Carvedilol vs endoscopic variceal ligation for primary and secondary prevention of variceal bleeding: Systematic review and metaanalysis

BACKGROUND Variceal hemorrhage is associated with high mortality and is the cause of death for 20–30% of patients with cirrhosis. Nonselective β blockers(NSBBs) or endoscopic variceal ligation(EVL) are recommended for primary prevention of variceal bleeding in patients with medium to large esophageal varices.Meanwhile, combination of EVL and NSBBs is the recommended approach for the secondary prevention. Carvedilol has greater efficacy than other NSBBs as it decreases intrahepatic resistance. We hypothesized that there was no difference between carvedilol and EVL intervention for primary and secondary prevention of variceal bleeding in cirrhosis patients.AIM To evaluate the efficacy of carvedilol compared to EVL for primary and secondary prevention of variceal bleeding in cirrhotic patients METHODS We searched relevant literatures in major journal databases(CENTRAL,MEDLINE, and EMBASE) from March to August 2018. Patients with cirrhosis and portal hypertension, regardless of aetiology and severity, with or without a history of variceal bleeding, and aged ≥ 18 years old were included in this review.Only randomized controlled trials(RCTs) that compared the efficacy of carvedilol and that of EVL for primary and secondary prevention of variceal bleeding and mortality in patients with cirrhosis and portal hypertension were considered, irrespective of publication status, year of publication, and language.RESULTS Seven RCTs were included. In four trials assessing the primary prevention, no significant difference was found on the events of variceal bleeding(RR: 0.74,95%CI: 0.37-1.49), all-cause mortality(RR: 1.10, 95%CI: 0.76-1.58), and bleedingrelated mortality(RR: 1.02, 95%CI: 0.34-3.10) in patients who were treated with carvedilol compared to EVL. In three trials assessing secondary prevention, there was no difference between two interventions for the incidence of rebleeding(RR:1.10, 95%CI: 0.75-1.61). The fixed-effect model showed that, compared to EVL,carvedilol decreased all-cause mortality by 49%(RR: 0.51, 95%CI: 0.33-0.79), with little or no evidence of heterogeneity.CONCLUSION Carvedilol had similar efficacy to EVL in preventing the first variceal bleeding in cirrhosis patients with esophageal varices. It was superior to EVL alone for secondary prevention of variceal bleeding in regard to all-cause mortality reduction.     

Combined ligation and sclerotherapy versus ligation alone for secondary prophylaxis of esophageal variceal bleeding: a meta-analysis

OBJECTIVES: Variceal ligation has been shown to be superior to sclerotherapy in prevention of rebleeding and improving survival in patients with cirrhosis. However, 25% of patients will rebleed before completion of treatment. A number of trials have compared the combination of ligation and sclerotherapy to ligation alone in achieving rapid and complete eradication of esophageal varices, with conflicting results. METHODS: Two reviewers independently identified seven randomized, controlled trials that compared endoscopic variceal ligation with the combination of sclerotherapy and ligation for the treatment of esophageal varices. Studies were identified by searching MEDLINE, reviewing references from retrieved articles, and scanning abstracts from conference proceedings. For each outcome, odds ratios (ORs) were calculated using fixed-effects and random-effects models. The Mantel-Haenszel test for statistical heterogeneity was used to assess the validity of combining results from individual studies. RESULTS: No significant difference was seen in cessation of actively bleeding varices (OR = 1.01, 95% CI = 0.43-2.36), variceal rebleeding (OR = 1.12, CI = 0.69-1.81), and mortality (OR = 1.1, CI = 0.70-1.74) in patients with variceal ligation versus patients receiving the combination treatment of ligation and sclerotherapy. Treatment sessions required to achieve complete variceal eradication were similar in the two treatment arms. A significantly higher incidence of esophageal stricture was seen in combination therapy (p < 0.001). CONCLUSIONS: The combination of ligation and sclerotherapy offers no advantage over ligation alone in prevention of rebleeding and in reduction of mortality. It is also associated with a higher complication rate of esophageal stricture.     

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.     

Factors predicting success of endoscopic variceal ligation for secondary prophylaxis of esophageal variceal bleeding

Introduction: Endoscopic obliteration of esophageal varices by endoscopic variceal ligation (EVL) is an effective form of secondary prophylaxis. However, there is no consensus regarding the technical aspects of EVL for secondary prophylaxis. The present study compares the technical aspects of EVL (frequency of sessions, number of sessions and number of bands used) in patients who rebled following secondary prophylaxis of esophageal varices by EVL compared to those who did not rebleed. Methods: All patients who underwent EVL for treatment of acute variceal bleeding followed by EVL for secondary prophylaxis and who subsequently developed recurrent variceal bleeding at Mayo Clinic, Rochester between January 1995 and May 2003 were identified. A control group of patients undergoing EVL for secondary prophylaxis who did not rebleed was identified. Results: During the study period, 216 patients with acute esophageal variceal hemorrhage underwent emergent EVL treatment with follow‐up EVL for secondary prophylaxis, of whom 20 (9.3%) subsequently rebled. Both rebleeding and non‐rebleeding patient groups were well‐matched with respect to liver function (Child–Pugh class), number and size of variceal trunks, endoscopic stigmata of hemorrhage and beta‐blocker usage. The median interval between EVL sessions in the rebleeding group (2 weeks, interquartile range 0–2 weeks) was significantly shorter compared to the non‐rebleeding group (5 weeks, interquartile range 3–7 weeks; P = 0.004). Adjusting for age, gender, and Child–Pugh class, interbanding interval ≥ 3 weeks was associated with increased likelihood of not rebleeding, hazard ratio 3.84 (95% confidence interval: 1.69–11.79; P = 0.0007). Conclusions: These findings demonstrate the importance of technical aspects of EVL on patient outcome, suggesting the benefit of longer interbanding intervals. Future prospective studies are required to define the optimal intersession interval. Standardizing procedural aspects of EVL will aid in objectively evaluating the benefit of this procedure when compared to other modalities such as medical treatment.     

Cost-effectiveness analysis of variceal ligation vs. beta-blockers for primary prevention of variceal bleeding

Although both beta-blockade (BB) and endoscopic variceal ligation (EVL) are used for primary prevention of variceal bleeding (VB) in patients with cirrhosis with moderate to large esophageal varices (EVs), the more cost-effective option is uncertain. We created a Markov decision model to compare BB and EVL in such patients, examining both cost-effectiveness (cost per life year [LY]) and cost-utility (cost per quality-adjusted life year [QALY]). Outcomes included cost per LY, cost per QALY, proportions of persons with VB, TIPS, and all-cause mortality. EVL and BB were compared using the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR). When considering only LYs, initial EVL exceeds the benchmark of 50,000 dollars/LY, with an ICER of 98,407 dollars. However, when quality of life (QoL) is considered, EVL is cost-effective compared to BB (ICUR of 25,548 dollars/QALY). In sensitivity analysis, EVL is cost-effective if the yearly risk of EV bleeding is > or = 0.26 (base case 0.15), the relative risk of bleeding on BB is > or = 0.69 (base case 0.58), or if the relative risk of bleeding with EVL is < 0.27 (base case 0.35). The ICUR favored EVL unless the relative risk of bleeding on BB is < 0.46, the relative risk of bleeding with EVL is > 0.46, or the time horizon is < or = 24 months. Whether EVL is "cost-effective" relative to BB therapy for primary prevention of EV bleeding depends on whether LYs or QALYs are considered. If only LYs are considered, then EVL is not cost-effective compared to BB therapy; however, if QoL is considered, then EVL is cost-effective.     

Therapeutic results of endoscopic variceal ligation for acute bleeding of oesophageal and gastric varices

Endoscopic variceal ligation (EVL) using 'O' rings is widely accepted as a treatment of oesophageal varices that is at least as effective as endoscopic injection sclerotherapy but which produces fewer complications. Endoscopic variceal ligation using detachable snares has attracted attention as a safe and easy method of endoscopic treatment for gastric varices. Nineteen patients with acute bleeding from oesophageal or gastric varices were treated in the present study. Of these, 14 patients were treated with EVL using 'O' rings and five patients were treated with EVL using detachable snares and the treatment results were evaluated. Haemostasis was achieved in all patients. No serious complications of the procedures were observed. However, recurrences and rebleeding were observed in some patients during the maximum follow-up period of 24 months. Endoscopic variceal ligation using 'O' rings and detachable snares is useful for achieving haemostasis in cases of acute bleeding from oesophageal or gastric varices. However, additional endoscopic sclerotherapy may be needed to eliminate the variceal feeding vessels to further improve the long-term prognosis of these patients.     

内镜下组织胶注射联合套扎治疗急性胃食管静脉曲张出血的临床应用

目的探讨内镜下组织胶注射联合套扎治疗急性胃食管静脉曲张出血的临床价值。方法23例临床确诊为肝硬化急性胃食管静脉曲张破裂出血患者,均于出血稳定12h内采用胃曲张静脉三明治法组织胶注射后联合食管曲张静脉套扎治疗,术后2周、3个月进行内镜随访。观察治疗后再出血率、死亡率、食管胃静脉曲张程度。结果所有患者均一次成功止血。6例患者于术后2周,再次行EVL术。食管胃静脉曲张程度明显减轻,食管静脉治疗有效率95．65％,胃底静脉曲张治疗有效率91．30％。随访期3个月内无一例再出血及死亡病例。结论内镜下组织胶注射联合套扎是治疗胃食管静脉曲张急性出血一种安全可靠的方法。     

Endoscopic variceal ligation vs. propranolol for prevention of first variceal bleeding: a randomized controlled trial

OBJECTIVES: Data in the literature regarding the role of endoscopic variceal ligation for the prevention of first variceal bleeding in cirrhotic patients are controversial. To further explore this issue we have compared ligation and propranolol treatment in a prospective randomized study. METHODS: Sixty patients with cirrhosis and oesophageal varices with no history but at high risk of bleeding were randomized to ligation treatment (30 patients) or propranolol (30 patients). Patients were followed for approximately 27.5 months. RESULTS: Variceal obliteration was achieved in 28 patients (93.3%) after 3+/-1 sessions. The mean daily dose of propranolol was 60.3+/-13.3 mg. Two patients (6.7%) in the ligation group and nine patients (30%) in the propranolol group developed variceal bleeding (P = 0.043). The actuarial risks of variceal bleeding at 2 years were 6.7% and 25%, respectively. On multivariate analysis, propranolol treatment and grade III varices turned out to be predictive factors for the risk of variceal bleeding. Mortality was not different between the two groups. There were no serious complications due to ligation. Propranolol treatment was discontinued in four patients because of side effects. CONCLUSIONS: Variceal ligation is a safe and more effective method than propranolol treatment for the prevention of first variceal bleeding in cirrhotic patients with high-risk varices.     

食管静脉曲张套扎术和β-受体阻滞剂预防肝硬化初次出血的Meta分析

目的评价食管静脉曲张套扎术(EVL)和β-受体阻滞剂(BB)预防肝硬化初次静脉破裂出血的有效性和安全性。方法计算机检索Cochrane临床对照试验资料库(2006年第4期)、MEDLINE(1966年至2006年11月)、EMBASE(1985年至2006年11月)和中国期刊全文数据库(1994—2006年),并辅以手工检索有关EVL和BB预防食管静脉曲张初次破裂出血的随机对照临床试验,按Cochrane协作网推荐的方法进行Meta分析。结果共纳入8个随机对照试验(RCT)。Meta分析结果显示,EVL和BB比较,EVL可降低肝硬化初次静脉破裂出血的发生率[相对危险度(RR)=0.63,95%可信区间(CI):0.46~0.85;P=0.003;相对危险度减少(RRR)=0.37,需要治疗的患者数(NNT)为12例]和严重副反应发生率(RR=0.23,95%CI:0.12~0.43;P<0.01;RRR=0.77,NNT为8例);但二者对总病死率的影响差异无显著性意义(RR=1.03,95%CI:0.81~1.31;P=0.82)。结论预防肝硬化初次静脉破裂出血EVL比BB更有效和安全。     

Influence of endoscopic variceal ligation on oesophageal motility

BACKGROUND: To determine the change of oesophageal manometry in patients with oesophageal varices before and after oesophageal variceal ligation (EVL). METHODS: Forty-five patients who had liver cirrhosis and oesophageal varices with high risk of bleeding were managed by EVL. Oesophageal manometry was performed just prior to the ligation and 4-6 weeks after obliteration of varices. Another 45 age- and sex-matched patients without hepatic, oesophageal or systemic disease served as the control group. RESULTS: At 5 cm above the lower oesophageal sphincter (LES), the amplitude of the contractive wave was significantly lower in patients before EVL (56.9 +/- 31.8 vs 80.1 +/- 30.1, P< 1.05) and returned to the level of control subjects after EVL (76.5 +/- 37.0 vs 80.1 +/- 30.1, P> 0.05). At 10 cm above LES, the amplitude of the contractive wave was significantly lower in patients before and after EVL than the control group (54.3 +/- 29.2 vs 68.1 +/- 29.5, 54.2 +/- 26.0 vs 68.1 +/- 29.5, respectively, P< 0.05). The percentage of tertiary waves was significantly higher in patients before and after EVL than in the control group (31.4 +/- 36.6 vs 5.8 +/- 15.1, 26.9 +/- 32.9 vs 5.8 +/- 15.1, respectively, P< 0.05). However, no significant swallowing disturbance was noted in patients after EVL. There was significantly greater LES length in patients before EVL (4.0 +/- 0.9 vs 3.4 +/- 0.7, P<0.05) but there was no significant difference in the LES length after EVL as compared with the control group. Eighty-six per cent (39/45) of patients developed paraoesophageal varices and 31% (14/45) developed new varices 6 months after variceal obliteration. However, there was no significant difference in manometry at the time of variceal obliteration between patients with variceal recurrence and those without. CONCLUSIONS: The presence of varices affected oesophageal motility. However, such abnormality had little clinical significance. Endoscopic variceal ligation normalized oesophageal motility and may not induce abnormal oesophageal motility. The manometric change can not be used to predict the recurrence of varices in cirrhotic patients after variceal obliteration.     

Effective treatment for duodenal variceal bleeding using endoscopic ligation

Duodenal variceal rupture is rare, and there is little agreement on the best therapeutic option. A 72-year old man treated for liver cirrhosis with HCV visited the emergency room complaining of dizziness and tarry stool. Fiberscope images showed varices (F2CbRC+) with white plaques at the horizontal region of the duodenum. The patient was treated using endoscopic variceal ligation (EVL), and no more bleeding has been detected.     

内镜套扎术在治疗食管静脉曲张破裂出血中的临床应用价值

目的探讨内镜下食管静脉曲张套扎术（EVL）治疗和预防肝硬化患者食管静脉曲张破裂出血的临床应用价值。方法回顾性分析2008-01～2012-01该院142例肝硬化食管静脉曲张破裂出血患者,其中行EVL治疗74例（治疗组）,内科保守治疗68例（对照组）,并对其临床疗效进行随访观察。结果所有患者随访6个月以上,治疗组的早期再出血率、迟发出血率、曲张静脉好转率、复发率、手术率及病死率均低于对照组（P〈0.05或〈0.01）。结论 EVL能有效地降低肝硬化门脉高压患者食管静脉曲张的程度,降低再出血率、复发率、手术率和病死率,是一种有效的内镜治疗手段。