Meta-Analysis: Efficacy of Therapeutic Regimens in Ongoing Variceal Bleeding

Background and Study Aims: Variceal bleeding is a major cause of mortality in liver cirrhosis. Therapeutic options include medical (vasoconstrictive/vasoactive drugs) and endoscopic (sclerotherapy/ligation) treatments. Most studies evaluating acute esophageal bleeding have included patients with both ongoing and recent bleeding. Therefore therapeutic efficacy in ongoing bleeding may not have been adequately determined in these studies. A meta-analysis was performed for two reasons: first to compare directly the various treatments in the case of ongoing bleeding, as this would not be accomplished by a single trial, and secondly, to determine the success rates of each treatment option based on a larger number of patients.

Methods: An extensive Medline search identified 13 randomized controlled trials with precise statements of the number of patients with ongoing bleeding and their clinical outcomes. All studies followed a similar design and a Q test excluded heterogeneity of the studies. Data were pooled and cumulative success rates were calculated.

Results: Ligation appeared to be the most effective treatment (91.0 %, 95 % CI 82.4 - 96.3 %); it was significantly more successful than vasoconstrictive treatment (vasopressin/terlipressin 68.7 %, 61.7 - 75.2 %; P < 0.002, chi-squared-test) or vasoactive treatment (somatostatin/octreotide, 75.9 %, 68.1 - 82.6 %; P < 0.02) treatment, but was not statistically better than sclerotherapy (81.1 %, 71.7 - 88.4 %). The latter therapy was not statistically superior to medical treatment options. Calculations of estimated true effects, which take into account the weight of each study, rendered similar results.

Conclusion: Ligation is the most effective treatment option. No significant difference was found between the efficacy of sclerotherapy and treatment with somatostatin or octreotide.

References

• 1 Burroughs A K, D’Heygere F, McIntyre N. Pitfalls in studies of prophylactic therapy for variceal bleeding in cirrhotics.  Hepatology. 1986;  6 1407-1413
• 2 Graham D Y, Smith J L. The course of patients after variceal hemorrhage.  Gastroenterology. 1981;  80 800-809
• 3 Pascal J -P. Non-surgical treatment of hemorrhage caused by portal hypertension in cirrhosis: hemostatic treatment, prevention of the first hemorrhage, prevention of recurrence.  Rev Prat. 1990;  40 1458-1461
• 4 Macdougall B R, Westaby D, Theodossi A, et al. Increased long-term survival in variceal haemorrhage using injection sclerotherapy.  Lancet. 1982;  1 124-127
• 5 Project T CEVS. Sclerotherapy after first variceal hemorrhage in cirrhosis.  N Engl J Med. 1984;  311 1594-1600
• 6 Imperiale T F, Teran J C, McCullough A J. A meta-analysis of somatostatin versus vasopressin in the management of acute esophageal variceal hemorrhage.  Gastroenterology. 1995;  109 1289-1294
• 7 Stiegmann G V, Goff J S, Michaletz-Onody P A, et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices.  N Engl J Med. 1992;  326 1527-1532
• 8 Lo G H, Lai K H, Cheng J S, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices.  Hepatology. 1995;  22 466-471
• 9 Nicolucci A, Grilli R, Alexanian A A, et al. Quality, evolution, and clinical implications of randomized, controlled trials on the treatment of lung cancer.  JAMA. 1989;  262 2101-2107
• 10 Pagliaro L, D'Amico G, Sörensen T IA, et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment.  Ann Intern Med. 1992;  117 59-70
• 11 DerSimonian R, Laird N. Meta-analysis in clinical trials.  Controlled Clin Trials. 1986;  7 177-188
• 12 Friedmann H P, Goldberg J D. Meta-analysis: an introduction and point of view.  Hepatology. 1996;  23 917-928
• 13 Freemann J G, Lishman A H, Cobden I, Record C O. Controlled trial of terlipressin (‘glypressin’) versus vasopressin in the early treatment of oesophageal varices.  Lancet. 1982;  1 66-68
• 14 Kravetz D, Bosch J, Terés J, et al. Comparison of intravenous somatostatin and vasopressin infusions in treatment of acute variceal hemorrhage.  Hepatology. 1984;  4 442-426
• 15 Jenkins S A, Baxter J N, Corbett W, et al. A prospective randomized controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage.  BMJ. 1985;  290 275-278
• 16 Teres J, Planas R, Panes J, et al. Vasopressin/nitroglycerin infusion vs. esophageal tamponade in the treatment of acute variceal bleeding: a randomized controlled trial.  Hepatology. 1990;  11 964-968
• 17 Söderlund C, Magnusson I, Törngren S, Lundell L. Terlipressin (triglycyl-lysine vasopressin) controls acute bleeding oesophageal varices.  Scand J Gastroenterol. 1990;  25 622-630
• 18 Saari A, Klvilaakso E, Inberg M, et al. Comparison of somatostatin and vasopressin in bleeding esophageal varices.  Am J Gastroenterol. 1990;  85 804-807
• 19 Walker S, Kreichgauer H P, Bode C. Terlipressin vs. somatostatin in bleeding esophageal varices: a controlled, double-blind study.  Hepatology. 1992;  15 1023-1030
• 20 Huang S J, Lin H C, Chang C F, et al. A randomized controlled trial comparing octreotide and vasopressin in the control of acute esophageal variceal bleeding.  J Hepatol. 1992;  16 320-325
• 21 Shields R, Jenkins S A, Baxter J N, et al. A prospective randomised controlled trial comparing the efficacy of somatostatin with injection sclerotherapy in the control of bleeding oesophageal varices.  J Hepatol. 1992;  16 128-137
• 22 Huang C C, Sheen I S, Chu C M, et al. A prospective randomized controlled trial of sandostatin and vasopressin in the management of acute bleeding esophageal varices.  Chang Keng I Hsueh. 1992;  15 (2) 78-83
• 23 Silvain C, Carpentier S, Sautereau D, et al. Terlipressin plus transdermal nitroglycerin vs. octreotide in the control of acute bleeding from esophageal varices: a multicenter randomized trial.  Hepatology. 1993;  18 61-65
• 24 Sung JJY C S, Lai C -W, Chan F KL, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage.  Lancet. 1993;  342 637-641
• 25 Gimson A ES, Ramage J K, Panos M Z, et al. Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding oesophageal varices.  Lancet. 1993;  342 391-394
• 26 de Franchis R, Arcidiacono P G, Carpinelli L, et al. Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian Endoscopic Club.  Hepatology. 1993;  18 1102-1107
• 27 Laine L, el-Newihi H M, Migikovsky B, et al. Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices.  Ann Intern Med. 1993;  119 1-7
• 28 Planas R, Quer J C, Boix J, et al. A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding.  Hepatology. 1994;  20 370-375
• 29 D’Amico G, Traina M, Vizzini G, et al. Terlipressin or vasopressin plus transdermal nitroglycerin in a treatment strategy for digestive bleeding in cirrhosis. A randomized clinical trial. Liver Study group of V. Cervello Hospital.  J Hepatol. 1994;  20 206-212
• 30 Pedretti G, Elia G, Calzetti C, et al. Octreotide versus terlipressin in acute variceal hemorrhage in liver cirrhosis.  Clin Invest. 1994;  72 653-659
• 31 Lo G H, Lai K H, Cheng J S, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices.  Hepatology. 1995;  22 466-471
• 32 Hou M C, Lin H C, Kuo B I, et al. Comparison of endoscopic variceal injection sclerotherapy and ligation for the treatment of esophageal variceal hemorrhage: a prospective randomized trial.  Hepatology. 1995;  21 1517-1522
• 33 Besson I, Ingrand P, Person B, et al. Sclerotherapy with or without octreotide for acute variceal bleeding.  N Engl J Med. 1995;  333 555-560
• 34 Gotzsche P, Gjorup I, Bonnén H, et al. Somatostatin vs. placebo in bleeding oesophageal varices: randomised trial and meta-analysis.  BMJ. 1995;  310 1495-1498
• 35 Walker S, Kreichgauer H P, Bode J C. Terlipressin (glypressin) versus somatostatin in the treatment of bleeding esophageal varices - final report of a placebo-controlled, double-blind study.  Z Gastroenterol. 1996;  34 692-698
• 36 Feu F, Ruiz del Arbol L, et al. Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Variceal Bleeding Study Group (see comments).  Gastroenterology. 1996;  111 1291-1299
• 37 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
• 38 Jenkins S A, Shields R, Davies M, et al. A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage.  Gut. 1997;  41 526-533
• 39 Lo G H, Lai K H, Cheng J S, et al. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices.  Hepatology. 1997;  25 1101-1104
• 40 Sarin S K, Govil A, Jain A K, et al. Prospective randomized trial of endoscopic sclerotherapy versus variceal band ligation for esophageal varices: influence on gastropathy, gastric varices and variceal recurrence.  J Hepatol. 1997;  26 (4) 826-832
• 41 Avgerinos A, Nevens F, Raptis S, Fevery J. Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial.  Lancet. 1997;  350 1495-1499
• 42 Villanueva C, Ortiz J, Sàbat M, et al. Somatostatin alone or combined with emergency sclerotherapy in the treatment of acute esophageal variceal bleeding: a prospective randomized trial.  Hepatology. 1999;  30 384-389
• 43 Murata I, Yoshikawa I, Kume K, Otsuki M. Short- and long-term results of endoscopic variceal ligation for esophageal varices compared with injection sclerotherapy.  J UOEH. 1999;  21 119-131
• 44 Djurdjevic D, Janosevic S, Dapcevic B, et al. Combined ligation and sclerotherapy versus ligation alone for eradication of bleeding esophageal varices: a randomized and prospective trial.  Endoscopy. 1999;  31 (4) 286-290
• 45 Zoller W G, Gross M. Drug treatment of esophageal variceal bleeding: alternative or supplement to endoscopic therapy?.  Endoscopy. 1995;  27 616-621
• 46 Gross M, Zoller W G. Medical prophylaxis of haemorrhage from oesophageal varices in patients with liver cirrhosis.  Eur J Gastroenterol Hepatol. 1997;  9 1-10