Corremondence Somatostatin and Acute Variceal Hemorrhage To the Editor: We read with some concern the conclusions of the multicenter, randomized double-blind trial (1) suggesting that somatostatin was ineffective, perhaps even harmful, in the treatment of acute hemorrhage caused by esophageal varices. This experience is contrary not only to earlier reports (2-4)but also to two controlled trials that have been completed-Burroughs et al. (3, which has now been accepted for publication in full (61, and our own, in which somatostatin was compared with injection sclerotherapy in the control of significant variceal bleeding. In this last study of 80 patients, somatostatin was shown to be effective and safe, producing results equal to those with injection sclerotherapy (7). The discrepancy between the reported study and the experience of others must surely lie in differences in patient selection. From the paper, one can identify the following factors. First, a remarkably high success rate in controlling hemorrhage is enjoyed by the placebo. Most studies suggest that variceal bleeding will stop spontaneously in 30% to 40% of patients; a control rate of 83% with a placebo is, therefore, difficult to explain. Important relevant information is not provided in the paper. For example, no data are given on the relationship between the onset of the bleeding and the time of entry into the trial, the severity of the continued bleeding, the frequency with which alternative therapy had to be instituted and the number of occasions when the rate of somatostatin infusion had to be increased. Second, the multicenter trial was carried out on 102 patients in 14 participating centers. This implies that the input per center, or at least in the majority of those participating, must have been remarkably low; yet some of the centers have previously reported considerable experience with bleeding varices. The obvious conclusion must be that, of the total experience of varices in each center, only a small proportion of patients were submitted for the trial. It is not clear what selection mechanisms were used, nor are we informed on the number of patients with acute variceal hemorrhage admitted to the centers during the period of study who were not selected for the trial. Third, the authors state that, to be included in the trial, the patients were either actively bleeding from esophageal varices or showed the stigmata of recent hemorrhage but would be excluded if immediate therapeutic intervention was required, such as balloon tamponade, other vasoconstrictors, vasopressin or sclerotherapy. The patients in the trial, therefore, must form a highly selected group-bleeding actively, yet judged not to require conventional treatment. Finally, although the authors state that the severity of

liver disease was not significantly different between the somatostatin and placebo groups, there were more patients (40)in the somatostatin group with moderate (Child grade B)and severe (Child grade C) liver disease than in the placebo group (28 patients). It would have been interesting to determine whether the degree of hepatic dysfunction was a significant prognostic factor with respect to control of bleeding and mortality using a Cox’s proportional hazard model. The authors support their view that somatostatin may be “potentially harmful” in the treatment of variceal hemorrhage by quoting a previous report in which the hormone increased intravariceal pressure in cirrhotic patients (8).However, other studies in experimental animals and in man have shown that somatostatin greatly reduces the flow of blood in the collateral circulation (9-10),suggesting that the hormone may have direct or indirect vasoconstrictor effects on collateral vessels, including varices. Vasoconstriction of the variceal complex in response to somatostatin would explain the increase in intravariceal pressure, but this effect may not necessarily be detrimental to the control of bleeding because flow is reduced.

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R. SHIELDS, M.D., FRCS, FRCS Ed. S.A. JENKINS, Ph.D., FRCS Department of Surgery The University of Liverpool Liverpool L69 3BX, United Kingdom REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM,Levine J, Mills

PR, Fabry TL. A multicenter, randomised double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varies. HEPATOLDGY 1989;10:958-961. 2. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rod& J. Comparison of intravenous somatostatin and vasopressin infusions in treatment of acute variceal hemorrhage. HEPATOLOCY 1984;4:442-446. 3. Jenkins SA, Baxter JN,Corbett W, Devitt P, Ware J, Shields R. A

prospective randomised controlled trial comparing somatostatin and vasopressinin controllingacute variceal haemorrhage.Br Med

J 1985;290:275-278. 4. Testoni PA, Masci E, Passaretti A, Malesci A, Tittobello A, Comin U, Ballarin E, et al. Comparisonof somatostatin and cimetidine in the treatment of acute bleeding oesophageal varices. Curr Ther Re5 1986;39:758-766. 5. Burroughs AK, McCormick PA, Sprengers D, Hughes M, D’Heygere FR, McIntyre N. Randomised double-blind placebo controlled study of somatostatin for the control of variceal bleeding [Abstract]. Gut 1988A1495. 6. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D’Heygere F, McIntyre N. Randomiaed double-blind placebo controlled trial of somatostatin for variceal bleeding. Gastroenterology (In press). 7. Jenkins SA, Baxter JN,Ellenbogen S, Makin C, Kingsnorth A, Gilmore I, Morris AI, et al. A prospective randomised controlled

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trial comparing somatostatin and injection sclerotherapy in the control of acute variceal haemorrhage [Abstract].Br J Surg 1990; 77:A702. 8. Kleber G, Sauerbruch T, Fisher C, Paumgartner G. Somatostatin does not reduce oesophageal variceal pressure in liver cirrhotics. Gut 1988;29:153-156. 9. Yates J , Nott D, Ellenbogen S, Cooke T, Shields R, Jenluns SA.

Effects of somatostatin, sandostatin and vasopressin on portal pressure and collateral blood flow in portal hypertensive rats [Abstract]. Gut 1989;30:A1498. 10. Bosch J, Kravetz D, Mastai R, Bruix J, Rigau J, Mes J . Azygos blood flow in cirrhosis: effects of balloon tamponade, vasopressin, somatostatin and propranolol [Abstractl. HEPATOLOGY 1983;3: 855.

Acute Variceal Bleeding: Still Searching for the Right Treatment To the Editor: We have read with interest the article of Valenzuela et al. (1) suggesting that somatostatin administered under their study conditions is ineffective, but it is most striking that placebo is successful in 34 of 41 (83%) patients. These conclusions led us to emphasize two points. First, the only study in which placebo has been as effective is the study of Walker et al. (2). In their placebo group, 80% of the patients stopped bleeding, but balloon tamponade was used in 20 of 25 patients (75%). In fact, if a real placebo-controlled trial (3)is considered, the controlled bleeding rate is 35% at 6 hr and 45% at 24 hr after initiation of the treatment. It is more likely that in the Valenzuela et al. study (1) some bias in the inclusion criteria may have occurred. These authors described in great detail their inclusion criteria. In most studies (4, 5 ) like ours (61, the description is shorter: an emergency esogastroduodenoscopy demonstrates active bleeding from a varix and the treatment is applied right away. Efficacy of the considered treatment is evaluated within 12 hr after initiation of therapy, that is to say, almost 12 hr after seeing an active hemorrhage during endoscopy. In the Valenzuela et al. study (11, some delay might have occurred between the onset of the variceal bleeding and the initiation of the treatment. This might constitute a bias because a spontaneous stop in bleeding could have happened and so would explain the discrepancy between their results and the others. The second point is that to demonstrate that a treatment is more effective with a rate of 90% than a placebo with a rate of 80%with a subsequent a risk of 5% and p risk of 5%, 640 patients must be included in the two groups to be studied. Besides, if the lowest limit is taken into account (a = 5%, p = 20961, 370 patients would still be necessary. Thus, small groups of patients may lead to imprudent conclusions. On the other side, who would be able to demonstrate that a designated treatment is

Reply: We thank Drs. Shields and Jenkins and Dr. Silvain et al. for their interest and comments on our article (1).We are pleased to offer our points of view on the interesting issues that were raised. We do not believe that our results are contrary to earlier reports (2-4) that compared somatostatin-effects to those of vaso-

better than placebo when such a large number of patients is needed to reach a statistically significant effective rate? Finally, under these conditions, endoscopic sclerosis performed in the emergency department (4)seems actually to be the more beneficial treatment. In the future, we should emphasize that comparisons between studies would be feasible only if everyone used the same methodology.

CHRISTINESILVAIN, M.D. ERICFORT,M.D. PIERRE INGRAND, M.D. MICHEL BEAUCHANT, M.D. Hepatogastroenterology Unit Hbpital La MilBtrie 86000 Poitiers, France REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J , Mills PR, Fabry TL. A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. HEPATOLOGY 1989;10:958-961. 2. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleedmg esophageal varices: a placebo-controlled, double-blind 1986;6:112-115. study. HF,PATOLOGY 3. Fogel MR, Knauer CM, Andres LL, Mahal AS, Stein DET, Kemeny MJ, Rink MM, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding: a placebo-controlled trial. Ann Intern Med 1982;96:565-569. 4. Westaby D, Hayes PC, Gimson AES, Polson RT, Williams R. Controlled clinical trial of injection sclerotherapy for active variceal bleeding. HEPATOLOGY 1989;9:274-277. 5. Tmi XT, Lay CS, Lai KH, Ng WW, Yeh YS, Wang JY,Chiang TT, et al. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding eeophageal varices. 1986;6:406-409. HEPATOLOGY 6. Fort E, Sautereau D, Silvain C, Ingrand P, Pillegand B, Eeauchant M. A randomized trial of terlipressin plus nitroglycerin vs. balloon tamponade in the control of acute variceal hemorrhage. HEPATOLOGY 1990;11:678-681.

pressin or cimetidine. It is true that in the preliminary report by Burroughs et al. ( 5 ) the placebo response was only 41% compared with our 83% response. Because the report by Burroughs et al. is available only as an abstract, we cannot elaborate on the possible emlanations and unwblished data. However, we were surprised by the k g h success rate