Primary and secondary prophylaxis of esophageal variceal bleeding

Cirrhosis is a chronic condition with high-mortality. Portal hypertension (PH) is the initial and main consequence of cirrhosis and is responsible for most of its complications, including esophageal varices. A portal pressure, as determined by the hepatic venous pressure gradient (HVPG) >5 mm Hg defines PH. When the HVPG reaches 10 mm Hg or greater, the patient with compensated cirrhosis has developed clinically significant PH and is at a higher risk of developing varices and clinical decompensation. Patients with varices that have not bled are still in the compensated stage but are at a higher risk of decompensation than those without varices. Variceal hemorrhage constitutes a decompensating event, but its mortality differs whether it presents as an isolated complication of cirrhosis (20% 5-year mortality) or whether it presents in association with other complications (more than 80% 5-year mortality). While in the past, emphasis had been placed on managing the direct complications of PH, varices and variceal hemorrhage, it is now clear that these complications cannot be considered in an isolated manner. Rather, they should be considered in the context of advances in the staging of cirrhosis and other complications of cirrhosis that might occur concomitant or subsequent to the development of varices and variceal hemorrhage.     

Primary prophylaxis of variceal bleeding in patients with cirrhosis: A comparison of different strategies

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%, and, when variceal hemorrhage develops, mortality reaches 20%. Patients are deemed at high risk of bleeding when they present with medium or large-sized varices, when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size. In order to avoid variceal bleeding and death, individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis, for which currently recommended strategies are the use of traditional non-selective beta-blockers (NSBBs) (i.e., propranolol or nadolol), carvedilol (a NSBB with additional alpha-adrenergic blocking effect) or endoscopic variceal ligation (EVL). The superiority of one of these alternatives over the others is controversial. While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode, either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction, probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension. A sequential strategy, in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment, or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.     

Primary prophylaxis of variceal bleeding in liver cirrhosis: failure to learn from past experience.

In patients with cirrhosis of liver, variceal bleeding is the most serious complication, with a mortality of up to 50%. Primary prophylaxis of variceal bleeding with shunt surgery or endoscopic variceal sclerotherapy was attempted and then abandoned, as higher rates of complications and mortality were observed. Endoscopic variceal ligation is now being recommended for primary prophylaxis in some centers, as it has fewer complications than sclerotherapy. But this has been done with inadequate evaluation of the cost-effectiveness of variceal ligation. Propranolol therapy is also being widely used for a selected group of patients (large varices with cherry red spots), despite its several limitations and side effects, to reduce frequency of bleeding but without improving survival. Is primary prophylaxis of variceal bleeding cost-effective? The cost involved needs to be accurately assessed in different countries.     

Endoscopic variceal ligation versus propranolol in prophylaxis of first variceal bleeding in patients with cirrhosis

BACKGROUND AND AIM: To compare the efficacy and safety of endoscopic variceal ligation (EVL) with propranolol in prophylaxis on the rate of first esophageal variceal bleeding in patients with cirrhosis. METHODS: A prospective, randomized trial was conducted in 100 cirrhotic patients with no history of previous upper gastrointestinal bleeding and with esophageal varices endoscopically judged to be at high risk of hemorrhage. The end-points of the study were bleeding and death. RESULTS: Life-table curves showed that prophylactic EVL and propranolol were similarly effective for primary prophylaxis of variceal bleeding (11/50 [22%]vs 12/50 [24%]; P = 0.68) and overall mortality (14/50 [28%]vs 12/50 [24%]; P = 0.49). The 2-year cumulative bleeding rate was 18% (9/50) in the EVL group and 16% (8/50) in the propranolol group. The 2-year cumulative mortality rate was 28% (14/50) in the EVL group and 24% (12/50) in the propranolol group. Comparison of Kaplan-Meier estimates of the time to death of both groups showed no significant difference in mortality in both groups (P = 0.86). Patients undergoing EVL had few treatment failures and died mainly of hepatic failure. In the propranolol group, the mean daily dosage of the drug was 68.2 +/- 32.8 mg, which was sufficient to reduce the pulse rate by 25%. 20% of patients withdrew from propranolol treatment due to adverse events. CONCLUSIONS: Prophylaxis EVL is as effective and as safe as treatment with propranolol in decreasing the incidence of first variceal bleeding and death in cirrhotic patients with high-risk esophageal varices.     

Primary prophylaxis of variceal bleeding in cirrhotics awaiting liver transplantation

BACKGROUND/AIMS: To evaluate the efficacy and safety of prophylactic band ligation and propranolol versus propranolol alone for the primary prophylaxis of variceal bleeding in patients with high-risk esophageal varices listed for liver transplantation. METHODOLOGY: Out of 152 cirrhotic patients included on the waiting list between January 2001 and January 2003, high-risk esophageal varices were detected in 72. These patients were randomized to undergo combined therapy or propranolol monotherapy. The actuarial probabilities of bleeding from esophageal varices and bleeding-related death were calculated by Kaplan-Meier method and compared using the log-rank test. RESULTS: Variceal eradication was achieved in 33 patients (91.6%) in 2.5 +/- 1.4 ligation sessions. The mean daily dose of propranolol was 72 +/- 25mg in the propranolol group and 68 +/- 21 mg in the ligation group. Six percent of patients in the ligation group and 31% in the propranolol group had one episode of bleeding during the 18 months of follow-up (p = 0.03). The actuarial probabilities of bleeding-free survival after 18 months of follow-up, in the ligation and monotherapy groups were 96% and, respectively, 69% (p = 0.04). CONCLUSIONS: Endoscopic band ligation associated with propranolol significantly reduces the occurrence of the first episode of variceal bleeding and improves bleeding-related survival in cirrhotics included on the waiting list.     

Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis

In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty-two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n = 75) or PPL (n = 77). The groups were well matched with respect to baseline characteristics (age 56 +/- 10 years, alcoholic etiology 51%, Child-Pugh score 7.2 +/- 1.8). The mean follow-up was 34 +/- 19 months. Data were analyzed on an intention-to-treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2-year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for long-term PPL treatment.     

内镜下套扎术预防肝硬化食管静脉曲张破裂出血的远期随访观察

目的 观察肝硬化食管静脉曲张患者分别行食管静脉曲张套扎术(endoscopic variceal ligation,EVL)和口服普萘洛尔后的再出血发生率、死亡率、治疗前后静脉曲张程度以及肝功能分级变化.方法 共纳入患者118例,其中66例采用EVL治疗,52例采用药物预防治疗.EVL 治疗组给予多次套扎,直到曲张静脉消失;药物治疗组给予普萘洛尔,起始剂量10 mg,每日2次,逐渐增至最大耐受剂量.对所有患者随访20个月,观察比较两组出血发生率和死亡率、治疗前后静脉曲张程度以及肝功能分级变化.结果 EVL治疗组有效随访58例,其问发生出血7例(12.1%),死亡2例(3.4%);药物治疗组有效随访46例,期间发生出血14例(30.4%),死亡6例(13.0%),两组间差异有统计学意义(P<0.05).EVL治疗组总静脉消失率为41.3%(24/58),药物治疗组46例曲张静脉均未消失;比较两组治疗前后肝功能未见明显变化(P>0.05).结论 与服用普萘洛尔相比,EVL能显著降低出血率、死亡率和静脉曲张程度,且对肝功能无明显损害作用.     

Primary prophylaxis of variceal bleeding in cirrhotic patients: A cohort study

BackgroundCurrent guidelines recommend beta-blockers for primary prevention of variceal haemorrhage in cirrhotic patients, and band ligation for patients with contraindications or intolerance to beta-blockers. However, it has been suggested that these patients may respond poorly to band ligation.AimWe evaluated the usefulness of a strategy in which band ligation was used to treat patients with contraindications or intolerance and patients not responding to beta-blockers identified by hepatic vein pressure gradient measurement. Haemodynamic responders and patients refusing hepatic vein pressure gradient measurement were given long-term beta-blockers.MethodsOne hundred and thirty-five consecutive patients with high-risk oesophageal varices and no prior bleeding were enrolled. Twenty-five patients with contraindications (group A), 26 with intolerance to beta-blockers (group B) and 25 showing a poor haemodynamic response (Group C) underwent band ligation. Twenty-two haemodynamic responders (Group D) and 37 refusing hepatic vein pressure gradient measurement (Group E) were treated with beta-blockers.ResultsMedian follow-up was 32 months. 12/135 patients (8.9%) bled: 3/25 (12%) in group A, 1/26 (3.8%) in group B, 0/25 (0%) in group C, 0/22 (0%) in group D and 8/37 (22.2%) in group E. Mortality was 8/135 (5.9%).ConclusionsPatients with contraindications, intolerance or not responding to beta-blockers treated with band ligation achieve protection from variceal bleeding comparable to that of good responders to beta-blockers.     

Pre-primary prophylaxis of variceal bleeding]

Portosystemic collateral formation, particularly at the gastroesophageal junction, is a most serious consequence of portal hypertension. Increased portal pressure is the most significant force underlying gastroesophageal variceal formation, to which end portal pressure (estimated from the hepatic venous pressure gradient) must reach at least 10 mmHg. Subsequently, splanchnic hyperemia also contributes to variceal development. Portoystemic collaterals result from repermeabilization of pre-extant vessels, vascular remodeling, and angiogenesis. The goal of pre-primary prophylaxis is preventing or delaying the formation of gastroesophageal varices. In experimental models of portal hypertension, early administration of splanchnic vasoconstrictors such as beta-blockers, nitric oxide synthesis inhibitors, or antiangiogenic substances inhibits portosystemic collateral formation. However, clinical trials of beta-blockers in patients with cirrhosis and no varices to delay variceal formation have failed to yield expected results.     

Infection and variceal bleeding in cirrhosis

Endotoxemia and bacterial infection are frequent in patients with cirrhosis. They alter systemic and splanchnic hemodynamics, worsen coagulation disorders, impair liver function and thus may induce variceal bleeding. In variceal bleeding, bacterial infection favours failure to control bleeding, early rebleeding, and death. In patients with cirrhosis and variceal bleeding, antibiotic-prophylaxis decreases bacterial infection and the incidence of early rebleeding, and, more important, significantly decreases the death rate in these patients.     

Primary prophylaxis of variceal hemorrhage

Figure 3 shows an algorithm for the primary prevention of variceal hemorrhage. Pharmacologic therapy is the current standard of treatment for the primary prophylaxis of esophageal variceal bleeding. Patients with medium or large varices should be treated with a nonselective beta-blocker with the dose titrated to achieve a 25% decrement in resting heart rate or a heart rate of 55 to 60 bpm. The development of symptoms will, of course, limit the dose used. As discussed previously, these therapeutic endpoints are not well correlated with decreases in portal pressure. Measurement of the HVPG before therapy and after 3 months of therapy provides a rational approach to drug dosing. If the HVPG decreases by 20% or to less than 12 mm Hg, the medication dose will be effective in preventing hemorrhage. If, however, the HVPG is not appropriately lowered, a long-acting nitrate may be added. Patients with small varices should be observed, with endoscopic examinations every 2 years to assess progression of variceal size. Endoscopic therapy is not indicated for the primary prevention of variceal bleeding.     

Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary prophylaxis of variceal bleeding

BACKGROUND AND AIMS: The role of propranolol in addition to EVL in the prevention of first variceal bleed has not been evaluated. This prospective randomized controlled trial compared endoscopic variceal ligation (EVL) with propranolol and EVL alone in the prevention of first variceal bleed among patients with high-risk varices. PATIENTS AND METHODS: One hundred and forty-four consecutive patients with high-risk varices were randomly allocated to EVL plus propranolol (Gr I, n = 72) or EVL alone (Gr II, n = 72). EVL was done at 2-wk interval till obliteration of varices. In Gr I, incremental dosage of propranolol (sufficient to reduce heart rate to 55 beats/min or 25% reduction from baseline) was administered and continued after obliteration of varices. The endpoints of the study were bleeding and death. RESULTS: The two groups of patients had comparable baseline characteristics; follow-up (Gr I: 13.1 +/- 11.5 months, Gr II: 11.2 +/- 9.9 months), number of cirrhotic and noncirrhotic portal hypertension patients [Gr I 64 (88.6%) and 8 (11.4%), Gr II 63 (87.5%) and 9 (12.5%)], and frequency of Child's A (15 vs 18), B (38 vs 35), and C (19 vs 19). The mean daily propranolol dose achieved in Gr I was 95.6 +/- 38.6 mg. Eleven patients had bleeds, 5 in Gr I and 6 in Gr II. All patients bled before the obliteration of varices, the actuarial probability of first bleed at 20 months was 7% in Gr I and 11% in Gr II (p= 0.72). Six patients died in the combination and 8 in EVL group. All deaths in Gr I were due to nonbleed-related causes, while in Gr II, 2 deaths were bleed related, the actuarial probability of death at 20 months was 8% and 15%, respectively (p= 0.37). The probability of bleed-related death was comparable (p= 0.15). At the end of follow-up, 4 patients in Gr I and 11 in Gr II had recurrence of varices (p= 0.03). Side effects on propranolol were seen in 22% patients, in 8% it had to be stopped. There were no serious complications of EVL. CONCLUSIONS: Both EVL plus propranolol and EVL alone are effective in primary prophylaxis of bleed from high-risk varices. Addition of propranolol does not decrease the probability of first bleed or death in patients on EVL. However, the recurrence of varices is lower if propranolol is added to EVL.     

A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding

Despite publication of several randomized trials of prophylactic variceal ligation, the effect on bleeding-related outcomes is unclear. We performed a meta-analysis of the trials, as identified by electronic database searching and cross-referencing. Both investigators independently applied inclusion and exclusion criteria, and abstracted data from each trial. Standard meta-analytic techniques were used to compute relative risks and the number needed to treat (NNT) for first variceal bleed, bleed-related mortality, and all-cause mortality. Among 601 patients in 5 homogeneous trials comparing prophylactic ligation with untreated controls, relative risks of first variceal bleed, bleed-related mortality, and all-cause mortality were 0.36 (0.26-0.50), 0.20 (0.11-0.39), and 0.55 (0.43-0.71), with respective NNTs of 4.1, 6.7, and 5.3. Among 283 subjects from 4 trials comparing ligation with beta-blocker therapy, the relative risk of first variceal bleed was 0.48 (0.24-0.96), with NNT of 13; however, there was no effect on either bleed-related mortality (relative risk [RR], 0.61; confidence interval [CI], 0.20-1.88) or all-cause mortality (RR, 0.95; CI, 0.56-1.62). In conclusion, compared with untreated controls, prophylactic ligation reduces the risks of variceal bleeding and mortality. Compared with beta-blockers, ligation reduces the risk for first variceal bleed but has no effect on mortality. Prophylactic ligation should be considered for patients with large esophageal varices who cannot tolerate beta-blockers. Subsequent research should further compare ligation and beta-blockers to determine the effect on mortality, and measure ligation's cost-effectiveness.     

门脉高压首次出血的预防进展

静脉曲张出血是肝硬化门脉高压的严重并发症,尽管近年首次静脉曲张出血的死亡率有所下降,但仍是主要死亡原因。目前有人提出用非选择性β受体阻滞剂预防曲张静脉的形成和发展,即一级前预防,并受到重视。非选择性β受体阻滞剂和内镜套扎术(EVL)用于一级预防已较明确。此外,血管紧张素受体抑制剂等药物的运用尚需进一步研究。     

Endoscopic variceal band ligation compared with propranolol for prophylaxis of first variceal bleeding

Administration of nonselective beta-blockers in prophylaxis of first variceal bleeding is not suitable for all patients. Thus, we evaluated endoscopic variceal band ligation (EVBL) in primary prevention of bleeding in patients with cirrhosis and large esophageal varices. A total of 73 consecutive patients with liver cirrhosis and large esophageal varices without a history of gastrointestinal bleeding were randomized to receive either EVBL or propranolol and were followed for up to 18 months. Forty patients underwent EVBL and 33 patients received propranolol. Variceal bleeding occurred in 2 patients in the EVBL (5%) and in 2 patients in the propranolol group (6%, NS). The 18 month actuarial risk for first variceal bleed was 5% in the EVBL (95% CI, 0-12%) and 20% in the propranolol group (95% CI, 0-49%, NS). The actuarial probability of death at 18 months of follow-up was 5% (95% CI, 0-11%) in the EVBL group and 7% (95% CI, 0-17%, NS) in the propranolol arm. In conclusion, EVBL was an effective and safe alternative to propranolol in primary prophylaxis of bleeding in patients with large esophageal varices.