GASTROENTEROLOGY
LIVER,
PANCREAS,
AND BILIARY
1990;99:1388-1395
TRACT
Randomized, Double-Blind, Placebo-Controlled Trial of Somatostatin for Variceal Bleeding Emergency Control and Prevention Variceal Rebleeding
of Early
ANDREW K. BURROUGHS, P. AIDEN MCCORMICK, MICHAEL D. HUGHES, DIRK SPRENGERS, FRANCOIS D’HEYGERE, and NEIL MCINTYRE Hepato-biliary and Liver Transplantation Unit and Department General Practice, Royal Free Hospital and School of Medicine,
A randomized, double-blind, placebo-controlled trial of somatostatin was conducted among 120 patients admitted for bleeding esophageal varices (59 placebo, 61 somatostatin). An initial 250-pg bolus of somatostatin followed by a &day continuous infusion of 250 pg/h and an identical administration of placebo were evaluated for both the control of bleeding and prevention of early rebleeding from varices. Failure to control bleeding occurred in 22 (36%) somatostatin patients vs. 35 (59%) placebo patients, with time to failure occurring earlier with placebo (P = 0.036). Blood and plasma transfused per hour during drug infusion of trial drug was reduced in the somatostatin group: median 0.033 vs. 0.105 unit/h (P = 0.025). Use of balloon tamponade was halved in somatostatin-treated patients. The average effect of somatostatin was a 41% reduction in the hazard of failure (95% confidence interval, - 1% to 65%, P = 0.0545) after adjustment for the severity of liver disease, which was the only other variable having a significant influence on time to failure. There was no difference in 30-day mortality per admission (7 placebo, 9 somatostatin) or complications. It is concluded that somatostatin is safe and more effective than placebo for the control of variceal bleeding.
S
omatostatin is a peptide, containing 14 amino acids (l), that reduces splanchnic blood flow in normal 12-4) and anesthetized humans (5). In cirrhotic patients, a modest reduction in hepatic blood flow (61and wedged hepatic venous pressure (7-11) have been reported in some studies, but other investigators have shown only a transient effect (12) or no effect on portal
of Clinical Epidemiology and Hampstead, London, England
pressure (6,13) or intravariceal pressure (14). However, azygous blood flow as a measure of collateral blood flow is reduced more markedly with somatostatin than with vasopressin, given a similar reduction in portal pressure (11). Uncontrolled studies of somatostatin as therapy for variceal bleeding have shown benefit in two (8,15) and no benefit in one study (16). Randomized trials have shown that somatostatin was at least as effective (17) or more effective (18,191 than vasopressin and as effective as vasopressin and nitroglycerin combined (20). Compared with ranitidine there was no benefit in one trial (2l), but compared with cimetidine there was a significant reduction in the period of active bleeding in another trial (22). Although vasopressin with or without vasodilators is standard treatment in many medical centers, there are conflicting data about the efficacy of vasopressin (23) (which can have serious side effects) as well as the efficacy of somatostatin. Furthermore, close analysis of efficacy of the combination of nitroglycerin preparations with vasopressin compared with vasopressin alone shows no reduction in transfusion requirements in two of three trial studies (24-26). This confusion in the literature and the lack of side effects reported in all studies of somatostatin led us to perform a doubleblind placebo-controlled trial of somatostatin for the control of variceal bleeding. We wanted to test somatostatin in a setting that best reflects its potential use in clinical practice by (1) 0 1990by
the American
Gastroenterological
0018~5085/90/$3.00
Association
SOMATOSTATIN AND VARICEAL BLEEDING 1389
November 1990
giving it as soon as possible following admission to hospital on the basis of a clinical suspicion of bleeding varices; (21 administering it for 5 days to assess its efficacy both for the period immediately after admission and also for the prevention of the very early frequently seen rebleeding (27-29); (3) defining failure of therapy as a clinically important end point requiring a change to more invasive therapy, such as sclerotherapy or surgery; (4) taking into account that many patients are repeatedly admitted for bleeding; and (5) evaluating the variable time interval before administration as a confounding factor in the analysis of efficacy, considering the great number of patients referred to our center, a feature common in centers performing trials in this field.
Materials and Methods Definition
of Time Zero
Time of admission to the first hospital after hematemesis and/or melena was defined as time zero; or if already in hospital, time zero was the time when hematemesis and/or melena occurred.
Selection
of Patients
All patients admitted to the Royal Free Hospital Liver Unit between December 1985 and October 1987 with hematemesis or melena were included in the study if they met the following conditions: (1) age was over 16 years; (2) initial systolic blood pressure was 100 mm Hg or below and/or pulse 100 per minute or above: [3] noncirrhotic portal hypertension or absence of portal hypertension had not been diagnosed previously; (4) in patients not previously seen, there was a history and examination compatible with the presence of portal hypertension because of cirrhosis; (5) no decision had been made before bleeding to avoid specific medical therapy (e.g., in patients with terminal liver disease or cancer); (6) referred patients had been seen within 24 hours of admission at the referring hospital and should have not received vasoactive drugs, balloon tamponade, or emergency sclerothrapy; (7) in these referred patients, there should not have been failure of blood and plasma to “control” bleeding. This was defined as: (a) if six or more units of blood or plasma had been transfused within a B-hour period [two units of fresh frozen plasma were considered equivalent to one unit of plasma protein fraction]; (b) if between 18and 24 hours, there was either hematemesis or melena associated with a change in vital signs (a reduction in systolic blood pressure of 20 mm Hg or more, an increase in pulse rate of at least 20 beats/min. or both] or the need to transfuse two units of blood or plasma to maintain stable vital signs. Medical and nursing charts were reviewed immediately on arrival to assess if the above criteria were present. Final criteria for patient selection included (8) no randomization within previous 30 days. The study was approved by the ethics committee of the Royal Free Hospi-
tal. Written or verbal consent was obtained from patients or their next of kin if they had severe encephalopathy.
Randomization Providing no exclusion criteria had been met, randomization was done at admission to the Royal Free Hospital. To ensure similarity in prognostic variables, patients were stratified into four groups, based on Pugh’s modification of Child’s grading (30): (i] grade A and B alcoholic, [ii) grade A and B nonalcoholic, [iii] grade C alcoholic, (iv] grade C nonalcoholic. For each group there was a consecutively numbered series of opaque sealed envelopes containing the allocated treatment derived from a table of random numbers.
Treatment Protocols and Definitions of Failure to Control Variceal Bleeding With Transfusion of Blood Products and Trial Drug Placebo and somatostatin (Stilamin, a synthetic peptide identical to the biological form; Serono Laboratories U.K. Ltd., Welwyn Garden City, U.K.) were packaged in identical ampules, so that both physicians and patients were blinded to the treatment given. The drugs were administered immediately after randomization as a single bolus of either placebo or 250 pg of somatostatin; at the same time, an infusion was started for a total of 5 days consisting of 1 ampule of placebo or 3 mg of somatostatin every 12 hours (250 pg/h) diluted in 50 mL of 5% dextrose using a Graseby 2000 syringe pump (Graseby Medical Ltd., Watford, U.K.). If there was more than 2-3 minutes delay in the change over, an additional blinded bolus of placebo or 250 pg somatostatin was given. At the same time, blood, plasma, and, in some cases, platelets were transfused according to clinical need to restore vital signs to normal, aiming for a hemoglobin concentration of 10 g/dL. Diagnostic endoscopy was performed as soon as possible after admission to the Royal Free Hospital after initial resuscitation. Depending on their initial hemodynamic status, some patients began trial drug administration before diagnostic endoscopy and some immediately afterwards. During the 5 days of trial drug administration, the drug administration was stopped if the criteria of failure had been fulfilled. These were the same as those outlined in the description of patient selection: (1)as in section 7a in which case balloon tamponade was used immediately; (21 as in section 7b with the interval extended to 5 days, with the addition of melena followed by a 2 g/dL decrease in hemoglobin 1evel;and (3) death during infusion of trial drug. Failure of trial drug therapy [whether followed by immediate balloon tamponade or not) was an indication for either endoscopic sclerotherapy or esophageal staple transection, which were performed in the context of a randomized study (31).
Patients During the trial period, there were 242 separate admissions because of hematemesis and/or melena in pa-
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tients with chronic liver disease. In 109 patients, there were reasons for exclusion; 133 were randomized, 120 bleeding from varices and 13 from nonvariceal sources [Table 1). The latter group was excluded from the analysis because the trial drug administration was stopped at the moment of diagnostic endoscopy. The 120 randomizations represent separate admissions in 92 patients with a minimum interval of 30 days between admission. Characteristics of the patient admissions analyzed are shown in Tables z and 3. Clinical and laboratory variables were recorded at time zero and at randomization. The presence and cause of cirrhosis were diagnosed by liver biopsy, autopsy, or by a combination of clinical and biochemical findings.
Statistical
Analysis
Sample size estimation was based on an expected efficacy in controlling variceal bleeding for 5 days of 50% in the placebo group and 80% in the somatostatin group (based on the published reports available at the time of planning the study) with a two-tailed test (80% power and an (Yerror of 5%); at least 88 patients with 30 treatment failures were required (32). The trial was stopped once the required number of patients, rather than patient admissions, was achieved, because we did not know if re-randomization would influence the interpretation of results. Analyses were carried out according to the intention to treat principle, under blinded code by an independent statistician (M.D.H.). Kaplan-Meier plots were used to trace curves of the percentage of patients who had not failed either trial therapy, and differences were tested using the log-rank analysis. The transfusion rate of blood and plasma in units per hour was compared both before randomization
Table 1. Separate Admissions for Hematemesis and/or Melena in Patients With Chronic Liver Disease Seen During the Trial Period Source of bleeding Patient data Randomized Exclusions Failure of transfusion or use of balloon tamponade before admission to Royal Free Hospital” Previous randomization 30 days Insufficient hemodynamic changes on admission Seen 24 h from admission Prior decision not to treat bleeding Previous emergency sclerotherapy Refusals of consent Mistakes Immediate endoscopy showed nonvariceal source
Variceal 120
78
Nonvariceal 13 31
22 19
1
16 8 4 4
13 8 -
3 2
-
9
“Median (range] of blood and plasma units used before emergency transection [n = 10) or emergency sclerotherapy [n = 11) was 13 (6-45). One patient died before either treatment could be given. The nonvariceal lesion was a duodenal ulcer requiring emergency surgery.
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and during and up to time when infusion of trial drug was stopped (either at 5 days or at failure of trial drug). Variables marked with an asterisk in Table 2 and 3 and the transfusion rate of blood and plasma before randomization [Table 4) were evaluated as potential confounding variables affecting treatment efficacy. Those significant univariately were considered in a multivariate analysis. Each variable was also examined for an interaction with treatment effect. Survival was evaluated at 30 days.
Results All patients received their allocated treatment [placebo, n = 59; somatostatin, n = 61). Additional
boluses were given to 34 (56%) somatostatin patient admissions (88 boluses) and 31 (53%) placebo patient admissions (94 boluses). One patient (Pugh’s grade C) died before endoscopy could be performed, 16 hours from randomization, of cardiorespiratory arrest caused by sepsis. He was the only trial drug failure because of death during infusion (somatostatin). Four other patients, all on somatostatin, had the trial infusion stopped in error without restarting it at 2, 13, 37, and 108 hours, but none subsequently failed up to 5 days from randomization. Somatostatin was more effective than placebo with 22 failures (36%] vs. 35 failures (59%) (P < 0.01). In the Kaplan-Meier plots, the patients who discontinued somatostatin prematurely were censored at these time points. Because none of them failed, the increased efficacy of somatostatin shown in Figure 1A represents a slightly more conservative estimate (P = 0.036). Blood and plasma transfusion requirements before randomization both in absolute terms and per hour (to allow for the variable time between admission and randomization) were similar in the two trial groups. In contrast, there was a significant reduction during somatostatin treatment: the median number of units of blood or plasma transfused was 6 (placebo) and 3 (somatostatin) (P = 0.0045). The median number of units of blood and/or plasma transfused per hour was 0.105 (placebo) and 0.033 (somatostatin), with P = 0.025 (the transfusion requirements of the four patients who had somatostatin stopped in error were evaluated for the whole 5-day period). If blood transfused was considered, solely, median was 0.066 unit/h (placebo), 0 unit/h (somatostatin) before trial drug [P = 0.42) and 0.058 unit/H (placebo), 0.019 unit/h (somatostatin) during trial drug infusion (P = 0.035). Balloon tamponade was required twice as often in the placebo group as in the somatostatin group: 8 (13%) vs. 15 (25%) with P = 0.14; it was used in similar proportion of failures in the placebo group, 15 of 35 (43%), as in the somatostatin group, 8 of 22 (36%). The Cox model showed that the only factor influencing the time to failure (or death) within 120 hours besides trial treatment was Pugh’s grade. Ignoring
November
SOMATOSTATIN
1990
Table 2. Characteristics of Trial Groups and Variables Analyzed in a Cox
Age” (yr; mean [range]) Male:femaIe” Etiology cirrhosis Alcoholic” Cryptogenic Biliary Autoimmuno “lupoid” Others Pugh’s grade A:B:C at randomization” Pugh’s score At admission At randomization Presentation with hematemesis:melena alone” Patients referred History of variceal bleeding” Systolic blood pressure” at randomization [mm Hg; mean [range]) Pulse” at randomization (mean [range]) Urea” at admission, (mmoVL; geometric mean [range]] Creatinine at admission (PmoVL; geometric mean [range]] Hemoglobin” at admission [g/L; mean [range]) Platelet count (x log/L)” at admission Bilirubin (pmol/L geometric mean [range]) Albumin (g/L; mean [range]) Prothrombin time (s; mean [range]] Ascites [with moderate or severe ascites) Encephalopathy (with moderate or severe encephalopathy) Endoscopy before start of trial drug Active bleeding at endoscopy Before start of trial drug” After start of trial drug” Previous randomization’
AND VARICEAL BLEEDING
1391
Proportional Hazard Model Placebo (n = 59)
Somatostatin (n = 61)
57 (23-79) 3524
51(18-82)
29 11
33
12
5 2 14:24:21
3922
7 8
7 15:2k9"
8.6 (5-14) 8.6 (5-15) 53:6 25 45 118 (60-170) 98 (74-135) 8.1 (2-21) 84 (46-171) 9.8 (6-14.3) 134 (17-267) 41.2 (4-256) 31.2 (21-43) 18 (11-36) 15 9 30
8.5 (5-15) 8.8 (5-15) 53:8 23 38 116 (80-160) 98 (64-140) 9.6 (3-73) 88 (49-206) 10.0 [2.6-16.8) 133 (32-324) 41.5 (6-4981 32.1 (16-48) 18.5 (12-37) 13 7 32
16 10 13
19 12 15
“Variables analyzed in the Cox model. hIn one patient, the bilirubin and albumin values were not available, and the Pugh’s grade could not be assigned.
treatment group, 6 of 29 (21%) Pugh’s grade A patients, 24 of 50 (48%) grade B patients, and 27 of 40 (68%) grade C patients failed. When Pugh’s score is considered (Table 51, the average effect of somatostatin treatment is estimated as a 40.8% reduction in the hazard of failure (or death] (95% confidence interval 65.3% reduction to 1% increase, P = 0.0545). The interaction of the Pugh’s grade or score with the allocated treatment was not significant at any formal level. Neither previous variceal bleeding nor the interval in days from previous variceal bleeding were associated with failure of trial drug. In those actively bleeding at endoscopy (variceal spurting or oozing) before administration of trial drug, there were 19 failures (63%) in 30 patients receiving placebo and 10 failures (30%) in 32 patients receiving somatostatin. In those actively bleeding at endoscopy after beginning of trial drug administration, there were 16 failures (55%) in 29 placebo patients and 12 failures (43%) in 28 somatostatin patients. We also evaluated the first hematemesis following start of infusion (or death without hematemesis during infusion) as an end point. Again somatostatin was
more effective than placebo: 38 (64%) (placebo) vs. 25 (41%) (somatostatin), P = 0.021. Mortality per admission within 30 days was no different: seven (12%) in placebo group (six related to liver disease] and nine (15%) in somatostatin group (eight related to liver disease]. Only 1 of 24 placebo and 2 of 39 somatostatin patients who did not fail the trial drug died within the next 30 days. Emergency sclerotherapy was used in 21 (60%) of the 35 placebo failures compared with 12 (55%) of the 22 somatostatin failures. The remainder in both groups had esophageal staple transection or no therapy because of intercurrent terminal complications of their liver disease (two placebo, one somatostatin). There was no difference in complications per patient diagnosed during placebo or somatostatin infusion or within 30 days: infection (14 and 14 patients); renal failure (6 and 4); cardiorespiratory failure (2 and 31, and hepatic failure (5 and 4). No complication was attributed specifically to either trial drug. Evaluation of treatment efficacy based only on the first randomization in 92 patients showed similar transfusion requirements (before trial drug administra-
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Table 3. Time-Related Variables in Trial Groups and Those Analyzed in a Cox Proportional Hazard Model Placebo (n = 59) Interval from first manifestationof bleeding to admission (h; median [range]] To first hospital To Royal Free Hospital To start of trial drug” Interval from admission to first hospital and start of trial drug” Patients admitted to first hospital within 24 h of first manifestation of bleeding Patients starting drug within 24 h Of first manifestation of bleeding Of first admission to hospital
Somatostatin (n = 61)
Placebo =
3 (O-58) 7 (O-63) 11 (0.5-64) 5.5 (0.5-31)
4 (O-96) 10 [O-106] 15 (l-107)
304 0
20
40
80
60
120
100
Hours from start of therapy
6 (0.5-73.5)
53
53
48 54
42 51
“Variables analyzed in the Cox model.
tion) and clinical, laboratory endoscopic characteristics in the two trial groups. Somatostatin was more effective than placebo: 30 failures (65%) in 46 placebo patients vs. 18 failures (31%) in 46 somatostatin patients as shown in Figure 1B (P = 0.047, log-rank test]. Blood and plasma transfused per hour during infusion was significantly more for placebo, with a median of 0.158 (O-1.67), than with somatostatin, with a median of 0.039 (O-4), P = 0.036. Also, balloon tamponade was used twice as often in the placebo group, i.e., in 15 patients (33%) vs. 7 (15%) in the somatostatin group. Discussion The role of vasoconstrictor therapy in the management of variceal bleeding remains controversial. Close scrutiny of the trials of vasopressin vs. placebo (33,341 or standard medical treatment (35,36) shows the difficulty in evaluating efficacy, because the trial studies are small and because success of therapy is defined in different ways. The best designed study could not Table 4. Comparison
of Blood and Plasma Transfusion
30-1 0
20
80
60
Figure 1. Time to failure after beginning drug of somatostatin or placebo.
100
120
administration
of trial
A. One hundred twenty patient admissions (P = 0.036). B. Ninety-two (P = 0.047).
patients, considering
only their first randomization
demonstrate vasopressin to be effective (34). In a study by Merigan et al. (33), vasopressin was more effective than placebo, as assessed after only 1 hour following a bolus injection. In two studies (35-361, vasopressin was said to be superior to standard medical therapy based on a N-hour interval with stable vital signs. However, success was evaluated at different time points because the vasopressin infusions were given for varying periods: 7-74 hours (35) and 1-196 hours (36). Furthermore, in a study by Conn et al. (35), there was no difference in transfusion rate per hour, which contrasts with the large difference reported in treatment
Requirements
per Hour and Use of Balloon Tamponode Placebo (n = 59)
Trial failures Total number of units of blood and/or plasma used [median [range]] Before trial infusion During trial infusion Transfusion rate of blood and/or plasma per hour [median [range]) Before trial infusion During trial infusion Balloon tamponade used
40
Hours from start of therapy
Somatostatin (n = 611
P
35 (59%)
22”(36%)
2 (O-17) 6 (O-18)
2 (O-19) 3 (3-13)
0.74 0.0045
0.18 (O-5) 0.033 (O-4)” 8 (13%)
0.62 0.025 0.14
0.22 (O-4) 0.105 (O-1.67) 15 (25%)
0.01
“Includes one patient who died at 16 hours “without failing,” according to hemodynamic criteria. bIncluded four patients who had somatostatin discontinued in error. Transfusion rates include those used up to the end of the 5-day trial period.
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SOMATOSTATIN
1990
AND VARICEAL BLEEDING
1393
Table 5. The Relative Hazard of Failure or Death Within 5 Days of Trial Drug Administration in Relation to Pugh’s Score and the Effect of Somatostatin Treatment
Pugh’s score
No. of patients
Relative hazard independent of treatment effect (95% confidence intervals)
Trial failures (%) Placebo
Somatostatin”
5-6 7-8 9-10
29 28 36
1.00 2.76 (1.06-7.19) P = 0.038 3.04 (1.21-7.62) P = 0.018
29 60 72
13 38 33
11-15
26
4.9611.96-12.531 I'= 0.0007
75
57
“rhe effect of somatostatin is estimated using a Cox proportional hazard model to be a 40.8% reduction in hazard of failure (or death) (P = 0.0545; 95% confidence intervals, 65.3% reduction to 1% increase). Only one patient died without failing during infusion of trial drug (somatostatin group).
efficacy (25% placebo vs. 71% vasopressin). This dichotomy is also found in more recent trials of vasopressin vs. vasopressin and nitroglycerin combined (24,25). The increased efficacy claimed for the latter was not paralleled by a reduction in transfusion requirements in either study. This may suggest that trial end points chosen in these studies did not reflect end points of importance in clinical practice. A recent study (26) shows a difference in transfusion requirements and need for balloon tamponade in favor of vasopressin and transdermal nitroglycerin compared with vasopressin and placebo, although the primary end point, control of bleeding, as defined in the study, was not significantly different. A further factor complicating the interpretation of trial results is the concomitant use of other therapies. In a glypressin trial, Walker et al. (37) used balloon tamponade and sclerotherapy in 75% and 25% of patients, respectively. Jenkins et al (18)used emergency sclerotherapy in 3 of 10 somatostatin patients compared with only 1 of 12 vasopressin patients and considered somatostatin more effective. In the current study, somatostatin or placebo was given for 5 days because this period encompasses greatest risk of continued bleeding and early rebleeding from varices (27-29), during which time drug therapy might be most useful. Over 50% of patients started the drug administration within 6 hours of admission to hospital; we deliberately did not delay giving drugs when more prolonged resuscitation was needed before diagnostic endoscopy. We evaluated active bleeding at endoscopy both before and after the start of trial drug. In clinical practice, an effective drug with virtually no side effects, such as somatostatin, could be given in the emergency room before diagnostic endoscopy if there are clinical grounds to suspect bleeding varices; furthermore, the drug could even be given at home or during ambulance transfer. This trial is only the second double-blind placebocontrolled trial of somatostatin for the control of variceal bleeding; it is also the largest randomized trial of any therapy in this field. The first, recently pub-
lished study (38), could not demonstrate an advantage of somatostatin over placebo. However, the 83% response rate seen in placebo-treated patients in 11 centers suggests a severe selection of patients. It is thus difficult to believe that the variceal bleeding seen in this study is representative of that seen in other centers, considering previously published trials and response rates to pharmacological therapies. In our study, somatostatin was significantly more effective than placebo in controlling variceal bleeding in cirrhotic patients over a &day period, i.e., 64% success rate with somatostatin vs. a 41% success rate with placebo. The increased efficacy of somatostatin was accompanied by a statistically significant reduction in transfusion requirements, and the need for balloon tamponade and emergency procedures (sclerotherapy or staple transection of the esophagus) was halved, although this did not achieve statistical significance (Table 4). The Cox model evaluated factors associated with failure of drug therapy and included important time intervals that could have biased the interpretation of the efficacy of somatostatin [interval to admission and to drug administration), as well as variables related to the severity of bleeding and liver disease, referral pattern, timing of endoscopy and re-randomization, all of which have not been evaluated in other studies. Besides treatment group, only the severity of liver disease was independently associated with an increased risk of failure. There was no statistically significant interaction of somatostatin treatment with severity of liver disease, in that it was more effective than placebo regardless of the degree of hepatic decompensation. Furthermore, the patient characteristics and treatment differences are not affected by considering only the first randomization in the study (92 patients). There was no difference in mortality between placebo and somatostatin groups, which is a finding similar to all the other trials of vasoconstrictor therapy. However, we did not design the study to examine mortality, as our exclusion criteria automatically excluded a large proportion of the patients with the
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worst liver disease and the highest risk of death. In this study, referred patients who had already failed conservative management, those with repeated rebleeding within 30 days, and those with terminal disease were excluded. Consequently, the mortality rate was low. In conclusion, the current study has shown that somatostatin is more effective than placebo for the control of variceal hemorrhage in cirrhotics. Further experimental studies are needed to elucidate the mechanism of action. It may not take place through splanchnic arteriolar vasoconstriction, since pressure reduction in the portal bed appears to be modest (Y-10) in stable cirrhotics. However, or nonexistent (6,12-14) the effects of somatostatin during bleeding may be different from these; thus, experimental models of hemorrhage should be studied. New clinical trials with different regimens of somatostatin should be performed to evaluate whether it can take the place of currently used pharmacological regimens and to assess its role in association with emergency sclerotherapy. Repeated boluses appear more effective than constant infusion (11,391. Preliminary reports of trials of acute variceal bleeding suggest that somatostatin combined with balloon tamponade is more effective than tamponade alone (40) and that a 5day infusion of somatostatin with daily bolus doses is comparable to a regimen of sclerotherapy at diagnostic endoscopy (41). References 1. Reichlin S. Medical Progress. Somatostatin.
[Part II). N Engl J Med 1983;309:1556-1563. 2. Wahren J, Fleig G. Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. Lancet 1976;2:12131216. 3. Jaspan J, Polonsky K. Lewis M, Moosa AR. Reduction
in portal vein flow by somatostatin. Diabetes 1979;28:888-892. 4. Sonnenberg GE, Keller U, Perruchud A, Burckhardt D, Gyrk. Effect of somatostatin on splanchnic haemodynamics in patients with cirrhosis of the liver and in normal subjects. Gastroenterology 1981:80:526-532. 5. Tyden G. Samnegaard H, Thulin L, Muhrbeck 0, Efendic S. Circulatory effects of somatostatin in anaesthetised man. Acta Chir Stand 1979:145:443-446. 6. Merkel C, Gatta A, Zuin R, Finucci GF, Arnaboldi L. Roul A. Effects of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis and portal hypertension. Digestion 1985:32:92-98. 7. Bosch J, Karvetz D, Rodes J. Effects of somatostatin on hepatic and systemic haemodynamics in patients with cirrhosis of the liver. Comparison with vasopressin. Gastroenterology 1981:80: 518-525. 8. Thulin L, Tyuden G, Samnegaard H, Muhrbeck 0, Efendic S. Treatment of bleeding oesophageal varices with somatostatin. Acta Chir Stand 1979;145:395-398. 9. Bories P, Pomler-Layrargues G, Chotard JP, Jacob C, Michel H. La somatostatine diminue l’hypertension portale chez le cirrhotique. Gastroenterol Clin Biol1980;4:616-617. 10. Eriksson LS, Law DH. Wahren J. Influence of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis. Clin Physiology 1984;4:5-11.
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11. Mastai R, Bosch J, Navasa M, Silva G, Kravetz D, Bruix J. Viola C, Rodes J. Effect of continuous infusion and bolus injections of somatostatin on azygous blood flow and hepatic and systemic hemodynamics in patients with portal hypertension. Comparison with vasopressin (abstr]. J Hepatol1986;3(Suppl. l):S53. 12. Naeije R. Hallemans R. Mols P, Meclot C, Reding P. Effect of vasopressin and somatostatin on haemodynamics and blood gases in patients with liver cirrhosis. Crit Care Med 1982;10:578582. 13. Sonnenberg A, West C. Somatostatin reduces gastric mucosal blood flow in normal subjects but not in patients with cirrhosis of the liver. Gut 1983;24:148-153. 14. Kleber G, Sauerbruch T, Fischer G, Paumgartner G. Somatostatin does not reduce oesophageal variceal pressure in liver cirrhotics. Gut 1988;29:153-156. 15. Limberg B, Kommerell B. Somatostatin and bleeding esophageal varices: peer review anyone? Gastroenterology 1980;78: 658-659.
16. Raptis S, Zoupas C. Somatostatin not helpful in bleeding oesophageal varices. N Engl J Med 1979;300:736. 17. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rodes J. Comparison of intravenous somatostatin and vasopressin infusions in the treatment of acute variceal haemorrhage. Hepatology 1984;4:422-446. 18. Jenkins SA, Baxter JN, Corbett WA, Devitt P. Ware J, Shields R. A prospective randomised controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage. Br Med J 1985;290:275-278. 19. Bagarani M, Albertini V, Anza M, Barlattani A, Bracci F, Cucchiara G. Gizzonio D, Grassini G, Mari T, Procaccinate F, Ziparo V, Materia A, Basso N. Effect of somatostatin in controlling bleeding from esophageal varices. Ital J Surg Sci 1987;17:2126. 20. Cardona C. Vida F, Balanzo J, Cuss0 X, Farre A, Guarner C. Eficacia terapeutica de la somatostatina versus vasopressina mas nitroglycerina en la hemorragia activa por varices esotagogastrica. Gastroenterol Hepatol 1989;12:30-34. 21. Loperfido S, Godena F, Tosolini G, De matte P, Burei F, Gasparini G, Sartori C, Valbusa A, Bulfoni A, Buttolo Q, Del Fabbro F, Grassi L, Paniek M. Perrano F. La somatostatina nel trattamento dell’ emorragia da varici esofago-gastriche. Recent Prog Med 1987;78:82-86. 22. Testoni PA, Masci E, Passaretti S, Malesci A, Tittobello A, Comin U, Ballarin E, Maggi CM, Arcidiacono R. Comparison of somatostatin and cimetidine in the treatment of acute variceal bleeding esophageal varices. Curr Ther Res 1986;39:759-766. 23. Hussey KP. Vasopressin therapy for upper gastrointestinal tract haemorrhage. Has its efficacy been proven? Arch Intern Med 1985;145:1263-1267. 24. Tsai Y-T, Lay C-S, Lai K-H, Ng W-W, Yeh Y-S, Wang J-Y, Chiang T-T, Lee S-P, Chiang BP, Lo K-J. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding oesophageal varices. Hepatology 1986;6: 406-409. 25. Grimson AES, Westaby D, Hegarty J, et al. A randomised trial of vasopressin and vasopressin plus nitroglycerin in the control of actue variceal haemorrhage. Hepatology 1986;6:410-413. 26. Bosch J, Groszmann RJ, Garcia-Pagan JC, et al. Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal haemorrhage: a placebo-controlled clinical trial. Hepatology 1989;10:962-968. 27. De Dombal FT. Clarke JR, Clamp SE, Malizia G, Kotwal MR, Morgan AG. Prognostic factors in upper GI bleeding Endoscopy 1986;18(Suppl. 2):6-10. 28. Burroughs AK, Mezzanotte G, Phillips A, McCormick PA, McIntyre N. Cirrhotics with variceal haemorrhage: the importance of the time interval between admission and the start of
November
SOMATUSTATIN
1990
analysis for survival and rebleeding rates. Hepatology 1989;9: 801-807. 29. Graham DY, Smith JL. The course of patients after variceal haemorrhage. Gastroenterology 1981;80:800-809. 30. Pugh RNH. Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. 31. Burroughs AK, McCormick PA, Mezzanotte G, Hamilton G, Hobbs KEF, McIntyre N. A comparison of sclerotherapy with staple transection of the oesophagus for the emergency control of bleeding from oesophageal varices. N Engl J Med 1989:3X: 857-862. 32. Freedman LS. Tables of the numbers of patients required in clinical trials using the log rank test. Stat Med 1982;1:121-129. 33. Merigan TC, Poltkin GR, Davidson CS. Effect of intravenously administered posterior pituitary extract on haemorrhage from bleeding esophageal varices. N Engl J Med 1962;266:134-135. 34. Fogel MR. Knaver M. Andrew LL, Mahal AS, Stein DE, Kemeny MJ, Rinki MM, Walker JE, Siegmund D, Gregory PB. Continuous intravenous vasopressin in active upper gastrointestinal bleeding. Ann Intern Med 1982;96:565-569. 35. Conn HO, Ramsby CR, Storer EH, Milton G, Mutchnick MG, Hoshi PH, Phillips MM, Cohen GA, Fields GN, Petroski D. Intra-arterial vasopressin in the treatment of upper gastrointestinal tract haemorrhage: a prospective, controlled clinical trial. Gastroenterology 1975;68:211-221. 36. Mallory A, Schaefer JW, Cohen JR, Holt SA, Norton LW. Selective intraarterial vasopressin infusion for upper gastrointestinal tract haemorrhage: a controlled trial. Arch Surg 1980;115: 30-32. 37. Walker S. Stiehl A, Raedsch
R, Kommerell B. Terlipressin in bleeding, oesophageal varices: a placebo controlled, double blind study. Hepatology 1986;6:112-115. 38. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J, Mills PR, Fabry TL, Taylor LW. Conn HO, Posillico JT. and a multicentre study group. A multicentre, randomised, doubleblind trial of somatostatin in the management of acute haemorrhage from esophageal varices. Hepatology 1989;10:958-961.
AND VARICEAL BLEEDING
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Morgan JS, Groszmann RJ. Somatostatin in portal hypertension. Dig Dis Sci 1989;34 (Suppl.):4OS-47s. 40. Avgerinos A, Klonis Ch, Rekoumis G. Gouma P, Papedimitriuou N. Controlled trial of somatostatin and balloon tamponade in bleeding esophageal varices (abstr). Gastroenterology 1989;96: A18. 41. Jenkins SA. Baxter JN, Ellenbogen S, Shields R. A prospective randomised controlled clinical trial comparing somatostatin and injection sclerotherapy in the control of acute variceal haemorrhage: preliminary results (abstr). Gut 1988;29:A1431. 39.
Received July 26,1989. Accepted March 16,199O. Address requests for reprints to: Andrew K. Burroughs, M.R.C.P., Academic Department of Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, England. The authors would like to thank Serono Laboratories Ltd. for the supply of coded drugs, Drs. H. Thomas, P. Mistry, G. Kaye, and A. Sawyerr (Royal Free Hospital) and Dr. K. Wallace (Serono Laboratories, Welwyn Garden City, U.K.), who contributed to the smooth running of the trial. The authors would also like to thank the following consultant physicians and surgeons for referring patients included in this trial: Drs. Armstrong and Storring (Barking Hospital): Drs. Apthorpe, Greenacre, Spence, and Williams and Mr. Sagor (St. Alban’s City Hospital); Drs. Borthwick and Willoughby (Lister Hospital); Drs. Barnes, Gray, and Pearson (Barnet General Hospital); Drs. Freedman, Kinlock, and Peters and Mr. Bolton [Chase Farm Hospital); Drs. Diggle and Fairman (Pilgrim Hospital]; Drs. Ekdman and Farrington [King George’s Hospital, Ilford); Dr. Farrow (Watford General Hospital): Dr. Govan (Hillingdon Hospital); Drs. Glick, Hanson, and Wright (Whipps Cross Hospital); Dr. Hamblin (Southend General Hospital); Dr. Hodgson (RPMS-Hammersmith Hospital); Drs. Jain and Nicoll and Mr. Rothwell-Jackson (Luton & Dunstable Hospital): Dr. Keir (Queen Elizabeth II Hospital, Welwyn Garden City): Dr. McMichael (Ealing General Hospital); Dr. Misiewicz (Central Middlesex Hospital); Drs. Pringle, Ramsay, and Woolf [North Middlesex Hospital); Dr. Saunders (Bedford General Hospital): and Dr. Theodossi (May Day Hospital).
LIVER,
PANCREAS,
AND BILIARY
1990;99:1388-1395
TRACT
Randomized, Double-Blind, Placebo-Controlled Trial of Somatostatin for Variceal Bleeding Emergency Control and Prevention Variceal Rebleeding
of Early
ANDREW K. BURROUGHS, P. AIDEN MCCORMICK, MICHAEL D. HUGHES, DIRK SPRENGERS, FRANCOIS D’HEYGERE, and NEIL MCINTYRE Hepato-biliary and Liver Transplantation Unit and Department General Practice, Royal Free Hospital and School of Medicine,
A randomized, double-blind, placebo-controlled trial of somatostatin was conducted among 120 patients admitted for bleeding esophageal varices (59 placebo, 61 somatostatin). An initial 250-pg bolus of somatostatin followed by a &day continuous infusion of 250 pg/h and an identical administration of placebo were evaluated for both the control of bleeding and prevention of early rebleeding from varices. Failure to control bleeding occurred in 22 (36%) somatostatin patients vs. 35 (59%) placebo patients, with time to failure occurring earlier with placebo (P = 0.036). Blood and plasma transfused per hour during drug infusion of trial drug was reduced in the somatostatin group: median 0.033 vs. 0.105 unit/h (P = 0.025). Use of balloon tamponade was halved in somatostatin-treated patients. The average effect of somatostatin was a 41% reduction in the hazard of failure (95% confidence interval, - 1% to 65%, P = 0.0545) after adjustment for the severity of liver disease, which was the only other variable having a significant influence on time to failure. There was no difference in 30-day mortality per admission (7 placebo, 9 somatostatin) or complications. It is concluded that somatostatin is safe and more effective than placebo for the control of variceal bleeding.
S
omatostatin is a peptide, containing 14 amino acids (l), that reduces splanchnic blood flow in normal 12-4) and anesthetized humans (5). In cirrhotic patients, a modest reduction in hepatic blood flow (61and wedged hepatic venous pressure (7-11) have been reported in some studies, but other investigators have shown only a transient effect (12) or no effect on portal
of Clinical Epidemiology and Hampstead, London, England
pressure (6,13) or intravariceal pressure (14). However, azygous blood flow as a measure of collateral blood flow is reduced more markedly with somatostatin than with vasopressin, given a similar reduction in portal pressure (11). Uncontrolled studies of somatostatin as therapy for variceal bleeding have shown benefit in two (8,15) and no benefit in one study (16). Randomized trials have shown that somatostatin was at least as effective (17) or more effective (18,191 than vasopressin and as effective as vasopressin and nitroglycerin combined (20). Compared with ranitidine there was no benefit in one trial (2l), but compared with cimetidine there was a significant reduction in the period of active bleeding in another trial (22). Although vasopressin with or without vasodilators is standard treatment in many medical centers, there are conflicting data about the efficacy of vasopressin (23) (which can have serious side effects) as well as the efficacy of somatostatin. Furthermore, close analysis of efficacy of the combination of nitroglycerin preparations with vasopressin compared with vasopressin alone shows no reduction in transfusion requirements in two of three trial studies (24-26). This confusion in the literature and the lack of side effects reported in all studies of somatostatin led us to perform a doubleblind placebo-controlled trial of somatostatin for the control of variceal bleeding. We wanted to test somatostatin in a setting that best reflects its potential use in clinical practice by (1) 0 1990by
the American
Gastroenterological
0018~5085/90/$3.00
Association
SOMATOSTATIN AND VARICEAL BLEEDING 1389
November 1990
giving it as soon as possible following admission to hospital on the basis of a clinical suspicion of bleeding varices; (21 administering it for 5 days to assess its efficacy both for the period immediately after admission and also for the prevention of the very early frequently seen rebleeding (27-29); (3) defining failure of therapy as a clinically important end point requiring a change to more invasive therapy, such as sclerotherapy or surgery; (4) taking into account that many patients are repeatedly admitted for bleeding; and (5) evaluating the variable time interval before administration as a confounding factor in the analysis of efficacy, considering the great number of patients referred to our center, a feature common in centers performing trials in this field.
Materials and Methods Definition
of Time Zero
Time of admission to the first hospital after hematemesis and/or melena was defined as time zero; or if already in hospital, time zero was the time when hematemesis and/or melena occurred.
Selection
of Patients
All patients admitted to the Royal Free Hospital Liver Unit between December 1985 and October 1987 with hematemesis or melena were included in the study if they met the following conditions: (1) age was over 16 years; (2) initial systolic blood pressure was 100 mm Hg or below and/or pulse 100 per minute or above: [3] noncirrhotic portal hypertension or absence of portal hypertension had not been diagnosed previously; (4) in patients not previously seen, there was a history and examination compatible with the presence of portal hypertension because of cirrhosis; (5) no decision had been made before bleeding to avoid specific medical therapy (e.g., in patients with terminal liver disease or cancer); (6) referred patients had been seen within 24 hours of admission at the referring hospital and should have not received vasoactive drugs, balloon tamponade, or emergency sclerothrapy; (7) in these referred patients, there should not have been failure of blood and plasma to “control” bleeding. This was defined as: (a) if six or more units of blood or plasma had been transfused within a B-hour period [two units of fresh frozen plasma were considered equivalent to one unit of plasma protein fraction]; (b) if between 18and 24 hours, there was either hematemesis or melena associated with a change in vital signs (a reduction in systolic blood pressure of 20 mm Hg or more, an increase in pulse rate of at least 20 beats/min. or both] or the need to transfuse two units of blood or plasma to maintain stable vital signs. Medical and nursing charts were reviewed immediately on arrival to assess if the above criteria were present. Final criteria for patient selection included (8) no randomization within previous 30 days. The study was approved by the ethics committee of the Royal Free Hospi-
tal. Written or verbal consent was obtained from patients or their next of kin if they had severe encephalopathy.
Randomization Providing no exclusion criteria had been met, randomization was done at admission to the Royal Free Hospital. To ensure similarity in prognostic variables, patients were stratified into four groups, based on Pugh’s modification of Child’s grading (30): (i] grade A and B alcoholic, [ii) grade A and B nonalcoholic, [iii] grade C alcoholic, (iv] grade C nonalcoholic. For each group there was a consecutively numbered series of opaque sealed envelopes containing the allocated treatment derived from a table of random numbers.
Treatment Protocols and Definitions of Failure to Control Variceal Bleeding With Transfusion of Blood Products and Trial Drug Placebo and somatostatin (Stilamin, a synthetic peptide identical to the biological form; Serono Laboratories U.K. Ltd., Welwyn Garden City, U.K.) were packaged in identical ampules, so that both physicians and patients were blinded to the treatment given. The drugs were administered immediately after randomization as a single bolus of either placebo or 250 pg of somatostatin; at the same time, an infusion was started for a total of 5 days consisting of 1 ampule of placebo or 3 mg of somatostatin every 12 hours (250 pg/h) diluted in 50 mL of 5% dextrose using a Graseby 2000 syringe pump (Graseby Medical Ltd., Watford, U.K.). If there was more than 2-3 minutes delay in the change over, an additional blinded bolus of placebo or 250 pg somatostatin was given. At the same time, blood, plasma, and, in some cases, platelets were transfused according to clinical need to restore vital signs to normal, aiming for a hemoglobin concentration of 10 g/dL. Diagnostic endoscopy was performed as soon as possible after admission to the Royal Free Hospital after initial resuscitation. Depending on their initial hemodynamic status, some patients began trial drug administration before diagnostic endoscopy and some immediately afterwards. During the 5 days of trial drug administration, the drug administration was stopped if the criteria of failure had been fulfilled. These were the same as those outlined in the description of patient selection: (1)as in section 7a in which case balloon tamponade was used immediately; (21 as in section 7b with the interval extended to 5 days, with the addition of melena followed by a 2 g/dL decrease in hemoglobin 1evel;and (3) death during infusion of trial drug. Failure of trial drug therapy [whether followed by immediate balloon tamponade or not) was an indication for either endoscopic sclerotherapy or esophageal staple transection, which were performed in the context of a randomized study (31).
Patients During the trial period, there were 242 separate admissions because of hematemesis and/or melena in pa-
1390 BURROUGHS
ET AL.
GASTROENTEROLOGY
tients with chronic liver disease. In 109 patients, there were reasons for exclusion; 133 were randomized, 120 bleeding from varices and 13 from nonvariceal sources [Table 1). The latter group was excluded from the analysis because the trial drug administration was stopped at the moment of diagnostic endoscopy. The 120 randomizations represent separate admissions in 92 patients with a minimum interval of 30 days between admission. Characteristics of the patient admissions analyzed are shown in Tables z and 3. Clinical and laboratory variables were recorded at time zero and at randomization. The presence and cause of cirrhosis were diagnosed by liver biopsy, autopsy, or by a combination of clinical and biochemical findings.
Statistical
Analysis
Sample size estimation was based on an expected efficacy in controlling variceal bleeding for 5 days of 50% in the placebo group and 80% in the somatostatin group (based on the published reports available at the time of planning the study) with a two-tailed test (80% power and an (Yerror of 5%); at least 88 patients with 30 treatment failures were required (32). The trial was stopped once the required number of patients, rather than patient admissions, was achieved, because we did not know if re-randomization would influence the interpretation of results. Analyses were carried out according to the intention to treat principle, under blinded code by an independent statistician (M.D.H.). Kaplan-Meier plots were used to trace curves of the percentage of patients who had not failed either trial therapy, and differences were tested using the log-rank analysis. The transfusion rate of blood and plasma in units per hour was compared both before randomization
Table 1. Separate Admissions for Hematemesis and/or Melena in Patients With Chronic Liver Disease Seen During the Trial Period Source of bleeding Patient data Randomized Exclusions Failure of transfusion or use of balloon tamponade before admission to Royal Free Hospital” Previous randomization 30 days Insufficient hemodynamic changes on admission Seen 24 h from admission Prior decision not to treat bleeding Previous emergency sclerotherapy Refusals of consent Mistakes Immediate endoscopy showed nonvariceal source
Variceal 120
78
Nonvariceal 13 31
22 19
1
16 8 4 4
13 8 -
3 2
-
9
“Median (range] of blood and plasma units used before emergency transection [n = 10) or emergency sclerotherapy [n = 11) was 13 (6-45). One patient died before either treatment could be given. The nonvariceal lesion was a duodenal ulcer requiring emergency surgery.
Vol. 99, No. 5
and during and up to time when infusion of trial drug was stopped (either at 5 days or at failure of trial drug). Variables marked with an asterisk in Table 2 and 3 and the transfusion rate of blood and plasma before randomization [Table 4) were evaluated as potential confounding variables affecting treatment efficacy. Those significant univariately were considered in a multivariate analysis. Each variable was also examined for an interaction with treatment effect. Survival was evaluated at 30 days.
Results All patients received their allocated treatment [placebo, n = 59; somatostatin, n = 61). Additional
boluses were given to 34 (56%) somatostatin patient admissions (88 boluses) and 31 (53%) placebo patient admissions (94 boluses). One patient (Pugh’s grade C) died before endoscopy could be performed, 16 hours from randomization, of cardiorespiratory arrest caused by sepsis. He was the only trial drug failure because of death during infusion (somatostatin). Four other patients, all on somatostatin, had the trial infusion stopped in error without restarting it at 2, 13, 37, and 108 hours, but none subsequently failed up to 5 days from randomization. Somatostatin was more effective than placebo with 22 failures (36%] vs. 35 failures (59%) (P < 0.01). In the Kaplan-Meier plots, the patients who discontinued somatostatin prematurely were censored at these time points. Because none of them failed, the increased efficacy of somatostatin shown in Figure 1A represents a slightly more conservative estimate (P = 0.036). Blood and plasma transfusion requirements before randomization both in absolute terms and per hour (to allow for the variable time between admission and randomization) were similar in the two trial groups. In contrast, there was a significant reduction during somatostatin treatment: the median number of units of blood or plasma transfused was 6 (placebo) and 3 (somatostatin) (P = 0.0045). The median number of units of blood and/or plasma transfused per hour was 0.105 (placebo) and 0.033 (somatostatin), with P = 0.025 (the transfusion requirements of the four patients who had somatostatin stopped in error were evaluated for the whole 5-day period). If blood transfused was considered, solely, median was 0.066 unit/h (placebo), 0 unit/h (somatostatin) before trial drug [P = 0.42) and 0.058 unit/H (placebo), 0.019 unit/h (somatostatin) during trial drug infusion (P = 0.035). Balloon tamponade was required twice as often in the placebo group as in the somatostatin group: 8 (13%) vs. 15 (25%) with P = 0.14; it was used in similar proportion of failures in the placebo group, 15 of 35 (43%), as in the somatostatin group, 8 of 22 (36%). The Cox model showed that the only factor influencing the time to failure (or death) within 120 hours besides trial treatment was Pugh’s grade. Ignoring
November
SOMATOSTATIN
1990
Table 2. Characteristics of Trial Groups and Variables Analyzed in a Cox
Age” (yr; mean [range]) Male:femaIe” Etiology cirrhosis Alcoholic” Cryptogenic Biliary Autoimmuno “lupoid” Others Pugh’s grade A:B:C at randomization” Pugh’s score At admission At randomization Presentation with hematemesis:melena alone” Patients referred History of variceal bleeding” Systolic blood pressure” at randomization [mm Hg; mean [range]) Pulse” at randomization (mean [range]) Urea” at admission, (mmoVL; geometric mean [range]] Creatinine at admission (PmoVL; geometric mean [range]] Hemoglobin” at admission [g/L; mean [range]) Platelet count (x log/L)” at admission Bilirubin (pmol/L geometric mean [range]) Albumin (g/L; mean [range]) Prothrombin time (s; mean [range]] Ascites [with moderate or severe ascites) Encephalopathy (with moderate or severe encephalopathy) Endoscopy before start of trial drug Active bleeding at endoscopy Before start of trial drug” After start of trial drug” Previous randomization’
AND VARICEAL BLEEDING
1391
Proportional Hazard Model Placebo (n = 59)
Somatostatin (n = 61)
57 (23-79) 3524
51(18-82)
29 11
33
12
5 2 14:24:21
3922
7 8
7 15:2k9"
8.6 (5-14) 8.6 (5-15) 53:6 25 45 118 (60-170) 98 (74-135) 8.1 (2-21) 84 (46-171) 9.8 (6-14.3) 134 (17-267) 41.2 (4-256) 31.2 (21-43) 18 (11-36) 15 9 30
8.5 (5-15) 8.8 (5-15) 53:8 23 38 116 (80-160) 98 (64-140) 9.6 (3-73) 88 (49-206) 10.0 [2.6-16.8) 133 (32-324) 41.5 (6-4981 32.1 (16-48) 18.5 (12-37) 13 7 32
16 10 13
19 12 15
“Variables analyzed in the Cox model. hIn one patient, the bilirubin and albumin values were not available, and the Pugh’s grade could not be assigned.
treatment group, 6 of 29 (21%) Pugh’s grade A patients, 24 of 50 (48%) grade B patients, and 27 of 40 (68%) grade C patients failed. When Pugh’s score is considered (Table 51, the average effect of somatostatin treatment is estimated as a 40.8% reduction in the hazard of failure (or death] (95% confidence interval 65.3% reduction to 1% increase, P = 0.0545). The interaction of the Pugh’s grade or score with the allocated treatment was not significant at any formal level. Neither previous variceal bleeding nor the interval in days from previous variceal bleeding were associated with failure of trial drug. In those actively bleeding at endoscopy (variceal spurting or oozing) before administration of trial drug, there were 19 failures (63%) in 30 patients receiving placebo and 10 failures (30%) in 32 patients receiving somatostatin. In those actively bleeding at endoscopy after beginning of trial drug administration, there were 16 failures (55%) in 29 placebo patients and 12 failures (43%) in 28 somatostatin patients. We also evaluated the first hematemesis following start of infusion (or death without hematemesis during infusion) as an end point. Again somatostatin was
more effective than placebo: 38 (64%) (placebo) vs. 25 (41%) (somatostatin), P = 0.021. Mortality per admission within 30 days was no different: seven (12%) in placebo group (six related to liver disease] and nine (15%) in somatostatin group (eight related to liver disease]. Only 1 of 24 placebo and 2 of 39 somatostatin patients who did not fail the trial drug died within the next 30 days. Emergency sclerotherapy was used in 21 (60%) of the 35 placebo failures compared with 12 (55%) of the 22 somatostatin failures. The remainder in both groups had esophageal staple transection or no therapy because of intercurrent terminal complications of their liver disease (two placebo, one somatostatin). There was no difference in complications per patient diagnosed during placebo or somatostatin infusion or within 30 days: infection (14 and 14 patients); renal failure (6 and 4); cardiorespiratory failure (2 and 31, and hepatic failure (5 and 4). No complication was attributed specifically to either trial drug. Evaluation of treatment efficacy based only on the first randomization in 92 patients showed similar transfusion requirements (before trial drug administra-
1392 BURROUGHS
GASTROENTEROLOGY
ET AL.
Vol. 99, No. 5
Table 3. Time-Related Variables in Trial Groups and Those Analyzed in a Cox Proportional Hazard Model Placebo (n = 59) Interval from first manifestationof bleeding to admission (h; median [range]] To first hospital To Royal Free Hospital To start of trial drug” Interval from admission to first hospital and start of trial drug” Patients admitted to first hospital within 24 h of first manifestation of bleeding Patients starting drug within 24 h Of first manifestation of bleeding Of first admission to hospital
Somatostatin (n = 61)
Placebo =
3 (O-58) 7 (O-63) 11 (0.5-64) 5.5 (0.5-31)
4 (O-96) 10 [O-106] 15 (l-107)
304 0
20
40
80
60
120
100
Hours from start of therapy
6 (0.5-73.5)
53
53
48 54
42 51
“Variables analyzed in the Cox model.
tion) and clinical, laboratory endoscopic characteristics in the two trial groups. Somatostatin was more effective than placebo: 30 failures (65%) in 46 placebo patients vs. 18 failures (31%) in 46 somatostatin patients as shown in Figure 1B (P = 0.047, log-rank test]. Blood and plasma transfused per hour during infusion was significantly more for placebo, with a median of 0.158 (O-1.67), than with somatostatin, with a median of 0.039 (O-4), P = 0.036. Also, balloon tamponade was used twice as often in the placebo group, i.e., in 15 patients (33%) vs. 7 (15%) in the somatostatin group. Discussion The role of vasoconstrictor therapy in the management of variceal bleeding remains controversial. Close scrutiny of the trials of vasopressin vs. placebo (33,341 or standard medical treatment (35,36) shows the difficulty in evaluating efficacy, because the trial studies are small and because success of therapy is defined in different ways. The best designed study could not Table 4. Comparison
of Blood and Plasma Transfusion
30-1 0
20
80
60
Figure 1. Time to failure after beginning drug of somatostatin or placebo.
100
120
administration
of trial
A. One hundred twenty patient admissions (P = 0.036). B. Ninety-two (P = 0.047).
patients, considering
only their first randomization
demonstrate vasopressin to be effective (34). In a study by Merigan et al. (33), vasopressin was more effective than placebo, as assessed after only 1 hour following a bolus injection. In two studies (35-361, vasopressin was said to be superior to standard medical therapy based on a N-hour interval with stable vital signs. However, success was evaluated at different time points because the vasopressin infusions were given for varying periods: 7-74 hours (35) and 1-196 hours (36). Furthermore, in a study by Conn et al. (35), there was no difference in transfusion rate per hour, which contrasts with the large difference reported in treatment
Requirements
per Hour and Use of Balloon Tamponode Placebo (n = 59)
Trial failures Total number of units of blood and/or plasma used [median [range]] Before trial infusion During trial infusion Transfusion rate of blood and/or plasma per hour [median [range]) Before trial infusion During trial infusion Balloon tamponade used
40
Hours from start of therapy
Somatostatin (n = 611
P
35 (59%)
22”(36%)
2 (O-17) 6 (O-18)
2 (O-19) 3 (3-13)
0.74 0.0045
0.18 (O-5) 0.033 (O-4)” 8 (13%)
0.62 0.025 0.14
0.22 (O-4) 0.105 (O-1.67) 15 (25%)
0.01
“Includes one patient who died at 16 hours “without failing,” according to hemodynamic criteria. bIncluded four patients who had somatostatin discontinued in error. Transfusion rates include those used up to the end of the 5-day trial period.
November
SOMATOSTATIN
1990
AND VARICEAL BLEEDING
1393
Table 5. The Relative Hazard of Failure or Death Within 5 Days of Trial Drug Administration in Relation to Pugh’s Score and the Effect of Somatostatin Treatment
Pugh’s score
No. of patients
Relative hazard independent of treatment effect (95% confidence intervals)
Trial failures (%) Placebo
Somatostatin”
5-6 7-8 9-10
29 28 36
1.00 2.76 (1.06-7.19) P = 0.038 3.04 (1.21-7.62) P = 0.018
29 60 72
13 38 33
11-15
26
4.9611.96-12.531 I'= 0.0007
75
57
“rhe effect of somatostatin is estimated using a Cox proportional hazard model to be a 40.8% reduction in hazard of failure (or death) (P = 0.0545; 95% confidence intervals, 65.3% reduction to 1% increase). Only one patient died without failing during infusion of trial drug (somatostatin group).
efficacy (25% placebo vs. 71% vasopressin). This dichotomy is also found in more recent trials of vasopressin vs. vasopressin and nitroglycerin combined (24,25). The increased efficacy claimed for the latter was not paralleled by a reduction in transfusion requirements in either study. This may suggest that trial end points chosen in these studies did not reflect end points of importance in clinical practice. A recent study (26) shows a difference in transfusion requirements and need for balloon tamponade in favor of vasopressin and transdermal nitroglycerin compared with vasopressin and placebo, although the primary end point, control of bleeding, as defined in the study, was not significantly different. A further factor complicating the interpretation of trial results is the concomitant use of other therapies. In a glypressin trial, Walker et al. (37) used balloon tamponade and sclerotherapy in 75% and 25% of patients, respectively. Jenkins et al (18)used emergency sclerotherapy in 3 of 10 somatostatin patients compared with only 1 of 12 vasopressin patients and considered somatostatin more effective. In the current study, somatostatin or placebo was given for 5 days because this period encompasses greatest risk of continued bleeding and early rebleeding from varices (27-29), during which time drug therapy might be most useful. Over 50% of patients started the drug administration within 6 hours of admission to hospital; we deliberately did not delay giving drugs when more prolonged resuscitation was needed before diagnostic endoscopy. We evaluated active bleeding at endoscopy both before and after the start of trial drug. In clinical practice, an effective drug with virtually no side effects, such as somatostatin, could be given in the emergency room before diagnostic endoscopy if there are clinical grounds to suspect bleeding varices; furthermore, the drug could even be given at home or during ambulance transfer. This trial is only the second double-blind placebocontrolled trial of somatostatin for the control of variceal bleeding; it is also the largest randomized trial of any therapy in this field. The first, recently pub-
lished study (38), could not demonstrate an advantage of somatostatin over placebo. However, the 83% response rate seen in placebo-treated patients in 11 centers suggests a severe selection of patients. It is thus difficult to believe that the variceal bleeding seen in this study is representative of that seen in other centers, considering previously published trials and response rates to pharmacological therapies. In our study, somatostatin was significantly more effective than placebo in controlling variceal bleeding in cirrhotic patients over a &day period, i.e., 64% success rate with somatostatin vs. a 41% success rate with placebo. The increased efficacy of somatostatin was accompanied by a statistically significant reduction in transfusion requirements, and the need for balloon tamponade and emergency procedures (sclerotherapy or staple transection of the esophagus) was halved, although this did not achieve statistical significance (Table 4). The Cox model evaluated factors associated with failure of drug therapy and included important time intervals that could have biased the interpretation of the efficacy of somatostatin [interval to admission and to drug administration), as well as variables related to the severity of bleeding and liver disease, referral pattern, timing of endoscopy and re-randomization, all of which have not been evaluated in other studies. Besides treatment group, only the severity of liver disease was independently associated with an increased risk of failure. There was no statistically significant interaction of somatostatin treatment with severity of liver disease, in that it was more effective than placebo regardless of the degree of hepatic decompensation. Furthermore, the patient characteristics and treatment differences are not affected by considering only the first randomization in the study (92 patients). There was no difference in mortality between placebo and somatostatin groups, which is a finding similar to all the other trials of vasoconstrictor therapy. However, we did not design the study to examine mortality, as our exclusion criteria automatically excluded a large proportion of the patients with the
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worst liver disease and the highest risk of death. In this study, referred patients who had already failed conservative management, those with repeated rebleeding within 30 days, and those with terminal disease were excluded. Consequently, the mortality rate was low. In conclusion, the current study has shown that somatostatin is more effective than placebo for the control of variceal hemorrhage in cirrhotics. Further experimental studies are needed to elucidate the mechanism of action. It may not take place through splanchnic arteriolar vasoconstriction, since pressure reduction in the portal bed appears to be modest (Y-10) in stable cirrhotics. However, or nonexistent (6,12-14) the effects of somatostatin during bleeding may be different from these; thus, experimental models of hemorrhage should be studied. New clinical trials with different regimens of somatostatin should be performed to evaluate whether it can take the place of currently used pharmacological regimens and to assess its role in association with emergency sclerotherapy. Repeated boluses appear more effective than constant infusion (11,391. Preliminary reports of trials of acute variceal bleeding suggest that somatostatin combined with balloon tamponade is more effective than tamponade alone (40) and that a 5day infusion of somatostatin with daily bolus doses is comparable to a regimen of sclerotherapy at diagnostic endoscopy (41). References 1. Reichlin S. Medical Progress. Somatostatin.
[Part II). N Engl J Med 1983;309:1556-1563. 2. Wahren J, Fleig G. Influence of somatostatin on carbohydrate disposal and absorption in diabetes mellitus. Lancet 1976;2:12131216. 3. Jaspan J, Polonsky K. Lewis M, Moosa AR. Reduction
in portal vein flow by somatostatin. Diabetes 1979;28:888-892. 4. Sonnenberg GE, Keller U, Perruchud A, Burckhardt D, Gyrk. Effect of somatostatin on splanchnic haemodynamics in patients with cirrhosis of the liver and in normal subjects. Gastroenterology 1981:80:526-532. 5. Tyden G. Samnegaard H, Thulin L, Muhrbeck 0, Efendic S. Circulatory effects of somatostatin in anaesthetised man. Acta Chir Stand 1979:145:443-446. 6. Merkel C, Gatta A, Zuin R, Finucci GF, Arnaboldi L. Roul A. Effects of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis and portal hypertension. Digestion 1985:32:92-98. 7. Bosch J, Karvetz D, Rodes J. Effects of somatostatin on hepatic and systemic haemodynamics in patients with cirrhosis of the liver. Comparison with vasopressin. Gastroenterology 1981:80: 518-525. 8. Thulin L, Tyuden G, Samnegaard H, Muhrbeck 0, Efendic S. Treatment of bleeding oesophageal varices with somatostatin. Acta Chir Stand 1979;145:395-398. 9. Bories P, Pomler-Layrargues G, Chotard JP, Jacob C, Michel H. La somatostatine diminue l’hypertension portale chez le cirrhotique. Gastroenterol Clin Biol1980;4:616-617. 10. Eriksson LS, Law DH. Wahren J. Influence of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis. Clin Physiology 1984;4:5-11.
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11. Mastai R, Bosch J, Navasa M, Silva G, Kravetz D, Bruix J. Viola C, Rodes J. Effect of continuous infusion and bolus injections of somatostatin on azygous blood flow and hepatic and systemic hemodynamics in patients with portal hypertension. Comparison with vasopressin (abstr]. J Hepatol1986;3(Suppl. l):S53. 12. Naeije R. Hallemans R. Mols P, Meclot C, Reding P. Effect of vasopressin and somatostatin on haemodynamics and blood gases in patients with liver cirrhosis. Crit Care Med 1982;10:578582. 13. Sonnenberg A, West C. Somatostatin reduces gastric mucosal blood flow in normal subjects but not in patients with cirrhosis of the liver. Gut 1983;24:148-153. 14. Kleber G, Sauerbruch T, Fischer G, Paumgartner G. Somatostatin does not reduce oesophageal variceal pressure in liver cirrhotics. Gut 1988;29:153-156. 15. Limberg B, Kommerell B. Somatostatin and bleeding esophageal varices: peer review anyone? Gastroenterology 1980;78: 658-659.
16. Raptis S, Zoupas C. Somatostatin not helpful in bleeding oesophageal varices. N Engl J Med 1979;300:736. 17. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rodes J. Comparison of intravenous somatostatin and vasopressin infusions in the treatment of acute variceal haemorrhage. Hepatology 1984;4:422-446. 18. Jenkins SA, Baxter JN, Corbett WA, Devitt P. Ware J, Shields R. A prospective randomised controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage. Br Med J 1985;290:275-278. 19. Bagarani M, Albertini V, Anza M, Barlattani A, Bracci F, Cucchiara G. Gizzonio D, Grassini G, Mari T, Procaccinate F, Ziparo V, Materia A, Basso N. Effect of somatostatin in controlling bleeding from esophageal varices. Ital J Surg Sci 1987;17:2126. 20. Cardona C. Vida F, Balanzo J, Cuss0 X, Farre A, Guarner C. Eficacia terapeutica de la somatostatina versus vasopressina mas nitroglycerina en la hemorragia activa por varices esotagogastrica. Gastroenterol Hepatol 1989;12:30-34. 21. Loperfido S, Godena F, Tosolini G, De matte P, Burei F, Gasparini G, Sartori C, Valbusa A, Bulfoni A, Buttolo Q, Del Fabbro F, Grassi L, Paniek M. Perrano F. La somatostatina nel trattamento dell’ emorragia da varici esofago-gastriche. Recent Prog Med 1987;78:82-86. 22. Testoni PA, Masci E, Passaretti S, Malesci A, Tittobello A, Comin U, Ballarin E, Maggi CM, Arcidiacono R. Comparison of somatostatin and cimetidine in the treatment of acute variceal bleeding esophageal varices. Curr Ther Res 1986;39:759-766. 23. Hussey KP. Vasopressin therapy for upper gastrointestinal tract haemorrhage. Has its efficacy been proven? Arch Intern Med 1985;145:1263-1267. 24. Tsai Y-T, Lay C-S, Lai K-H, Ng W-W, Yeh Y-S, Wang J-Y, Chiang T-T, Lee S-P, Chiang BP, Lo K-J. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding oesophageal varices. Hepatology 1986;6: 406-409. 25. Grimson AES, Westaby D, Hegarty J, et al. A randomised trial of vasopressin and vasopressin plus nitroglycerin in the control of actue variceal haemorrhage. Hepatology 1986;6:410-413. 26. Bosch J, Groszmann RJ, Garcia-Pagan JC, et al. Association of transdermal nitroglycerin to vasopressin infusion in the treatment of variceal haemorrhage: a placebo-controlled clinical trial. Hepatology 1989;10:962-968. 27. De Dombal FT. Clarke JR, Clamp SE, Malizia G, Kotwal MR, Morgan AG. Prognostic factors in upper GI bleeding Endoscopy 1986;18(Suppl. 2):6-10. 28. Burroughs AK, Mezzanotte G, Phillips A, McCormick PA, McIntyre N. Cirrhotics with variceal haemorrhage: the importance of the time interval between admission and the start of
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analysis for survival and rebleeding rates. Hepatology 1989;9: 801-807. 29. Graham DY, Smith JL. The course of patients after variceal haemorrhage. Gastroenterology 1981;80:800-809. 30. Pugh RNH. Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-649. 31. Burroughs AK, McCormick PA, Mezzanotte G, Hamilton G, Hobbs KEF, McIntyre N. A comparison of sclerotherapy with staple transection of the oesophagus for the emergency control of bleeding from oesophageal varices. N Engl J Med 1989:3X: 857-862. 32. Freedman LS. Tables of the numbers of patients required in clinical trials using the log rank test. Stat Med 1982;1:121-129. 33. Merigan TC, Poltkin GR, Davidson CS. Effect of intravenously administered posterior pituitary extract on haemorrhage from bleeding esophageal varices. N Engl J Med 1962;266:134-135. 34. Fogel MR. Knaver M. Andrew LL, Mahal AS, Stein DE, Kemeny MJ, Rinki MM, Walker JE, Siegmund D, Gregory PB. Continuous intravenous vasopressin in active upper gastrointestinal bleeding. Ann Intern Med 1982;96:565-569. 35. Conn HO, Ramsby CR, Storer EH, Milton G, Mutchnick MG, Hoshi PH, Phillips MM, Cohen GA, Fields GN, Petroski D. Intra-arterial vasopressin in the treatment of upper gastrointestinal tract haemorrhage: a prospective, controlled clinical trial. Gastroenterology 1975;68:211-221. 36. Mallory A, Schaefer JW, Cohen JR, Holt SA, Norton LW. Selective intraarterial vasopressin infusion for upper gastrointestinal tract haemorrhage: a controlled trial. Arch Surg 1980;115: 30-32. 37. Walker S. Stiehl A, Raedsch
R, Kommerell B. Terlipressin in bleeding, oesophageal varices: a placebo controlled, double blind study. Hepatology 1986;6:112-115. 38. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J, Mills PR, Fabry TL, Taylor LW. Conn HO, Posillico JT. and a multicentre study group. A multicentre, randomised, doubleblind trial of somatostatin in the management of acute haemorrhage from esophageal varices. Hepatology 1989;10:958-961.
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Morgan JS, Groszmann RJ. Somatostatin in portal hypertension. Dig Dis Sci 1989;34 (Suppl.):4OS-47s. 40. Avgerinos A, Klonis Ch, Rekoumis G. Gouma P, Papedimitriuou N. Controlled trial of somatostatin and balloon tamponade in bleeding esophageal varices (abstr). Gastroenterology 1989;96: A18. 41. Jenkins SA. Baxter JN, Ellenbogen S, Shields R. A prospective randomised controlled clinical trial comparing somatostatin and injection sclerotherapy in the control of acute variceal haemorrhage: preliminary results (abstr). Gut 1988;29:A1431. 39.
Received July 26,1989. Accepted March 16,199O. Address requests for reprints to: Andrew K. Burroughs, M.R.C.P., Academic Department of Medicine, Royal Free Hospital, Pond Street, London NW3 2QG, England. The authors would like to thank Serono Laboratories Ltd. for the supply of coded drugs, Drs. H. Thomas, P. Mistry, G. Kaye, and A. Sawyerr (Royal Free Hospital) and Dr. K. Wallace (Serono Laboratories, Welwyn Garden City, U.K.), who contributed to the smooth running of the trial. The authors would also like to thank the following consultant physicians and surgeons for referring patients included in this trial: Drs. Armstrong and Storring (Barking Hospital): Drs. Apthorpe, Greenacre, Spence, and Williams and Mr. Sagor (St. Alban’s City Hospital); Drs. Borthwick and Willoughby (Lister Hospital); Drs. Barnes, Gray, and Pearson (Barnet General Hospital); Drs. Freedman, Kinlock, and Peters and Mr. Bolton [Chase Farm Hospital); Drs. Diggle and Fairman (Pilgrim Hospital]; Drs. Ekdman and Farrington [King George’s Hospital, Ilford); Dr. Farrow (Watford General Hospital): Dr. Govan (Hillingdon Hospital); Drs. Glick, Hanson, and Wright (Whipps Cross Hospital); Dr. Hamblin (Southend General Hospital); Dr. Hodgson (RPMS-Hammersmith Hospital); Drs. Jain and Nicoll and Mr. Rothwell-Jackson (Luton & Dunstable Hospital): Dr. Keir (Queen Elizabeth II Hospital, Welwyn Garden City): Dr. McMichael (Ealing General Hospital); Dr. Misiewicz (Central Middlesex Hospital); Drs. Pringle, Ramsay, and Woolf [North Middlesex Hospital); Dr. Saunders (Bedford General Hospital): and Dr. Theodossi (May Day Hospital).
