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ABORDAJES COMBINADOS PARA EVITAR LA RECURRENCIA DE SANGRADO POR VARICES ESOFAGICAS.

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El tratamiento combinado parece una de las mejores estragegias para evitar nueva hemorragia por várices esofágicas en pacientes sin contraindicaciones específicas.
Autor:
Gin-Ho Lo
Columnista Experto de SIIC

Artículos publicados por Gin-Ho Lo
Recepción del artículo
31 de octubre, 2002 		Primera edición
6 de enero, 2003 		Segunda edición, ampliada y corregida
7 de junio, 2021
Resumen
En pacientes con hemorragia digestiva por várices esofágicas frecuentemente ocurre resangrado. Se han desarrollado múltiples procedimientos profilácticos. Dada la invasividad, las técnicas quirúrgicas o la derivación portosistémica intrahepática con stent por vía transyugular (TIPS) se reservan para aquellos enfermos en quienes fracasa el tratamiento médico o endoscópico. La escleroterapia por inyección endoscópica, por su mayor frecuencia de complicaciones y menor eficacia en reducir el índice de resangrado, ha sido reemplazada gradualmente por la ligadura en banda. El tratamiento médico con beta bloqueantes y mononitrato de isosorbide tiene la ventaja de asociarse con baja incidencia de complicaciones y con disminución importante de la presión portal. La terapia combinada con ligadura en banda y beta bloqueantes podría, en teoría, reducir la ocurrencia de resangrado por diferentes mecanismos. Nuestro estudio mostró que el tratamiento combinado con ligadura en banda, nadolol y sucralfato se acompaña de un índice de resangrado por várices esofágicas de sólo 12% luego de un seguimiento de 21 meses en promedio. Esta cifra fue definitivamente inferior a la que se logró mediante ligadura o tratamiento médico en forma exclusiva. Nuestros resultados sugieren que el abordaje combinado sería la alternativa de elección para prevenir una nueva hemorragia por várices esofágicas en pacientes sin contraindicaciones específicas.

Abstract
Rebleeding is frequently encountered in patients who have episodes of esophageal variceal hemorrhage. A lot of measures have been developed to prevent variceal rebleeding. Because of invasiveness, surgical procedures or transjujular intrahepatic porto-systemic stent shunt are reserved for patients who are treatment failure with medical or endoscopic therapies. Endoscopic injection sclerotherapy is gradually replaced by banding ligation because of a higher frequency of complications and lower effectiveness in reducing variceal rebleeding rate. Medical therapy with beta blocker and isosorbide mononitrate has the advantage of a low incidence of complications and substantial reduction of portal pressure. Combination therapy with banding ligation and beta blocker could theoretically enhance the occurrence of rebleeding via different mechanisms. Our study showed that combination therapy with banding ligation and nadolol and sucralfate had a variceal rebleeding rate of only 12% after a median follow-up of 21 months. This figure was definitely lower than which achieved by ligation or mdeical therapy alone. Our data recommended that combined approach may be the treatment of choice for prevention of variceal rebleeding in patients without specific contraindications.

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  Relacionadas: Medicina Interna, Salud Pública

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COMBINED APPROACHES FOR THE PREVENTION OF VARICEAL REBLEEDING



Introduction
Gastroesophageal variceal hemorhage is a devastating complication of portal hypertension. It is associated with a high morbidity and mortality (1). Once acute bleeding is successfully controlled by conservative measures, rebleeding may occur in approximately two thirds of patients if without preventive procedures (1). It is naturally that searching for an effective and safe modality to prevent variceal rebleeding is required. Before the advent of endoscopic injection sclerotherapy (EIS), surgery was the only effective method to prevent variceal bleeding. Operative measures such as distal splenorenal shunts and devascularization procedures were the two commonly employed surgeries. Variceal rebleeding rates may be reduced to between 10% and 20% (2). However, the associated morbidity and mortality could also be a nightmare. In the past three decades, surgery was gradually replaced by endoscopic therapies. Nowadays, surgery is reserved for patients with repeated bouts of rebleeding despite of repeated endoscopic treatments.

Endoscopic therapies
EIS was widely employed to stop acute variceal bleeding as well as to prevent variceal bleeding throughout the world for 2 decades (3). The advantages include easy to perform and can obliterate varices through repeated sessions of treatment. The mechanisms of EIS are via injection of sclerosants resulting in tissue necrosis and finally fibrosis, obliteration of varices. Recurrent variceal bleeding occurred in the range of 30% to 50% after repeated sessions of EIS. A lot of technical variations may be adopted among experienced endoscopists. These technical variations include different kinds and dosages of sclerosants and different intervals to perform another session of EIS. Also EIS may be performed via either intravariceal injection or extravariceal injection. It is difficult to recognize which method of EIS is the most optimal. Fortunately, each method of EIS appeared to be helpful to arrest acute bleeding as well as to prevent recurrent variceal bleeding. However, a number of complications may be encountered after EIS (4). These complications include ulcer bleeding, esophageal stricture, fever, pleural effusion, bacteremia, spontaneous bacterial peritonitis, distant embolism and distant abscess. Although patients with poor liver reserve are predisposed to acquire treated-related complications, it is difficult to predict what kind of complications may be encountered following treatment with EIS. Mortality results from complications may be noted in 2% of patients. In 1989, Stiegmann and Goff firstly introduced the application of endoscopic variceal ligation (EVL) to treat esophageal varices (5). Contrasted by the use of chemical action induced by EIS, EVL is through mechanical strangulation by rubber bands just like its use in the treatment of hemorrhoids. A number of studies have proven that EVL is superior to EIS in terms of reducing rebleeding rates and complication rates (6-10). Some studies even suggested that patients receiving EVL to prevent variceal rebleeding had an improved survival as compared with those who received EIS (6,9). It is well documented that EVL requires fewer sessions to obliterate esophageal varices than EIS. Thus, it is recommended that EVL is the endoscopic treatment of choice for the management of bleeding esophageal varices (11). The main disadvantage of EVL is a high frequency of recurrent varices (12). Fortunately, those recurrent varices can usually be treated with repeated ligation. Different from a lot of technical variations in EIS, the technique of EVL appears to be unanimously similar. Initially, a single ligator accompanied with an ovretube was employed to ligate varices. Subsequently, multiband ligator was invented to avoid the use of an overtube. No significant difference in efficacy has been reported between these ligators. Nevertheless, overtube-induced esophageal trauma could be avoided by the use of multiband ligator. Similar to EIS, the appropriate interval between sessions of EVL has not yet been determined. Most endoscopists appear to favor an interval of one or two weeks (13), whereas we feel that an interval of 3 to 4 weeks is more suitable. This is because of unhealed ulcers induced by ligation are frequently noted within 2 weeks of ligation. EVL at a longer interval does not result in a higher rebleeding rate. Actually, Our rebleeding rate was usually lower than other reports (9, 14). A study to evaluate the relative efficacy and complications between different intervals of treatment sessions is required. In order to enhance the effect of EVL, some studies have been undertaken to investigate the potential benefits of combination with EIS (15). Most studies combined with EIS and EVL synchronously failed to demonstrate any superiority over EVL alone. However, our study showed that EIS with low dose sclerosants following repeated EVL (metachronously) could reduce the variceal recurrence (16).

Medical therapy
On the other hand, the use of drug therapy for portal hypertension was innovated by Lebrec in 1981 (17). Drug therapy for portal hypertension has the advantages of lower risk and more economic than endoscopic therapies. A meta-analysis of 13 trials comparing beta blockers with EIS showed that although patients treated with beta blockers had higher rebleeding rates, significantly more complications were encountered in patients receiving EIS (18). Thus it has been recommended that beta blockers rather than EIS should be the first choice to prevent recurrent variceal bleeding. Furthermore, the addition of isosorbide mononitrate (ISMN) has been shown to enhance the effect of beta blocker in reducing portal pressure (19). A controlled trial has shown that the combination of nadolol and ISMN is superior to EIS in the prevention of variceal rebleeding (20).

Combined therapy
The combination of endoscopic therapy and drug therapy for portal hypertension is intriguing. Several reasons support the addition of drug therapy during endoscopic therapy. First, rebleeding rate remains rather high after endoscopic therapy, especially before variceal obliteration is achieved. As mentioned before, the rebleeding rate is about 30% to 50% in patients treated with EIS and 20% to 40% in patients treated with EVL (13). Second, portal hypertensive gastropathy may develop or accentuate after endoscopic therapy (21). An increased incidence of gastric variceal bleeding (9,22-23) after endoscopic therapy was also noted. Third, portal pressure was noted to be elevated in approximately 70% of patients achieved variceal obliteration by either EIS or EVL (24-25). It is anticipated that all of these undesirable or untoward effects by endoscopic therapy could be alleviated by drug therapy. A number of studies had been carried out to compare the combination of propranolol to EIS with propranolol or EIS alone (26). Unfortunately, most studies did not show the benefit of combination with EIS and propranolol over single therapy. The variceal rebleeding rates and complications were similar between the two treatments in these studies. It is very probable that each of these studies had insufficient sample size to show the benefit of combination with EIS and propranolol. Meta-analysis suggested that the combined treatment with EIS and propranolol was significantly better than EIS alone in preventing rebleeding, but with similar survival in both modalities (27). Interpretation with caution was warned over the meta-analysis results because of qualitative heterogeneity (13). In view of the superiority of EVL over EIS and nadolol over propranolol, we tried to combine EVL with nadolol and sucralfate compared with EVL alone to prevent variceal rebleeding (28). The superiority of nadolol over propranolol includes longer half- life and renal metabolism. The use of sucralfate was to reduce ulcer bleeding provoked by EVL. It would be better to have an arm receiving EVL and nadolol to prove whether sucralfate was necessary during the course of EVL. However, in fear of inadequate sample size, we did not randomize study subjects into 3 groups. After a median follow-up of 21 months, our study showed that combination of nadolol, sucralfte and EVL was superior to EVL alone in terms of variceal rebleeding rates (12% vs.29%) and variceal recurrence (26% vs.50%). We presumed that the benefits of combination therapy were primarily from nadolol rather than sucralfate, since the incidence of ulcer bleeding during the course of EVL was appreciably low. After our publication of above work, experts specialized in portal hypertension had different comments. Garcia-Tsao suggested that patients with history of variceal bleeding could receive either beta blockers or EVL to prevent rebleeding, whereas combination of EVL and nadolol can be reserved for patients failed in EVL or beta blocker alone (29). Boyer suggested that beta blocker should be combined with EVL as the treatment of choice to prevent recurrent variceal hemorrhage (30). Beta blockers should be employed during the course of EVL as well as after variceal obliteration for preventing variceal recurrence. Up to now, two papers have compared nadolol and ISMN with EVL (31-32). Both studies had contradictory results regarding the relative efficacy of preventing rebleeding, however, survival was similar between both treatment methods in both studies. More studies are required to clarify whether drug therapy is comparable to EVL in the prevention of variceal rebleeding. Therefore, we can conclude that there are several methods for clinicians to choose for preventing variceal rebleeding. Either nadolol (combined with ISMN), EVL or combination with nadolol and EVL (or plus sucralfate) can be employed. If patients cannot tolerate the discomfort or complications induced by endoscopic therapies, then nadolol combined with ISMN is a good alternative. If rebleeding occurs, then EVL can be tried. If patients cannot tolerate or have contraindications to beta blockers, such as asthma, hypotension, or bradycardia, EVL is the treatment of choice. Repeated EVL followed by EIS can be applied to eradicate esophageal varices. For patients without specific contraindications, combined approach with EVL and nadolol (or plus sucralfate) can be the treatment of choice because of its efficacy in reducing rebleeding is comparable to TIPS or shunt surgery and with fewer complications (33).. Patients who fail with endoscopic and/or medical therapy may require shunt procedures or TIPS or even liver transplantation.
Bibliografía del artículo
  1. Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology 1981; 80:800-809.
  2. Henderson JM. Role of distal splenorenal shunt for long-term management of variceal bleeding. World J Surg 1994; 18:205-10.
  3. Infante-Rivard C, Esnaola S, Villeneuve JP. Role of endoscopic variceal sclerotherapy in the long- term management of variceal bleeding: a meta-analysis. Gastroenterology 1989; 96:1087-1092.
  4. Schuman BM, Beckman JW, Tedesco FJ, Griffin JW Jr, Assad RT. Complications of endoscopic injection sclerotherapy: a review. Am J Gastroenterol 1987; 82:823-30.
  5. Stiegmann GV, Goff JS, Sun JH, Davis D, Silas D. Technique and early clinical results of endoscopic variceal ligation (EVL). Surg Endosc 1989; 3:73-8.
  6. Stiegmann GV, Goff JS, Michaletz-Onody PA, et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med 1992; 326:1527-32.
  7. Laine L, El-Newihi HM, Migikovsky B, Sloane R, Garcia F. Endoscopic ligation compared with sclerotherapy for the treatment of bleeding esophageal varices. Ann Intern Med 1993;119:1-7.
  8. Gimson AES, Ramage JK, Panos MZ, et al. Randomised trial of variceal banding ligation versus injection sclerotherapy for bleeding esophageal varices. Lancet 1993; 342:391-4.
  9. Lo GH, Lai KH, Cheng JS, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995; 22: 466-71.
  10. Hou MC, Lin HC, Kuo BIT, Chen CH, Lee FY, Lee SD. Comparison of endoscopic variceal injection sclerotherapy and ligation for the treatment of esophageal variceal hemorrhage: A prospective randomized trial. Hepatology 1995; 21:1517-22.
  11. Laine L. Ligation: endoscopic treatment of choice for pateitns with bleeding esophageal varices Hepatology (Editorial) 1995; 22:663-665.
  12. Lo GH, Lai KH, Cheng JS, Huang RL, Wang SJ, Chiang HT. Prevalence of paraesophageal varices and gastric varices in patients achieving variceal obliteration by banding ligation and by injection sclerotherapy. Gastrointest Endosc 1999;49:428-36.
  13. de Franchis R, Primignani M. Endoscopic treatments for portal hypertension. Sem Liver Dise 1999; 19:439-55.
  14. 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.
  15. Singh P, Pooran N, Indaram A, Bank S. Combined ligation and sclerotherapy versus ligation alone for secondary prophylaxis of esophageal variceal bleeding: A meta-analysis. Am J Gastroenterol 2002;97:623-9.
  16. Lo GH, Lai KH, Cheng JS, Lin CK, Huang JS, Hsu PI, et al. The additive effect of sclerotherapy to patients receiving repeated endoscopic variceal ligation: A prospective, randomized trial. Hepatology 1998; 28:391-5.
  17. Lebrec D, Poynard T, Hillon P, Benhamou J-P. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl Med 1981; 305:1371-4.
  18. Bernard B, Lebrec D, Mathurin P, Opolon P, Poynard T. Propranolol and sclerotherapy in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. J Hepatol 1997; 26:312-324.
  19. Gournay J, Masliah C, Martin T, Perrin D, Galmiche JP. Isosorbide mononitrate and propranolol compared with propranolol alone for the prevention of variceal rebleeding. Hepatology 2000;31:1239-1245.
  20. Villanueva C, Balanzo J, Novella MT, Soriano G, Sainz S, Torras X, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996; 334:1624-1629.
  21. Lo GH, Lai KH, Cheng JS, Hsu PI, Chen TA, Wang EM, et al. The Effects of Endoscopic Variceal Ligation and Propranolol on Portal Hypertensive Gastropathy: A Prospective, Controlled Trial. Gastrointest Endosc 2001;53:579-584.
  22. Hosking SW, Johnson AG. Gastric varices: A proposed classification to management. Br J Surg 1988;75:195-6.
  23. Lo GH, Lai KH, Lee SD, Tsai YT, Lo KJ. Does propranolol maintain post-sclerotherapy variceal obliteration A prospective randomized study. J Gastroenterol Hepatol 1993;8:358-62.
  24. Korula J, Ralls P. The effect of chronic endoscopic sclerotherapy on portal pressure in cirrhotics. Gastroenterology 1991;101:800-5.
  25. Lo GH, Liang HL, Lai KH, Chang CF, Hwu JH, Chen SM, Lin CK, Chiang HT. The impact of endoscopic variceal ligation on the pressure of the portal venous system. J Hepatol 1996; 24: 74-80.
  26. Sanyal AJ, Shiffman ML. Pharmacologic treatment of portal hypertension. In: Lewis JH, Dubois A. Current clinical topics in gastrointestinal pharmacology. Blackwell Science 1999, Massachusetts. P242-275.
  27. D'Amico G, Pagliaro L, Bosch J. The treatment of portal hypertension: A meta-analytic review. Hepatotogy 1998;28:1206-1214.
  28. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI, Lin CK. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: A prospective, randomized trial. Hepatology 2000;32:461-465.
  29. Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 2001; 120: 726-748.
  30. Boyer TD. Pharmacologic treatment of portal hypertension: past, present, and future. Hepatology 2001;34:834-839.
  31. Villanueva C, Minyana J, Ortiz J, Gallego A, Soriano G, Torras X, Sainz S, Boadas J, Cusso S, Guarner C, Balanjo J.Endoscopic ligation compared with combined treatment with nadolol and isosorbide mononitrate to prevent recurrent variceal rebleeding. N Engl J Med 2001; 345:647-655.
  32. Lo GH, Chen WC, Chen MH, Hsu PI, Lin CK, Tsai WL, Lai KH. A Prospective, Randomized trial of endoscopic variceal ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal rebleeding. Gastroenterology 2002;123:728-734.
  33. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001; 345: 669-681.

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