Merkel C, Marin R, Enzo E, Donada C, Cavallarin G, Torboli P, Amodio P, Sebastianelli G, Sacerdoti D, Felder M, Mazzaro C, Beltrame P, Gatta A
Department of Clinical Medicine, University of Padua, Italy.
Lancet. 1996;348(9043):1677-81. doi: 10.1016/s0140-6736(96)05406-2.
The risk of having a first cirrhosis-associated variceal bleed is lowered by about 50% by beta-blockers. Use of beta-blockers is currently recommended for patients with cirrhosis and oesophageal varices that are at risk of bleeding. We aimed to test the effectiveness of isosorbide mononitrate as an adjunct to the beta-blocker nadolol in the prophylaxis of first variceal bleeding in these patients.
We did a randomised multicentre study to compare the non-selective beta-blocker, nadolol, with nadolol plus isosorbide mononitrate in 146 relatively well (Child-Pugh score < or = 11) patients who had oesophageal varices at risk of bleeding. Patients on nadolol alone received a single oral 40 mg daily dose. Every second day the dose was titrated to achieve 20-25% decrease in resting heart rate (maximum dose 160 mg daily). Patients receiving both drugs received nadolol as above then isosorbide mononitrate was added starting with 10 mg orally twice daily, which was increased to 20 mg unless hypotension or severe headache occurred. The main endpoint was the occurrence of variceal bleeding of any severity. Patients were followed up for up to 40 months.
During the study period 11 of 74 patients from the nadolol alone group and four of 72 from the nadolol plus isosorbide mononitrate group had variceal bleeding (log-rank test p = 0.03). Cumulative risk of variceal bleeding was 18% in the nadolol group and 7.5% in the combined treatment group (95% CI for difference 1-25%). Two patients in each group had a non-variceal bleed related to portal hypertension. 14 patients from the nadolol only group and eight from the combined treatment group died during the study period (log-rank test p = 0.09). Four and eight patients, respectively, had to discontinue one of the drugs because of side-effects.
Nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the primary prophylaxis of variceal bleeding in relatively well patients with cirrhosis, and has few side-effects.
β受体阻滞剂可使首次肝硬化相关静脉曲张出血的风险降低约50%。目前建议对有出血风险的肝硬化和食管静脉曲张患者使用β受体阻滞剂。我们旨在测试单硝酸异山梨酯作为β受体阻滞剂纳多洛尔的辅助药物在预防这些患者首次静脉曲张出血中的有效性。
我们进行了一项随机多中心研究，比较非选择性β受体阻滞剂纳多洛尔与纳多洛尔加单硝酸异山梨酯在146例病情相对较好（Child-Pugh评分≤11）且有出血风险的食管静脉曲张患者中的效果。单独使用纳多洛尔的患者每日口服单次剂量40mg。每隔一天调整剂量，以使静息心率降低20 - 25%（最大剂量每日160mg）。接受两种药物治疗的患者先按上述方法服用纳多洛尔，然后添加单硝酸异山梨酯，起始剂量为每日口服两次，每次10mg，除非出现低血压或严重头痛，否则增加至20mg。主要终点是任何严重程度的静脉曲张出血的发生。对患者进行长达40个月的随访。
在研究期间，单独使用纳多洛尔组的74例患者中有11例发生静脉曲张出血，纳多洛尔加单硝酸异山梨酯组的72例患者中有4例发生静脉曲张出血（对数秩检验p = 0.03）。纳多洛尔组静脉曲张出血的累积风险为18%，联合治疗组为7.5%（差异的95%置信区间为1 - 25%）。每组各有2例患者发生与门静脉高压相关的非静脉曲张出血。单独使用纳多洛尔组有14例患者、联合治疗组有8例患者在研究期间死亡（对数秩检验p = 0.09）。分别有4例和8例患者因副作用不得不停用其中一种药物。
在病情相对较好的肝硬化患者中，纳多洛尔加单硝酸异山梨酯在预防静脉曲张出血方面明显比单独使用纳多洛尔更有效，且副作用较少。
