Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review

Abstract

Background & Aims: Combined therapy with endoscopic variceal ligation (EVL) and b-blockers ± isosorbide mononitrate (ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and b-blockers ± ISMN as compared with each treatment alone to prevent rebleeding. Methods: Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and bblockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis. Results: We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used b-blockers plus ISMN. Variceal rebleeding decreased with combined therapy (P < 0.01) but rebleeding from oesophageal ulcers increased (P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). Conclusions: The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to b-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus b-blockers ± ISMN is adequate to prevent rebleeding, b-blockers + ISMN alone may be a valid alternative.Patients who have recovered from acute variceal haemorrhage have a median rebleeding rate of 63% within 1-2 years and mortality of 33% (1). For many years, nonselective b-blockers and endoscopic sclerotherapy (EST) were the first-line therapy to prevent rebleeding (1, 2). However, endoscopic variceal ligation (EVL) has been shown to improve the safety and the efficacy of EST and is the current endoscopic treatment of choice (2, 3). Adding EST to EVL to obliterate perforating veins has shown no additional beneficial effects as compared with EVL alone (4, 5). Pharmacological therapy also has been improved in recent years. The combination of b-blockers and isosorbide mononitrate (ISMN) enhances the reduction of portal pressure induced by b-blockers (6). This combined drug therapy has been shown to be superior to b-blockers alone and to EST (7,8). Meta-analyses of trials comparing b-blockers + ISMN with EVL have shown no significant differences in rebleeding or survival (9-11). A recent study suggests an improvement in survival favouring combined drug therapy over EVL in the long-term follow-up (12).Combining endoscopic and pharmacological therapies seems a rational approach because b-blockers may protect against rebleeding before variceal obl...

Current Management of the Complications of Cirrhosis and Portal Hypertension: Variceal Hemorrhage, Ascites, and Spontaneous Bacterial Peritonitis

“…A recent meta-analysis comparing combination therapy to monotherapy with EVL or drug therapy has demonstrated that, when compared to EVL, combination therapy is significantly more effective in preventing all-source GI hemorrhage. However, combination therapy is only marginally more effective than drug therapy (NSBB ± nitrates) alone with a tendency for an increased survival with drugs alone [9] . This suggests that pharmacological therapy is the cornerstone of combination therapy and that EVL should not be used as sole therapy in the prevention of recurrent hemorrhage.…”

Comparison of endoscopic variceal ligation and beta-blocker (carvedilol) plus nitrate for the primary prevention of variceal bleeding

“…Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). 27 The risk for all-cause deaths in the EVL group was significantly higher than in the medical group [RR 1.25 (95% CI 1.01 to 1.55)]; however, the rate of bleeding related deaths was unaffected [RR 1.16 (95% CI 0.68 to 1.97)]. 26 In the present study subjects, who had decompensated cirrhosis with Child Pugh Score >12 were excluded to avoid higher mortality in the treatment groups.…”

Favorable Effects of Endoscopic Ligation Combined with Drugs on Rebleeding and Mortality in Cirrhotic Patients: A Network Meta-Analysis

“…Six trials [5,22,27,35,37,42] were multicenter trials. Beta-blockers were administrated in 9 trials, including nadolol used in 6 trials [5,6,12,27,35,41] and propranolol in the other 3 [20,24,42]. Followup time of 4 trials [23,33,40,42] was less than 3 months, but there were 15 RCTs followed up for 1 year or more.…”

“…The investigators agreed to exclude octreotide and sclerotherapy plus octreotide from our study since octreotide is rarely used nowadays, especially for non-ER patients. Finally, 26 eligible RCTs [5,6,12, involving 2,536 adults were incorporated into our quantitative network meta-analysis. A flowchart summarizing the entire search process and resultant reports is provided in Figure 1.…”

“…Meanwhile, the combined drugs demonstrate superior benefits for variceal rebleeding over β-blockers alone [10] or EIS [11]. An updated meta-analysis consistently claims that adding drug therapy with β-blockers with or without isosorbide mononitrate (ISMN) to EVL will significantly reduce the probability of rebleeding as compared with EVL alone, with a trend toward lower mortality [12]. However, a recent network meta-analysis concluded that EVL combined with EIS might be the first choice in the secondary prophylaxis of varices bleeding [13].…”