β阻滞剂预防失败者静脉曲张再出血风险翻倍

巴塞罗那大学的Andrea Ribeiro de Souza博士及其同事在6月刊《临床胃肠病学与肝病学》杂志上发表的一项研究显示，在预防性服用β受体阻滞剂期间首次发生静脉曲张出血的肝硬化患者再次发生出血的风险，比首次出血时未服用β受体阻滞剂的患者增加近1倍(Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.02.011])。

即使是在β受体阻滞剂预防失败后接受了目前推荐的后续治疗(内镜套扎术联合继续β受体阻滞剂治疗，加或不加异山梨醇-5-单硝酸盐)的患者，再出血风险的差异也依然存在。

目前β受体阻滞剂已被广泛用于静脉曲张出血的一级预防，因此在预防性服用该药时首次发生静脉曲张出血的肝硬化患者正不断增加。但迄今尚无研究探讨这些患者与首次出血时未服药的患者有哪些显著差异。

为此，研究者采用了其所在医院肝病科2007~2011年的数据，共连续入组89例因急性静脉曲张出血而接受治疗的患者。其中34例患者在接受β受体阻滞剂预防的情况下首次发生出血，其余55例首次出血时未服用该药。根据现行推荐意见对这些患者进行治疗。入院时静脉输注血管收缩剂(特利加压素或生长抑素)和预防性抗生素，并在12 h内实施内镜套扎术(EBL)。21例患者启动了异山梨醇治疗。每2周实施1次内镜套扎术，患者一直服用质子泵抑制剂，均直至静脉曲张被根除。所有患者均在1~3个月时接受内镜复查，此后每6个月内镜复查1次。如果静脉曲张复现，则再次行内镜套扎术。随访2年，或直至患者接受肝移植或死亡。

结果显示，在已开始预防性服用β受体阻滞剂的患者中仅有67%达到了静脉曲张消除，而未服用者的消除率达80%。主要终点——随访期间任何部位发生再出血的累计发生率，已开始服用β受体阻滞剂的患者为48%，而另一组仅为24%。如果仅分析静脉曲张再出血，两组的累计发生率仍有显著差异(39% vs. 17%)。

进一步分析显示，上述差异在所有亚组中均存在，不论肝硬化是否与酒精相关，不论首次静脉曲张出血是否在患者大量饮酒时发生，也不论患者是否接受了异山梨醇治疗。

将上述结果与另两项近期研究结果综合考虑，提示对预防性β受体阻滞剂无应答的患者倾向于对内镜治疗也反应不佳。这两项研究显示，接受内镜套扎术的患者发生静脉曲张再出血的几率较高。“可能宜采用新的、更有效的药物进行治疗以降低门脉压，具有血管舒张活性的非选择性β受体阻滞剂卡维地洛可能是不错的选择。”一种更好的治疗选择或许是经颈静脉肝内门体循环分流术，因为药物通常仅能轻度降低肝静脉压力梯度而不足以预防再出血。

“由于缺乏可识别这一人群的基线临床或血液动力学特征，我们猜测其出血风险增加可能与其他因素有关，例如食管血液循环的特点，但迄今这方面尚无研究数据。”

这项研究获得了Salud Carlos III研究所和科学创新部提供的部分资金支持。Ciberehd由Salud Carlos III研究所资助。Andrea Ribeiro de Souza博士获得了BBVA基金会的资助。研究者报告无相关利益冲突。

Patients with cirrhosis whose first episode of acute variceal bleeding occurs when they are already taking prophylactic beta-blockers are at increased risk for recurrent bleeding, Dr. Andrea Ribeiro de Souza and colleagues reported in the June issue of Clinical Gastroenterology and Hepatology.

The risk of recurrence is approximately twice as high in such patients as in those who are not taking prophylactic beta-blockers when their first variceal bleed occurs. This is true even when patients receive the currently recommended secondary therapy after nonselective beta-blocker prophylaxis fails, which is a combination of endoscopic band ligation and further beta-blocker treatment, with or without the addition of isosorbide-5-mononitrate.

These results, taken together with those of two recent studies showing that patients who undergo endoscopic band ligation have a “dismal” rate of variceal rebleeding, suggest that patients who don’t respond to prophylactic beta-blockers “have an idiosyncrasy that makes them also poor responders to endoscopic therapy.

“Since there are no baseline clinical or hemodynamic characteristics that could differentiate this population, it can be speculated that their increased bleeding risk may be related to other factors, perhaps ... peculiarities of the esophageal circulation, which [have] never been investigated so far,” said Dr. de Souza and associates at the University of Barcelona and Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (Ciberehd) (Clin. Gastroenterol. Hepatol. 2012 [doi:10.1016/j.cgh.2012.02.011]).

Primary prophylaxis of variceal bleeding with nonselective beta-blockers is now widely used, so the number of cirrhosis patients who experience their first episode of bleeding while taking these drugs is increasing. Until now, no study has explored whether these patients differ significantly from those who aren’t taking the drugs when they have their first variceal bleed.

Dr. de Souza and colleagues examined this question using data from the liver unit of their hospital during 2007-2011, on 89 consecutive patients treated for acute variceal bleeding. Thirty-four of the study subjects had their first bleed while on beta-blocker prophylaxis, and 55 subjects were not taking the medication.

Subjects were treated according to current recommendations. On admission they received an intravenous vasoconstrictor (terlipressin or somatostatin) and prophylactic antibiotics, and they underwent endoscopic band ligation (EBL) within 12 hours. Those whose bleeding was controlled were started on oral propanolol or nadolol, which was increased until heart rate or systolic blood pressure had fallen to appropriate levels.

Isosorbide was started in 21 patients. EBL sessions were scheduled every 2 weeks until varices were eradicated, and patients took proton pump inhibitors until that time as well.

Variceal obliteration was achieved in only 67% of patients who had already been taking beta-blocker prophylaxis, compared with 80% of those who had not.

All subjects underwent surveillance endoscopy at 1-3 months, and at 6-month intervals thereafter. Further EBL was done if varices reappeared. Patients were followed for 2 years, or until liver transplantation or death occurred.

The primary end point of the study was rebleeding from any source during follow-up. The cumulative incidence of rebleeding from any source was 48% for patients already taking beta-blocker prophylaxis, compared with 24% in the other group.

When the analysis was restricted to rebleeding from varices only, the rate was still significantly higher among patients already taking beta-blocker prophylaxis (39%) than in the other group (17%).

This discrepancy persisted across all subgroups in further analyses, regardless of whether the cirrhosis was or was not alcohol related, whether or not the subjects were actively drinking at the time of the first variceal bleed, and whether or not patients were treated with isosorbide.

These findings indicate that patients whose first variceal bleed occurs while they are taking prophylactic beta-blockers are not likely to benefit from EBL, “and would probably be best treated with new and more effective drugs to achieve target reductions in portal pressure. A possibility is the use of carvedilol, a nonselective beta-blocker with intrinsic vasodilator activity that causes a greater reduction in hepatic vein pressure gradient than propranolol or nadolol,” the researchers said.

An even better option might be transjugular intrahepatic portosystemic shunting, since medication typically achieves only a modest decrease in hepatic vein pressure gradient, which may not be sufficient to prevent bleeding recurrences, they added.

The study was supported in part by grants from Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación. The Ciberehd is funded by Instituto de Salud Carlos III. Dr. Andrea Ribeiro de Souza’s work is funded by grant of the BBVA foundation. The investigators reported no financial conflicts of interest.