Vapreotide in variceal bleeding
Authors: David Patch, Andrew Burroughs
Journal: Journal of Hepatology (2002)

Early administration of vapreotide for variceal bleeding in patients with cirrhosis. French Club for the Study of Portal Hypertension. Cales P, Masliah C, Bernard B, Garnier PP, Silvain C, Szostak-Talbodec N, Bronowicki JP, Ribard D, Botta-Fridlund D, Hillon P, Besseghir K, Lebrec D. Services d'Hepato-Gastoenterologie, Centres Hospitaliers of Angers, France Background: In patients with cirrhosis, pharmacologic or endoscopic treatment may control variceal bleeding. However, the effects of early administration of a somatostatin analogue followed by endoscopic treatment are unknown. Methods: We studied the effects of treatment with vapreotide, a somatostatin analogue, begun before endoscopic treatment in 227 patients with cirrhosis who were hospitalised for acute upper gastrointestinal bleeding. The patients were randomly assigned to receive vapreotide (a 50-μg intravenous bolus followed by an infusion at a rate of 50 μg per h for 5 days) or placebo within a mean (±SD) of 2.3±1.5 h after admission. All the patients received endoscopic treatment a mean of 2.6±3.3 h after the infusion was begun. After the exclusion of 31 patients whose bleeding was not caused by portal hypertension, there were 98 patients in each group. Results: At the time of endoscopy, active bleeding was evident in 28 of 91 patients in the vapreotide group (31%), as compared with 43 of 93 patients in the placebo group (46%) (P=0.03). During the 5-day infusion, the primary objective – survival and control of bleeding – was achieved in 65 of 98 patients in the vapreotide group (66%) as compared with 49 of 98 patients in the placebo group (50%) (P=0.02). The patients in the vapreotide group received significantly fewer blood transfusions (2.0±2.2 versus 2.8±2.8 units, P=0.04). Overall mortality rates at 42 days were not significantly different in the two groups. Conclusions: In patients with cirrhosis and variceal bleeding, the combination of vapreotide and endoscopic treatment is more effective than endoscopic treatment alone as a method of controlling acute bleeding. However, the use of combination therapy does not affect mortality rates at 42 days.N Engl J Med 2002;344:23–28 Designing the 'perfect trial' is fraught with difficulty, as is the critical review prior to publication. The recently published trial on the early administration of vapreotide for variceal bleeding in patients with cirrhosis illustrates many of these difficulties [[1]Cales P Masliah C Bernard B Garnier P Silvain C et al.Early administration of vapreotide for variceal bleeding in patients with cirrhosis.N Engl J Med. 2002; 344: 23-28Crossref Scopus (171) Google Scholar]. This large study involved over 220 patients, was conducted in 22 centres and compared endoscopic therapy (sclerotherapy or banding, depending on physicians preference) versus vapreotide plus endoscopic therapy. Vapreotide or placebo was administered before endoscopy, a design feature that we believe is the logical way to use drugs in the management of variceal bleeding. Patients had to be enrolled within 24 h of their index bleed, and as a consequence 35% of 892 patients with GI bleeding were excluded. This rigorous application of a time interval is important-it means the trial groups are homogeneous, and explains why so many centres were required. A large tertiary referral unit would not always be able to receive transfers within this time interval. The two groups appeared to be well matched, and were predominantly alcoholic cirrhotics. There were no differences between the two groups with respect to the time intervals from bleeding to admission, bleed to trial drug, and time from bleeding to endoscopy, factors that should always be documented in the ideal trial. Trial end-points and definitions are clearly identified in this study, but they do not stick to the letter of the Baveno II definitions [[2]de Franchis R Portal Hypertension II. Proceedings of the Second International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies. Blackwell Science Ltd, Oxford1996Google Scholar], and define both haemostasis and rebleeding, as opposed to failure of control, which the authors themselves recognise is a better end point in their paper based on the same patient group published in this journal [[3]Cales P Lacave N Silvain C Vinel J.P Besseghir K Lebrec D Prospective study on the application of the Baveno II Consensus Conference criteria in patients with cirrhosis and gastrointestinal bleeding.J Hepatol. 2002; 33: 738-741Abstract Full Text Full Text PDF Scopus (19) Google Scholar]. Unusually, time zero is defined as the time following the first endoscopy. Norfloxacin was used prophylactically in all patients, although no comment was made on the number of patients with sepsis. No additional clotting products were used, and transfusions were given to achieve a haematocrit of 27% or higher. This latter statement has critical importance with respect to the trial outcome, and the use of 'internal controls' to establish the validity of trials. For example, if drug x is successful at controlling bleeding, this should be reflected by the need for reduced transfusion rates. Therefore, a target haematocrit must be identified at initiation of the study. Unfortunately, this is now being used as the only validation of end points, and other internal controls are required. The use of 'salvage' procedures such as additional endoscopies during the trial period, use of Sengstaken tubes and emergency transjugular intrahepatic stent shunt may all reflect poor control of bleeding, and is information that should be provided. In the trial under discussion, there is a significant difference in the mean haematocrit on admission between the placebo group (26.5%) and the vapreotide group (29.0%). This is equivalent to a unit of blood, and may explain the difference in total blood requirements between the placebo group (2.8±2.8 units) and the vapreotide group (2.0±2.2 units) at 5 days. This difference should also be borne in mind when considering the subsequent results as volumes of blood transfused make up some of the end-point criteria. With respect to outcome, the presentation is potentially misleading as survival (a secondary end-point) is combined with control of bleeding, and results should have been presented with control of bleeding and survival clearly separated. With respect to internal validation, a patient group which seems to be bleeding so much more, would be in hospital for longer, and have a higher frequency of early rebleeding, although the authors do not find this, with an average hospital stay of 15 days in the two arms, and no difference in rebleeding at day 5, and between days 6 and 42. Whilst length of stay is affected by survival, patients who have died generally are no longer deemed to occupy a hospital bed; no survival difference was seen in this study. We are therefore left with a concern that the end-points may not have necessarily reflected clinical events-perhaps a view shared by the authors themselves [[3]Cales P Lacave N Silvain C Vinel J.P Besseghir K Lebrec D Prospective study on the application of the Baveno II Consensus Conference criteria in patients with cirrhosis and gastrointestinal bleeding.J Hepatol. 2002; 33: 738-741Abstract Full Text Full Text PDF Scopus (19) Google Scholar]. The presentation of the results is further confused with respect to the significance between the two groups at different time intervals. At 6 h post endoscopy, 12/98 patients in the vapreotide arm had reached the primary end-point, compared with 49/98 in the placebo group. However, at 48 h, 14/86 (16%) evaluable patients in the vapreotide arm had reached endpoints, compared with 6/59 (10%) in the placebo arm, as patients who have already achieved end points are censored. The authors identify this problem in their Journal of Hepatology paper, and argue that life table analysis based on the failure time point described by Kaplan–Meier plots is a more accurate way of depicting events over time. When one then studies the Kaplan–Meier plots comparing the combined end points, all the differences occur in the first 6 h. Conceptually it is hard to understand why a drug should be so effective in the first 6 h, without some continued beneficial effect thereafter, unless tachyphylaxis with somatostatin analogues is not confined to octreotide [[4]Escorsell A Bandi J.C Francois E Moitinho E Andrew A Palacios A et al.Desensitisation to the effects of intravenous octreotide in cirrhotic patients with portal hypertension.Hepatology. 1996; 24: 207AGoogle Scholar]. Two further important issues are raised by this trial. Increasingly, great emphasis has been placed on the control of bleeding. However, for the individual patient this is of little relevance. For him or her, what is important is whether they get out of hospital alive, and in what state. This could be addressed easily by providing the Pugh's score at discharge, or with difficulty by developing a new composite score – perhaps called the PAtCH score, 'Melding' together Pughs, and ApaCHe, to render this issue completely unworkable! The second important issue is that in this trial, the survival figures are excellent, and confirm the expertise of this group, with 82% of patients alive at 42 days. Indeed, the improved survival figure for patients with variceal haemorrhage has been the subject of a further paper by McCormick et al. in GUT, who demonstrate the halving in mortality related to variceal haemorrhage over a 40-year period [[5]McCormick P.A O'Keefe C Improving prognosis following a first variceal haemorrhage over four decades.Gut. 2002; 49: 682-685Crossref Scopus (181) Google Scholar]. This is of relevance to trial design, as numbers required will be greater. We come away feeling that the authors have performed as good a study as was possible at the time, but it remains clear that trial design and presentation continue to require development. As to whether we should all be using vapreotide? We are not convinced.