GA, Allgoewer M Somatostatin in acute gastroduodenal haemorrhage Lancet 1978; ii 833-34 7 Gyr K, Kayasseh L, Moyer FD, Stalder GA Somatostatin and cimetidine in gastroduodenal haemorrhage Proceedings of an international symposium on histamine H receptor antagonists Amsterdam: Excerpta Medica, 1978 299-303 8. Kayasseh L, Gyr K, Stalder GA, Allgoewer M Konservative: Therapie der akuten Ulkusblutung mit Somatostatin Schweiz Med Wschr 1978; 1083-84 9 Kayasseh L, Gyr K. Keller U, Stalder GA, Wall M Somatostatin and cimetidine in peptic-ulcer haemorrhage. Lancet 1980, i: 844-46. 10 Kayasseh L. Gyr K, Keller U, Stalder GA Somatostatin und Cimetidin bei akuter Ulkusblutung—eine randomisierte, kontrollierte studie Z Gastroenterol 1980; 18: 342-43 11 Magnusson I, Ihre T, Johansson C, Seligson U, Torngren S, Uvnasmoberg K Somatostatin or surgery for massive upper gastrointestinal haemorrhage? Gut 1984, 25: A582 (abstr) 12 Coraggio F, Scarpato P, Spina M, Lombardi S. Somatostatin and ranitidine in the control of iatrogenic haemorchage of the upper gastrointestinal tract Br Med J 1984 289: 224 13 Barer D, Ogilvie A, Henry D, et al Cimetidine and tranexamic acid in the treatment of acute upper gastrointestinal-tract bleeding N Engl J Med 1983: 308: 1571-75 14 Fleiss JL Statistical methods for rates and proportions, 2nd ed. New York. John Wiley. 1981