Multicenter Randomized Controlled Trial of Terlipressin Versus ...

Multicenter Randomized Controlled Trial of Terlipressin Versus Sclerotherapy in the Treatment of Acute Variceal Bleeding: The TEST Study ˜ A`NGELS ESCORSELL,1 LUIS RUIZ DEL ARBOL,2 RAMON PLANAS,3 AGUSTıŃ ALBILLOS,4 RAFAEL BANARES ,5 PAUL CALE` S,6 7 8 9 1 DOMINIQUE PATERON, BRIGITTE BERNARD, JEAN-PIERRE VINEL, JAUME BOSCH, AND THE TEST STUDY MEMBERS*

Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in-hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy-proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n ⴝ 105) or emergency sclerotherapy (n ⴝ 114). Success was defined as obtaining control of bleeding (24-hour bleeding-free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant [NS]). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child-Pugh class A ⴙ B and Child-Pugh class C patients. Both treatments were similar regarding transfusion requirements, in-hospital stay, and 6-week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P ⴝ .06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipres-

Abbreviations: EIS, endoscopic injection sclerotherapy; RCT, randomized controlled trial; CHU, Centre Hospitalier Universitaire; TIPS, transjugular intrahepatic portosystemic shunt; OR, odds ratio; CI, confidence interval. From the 1Liver Unit and Endoscopy Unit, Hospital Clıńic, IDIBAPS, Department of Medicine, University of Barcelona, Barcelona, Spain; 2Department of Gastroenterology, Hospital Ramoń y Cajal, University of Alcala´ de Henares, Madrid, Spain; 3Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 4Department of Gastroenterology, Clıńica Puerta de Hierro, University of Alcala´ de Henares, Madrid, Spain; 5Department of Gastroenterology, Hospital General Gregorio Maranõń, Universidad Complutense, Madrid, Spain; 6CHU Angers, Angers, France; 7Intensive Care Unit, CHU Jean Verdier, Bondy, France; 8CHU Pitie´-Salpetrie`re, Paris, France; and 9CHU Purpan, Toulouse, France. Received February 2, 2000; accepted June 29, 2000. Supported in part by grants from the Fondo de Investigaciones Sanitarias (FIS 97/ 1309) and by Ferring AB (Malmo¨, Sweden). *Members of the TEST Study Group are listed in the Appendix. Address reprint requests to: Jaume Bosch, M.D., Liver Unit, IMD, Hospital Clıńic, C/Villarroel, 170, 08036 Barcelona, Spain. E-mail: [email protected]; fax: (34) 93 451 55 22. Copyright © 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3203-0005$3.00/0 doi:10.1053/jhep.2000.16601

sin may represent a first-line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day. (HEPATOLOGY 2000;32:471-476.) Variceal bleeding complicating cirrhosis results in a high mortality (24% to 35%), mainly determined by the impairment in liver function, the failure to control bleeding, and the development of early rebleeding.1 The high frequency of early rebleeding (30% to 50%)2 has led to the recommendation that treatments for variceal hemorrhage should be aimed, not only at arresting bleeding, but also at preventing early rebleeding.3 Emergency endoscopic injection sclerotherapy (EIS) is widely considered as the best treatment for variceal bleeding.3,4 However, EIS has limitations because of the difficulties in having an experienced endoscopist on a 24-hours-a-day basis and the risk of causing severe side effects, known to be more frequent following emergency than elective procedures.5 It is doubtful that banding ligation is better than EIS in acute bleeding.5 This has encouraged the search for pharmacologic alternatives overcoming these limitations. Recent large randomized controlled trials (RCTs) showed that terlipressin effectively controls variceal bleeding with a low rate of side-effects6-12 even when used for an extended period.13,14 Terlipressin has optimal applicability, does not require specialized staff or sophisticated equipment, and is the only drug shown to improve survival from variceal bleeding in placebocontrolled trials9,15 and meta-analyses.3 This multicenter RCT was aimed at investigating whether, in cirrhotic patients with acute variceal bleeding, prolonged therapy with terlipressin is as effective as emergency EIS in (1) controlling bleeding, (2) preventing early rebleeding, (3) survival, and (4) incidence of side effects. PATIENTS AND METHODS Selection of Patients. This multicenter RCT was conducted in 5 Spanish and 4 French teaching hospitals with extensive experience in the treatment of acute variceal bleeding and its complications: Hospital Clinic, Barcelona, Spain (Coordinating Center); Hospital Ramoń y Cajal, Madrid, Spain; Hospital Germans Trias i Pujol, Badalona, Spain; Clıńica Puerta de Hierro, Madrid, Spain; Hospital Gregorio Maranõń, Madrid, Spain; Centre Hospitalier Universitaire (CHU) Angers, Angers, France; CHU Pitie´-Salpetrie`re, Paris, France; CHU Jean Verdier, Bondy, France; and CHU Purpan-Toulouse, Toulouse, France. Patients with histologically proven cirrhosis or clinical and ultrasonographic data compatible with the diagnosis of cirrhosis admitted to any of the participating hospitals because of hematemesis and/or

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472 ESCORSELL ET AL. melena were considered eligible for this study if they met the following criteria: (1) clinical evidence of bleeding (hematemesis and/or melena) during the previous 24 hours; (2) endoscopically proven hemorrhage from esophageal varices as shown by the finding on emergency endoscopy, performed within 6 hours of admission, of active bleeding from a varix, stigmata of recent hemorrhage, or fresh blood in the stomach and esophageal varices as the only potential source of bleeding4; (3) age between 18 and 70 years; (4) no previous randomization in this study (therefore patients, not episodes, could be analyzed); (5) no previous use of vasopressin and/or terlipressin and/or endoscopic injection sclerotherapy to control the bleeding episode; and (6) signed informed consent to participate in the study. Patients referred from other hospitals were included only if they fulfilled all the above-mentioned criteria. The study protocol was approved by the Ethical Committee of each participating hospital. The protocol and all the procedures scheduled conformed to the guidelines and rules of Good Clinical Practice in clinical trials. Exclusion criteria were failure to fulfill entry criteria; bleeding from fundal varices; concomitant gastrointestinal bleeding from sources other than esophageal varices; previous (5-day period) EIS or variceal banding ligation; earlier transjugular intrahepatic portalsystemic shunt (TIPS) to treat previous episodes of variceal hemorrhage; a history of severe cardiovascular disease, including acute myocardial infarction, atrioventricular block, heart failure, chronic peripheral ischemia, and arterial hypertension (defined by a systolic blood pressure of ⬎180 mm Hg and/or a diastolic blood pressure ⬎100 mm Hg); a known hypersensitivity to terlipressin or sclerosing agents; known hepatocellular carcinoma; pregnancy; chronic renal failure; ongoing treatment for bronchial asthma; and body weight ⬍50 kg. Randomization. Randomization was performed while the patient was in the endoscopy suite, after the emergency endoscopy disclosed that bleeding originated from the esophageal varices. Separate blocked lists of randomization were generated by computer for each participating center by Ferring AB (Malmo¨, Sweden). The assigned treatments were kept, by each investigator, in sealed, consecutively numbered, opaque envelopes until randomization. Patients were randomized to receive terlipressin injections or EIS (see below). The study coordinator had the treatment code that was broken in no case. Clinical Assessment and General Management. Before emergency endoscopy, clinical history, physical examination, electrocardiogram, chest radiograph, and laboratory tests were obtained. The period of time between the last evidence of bleeding and admission and from admission to randomization into the study were recorded for each patient. Patients were closely monitored throughout the study. Whenever possible, the therapy was performed in intensive care units. A nasogastric tube was placed after emergency endoscopy for hourly examination of gastric content for the first 24 hours after randomization. Blood pressure, heart rate, and central venous pressure were recorded every 4 hours. Hematocrit was determined every 8 hours. Patients were subjected to chest radiography on day 2 and to repeat endoscopy at the end of the study period. Hypovolemia was corrected using whole blood, packed red cells, fresh frozen plasma, or plasma expanders. Blood transfusion was aimed at maintaining hematocrit between 0.28 to 0.30. All patients received oral lactulose and nonabsorbable oral antibiotics to prevent hepatic encephalopathy and infections by enteric organisms, respectively. Treatment Protocols. Terlipressin (Glypressin,® Ferring AB) was initiated as intravenous injections of 2 mg/4 h until achieving the initial control of bleeding or failure criteria and up to a maximum of 48 hours. The first injection of terlipressin was administered immediately after randomization, i.e., during or immediately after the diagnostic endoscopy. After achieving the initial control of bleeding (see below), the dose of terlipressin was halved (1 mg/4 h) and maintained for 5 more days; the treatment period being 6 to 7 days. Patients allocated to endoscopic injection sclerotherapy underwent a single session of emergency sclerotherapy (intra-paravariceal injection of either 5% ethanolamine or 1% polidocanol) immediately

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after randomization, i.e., during diagnostic endoscopy. After this, no further sclerotherapy was allowed until one of the study end points was reached. Clinical, biochemical, and endoscopic controls were performed in all patients on inclusion and at the end of the study (5 days after the initial control of bleeding). In addition, patients were followed to day 42 after inclusion into the study to assess bleeding-related mortality and complications.4 Definitions. Success of therapy was a combined variable including initial control of bleeding, absence of early rebleeding, and survival during the study period. Definitions for each parameter followed the guidelines set at the first Baveno consensus meeting4: Initial control of bleeding was defined as obtaining a 24-hour bleeding-free period within the first 48 hours after randomization. Bleeding was defined by hematemesis, presence of fresh blood in 6 consecutive hourly gastric aspirates, or signs of hypovolemia with a direct confirmation of bleeding (repeated endoscopy and/or fresh melena and/or fresh blood in gastric aspirate). Hypovolemia was considered when at least 2 of the following were simultaneously met: heart rate ⬎120 bpm; systolic blood pressure ⬍80 mm Hg; hematocrit decrease ⱖ10 points from the previous; central venous pressure ⬍0 cm H2O. Early rebleeding was any further bleeding from the upper gastrointestinal tract occurring from the initial control of bleeding to 5 days later. Rebleeding was defined by any single or combination of presence of fresh blood in gastric aspirates during a consecutive period of at least 6 hours, signs of hypovolemia in conjunction with a direct confirmation of bleeding by either repeat endoscopy and/or fresh melena and/or fresh blood in the gastric aspirate, or hematemesis. Failure of therapy was considered when any of the following occurred: inability to achieve initial control of bleeding, need for alternative therapy, early rebleeding, or death during the study. Alternative therapy was considered necessary when bleeding could not be controlled or massive bleeding occurred (hematemesis with hypovolemic signs and/or fresh blood in 6 consecutive hourly gastric aspirates with hypovolemic signs and/or need to transfuse 6 or more units of blood within a period of 6 hours to maintain hemodynamic stability). All patients developing failure to control bleeding or early rebleeding received an appropriate therapy (vasoactive drugs, endoscopic treatment, surgical shunt, or TIPS) although they may not have met the criteria of need for alternative therapy. When failure occurred, patients received alternative therapy to control the bleeding, using either pharmacologic therapy (except terlipressin), emergency sclerotherapy, balloon tamponade, TIPS, surgery, or any combination thereof. Time zero was defined as the time of arrival to hospital or the start of bleeding in patients already hospitalized.4 Death related to bleeding was defined as any death occurring within 6 weeks of time zero.4 The trial was stopped after meeting success or failure criteria, if the patient died, if severe side effects occurred, or if the patient withdrew consent to continue. Secondary End Points. To better compare the therapies in this study, the following parameters were assessed: transfusion requirements, length of intensive care unit and hospital stay, need and type of alternative therapy, and late rebleeding (from the end of the study period up to 6 weeks). Assessment of Side Effects. Side effects were defined as any abnormal physical sign, symptom, or laboratory change occurring during participation in the trial and considered to be related to the treatments under study. The severity of the side effects was classified according to the following criteria: mild (noticeable abnormality but that causes little or no discomfort or interference with normal activity and requires no specific treatment), moderate (may cause considerable discomfort or interference with normal activity and require specific therapy but does not pose significant danger to the patient), and severe (considered to endanger the health or safety of the patient and may require discontinuation of drug and specific treatment). All side effects were similarly and specifically looked for in all patients, regardless of the allocated and received treatment.

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age (SPSS Inc., Chicago, IL) was used for this analysis. Data are reported as means with standard deviations. Categorical variables were compared using the Fisher’s exact test and continuous variables were compared with the unpaired Student’s t test (or the nonparametric Mann-Whitney rank-sum test for unpaired data). The actuarial probability curves of early rebleeding and 6-week survival were constructed by using the Kaplan-Meier method and compared with the log-rank test. Stepwise logistic regression was used to identify independent predictive variables for failure of treatment and death. Odds ratio (OR) and the 95% confidence interval (CI) are given. Statistical significance was established at a P value less than .05. RESULTS

FIG. 1.

Flow-chart of the study.

Sample Size Calculation. The sample size calculation was based on the results of 10 published studies for terlipressin and 15 for emergency sclerotherapy (at the time the study was planned). The estimated overall failure rate for terlipressin was 40% (failure to control bleeding 20% ⫹ development of early rebleeding 20%),6-13,15,16 and 30% (10% ⫹ 20%, respectively) for sclerotherapy.3,14,17-19 The sample size needed to detect clinical equivalence (a difference lower than the maximum expected, was established at 10%) in efficacy was calculated as 83 patients on each arm using a 2-sided test with 80% power at a significance level of 5%. The expected incidence of severe side effects was 4% for terlipressin6-13,15,16 and 16% for EIS.3,14 To detect such differences in the incidence of severe side effects (2-sided test, ␣ ⫽ 0.05, ␤ ⫽ 0.20), 95 patients were required in each group. Assuming a 5% drop-out rate, a total of 200 patients was required to test the study hypothesis: (1) terlipressin is as effective as EIS both in controlling variceal bleeding and in preventing early rebleeding, and (2) terlipressin is associated with less severe side effects than EIS. Patients. From June 1994 to April 1996, 346 cirrhotic patients were admitted because of acute variceal bleeding in the 9 participating hospitals. A total of 125 of these patients were not included in the study for the following reasons: age ⬎70 years (n ⫽ 37), emergency treatment of the index bleed with the therapies in study (n ⫽ 10), previous (5-day period) endoscopic injection sclerotherapy or variceal banding ligation (n ⫽ 10), earlier TIPS in situ (n ⫽ 8), previous randomization to this study (n ⫽ 5), history of severe cardiovascular disease (n ⫽ 13), chronic renal failure (n ⫽ 1), ongoing treatment of bronchial asthma (n ⫽ 2), bleeding from fundal varices (n ⫽ 4) or other sources than varices (n ⫽ 5), refusal of consent (n ⫽ 3), interval from last manifestation of bleeding to inclusion greater than 24 hours (n ⫽ 4), hemorrhage considered as a terminal event (n ⫽ 6), known hepatocellular carcinoma (n ⫽ 14), and massive bleeding requiring emergency portal-systemic shunt or TIPS before randomization (n ⫽ 3). Two patients were nonassessable because of major protocol violations (they received elective therapy before ending the 6-day study period). Therefore, 219 assessable patients were finally included in the study: 50 in the Hospital Clıńic, Barcelona; 40 in the Hospital Ramoń y Cajal, Madrid; 28 in the Hospital Germans Trias i Pujol, Badalona; 24 in the Hospital Gregorio Maranõń, Madrid; 22 in the Clıńica Puerta de Hierro, Madrid; 17 in the CHU Angers, Angers; 16 in the CHU Jean Verdier, Bondy; 14 in the CHU Pitie´-Salpetrie`re, Paris; and 8 in the CHU Purpan-Toulouse, Toulouse. Follow-up. Twenty-four hours after finishing the study, patients underwent physical examination, laboratory determinations, and upper gastrointestinal endoscopy. Patients were followed to day 42 after inclusion to assess side effects and bleeding-related mortality.4 Statistical Analysis. Statistical analysis was performed by the Laboratori d’Estadı´stica Aplicada of the Universitat Auto`noma of Barcelona following an intention-to-treat basis. The SPSS statistical pack-

The results of this study are reported in the flow chart in Fig. 1. Of the 219 patients, 105 were allocated to receive terlipressin injections and 114 emergency EIS. The 2 groups were similar with respect to baseline data (Table 1). After completing the initial 6 to 7 days of the study, all patients underwent elective therapy to prevent recurrent bleeding using either repeated sessions of EIS (n ⫽ 69) or variceal banding ligation (n ⫽ 27), pharmacologic therapy (n ⫽ 38), a combination of endoscopic and pharmacologic treatment (n ⫽ 11) or portal-systemic anastomosis, either surgical (n ⫽ 20) or TIPS (n ⫽ 14), according to the protocol prevailing at each participating center. Twenty-five patients died before starting elective therapy and 15 were lost to follow-up. Overall, there were no significant differences between the 2 treatment groups regarding the elective therapy received. Failure of Therapy. Treatment failure occurred in 35 of 105 patients in the terlipressin group and in 36 of 114 patients in the EIS group (P ⫽ .45) (Table 2 and Fig. 2). Failure rates in the subset of patients with active bleeding at initial endoscopy were similar in both groups (46% vs. 35%, respectively; OR, 0.63; 95% CI, 0.26-1.49; P ⫽ .62) and did not differ from those TABLE 1. Clinical Parameters of the Patients Included at the Time of Randomization (According to the Recommendations Set at the Reston Consensus Meeting)

Sex (M/F) Age (yr)* Etiology of cirrhosis (alcoholic/other) Bilirubin (mg/dL)* Plasma albumin (g/L)* Prothrombin index (%)* Platelet count (⫻109/mL)* Serum creatinine (mg/dL)* Child-Pugh class (A/B/C) Previous variceal bleeding Active bleeding at endoscopy Transfusion before randomization (U)* Systolic blood pressure (mm Hg)* Diastolic blood pressure (mm Hg)* Heart rate (bpm)* Hypovolemic shock (n) Hematocrit (%)* Intervals (h)* Last manifestation to admission Admission to randomization Randomization to start of therapy * Results are mean ⫾ SD.

Terlipressin (n ⴝ 105)

Sclerotherapy (n ⴝ 114)

P

80/25 56 ⫾ 9

78/36 55 ⫾ 11

.23 .51

41/64 3.2 ⫾ 4.1 29 ⫾ 6 58 ⫾ 18 107 ⫾ 55 0.9 ⫾ 0.4 24/47/34 40 37

47/67 3.2 ⫾ 2.3 29 ⫾ 6 56 ⫾ 16 98 ⫾ 48 1 ⫾ 0.7 20/59/35 23 49

.87 .93 .78 .33 .19 .44 .49 .04 .24

0.7 ⫾ 1.3 120 ⫾ 25 68 ⫾ 13 92 ⫾ 18 12 29 ⫾ 6

0.5 ⫾ 1.1 122 ⫾ 22 69 ⫾ 13 97 ⫾ 18 9 28 ⫾ 6

.30 .55 .31 .04 .26 .55

0.1 ⫾ 6 5.7 ⫾ 6.3 1 ⫾ 2.8

1 ⫾ 12 6.4 ⫾ 11.5 0.3 ⫾ 0.6

.53 .57 .009

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TABLE 2. Results of Therapy: Primary and Secondary End Points

Failure of therapy Overall Child-Pugh class A ⫹ B Child-Pugh class C Causes of failure No control of bleeding Early variceal rebleeding Alternative treatment performed in failures Sclerotherapy Vasoactive drugs Endoscopic Rx ⫹ Drugs Surgery or TIPS Balloon tamponade None Units of blood transfused* Days in ICU* Days in hospital* Late rebleeding

Terlipressin (n ⴝ 105)


P

35/105 (33%) 22/71 (31%) 13/34 (38%)

36/114 (32%) 26/79 (33%) 10/35 (29%)

.45 .47 .28

20/105 (19%) 15/105 (14%)

20/114 (18%) 16/114 (14%)

.45 .55

8 11 8 5 1 2 4.7 ⫾ 4.8 5⫾5 17 ⫾ 10 26/105 (25%)

6 18 7 4 0 1 4.5 ⫾ 4.3 5⫾6 18 ⫾ 10 29/114 (25%)

.36 .09 .47 .48 .49 .49 .80 .84 .47 .95

* Results are mean ⫾ SD.

observed in nonactive bleeders (34% vs. 29%; OR, 0.81; 95% CI, 0.39-1.68; P ⫽ .35). The failure rate was not significantly influenced by the severity of liver impairment, assessed by the Child-Pugh classification (Table 2). Failure to achieve the initial control of bleeding accounted for 57% of failures in the terlipressin group and for 56% in the EIS group (P ⫽ .45). Failure was due to early rebleeding in 43% and 44%, respectively (P ⫽ .55) (Table 2). The 2 treatment groups were similar regarding the length of intensive care unit and overall hospital stay and transfusion requirements (Table 2). Twenty-two patients in the terlipressin group and 21 in the EIS group reached the criteria of need for alternative therapy (P ⫽ .38). Multivariate analysis including cause of cirrhosis, active alcoholism, previous variceal bleeding, hypovolemic shock at admission, transfusion requirements before randomization, Child-Pugh class, size of varices, active bleeding at endoscopy, and allocated treatment identified the presence of hypovolemic shock at admission as the only independent predictor of treatment failure (OR, 2.71;

FIG. 2. Actuarial probability of remaining free of treatment failure. The actuarial probability of remaining free of failure to control the initial bleeding (2 days after randomization) was 81% in the terlipressin group and 82% in the sclerotherapy group. At 5 days, the cumulative probability of remaining free of failure (failure to control initial bleeding or development of early rebleeding after the initial control of bleeding) was 67% and 68%, respectively.

95% CI, 1.01-7.31; P ⫽ .048). The allocated treatment had no predictive value (P ⫽ .86). Late rebleeding was not different in the 2 groups (Table 2). Overall, the incidence of 6-week rebleeding was significantly lower among patients successfully treated (26 of 144, 18%) than in those considered as treatment failures (29 of 75, 39%) (P ⫽ .0095). Side Effects. The incidence of side effects has a trend towards being higher in the sclerotherapy group than in the terlipressin group (30% vs. 20%; OR, 1.7; 95% CI, 0.91-3.17; P ⫽ .06) (Table 3). This was mostly because of a higher rate of moderate side effects in patients receiving EIS; the incidence of severe side effects being similar in both groups (Table 3). One Child-Pugh class C patient receiving sclerotherapy died from septic shock after pleural empyema. Mortality. There were no differences in mortality between the 2 treatment groups, in either Child-Pugh class A ⫹ B patients (8 patients in the terlipressin group vs. 5 in the sclerotherapy group; P ⫽ .22) or in Child-Pugh class C patients (18 vs. 14 patients, respectively; P ⫽ .21) (Fig. 3). Factors contributing to death did not significantly differ between the 2 groups: massive bleeding (14 terlipressin-treated vs. 8 EIStreated patients; P ⫽ .09), previously unknown hepatocellular carcinoma (3 vs. 2; P ⫽ .47), liver failure (8 vs. 6; P ⫽ .34), sepsis (0 vs. 2; P ⫽ .27), and other causes (1 in each group). In multivariate analysis, non–alcohol-induced cirrhosis (OR, 5; 95% CI, 3.8-12.5; P ⫽ .0007), Child-Pugh class C (OR, 4.7; 95% CI, 1.1-21.7; P ⫽ .04), and reaching the criteria of need for alternative therapy (OR, 9.5; 95% CI, 3.6-24.8; P ⫽ .00001) were identified as independent predictors of 6-week

TABLE 3. Side Effects and Complications Associated With the Therapies Under Study Terlipressin (n ⴝ 105)

Patients with side effects Total side effects Severe side effects

21/105 (20%)


34/114 (30%)

24 Episodes 44 Episodes 4 Episodes 8 Episodes 2 Ischemia (lower limbs) 4 Bleeding from esophageal ulcers 1 Severe hyponatremia 3 Aspiration pneumonia 1 Seizure 1 Sepsis from empyema* Moderate side effects 2 Episodes 14 Episodes 1 Auricular fibrillation 1 Chest pain 1 Ischemic change on 5 Bacteremia EKG 6 Esophageal ulcers requiring Rx 1 Bronchoaspiration 1 Dysphagia requiring therapy Mild side effects 18 Episodes 22 Episodes 1 Chest pain 7 Chest pain 5 Abdominal pain 2 Abdominal pain 1 Skin lymphangitis 3 Dysphagia 3 Hyponatremia 10 Isolated fever 1 Nausea 7 Isolated fever† * Resulting in death. † Considered as related to the emergency endoscopy.

P

.064

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FIG. 3. Actuarial probability of 6-week survival. No differences were found between both groups of patients regarding the 6-week survival (75% in the terlipressin group and 82% in the sclerotherapy group). Most deaths occurred in Child-Pugh class C patients, with the 6-week probability of survival being 54% in this subgroup of patients (vs. 90% in Child-Pugh class A ⫹ B patients).

mortality. The allocated therapy, as well as the elective therapy received, did not predict survival. DISCUSSION

The present RCT investigated whether a simple drug therapy, such as terlipressin injections, can be as effective as a specialized procedure, such as EIS, in controlling variceal bleeding and preventing early rebleeding, with a lower rate of side effects. We overcame the problem of equivalence trials by using a sample size large enough to test both hypotheses.20 Other salient features of this study were that it strictly followed the Baveno criteria,4 which were endorsed in the Baveno II21 and Reston consensus conferences,20 and the guidelines for Good Clinical Practice. Our results clearly show that terlipressin and EIS are both highly and equally effective in controlling variceal bleeding and preventing early rebleeding. The study further shows that terlipressin is associated with fewer side effects than EIS, although the incidence of severe side effects was very low with the 2 therapies. In the present study, sclerotherapy achieved initial control of bleeding in 82% of cases, which is close to the usually reported figures.3,17-19 The success rate for terlipressin, 81%, was almost identical to that of previous reports,3 including the recent double-blind RCT by Feu et al., which also adhered to the Baveno definitions.12 Another important finding of the present study is that both emergency sclerotherapy and continued terlipressin administration were equally highly effective in preventing early rebleeding, which occurred in only 14% of the cases in each group. This is relevant because early rebleeding very often occurs in the absence of specific therapy and carries a poor prognosis.2 The low incidence of early rebleeding agrees with the results of a recent RCT comparing sclerotherapy and continuous somatostatin infusion for the prevention of early rebleeding, which occurred in 16% of the somatostatin-treated patients and 15% of those receiving EIS.14 In contrast with the similar efficacy of terlipressin and EIS, our study shows differences in the incidence of side effects related to these therapies, which shows a trend towards being higher in the sclerotherapy group than in the terlipressin group. Altogether, these findings may indicate a better safety

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profile for terlipressin than for emergency sclerotherapy. The side effects for terlipressin in our study do not differ from those reported in previous double-blind studies3,12; whereas those of sclerotherapy, especially the severe ones, were somewhat less frequent than expected.3,5 These considerations should be tempered by the fact that in many centers endoscopic banding ligation is replacing injection sclerotherapy. Although it is well established that in elective conditions banding ligation is more effective and probably safer than injection sclerotherapy, this has not yet been proven in the emergency treatment of variceal bleeding.22,23 In any case, the complication rate in the present study is almost identical to that reported with banding ligation.19,22-24 These results should not be interpreted as evidence favoring the use of terlipressin over EIS, but as indicating that terlipressin can be used alternatively to or before endoscopic treatments. The final choice will be influenced by other factors, such as the availability of an experienced endoscopist able to perform emergency sclerotherapy/banding at the initial endoscopy. Moreover, accumulated evidence strongly suggest that there is no reason for denying the benefit of immediate drug therapy in patients suspected of bleeding from varices and in whom endoscopy will not be performed until several hours later.15,25 In conclusion, our study shows that terlipressin injection is as effective as emergency EIS in controlling variceal bleeding and in preventing early rebleeding, with no significant differences in mortality, transfusion requirements, need for alternative treatments, and use of hospital resources. Moreover, terlipressin injections were associated with less frequent side effects than sclerotherapy. APPENDIX Members of the TEST Study Group include Josep Llach, Josep M. Bordas, Joan M. Salmeron, Juan C. Garcıá-Pagań (IMD, Hospital Clıńic, Barcelona); Mońica Gonza´lez-Garcıá, Jesu´s M. Urman, Alberto Monescillo, Carlos de la Serna (Hospital Ramoń y Cajal, Madrid); Rosa M. Morillas, Jaume Boix, Pere Humbert (Hospital Germans Trias i Pujol, Badalona); Jose´ L. Calleja, Guillermo Cacho, J. Iborra (Clıńica Puerta de Hierro, Madrid); Ignacio Castellote, Pedro Menchen, Marta Casado (Hospital Gregorio Maranõń, Madrid); Bruno Person, Mehdi Kaassis (CHU Angers, Angers); Serge Levacher, Jean-Louis Pourriat (Intensive Care Unit, CHU Jean Verdier, Bondy); Eric Nguyen Khac, Thierry Poynard (CHU Pitie´-Salpetrie`re, Paris); Jeroˆme Sańchez (CHU Purpan, Toulouse); and Blas Navarro, Josep M. Dome`nech (Laboratori d’Estadı´stica Aplicada, UAB, Barcelona). REFERENCES 1. Bosch J, Burroughs AK. Clinical manifestations and management of bleeding episodes in cirrhotics. In: Bircher J, Benhamou JP, McIntyre N, Rizzetto M, Rode´s J, eds. Oxford Textbook of Clinical Hepatology. 2nd Ed. Oxford: Oxford University Press 1999;671-693. 2. D’Amico G, Morabito A, Pagliaro L, Marubini E, Liver Study Group of V Cervello Hospital. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig Dis Sci 1986;31:468-475. 3. D’Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: a meta-analytic review. HEPATOLOGY 1995;22:332-353. 4. De Franchis R, Pascal JP, Ancona E, Burroughs AK, Henderson M, Fleig W, Groszmann RJ, et al. Definitions, methodology and therapeutic strategies in portal hypertension. A consensus development workshop. J Hepatol 1992;15:256-261. 5. Westaby D. Emergency and elective endoscopic therapy for variceal hemorrhage. In: Shields R, ed. Portal Hypertension, Baillie`re’s Clinical Gastroenterology. London: Baillie`re Tindall 1992;3:465-480.

476 ESCORSELL ET AL. 6. D’Amico G, Traina M, Vizzini G, Tine` F, Politi F, Montalbano L, Luca A, Pasta L, et al. Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. A randomized clinical trial. J Hepatol 1994;20:206-212. 7. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleeding esophageal varices. A placebo controlled double-blind study. HEPATOLOGY 1986;6:112-115. 8. Freeman JG, Cobden MD, Record CO. Placebo-controlled trial of terlipressin (glypressin) in the management of acute variceal bleeding. J Clin Gastroenterol 1989;11:58-60. 9. Soderlund C, Magnusson I, Torngren S, Lundell L. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding esophageal varices. A double-blind, randomized, placebo-controlled trial. Scand J Gastroenterol 1990;25:622-630. 10. Desaint B, Florent C, Levy VG. A randomized trial of triglycyl-lysine vasopressin in active cirrhotic variceal hemorrhage. In: Lebrec D, Blei AT, eds. Vasopressin analogs and portal hypertension. Paris: John Libbey Eurotext 1987;155-157. 11. Fort E, Sautereau D, Silvaine C, Ingrand P, Pillegand B, Beauchant M. A randomized trial of terlipressin plus nitroglycerin vs balloon tamponade in the control of acute variceal hemorrhage. HEPATOLOGY 1990;11:678-681. 12. Feu F, Ruiz del Arbol L, Banãres R, Planas R, Bosch J, Members of the Variceal Bleeding Study Group. Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Gastroenterology 1996;111:1291-1299. 13. Fiaccadori F, Pedreti G, Biraghi M, Arcidiacono R. Terlipressin and endoscopic sclerotherapy control variceal bleeding and prevent early rebleeding in cirrhotic patients. Curr Ther Res 1993;54:1-10. 14. Escorsell A, Bordas JM, Ruiz del Arbol L, Jaramillo JL, Planas R, Banãres R, Albillos A, et al. Randomized controlled trial of sclerotherapy versus somatostatin infusion in the prevention of early rebleeding following acute variceal hemorrhage in patients with cirrhosis. J Hepatol 1998;29:779-788. 15. Levacher S, Letoumelin Ph, Pateron D, Blaise M, Lapandry C, Pourriat JL. Early administration of terlipressin plus glyceryl trinitrate to control active upper gastrointestinal hemorrhage in cirrhotic patients. Lancet 1995;346:865-868.

HEPATOLOGY September 2000 16. Garcıá-Compean D, Blanc P, Bories JM, Michel J, Desprez D, Pageaux GP, David XR, et al. Treatment of active gastrooesophageal variceal bleeding with terlipressin or hemostatic balloon in patients with cirrhosis. A randomized controlled trial. Arch Med Res 1997;28:241-245. 17. Planas R, Quer JC, Boix J, Canet J, Armengol M, Cabre´ E, Pintanel T, et al. A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding. HEPATOLOGY 1994;20:370375. 18. Shields R, Jenkins SA, Baxter AN, Kingsnorth AN, Ellenbogen S, Makin CA, Gilmore I, et al. A prospective randomized controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding esophageal varices. J Hepatol 1992;16:128-137. 19. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, Chiang HT. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. HEPATOLOGY 1997;25:1101-1104. 20. Grace ND, Groszmann RJ, Garcıá-Tsao G, Burroughs AK, Pagliaro L, Mackunch RW, Bosch J, et al. Portal hypertension and variceal bleeding: an AASLD single topic symposium. HEPATOLOGY 1998;28:868-880. 21. Burroughs AK, Alexandrino P, Cale`s P, Fleig W, Grace ND, Minoli G, Siringo S. ‘Sore Points’. In: De Franchis R, ed. Portal Hypertension II: Proceedings of the Second Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies. Oxford: Blackwell Science 1996;10-17. 22. Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding. A meta-analysis. Ann Intern Med 1995;123:280-287. 23. De Franchis R, Prigminani M. Endoscopic treatments for portal hypertension. Semin Liver Dis 1999;19:439-455. 24. Laine L, Stein C, Sharma V. Randomized comparison of ligation versus ligation plus sclerotherapy in patients with bleeding esophageal varices. Gastroenterology 1996;110:529-533. 25. Avgerinos A, Nevens F, Raptis S, Fevery J. Early administration of somatostatin and efficacy of sclerotherapy in acute esophageal variceal bleeds: the European Acute Bleeding Esophageal Variceal Episodes (ABOVE) randomized trial. Lancet 1997;350:1495-1499.