非选择性β受体阻滞剂在肝硬化并食管胃静脉曲张中的使用与争议

食管胃静脉曲张是肝硬化门脉高压常见并发症之一,发病率高,其破裂出血常导致肝硬化患者突然死亡。防治静脉曲张破裂出血及预防再出血十分重要。非选择性β受体阻滞剂能降低门脉压力,预防曲张静脉出血和再出血获得肯定疗效,但在部分肝硬化患者中应用存在争议,本文就非选择性β受体阻滞剂在食管胃静脉曲张中的使用和争议予以阐述。     

卡维地洛与非选择性β受体阻滞剂治疗成人肝硬化食管胃底静脉曲张效果比较

<正>【据《Cochrane Database Syst Rev》2018年10月报道】题:比较卡维地洛与非选择性β受体阻滞剂治疗成人肝硬化食管胃底静脉曲张的结局(作者Zacharias AP等)非选择性β受体阻滞剂被推荐用于预防肝硬化门静脉高压患者的食管胃底静脉曲张出血。卡维地洛是非选择性β受体阻滞剂,还可阻断α1受体,因此在降低门静脉压力和减少上消化道出血风险方面可能优于非选择性β受体     

肝硬化患者应用非选择性β-受体阻滞剂后首次静脉曲张破裂出血的风险和危险因素

<正>【据《Am J Gastroenterol》2016年9月报道】题:肝硬化患者应用非选择性β-受体阻滞剂后首次静脉曲张破裂出血的风险和危险因素(作者Shukla R等)既往研究已证实非选择性β-受体阻滞剂(nonselective beta-blocker,NSBB)预防肝硬化患者首次静脉曲张破裂出血的有效性。然而,NSBB在临床常规治疗中的总体有效率仍不明确。来自美国贝勒医学院的Shukla等     

非选择性β受体阻滞剂预防静脉曲张出血及再出血

胃食管静脉曲张出血是肝硬化失代偿期常见的并发症，出血后1年内再出血率高达60%,门静脉压力升高是食管胃底静脉破裂出血的主要原因。非选择性β受体阻滞剂(NSBB)通过阻断β肾上腺素能受体降低门静脉压力，从而达到降低静脉曲张出血的风险，目前已成为胃食管静脉曲张出血一级和二级预防的首选药物，以HVPG指导的NSBB治疗和预防门静脉高压症患者首次和复发静脉曲张出血的个体化方案已引起临床关注，本文将结合最新的研究结果，探讨NSBB预防静脉曲张出血及再出血的个体化治疗。     

非选择性β受体阻断剂与肝硬化门脉高压症

普萘洛尔为一种非选择性β-受体阻滞剂,由于其能有效降低门静脉压力,被国内外指南推荐用于预防食管胃底静脉曲张出血,但近年来研究发现普萘洛尔可增加肝硬化伴有顽固性腹水患者的病死率。新的非选择性β受体阻断剂卡维地洛在降低肝静脉压力梯度及安全性方面优于普萘洛尔。卡维地洛与内镜套扎预防食管胃静脉曲张出血的疗效无明显差异。无创测定肝静脉压力梯度及优化非手术治疗方法是今后该领域重要的研究方向。     

302例慢性肝外门静脉阻塞患者静脉曲张出血的长期结果

正关于肝外门静脉阻塞(EHPVO)患者静脉曲张出血或再出血治疗策略的研究非常少,本研究旨在评估按最新指南推荐意见进行管理EHPVO患者的长期结果和影响因素。纳入空军军医大学西京医院2009年-2016年EHPVO患者302例。59例无曲张静脉和55例小曲张静脉患者采用了观察的策略; 115例患者使用非选择性β受体阻滞剂进行初级预防,87例患者联合非选择性β受体阻滞剂和内     

卡维地洛对肝硬化门静脉高压食管胃静脉曲张出血的防治作用研究进展

门静脉高压是食管胃静脉曲张出血的主要原因,有效降低门静脉压力梯度是预防食管胃静脉曲张出血的关键。卡维地洛是一类具有潜在的非心脏选择性的β受体和α受体阻滞剂,可通过降低门静脉压力进而减少食管胃静脉曲张的出血风险。本文就卡维地洛相比于传统的β受体阻滞剂如普萘洛尔或奈比洛尔、内镜下套扎、β受体阻滞剂联合硝酸酯类等治疗方案对食管胃静脉曲张出血的防治作用和不良反应进行分析,以期更好的指导临床治疗。     

肝硬化食管胃静脉曲张破裂出血的临床处理动向

治疗肝硬化食管胃静脉曲张破裂出血的首选措施是药物治疗,可选用特利加压素、生长抑素类似物等;硝酸酯类药物、分流术或硬化疗法均不建议用于一级预防;非选择性β受体阻滞剂联合内镜下曲张静脉套扎术是目前二级预防中的首选措施。     

β受体阻滞剂是否为急性静脉曲张破裂出血预后的恶化因素

正【据《Hepatology》2015年12月报道】题:β受体阻滞剂是急性静脉曲张破裂出血预后的恶化因素吗?一项短期生存分析(作者de Souza AR等)非选择性β受体阻滞剂(NSBB)已证实可有效地预防急性静脉曲张破裂出血(AVB),现已得到广泛使用,然而,仍有不少患者在NSBB治疗期间出现AVB,NSBB对AVB预后的影响尚不清楚。作者旨在评估NSBB预防性治疗对肝硬化AVB患者5 d治疗失败和6周病死率的影响。共包括142例患者,其中49例接受     

肝静脉压力梯度在肝硬化门静脉高压症患者中的临床应用

测量肝静脉压力梯度（HVPG）是评估门静脉高压症最常用的方法。大量研究表明,HVPG可作为食管静脉曲张出血的预测因子,此外,HVPG还可作为一个预后指标,可方便临床医生以其做参考为静脉曲张出血的一级预防和二级预防来制定合适的治疗策略。现阶段的治疗目标是使HVPG下降到12 mm Hg以下或比基线值下降20%,达到此目标的患者其食管静脉曲张的首次出血和再出血的风险均大大降低。对于一级预防,非选择性的β受体阻滞剂,如心得安,临床已广泛应用;然而,再出血的发生率仍然很高,临床上常用包括非选择性β受体阻滞剂在内的药物联合治疗和内镜干预,如经颈静脉肝内门体静脉分流术（TIPS）、内镜下硬化剂注射和内镜下套扎。主要探讨目前HVPG的测量方法及其临床应用,并重点对在肝硬化中HVPG对食管静脉曲张出血和再出血及治疗反应的预测作用做详细阐述。     

Prevention of the development of varices and first portal hypertensive bleeding episode

Variceal bleeding is a serious complication in patients with cirrhosis. Although bleeding related mortality rates have fallen recently, it continues to be amongst the leading causes of death. Cirrhotics should be screened for varices at diagnosis. Data on preventing formation/growth of oesophageal varices (pre-primary prophylaxis) are conflicting, with insufficient evidence to use beta-blockers. In order to prevent first bleeding, there is strong evidence in patients with medium/large size oesophageal varices that either non-selective beta-blockers or banding ligation can be used. Banding is superior with respect to bleeding but mortality is similar. Non-selective beta-blockers should remain first line treatment being effective, cheap and without serious complications. In contrast banding ligation is more expensive, requires specialised staff, cannot prevent bleeding from portal hypertensive gastropathy and can cause iatrogenic bleeding. Patients with small varices, particularly if they have progressive liver disease also benefit from beta-blockers, but fewer studies confirm this therapeutic approach.     

Acute variceal bleeding: pharmacological treatment and primary/secondary prophylaxis

Variceal bleeding is one of the most severe complications of portal hypertension related to liver cirrhosis. Primary prophylaxis is considered mandatory in patients with cirrhosis and high-risk oesophageal varices, and once varices have bled, every effort should be made to arrest the haemorrhage and prevent further bleeding episodes. In acute variceal bleeding, vasoactive drugs that lower portal pressure should be started even before endoscopy, and should be maintained for up to 5 days. The choice of vasoactive drug should be made according to local resources. Terlipressin, somatostatin and octreotide can be used; vasopressin plus transdermal nitroglycerin may be used if no other drug is available. In variceal bleeding, antibiotic therapy is also mandatory. In primary and secondary prophylaxis, beta-blockers are the mainstay of therapy. In secondary prophylaxis (but not in primary prophylaxis) these drugs can be combined with organic nitrates.     

Current endoscopic therapy of variceal bleeding

Variceal ligation has proved more effective and safer than sclerotherapy and is currently the endoscopic treatment of choice for oesophageal varices. In acute bleeding, vasoactive drugs should be started before endoscopy and maintained for 2-5 days. The efficacy of drugs is improved when associated with emergency endoscopic therapy. Antibiotic prophylaxis should also be used. To prevent rebleeding, both endoscopic ligation and the combination of beta-blockers and nitrates may be used. Adding beta-blockers improves the efficacy of ligation. Haemodynamic responders to beta-blockers+/-nitrates (those with a decrease in portal pressure gradient HVPG to <12 mmHg or by >20% of baseline) have a marked reduction in the risk of haemorrhage and will not need further treatment. Beta-blockers significantly reduce the risk of a first haemorrhage in patients with large varices, and they improve survival. As compared to beta-blockers, endoscopic ligation reduces the risk of first bleeding without affecting mortality, and should be used in patients with contraindications or intolerance to beta-blockers.     

Oesophageal varices in cirrhotic patients: from variceal screening to primary prophylaxis of the first oesophageal variceal bleeding

Bleeding from oesophageal varices is still a lethal complication in cirrhotic patients with portal hypertension. Approximately 5–10% of patients with cirrhosis will develop oesophageal varices per year, and about 25–30% of cirrhotic patients with oesophageal varices and without previous variceal haemorrhage will bleed from ruptured varices. To date, data on preventing the formation/growth of oesophageal varices (preprimary prophylaxis) are conflicting, with insufficient evidence to use β‐blockers. There is evidence for the need for primary prophylaxis, and both β‐blockers and endoscopic variceal ligation have shown the same efficacy in preventing first bleeding, but which one to prefer is still controversial. The present article reviews the established and potential therapeutic strategies for preventing the development and rupture of oesophageal varices.     

Incidence of large oesophageal varices in patients with cirrhosis: application to prophylaxis of first bleeding.

Because several studies have suggested that beta blockers are effective in the prophylaxis of first variceal bleeding in cirrhosis, screening for oesophageal varices might be appropriate. We prospectively studied 84 cirrhotic patients without obvious evidence of large oesophageal varices and previous bleeding during a mean follow up of 16 months. At entry to the study 41 patients had no oesophageal varices and in 43 these were grade 1. The subsequent percentages of patients without large oesophageal varices were 74% at one year and 52% at two years. Univariate analysis showed that a longer duration of cirrhosis (p less than 0.05) and grade 1 oesophageal varices at entry (p less than 0.001) were predictive factors for the occurrence of large oesophageal varices, whereas, multivariate analysis showed that the initial size of the oesophageal varices (p less than 0.001), a high initial Child-Pugh score, and a smaller improvement in Child-Pugh score during the study were independent risk factors. Among patients with grades 0 and 1 oesophageal varices at the start of the study the proportions with large oesophageal varices at two years were 31% and 70% respectively. We have calculated that, accepting a maximum risk of first bleeding of 10% without prophylactic treatment, a patient without oesophageal varices should be screened endoscopically every other year, while a patient with grade 1 disease should benefit from one annual upper gastrointestinal endoscopy.     

Variceal hemorrhage

Opinion statement Reducing morbidity and mortality from esophageal varices remains a challenge for physicians managing patients with chronic liver disease. For patients who have never bled from varices, prophylactic therapy with nonselective beta-blockers reduces the risk of initial variceal bleeding and bleeding-related death. Thus, patients with newly diagnosed cirrhosis should be considered for endoscopic variceal screening. All patients with Child’s class B and C cirrhosis should be offered endoscopic screening, whereas those with Child’s class A with evidence of portal hypertension (eg, platelet count less than 140,000 per milliliter, portal vein diameter larger than 13 mm, evidence of splenic varices on ultrasound) should be screened. The principal risk factors for variceal bleeding are variceal size, the presence of color changes on the variceal wall (indicative of decreased wall thickness), and degree of liver dysfunction. Patients with moderate or large sized varices and those with varices exhibiting color changes (eg, red wale marks, cherry red spots) should be treated with beta-blockers. Individuals without varices and those with small varices should undergo repeat endoscopy at approximately 2-year intervals. Patients unwilling or unable to take beta-blockers do not need to be screened. For patients with acute variceal bleeding, the combination of pharmacologic therapy plus endoscopic therapy is superior to either therapy alone. Octreotide is the drug most often used as initial therapy in the United States. Terlipressin is the preferred agent; however, it is not available in the United States. Endoscopy is performed as early as possible, and endoscopic injection sclerotherapy or endoscopic variceal band ligation is employed if variceal bleeding is confirmed or suspected. Endoscopic therapy should be repeated until the varices are obliterated completely. The addition of beta-blockers to endoscopic sclerotherapy or ligation may decrease the rate of rebleeding compared with receiving endoscopic treatment alone. Patients with bleeding refractory to combined medical plus endoscopic therapy should be considered for transjugular intrahepatic portosystemic shunts or shunt surgery.     

Portal hypertension: Pre-primary and primary prophylaxis of variceal bleeding

In liver cirrhosis, variceal bleeding is the last in a chain of events initiated by the increase in portal pressure (estimated in clinical practice by the hepatic venous pressure gradient). When hepatic venous pressure gradient goes above 10 mmHg the patient is at risk of developing varices, and when hepatic venous pressure gradient reaches 12 mmHg variceal bleeding might develop. Currently, there is not any effective therapy for the prevention of the development of varices. When varices are small, beta-adrenergic blockers might prevent the enlargement of the varices, and may reduce the risk of variceal bleeding. In patients with medium to large varices, beta-blockers are clearly effective in reducing the risk of variceal bleeding. Endoscopic band ligation might be more effective than beta-blockers, but available evidence is still very weak.     

Variceal injection sclerotherapy

With the development and widespread use of flexible endoscopes, injection sclerotherapy of oesophageal varices has advanced beyond the early stages. Although slightly different techniques and different sclerosants are used, the results are not strikingly different. The cumulative rate of adverse effects is in the range of 20 to 40%, with a procedure-related mortality of around 1 to 2%. Sclerotherapy is the best available treatment for haemostasis of acute oesophageal variceal bleeding. However, as a long-term therapy it is less effective in the prevention of recurrent gastrointestinal bleeding events, since obliteration of all varices often takes several months. Furthermore, extra-oesophageal bleeding is not amenable to sclerotherapy. Thus, if repeated injections fail to prevent recurrent bleeding, other options such as shunt surgery, transection, chronic medical portal decompression with beta-blockers or even liver transplantation should be considered according to the needs of the individual patient. Prophylaxis of first variceal haemorrhage was beneficial in selected patients with a high bleeding risk. It cannot, however, be generally recommended at present.     

Cost-effectiveness analysis of beta-blockers vs endoscopic surveillance in patients with cirrhosis and small varices

AIM:To evaluate the most cost-effectiveness strategy for preventing variceal growth and bleeding in patients with cirrhosis and small esophageal varices.METHODS:A stochastic analysis based on decision trees was performed to compare the cost-effectiveness of beta-blockers therapy starting from a diagnosis of small varices(Strategy 1)with that of endoscopic surveillance followed by beta-blockers treatment when large varices are demonstrated(Strategy 2),for preventing variceal growth,bleeding and death in patients with cirrhosis and small esophageal varices.The basic nodes of the tree were gastrointestinal endoscopy,inpatient admission and treatment for bleeding,as required.All estimates were performed using a Monte Carlo microsimulation technique,consisting in simulating observations from known probability distributions depicted in the model.Eight-hundred-thousand simulations were performed to obtain the final estimates.All estimates were then subjected to Monte Carlo Probabilistic sensitivity analysis,to assess the impact of the variability of such estimates on the outcome distributions.RESULTS:The event rate(considered as progression of varices or bleeding or death)in Strategy 1[24.09%(95%CI:14.89%-33.29%)]was significantly lower than in Strategy 2[60.00%(95%CI:48.91%-71.08%)].The mean cost(up to the first event)associated with Strategy 1[823￡(95%CI:106￡-2036￡)]was not significantly different from that of Strategy 2[799￡(95%CI:0￡-3498￡)].The cost-effectiveness ratio with respect to this endpoint was equal to 50.26￡(95%CI:-504.37￡-604.89￡)per event avoided over the four-year follow-up.When bleeding episodes/deaths in subjects whose varices had grown were included,the mean cost associated with Strategy 1 was 1028￡(95%CI:122￡-2581￡),while 1699￡(95%CI:171￡-4674￡)in Strategy 2.CONCLUSION:Beta-blocker therapy turn out to be more effective and less expensive than endoscopic surveillance for primary prophylaxis of bleeding in patients with cirrhosis and small varices.     

Pharmacological treatment of portal hypertension: an evidence-based approach

Continuing advances in the knowledge of the pathophysiology of portal hypertension result in the progressive expansion of the spectrum of drugs with a potential role for clinical practice, with objectives that now tend to include the prevention of the enlargement or even the development of esophageal varices. This systematic review summarizes the evidence of efficacy of drug therapy for portal hypertension and draws recommendations for clinical practice. Although there is not yet enough evidence to support the treatment for the prevention of the development or enlargement of varices, nonselective beta-blockers are the first-choice therapy to prevent the first bleeding in patients with medium or large-sized varices and rebleeding in patients surviving a bleeding episode. The clinical role of isosorbide-5-mononitrate either alone or in association with beta-blockers still remains unsettled. Vasoactive drugs are generally effective and safe in controlling acute variceal bleeding, although the evidence is not equivalent for each of them.