Terlipressin vs. Somatostatin in Bleeding Esophageal Varices: A Controlled, Double-blind Study SIEGFRIED WALKER, HEINZ-PETER KREICHGAUER AND J. CHRISTIAN BODE Department of Gastroenterology, Robert-Bosch-Krunkenhaus, W-7000Stuttgart 50, Germany

Fifty episodes of bleeding from esophageal or gastric varices in 33 patients with cirrhosis were randomized to treatment with either intravenous terlipressin (2mg initially and 1 mg every 4 hr for 24 hr together with bolus injection and continuous infusion of placebo) or with somatostatin (250 pg as a bolus and continuous infusion of 250 pg/hr somatostatin for 24 hr and placebo injections). Standard therapy with transfusions, fluid and electrolyte correction and lactulose was administered in both groups. In the terlipressin group, 22 of 25 bleeding episodes (88%) were initially stopped by the vasoactive drugs, and in the somatostatin group 19 of 25 bleeding episodes (76%)were initially stopped by the vasoactive drugs. Two of the three bleeding episodes not arrested by terlipressin and five of the six bleeding episodes not arrested by somatostatin were controlled by balloon tamponade. In one patient in each group variceal bleeding initially could not be stopped, and the patients died. The failure rate of the vasoactive treatment alone, including rebleeding episodes within the study period, was 20% in the terlipressin group and 32% in the somatostatin group. The control rate, including balloon tamponade, was 96% in both groups. The hospital mortality rate was 16% (4of 25) in the terlipressin group and 24% (6of 25)in the somatostatin group. Blood transfusions, use of balloon tamponade and duration of bleeding did not differ significantly. This interim analysis of the ongoing study indicates that a large proportion of bleeding episodes from esophageal and fundic varices can be stopped initially (82%) and definitively controlled (74%) by vasoactive drugs alone. Differences in the effectiveness of terlipressin and somatostatin were not observed. (HEPATOLOGY 1992;15:1023-1030.) Hemorrhage from esophageal varices is a major complication of cirrhosis that carries a high mortality rate (1, 21, and a variety of treatments like balloon tamponade, sclerotherapy and vasoactive drugs are used. Terlipressin has been shown to be superior t o placebo (3, 4) and vasopressin (5) for this indication. Somatostatin was compared with placebo in two studies Received May 22, 1991; accepted January 8,1992. Address reprint requests to: Siegfried Walker, M.D., Robert-BoschKrankenhaus, Department of Gastroenterology, Auerbachstr. 110, W-7000 Stuttgart 50,Germany. 31/1/36486

(6, 7) and compared with vasopressin in four studies (8-11);it was more effective in one study (6) and three studies (9-111, respectively. Both vasoactive drugs have been shown to be of similar effectiveness in the management of bleeding varices in comparison with balloon tamponade (12-15) or superior (16). We report the first controlled trial comparing terlipressin and somatostatin in acute variceal bleeding.

PATIENTS AND METHODS Inclusion criteria were the following: endoscopically verified acute spurting or oozing bleeding from esophageal or gastric varices or recovery of fresh blood from the stomach in patients with a white “nipple” or clot on esophageal or gastric varices and no other potential source of bleeding demonstrated endoscopically not more than 12 hr before. Esophageal varices were graded in accordance with Paquet (17). Endoscopy was always performed within 2 hr after admission or within the same time interval with inpatients with hematemesis or melena. Exclusion criteria were a history of coronary heart disease or ventricular arrhythmia, stroke or transient ischemic attacks, bronchial asthma, epilepsy, pregnancy, treatment with an experimental drug in the 28 days preceding the start of the study or, for a former study participant still in the hospital, rebleeding. In addition, patients for whom a decision had been made to avoid invasive treatment (e.g.,patients in the terminal stage of cancer) were excluded. Between May 1988 and January 1991, 330 emergency esophagogastroduodenoscopies for suspected upper gastrointestinal bleeding were performed in the Robert-BoschKrankenhaus, Stuttgart, Germany, in all patients by one or another of the three authors of this article. In 46 bleeding episodes actively bleeding varices were demonstrated endoscopically in the esophagus (n = 371, fundus (n = 8) and the descending duodenum (n = 1).In seven patients with a history of hematemesis or melena on endoscopic examination a white fibrin clot on a varix was found, but no other bleeding source was discovered. However, because fresh blood was recovered from the stomach within 12 hr of endoscopy, these patients were included in the study. Not included were a 56-yr-old woman with duodenal variceal bleeding; a 25-yr-old woman with esophageal variceal bleeding and portal hypertension as a result of portal venous obstruction by a pancreatic carcinoma; and a 54-yr-old man with variceal bleeding and a recent cerebral apoplexy. No patient died before randomization. Cirrhosis had been revealed by laparoscopy or needle biopsy on previous admissions, typical laboratory and clinical findings or both. Only one patient, a 55-yr-old man, did not have

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WALKER. KREICHGAUER AND BODE

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-s r

HEPATOLOGY

If rebleeding, defined as aspiration of fresh blood from the stomach, occurred within the 24-hr study period, the study medication was continued, and, as for the initial bleeding, a Som-Ver balloon tamponade was used if necessary. If this action also Group failed emergency sclerotherapy was conducted. Rebleeding episodes occurring more than 24 hr after randomization were Ter-Ver treated with standard therapy, terlipressin and, if necessary, balloon tamponade or sclerotherapy. Som-Pla The calculation of the sample size indicated that, assuming estimated bleeding control rates of 60% and 80% (e.g., 50% difference in the estimated treatment failure rate) and ac0 4 8 12 16 20 24 h cepting an error of 5% for false-positive results and 10% for FIG.1. Flow chart for the terlipressin (group T ) and somatostatin false-negative results, a total of 106 bleeding episodes should (group S ) groups. At time zero, 2 mg terlipressin (Ter-Ver) or 250 kg be studied (20). The study protocol provided for a compulsory somatostatin @om-Ver) and placebo were injected, and infusion of 250 interim evaluation after treatment of 50 bleeding episodes; k g h r somatostatin or placebo was started. that evaluation is reported here. Categorical data were analyzed using Fisher’s exact test, and continuous data were compared with the Wilcoxon signed-rank test. For survival analysis the Kaplan-Meier cirrhosis, but he did have a prehepatic block of unknown method was used (20). The five components of the Child-Turcotte classification origin. In this patient and in two other patients, a portosystemic shunt operation was performed during the follow-up were assigned numerical values (A = 1, B = 2, C = 3), and the period on days 13,13and 10, respectively,after randomization. mean was calculated and reconverted to the nearest alphaStandard therapy consisting of blood and plasma transfu- betical notation (A = 5 to 7, B = 8 to 12, C = 13 to 15) in sions, fluid replacement, electrolyte correction and lactulose accordance with Conn et al. (21). The study protocol conformed to the ethical guidelinesof the was administered where necessary. Randomization to the terlipressin group or the somatostatin 1975 Declaration of Helsinki and was approved by the ethics group was performed on inclusion into the study. Initially, committee of the Robert-Bosch-Krankenhaus at their October patients in the terlipressin group received 2 mg terlipressin 7,1987, session. Although the authors had prepared a written and placebo intravenously. At the same time, continuous declaration of consent, the committee decided that patients infusion of placebo was started. In addition, 1mg terlipressin consent did not need to be obtained. was injected intravenously at 4,8, 12, 16,20 and 24 hr (Fig. 1). Patients in the somatostatin group initially received 250 pg RESULTS somatostatin and placebo intravenously. At the same time, continuous infusion of somatostatin, 250 pg/hr, was started. Fifty consecutive bleeding episodes from esophageal In addition, placebo was injected intravenously at 4, 8, 12, 16, and gastric varices in 33 patients were randomly 20 and 24 hr (Fig. 1). included in this study; 25 bleeding episodes were treated Terlipressin (“glypressin”; N-a-triglycyl-8-lysine-vasowith terlipressin (group T) and 25 bleeding episodes pressin) or somatostatin and placebo ampules, which were not were treated with somatostatin (group S). Clinical and distinguishable from the verum ampules, were packed together. The packages were numbered and used in random laboratory data on admission in groups T and S are order for one bleeding episode each. The terlipressin, somato- shown in Tables 1and 2. No significant differences were statin and identically packed placebo ampules were kindly do- seen between the two groups. nated by Ferring Pharmaceuticals, Kiel, Germany. Ten patients were included twice, two patients were Balloon tamponade (a Sengstaken-Blakemoretube modified included three times and one patient was included four in accordance to Boyce [181 or a Linton-Nachlas tube [19] in times. All patients had been discharged between study the case of bleeding gastric varices) was used if bleeding could periods and had at least one interim sclerotherapy not be arrested within 4 hr, or earlier if progressive shock session before rerandomization. Of the patients who developed despite standard therapy and vasoactive drugs. The were restudied, five were in the terlipressin group and tubes were passed through the nose. The Linton balloon was filled with 600 in1 of air, the gastric balloon of the Sengstaken eight were in the somatostatin group on first admission. tube was filled with 150 ml air and the esophageal balloon was In the second study period nine patients were ranfilled with air at 30 to 40 mm Hg pressure. A traction of 500 domized to group T and four patients were randomized to group S. On the third occasion one patient was gm was applied only to the Linton tube. Treatment was considered to have failed when a balloon randomized to group T and two patients were rantamponade was necessary or when rebleeding occurred within domized to group S. In the fourth study period, the a 24-hr period. Sclerotherapy was performed if the bleeding patient randomized for the fourth time was in group T. could not be stopped by the vasoactive treatment and addiIn the terlipressin group, 22 of 25 bleeding episodes tional balloon tamponade. (88%)were initially stopped by the vasoactive drug, and Intermittent siphonage of the gastric content was perof 25 bleedings (76%)were formed and cessation of bleeding was recorded when no fresh in the somatostatin group 19 blood could be aspirated from the stomach and hemodynamic initially stopped by the vasoactive drug (Table 3). In the parameters were stable. Bleeding was considered to be con- subgroup rerandomized 16 of 17 bleeding episodes were trolled by the medication studied when bleeding ceased within initially stopped by the vasoactive drugs (Table 4). Rebleeding after initial hemostasis occurred within the 24-hr study period and a period of at least 24 hr passed without any evidence of rebleeding. 24 hr in two patients in group T and in two patients in

0 0 0 0 0 0 Ter-P’a

Vol. 15, No. 6,1992

TABLE 1. Clinical data on admission Terlipressin Characteristic

Age (Yr)

M/F (no.) Cause of portal hypertension (no.) Alcoholic cirrhosis Posthepatitic cirrhosis PBC Cryptogenic cirrhosis Prehepatic block Child-Turcotte classification" A B C Variceal localization/ and grade' Esophagus, grade I Esophagus, grade I1 Esophagus, grade I11 Esophagus, grade IV Gastric fundus Previous variceal bleeding (no.) Previous sclerotherapy (no.) Broca indexf Ascites (no.) Encephalopathy (no.) Blood pressure Systolic (mm Hg) Diastolic (mm Hg) Pulse rate (min- ')

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TERLIPRESSIN VS. SOMATOSTATIN IN VARICEAL BLEEDING

P U P

*

Somatostatin group

p Value

51.2 ? 12.1 14/11

20 1

19 3

1 3 0

1 1 1

NSb NS NS 0

1.6 ? 1.5

2 12 6 4 4 1.2 ? 1.2

NS

* 3.2

2.1 ? 3.1

NS

1.0 ? 0.2 20 20

1.0 f 0.2 17 20

NS NS NS

3.2

111.2 f 21.2 65.0 5 21.0 108.8 ? 28.7

12

18

24

30

FIG.2.Survival rate after acute variceal hemorrhage. The patients or somatostatin and were treated with terlipressin and placebo (-) placebo (-). A total of 25 bleedingepisodes were treated in each group. The differences in survival did not reach statistical significance.

4 19 2 NS

2 9 5 7 4

6

Days

NS

5

.................................

Q)

c

53.3 14.6" 15/10

18 2

...............

115.0 ? 27.5 68.0 f 21.8 113.4 f 23.6

NS NS NS

"Mean 2 S.D. bNot statistically significant. 'According to Conn et al. (21). dIf varices are present in the esophagus and fundus, both are given. 'According to Paquet (17). 'Broca index = body weight (kg)/(length [cml - 100).

group S; it occurred after more than 24 hr but during the same period of hospitalization in seven patients in group T and four patients in group S. One patient in group T and three patients in group S died as a direct or indirect result of rebleeding episodes (Table 5). Only one patient in group S died of a hepatic coma despite initial control of the hemorrhage with no rebleeding episode. Treatment failures, including two rebleeding episodes in each group within 24 hr, were seen in 5 of 25 bleeding episodes in group T and in 8 of 25 bleeding episodes in group S (Table 3). The bleeding control rate in the subgroup rerandomized to terlipressin was 11 of 11, and in the rerandomized somatostatin subgroup the bleeding control rate was 6 of 6. No significant differences were seen between the results of the initial study and those of the restudy (Table 4).In addition, no significant differences were seen in either the initial control of bleeding

or the rebleeding episodes in patients previously treated with sclerotherapy compared with patients not previously exposed to this technique (Table 6). Two of the three bleeding episodes not controlled by terlipressin and five of the six bleeding episodes not controlled by somatostatin were stopped by balloon tamponade (Table 3). Transfusion of blood and plasma, use of balloon tamponade and duration of bleeding did not differ in the two groups. Side effects of the medical treatment were recorded in three patients in group S. In two patients an increase in blood pressure to 170/100 and 170/90 mm Hg was observed; one of them was treated with nitroglycerin and nifedipine. In one patient ventricular tachycardia occurred, which was possibly induced by a central venous line in the right cardiac atrium. No side effects were observed in group T. Changing or interrupting the therapy regimen was not necessary for any patient. In two patients variceal bleeding initially could not be stopped by vasoactive drugs and balloon tamponade, and these patients died of the initial bleeding or a complication of balloon tamponade. The hospital mortality rate was 16% (4of 25) in the terlipressin group and 24% (6 of 25)in the somatostatin group. The hospital mortality in the terlipressin subgroup that was restudied was 1of 11, and the hospital mortality in the somatostatin subgroup that was restudied was 0 of 6. The survival rates during the first 30 days after bleeding are shown in Figure 2. DISCUSSION

For more than 30 yr, posterior pituitary extract or vasopressin has been used in the treatment of bleeding esophageal varices (22-24).The rates of hemostasis achieved in the groups treated with vasopressin are extremely variable, ranging from 9% to 83%;if (ignoring differences in methodological procedure) the 13 controlled studies are combined, a total of 113 of 232 hemorrhages from esophageal varices (49%) were arrested by vasopressin (25). After intravenous injection of terlipressin (glypressin), the three glycine residues are split off and the actually vasoactive lysine-vasopressinis slowly released

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TABLE 2. Laboratory data on admission Normal

P U P

Somatostatin group

120-180 0.37-0.52 150-350 5.0-10.0 5-24 50-200 5 1.4 70-100 I 1.4 6.5- 8.0 3.6-5.6

83.9 f 26.4b 0.27 ? 0.07 126.7 f 68.8 9.5 f 4.3 18.0 f 14.4 142.2 f 70.4 2.1 f 2.1 54.0 f 15.2 1.0 ? 0.7 6.1 +- 1.4 3.0 f 0.7

84.1 f 22.5 0.26 f 0.07 118.3 ? 87.3 8.6 2 5.7 44.2 f 110.7 186.5 i 116.9 3.6 ? 5.7 53.7 f 15.4 1.1 i 1.2 6.2 f 1.3 3.0 f 0.5

Terlipressin

Test

Hemoglobin (gm/L) Hematocrit Platelets (i09/L) Leukocytes (109/L) ALT (IU/L) Alkaline phosphatase (IUIL) Bilirubin (mg/dl) Prothrombin time (%) Creatinine (mgldl) Serum proteins total (gm/dl) Serum albumin (gm/dl)

p value"

NS NS NS NS NS NS NS NS NS

NS NS

"Group T vs. group S. 'Mean t S.D.

TABLE3. Results of treatment Activity

Number of bleeding episodes Bleeding not stopped Initial stop of bleeding Using vasoactive drug Using drug and balloon TOTAL Rebleeding within 24 hours Treatment failureb Control of bleeding Using vasoactive drug Using drug and balloon TOTAL Balloon tamponade used Duration of bleeding (hr) Units of blood and plasma Rebleeding during hospital stay After 24 hr TOTAL Hospital stay (days) Patients discharged (no.) Hospital mortality (no.)

Total

Terlipressin group

Somatostatin P U P

p Value"

50 (100) 2 (4)

25 (100) 1(4)

25 (100) 1(4)

NS

41 (82) 7 (14) 48 (96) 4 (8) 13 (26)

22 (88) 2 (8) 24 (96) 2 (8) 5 (20)

19 (76) 5 (20) 24 (96) 2 (8) 8 (32)

NS NS NS NS NS

37 (74) 11(22) 48 (96) 13 (26) 5.4 f 3.2 5.2 f 4.0

20 (80) 4 (16) 24 (96) 5 (20) 5.2 f 2.2 5.4 ? 3.6

17 (68) 7 (28) 24 (96) 8 (32) 5.7 ? 4.0 5.1 ? 4.5

NS NS NS NS NS NS

11(22) 15 (30) 19.0 f 9.8 40 (80) 10 (20)

7 (28) 9 (36) 20.2 f 10.9 21 (84) 4 (16)

4 (16) 6 (24) 17.6 2 8.4 19 (76) 6 (24)

NS NS NS NS NS

Numbers in parentheses are the percentages. "Group T vs. group S. 'Bleeding initially not stopped by vasoactive drug and/or rebleeding during vasoactive treatment.

(26-28). This action results in an extension of the biological efficacy to 3 to 4 hr (28-311,as opposed to a few minutes with vasopressin, and makes intravenous bolus injections possible. In contrast to vasopressin (32-34), terlipressin does not lead to plasminogen activation, and no serious cardiac side effects have been seen. Although the systemic hemodynamic effects of vasopressin and terlipressin are similar (29), the administration of terlipressin, as opposed to vasopressin, results in an adequate compensatory rise in the hepatic arterial blood flow, which compensates for the reduced portal flow (29, 35). In humans a comparable reduction in portal pressure with vasopressin and terlipressin (31) and reductions of between 5%and 35%of portal or variceal

pressure have been measured by various methods with terlipressin (31, 36-40). In a controlled study (51, terlipressin treatment was compared with vasopressin. The rate of hemostasis in the terlipressin group (70%) was significantly higher than the rate of hemostasis in the vasopressin group (9%),which in turn was lower than the spontaneous rate of hemostasis in controlled studies (4, 6, 7, 41-43). A second comparative study was discontinued because of a fatal complication with vasopressin (necrosis of the perfused arm) (44). To date three placebo-controlled studies on terlipressin have been published (3, 4, 45), and in the two studies covering an adequate number of bleeding epi-

Vol. 15, No. 6, 1992

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TERLIPRESSIN VS. SOMATOSTATIN IN VARICEAL BLEEDING

TABLE 4. Results of treatment and effect of rerandomization Activity

Total

Number of bleeding episodes Bleeding not stopped Initial stop of bleeding Using vasoactive drug Using drug and balloon TOTAL Rebleeding within 24 hr Treatment failureb Control of bleeding Using vasoactive drug Using drug and balloon TOTAL Balloon tamponade used Duration of bleeding (hr) Units of blood and plasma Rebleeding during hospital stay After 24 hr TOTAL Hospital stay (days) Patients discharged (no.) Hospital mortality (no.)

First randomization

Rerandomization

p value=

50 (100) 2 (4)

33 (100) 1 (3)

17 (100) 1(6)

NS

41 (82) 7 (14) 48 (96) 4 (8) 13 (26)

25 (76) 6 (18) 31 (94) 3 (9) 11 (33)

16 (94) 1(6) 17 (100) 1(6) 2 (12)

NS NS NS NS NS

37 (74) 11 (22) 48 (96) 13 (26) 5.4 2 3.2 5.2 f 4.0

22 (67) 9 (27) 31 (94) 11 (33) 6.0 f 3.8 5.3 f 4.3

15 (88) 2 (12) 17 (100) 2 (12) 4.8 1.3 5.1 f 3.5

NS NS NS NS NS NS

11 (22) 15 (30) 19.0 2 9.8 40 (80) 10 (20)

9 (27) 12 (36) 19.7 ? 8.6 24 (73) 9 (27)

2 (12) 3 (18) 17.9 11.5 16 (94) 1 (6)

NS NS NS NS

+_

+_

NS

Numbers in parentheses are the percentages. "First randomization vs. rerandomization group. "Bleeding initially not stopped by vasoactive drug andor rebleeding during vasoactive treatment.

TABLE5. Cause of death Age

(w)

Sex (W)

Initial hemostasis

Rebleeding episode (day)

Death (day)

10 2

12 8

Group T 68 36

M M

Yes Yes

71

M

No

78

M

Yes

7

8

Group S 76 58 63

F F M

No Yes Yes

15 3

1 15 4

M

Yes Yes Yes

1 8, 14 -

3 14 13

54 71 64

F

M

36

sodes significantly more hemorrhages were stopped with terlipressin as compared with placebo (3,4).In the first placebo-controlled study with terlipressin (3), bleeding was stopped in all 25 cases in the terlipressin group and in 20 of 25 cases (80%) in the placebo group. However, a Sengstaken-Blakemore tube was used in 20 of the 25 hemorrhages in the terlipressin group and in 19 of the 25 hemorrhages in the placebo group. In a second study by Freeman, Cobden and Record ( 4 3 , 9 of 15 bleeding episodes in the terlipressin group and 6 of 16 bleeding episodes in the placebo group were initially controlled. In the recently published study by Soderlund et al. (4),

Cause of death

Hepatic coma Cerebral hypoxia Sinus venoms thrombosis Esophageal perforation Hepatic coma Recurrent variceal bleeding Hepatic coma Initial variceal bleeding Recurrent variceal bleeding Recurrent variceal bleeding Hepatic coma Hepatic coma Recurrent variceal bleeding Hepatic coma

bleeding was arrested in 28 of the 31 patients receiving terlipressin and in 17 of the 29 patients receiving placebo. Significantly fewer patients died before discharge in the terlipressin group (4). The administration of somatostatin results in a reduction in splanchnic circulation and portal pressure both in animal experiments and in healthy human subjects (46). In patients with cirrhosis the data are contradictory (47,48). Recently, a rise in transmural esophageal variceal pressure in patients with cirrhosis who received somatostatin was reported (49). Ten controlled studies have been performed on the

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HEPATOLOGY

TABLE 6. Results of treatment and effect of previous sclerotherapy Previous sclerotherapy Activity

Number of bleeding episodes Bleeding not stopped Initial stop of bleeding Using vasoactive drug Using drug and balloon TOTAL Rebleeding within 24 hr Treatment failureb Control of bleeding Using vasoactive drug Using drug and balloon

TOTAL Balloon tamponade used Duration of bleeding (hr) Units of blood and plasma Rebleeding during hospital stay After 24 hr TOTAL Hospital stay (days) Patients discharged (no.) Hospital mortality (no.)

Total

Yes

No

p value-

50 (100) 2 (4)

31 (100) 1 (4)

19 (100) 1 (4)

NS

41 (82) 7 (14) 48 (96) 4 (8) 13 (26)

27 (87) 3 (10) 30 (97) 3 (10) 7 (23)

14 (74) 4 (21) 18 (95) l(5) 6 (32)

NS NS NS NS NS

37 (74) 11 (22) 48 (96) 13 (26) 5.4 ? 3.2 5.2 f 4.0

24 (77) 6 (19) 30 (97) 7 (23) 4.7 f 2.2 5.5 k 4.5

13 (68) 5 (26) 18 (95) 6 (32) 6.1 2 4.5 4.8 ? 3.3

NS NS NS NS NS NS

11 (22) 15 (30) 19.0 2 9.8 40 (80) 10 (20)

4 (13) 7 (23) 18.4 ? 9.7 27 (87) 4 (13)

7 (37) 8 (42) 20.2 ? 10.1 13 (68) 6 (32)

NS

NS NS NS NS

Numbers in parentheses are the percentages. "Group with previous sclerotherapy vs. group without previous sclerotherapy. bBleedinginitially not stopped by vasoactive drug and/or rebleeding during vasoactive treatment.

treatment of bleeding esophageal varices with somatostatin (6-11,14-16,501, with the control group receiving vasopressin in four studies (8-11), cimetidine in one study (501, placebo in two studies (6, 7) and balloon tamponade in three studies (14-16); the hemostasis rates in the somatostatin groups were significantly higher in five reports (6,9-11,16). Somatostatin (15,161 or the long-acting somatostatin analogue, SMS 201-995 (141, was compared with esophageal tamponade and proved to be either equally effective (14, 15) or superior (16).During a 5-day period somatostatin was as effective as injection sclerotherapy (51). Although hemodynamic measurements in patients under somatostatin treatment who had cirrhosis and portal hypertension have produced contradictory results, the controlled studies indicate therapeutic effectiveness. The aim of this prospective, randomized study was to define the effect of conservative treatment and to compare two vasoactive drugs in the emergency management of esophageal and gastric variceal bleeding in patients with portal hypertension with regard to short-term effectiveness in controlling bleeding and mortality. In contrast to our earlier placebo-controlled terlipressin study (3), which was criticized for the simultaneous use of the Sengstaken-Blakemore tube (52), in this study our treatment approach was clearly defined, and the decision to go on from vasoactive drugs to the next step (balloon tube) was always made by the intensive care unit doctor together with one of the authors; thus, the effect of the vasoactive treatment itself could be assessed.

After the 50 treated bleeding episodes, more bleeding episodes were initially stopped and controlled,treatment failures were fewer, bleeding time was shorter and fewer deaths were seen in the terlipressin group than in the somatostatin group although the differences did not reach statistical significance. This lack of significant differences might have been the result of equal effectiveness, small differences or the relatively small number of bleeding episodes. However, many controlled studies of bleeding varices covered fewer (5, 9-11, 12, 14-16, 41-43, 45) or equal (3) numbers of bleeding episodes, and significant results were obtained nevertheless (3, 5, 9-11, 16, 41, 42). This study was not performed as a multiple center study to guarantee close adherence to the study protocol, and the study will be continued until 106 bleeding episodes have been included. The clinical and laboratory data (Tables 1and 2) of the terlipressin and somatostatin groups were similar at the time the patients entered the study, so the results were not influenced by differences between the groups. The same is true for the reinclusion of patients who had been discharged. This might be a selection of sorts because patients in better general condition would be expected to survive the initial hemorrhage more often and thus be able to experience further bleeding episodes. However, this point has not thus far been proven; on the other hand, patients with a rebleeding episode should be more likely to bleed again. This study showed that when the results of the first randomization were compared with those of the subsequent randomizations no significant

Vol. 15, No. 6, 1992

TERLIPRESSIN VS. SOMATOSTATIN IN VARICEAL BLEEDING

differences could be found (Table 4). Previous sclerotherapy did not significantly influence the results (Table 6). The percentage of bleeding control is comparable with that reported in earlier studies with vasoactive drugs (25) and with more invasive and potentially dangerous methods like balloon tamponade (12-16, 53, 54) and sclerotherapy (55). The esophageal perforation caused by balloon tamponade in our series reflects the risk of severe side effects associated with balloon tamponade (53, 54). In addition, the use of balloon tamponade is unpleasant for the patient. The reported effectiveness of emergency sclerotherapy in unselected cirrhotic patients and bleeding esophageal varices is quite variable (56-61) and ranges between 65%(60) and 95%(57, 58). Furthermore, the results of published studies are not necessarily typical because the effectiveness of this endoscopic measure depends on the skill and routine of the endoscopist, which may not be guaranteed everywhere and always, and therefore sclerotherapy is performed as a daytime procedure in many hospitals. Prindiville et al. (62) found a more frequent incidence of rebleeding after sclerotherapy when the procedure was performed during the acute bleeding (50%)rather than as elective treatment (30%).Elective sclerotherapy may be performed more easily and more safely than the emergency procedure during bleeding (63).In this study, bleeding was initially stopped and controlled by the vasoactive drugs plus balloon tamponade in 96%. In conclusion, the interim analysis of the ongoing study indicates that a relatively high proportion of bleeding episodes from esophageal varices can be initially stopped (82%)and definitively controlled (74%) by vasoadive drugs alone. In these patients, invasive emergency measures can be avoided through the use of vasoactive agents, and sclerotherapy can then be carried out during the bleeding-free interval. Differences in the efficacy of terlipressin and somatostatin were not observed.

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