ESOPHAGEAL VARICES BY B-ADRENERGIC BLOCKERS

B-肾上腺素能阻滞剂治疗食管静脉曲张

• 批准号: 6176227
• 负责人: ROBERTO J GROSZMANN
• 金额: $ 59.64万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-20 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176227
• 关键词: ascites; beta antiadrenergic agent; clinical trials; disease /disorder prevention /control; endoscopy; esophageal varices; hepatic coma /encephalopathy; human mortality; human subject; human therapy evaluation; liver cirrhosis; liver disorder chemotherapy; liver transplantation; placebos; portal hypertension; propranolol

Cirrhosis is the fifth leading cause of death in the United States in individuals under the age of 65, the productive years of life. It affects men and women equally, and impacts on all races and socio- economical levels. Portal hypertension is the main complication of cirrhosis, regardless of etiology. Gastroesophageal varices and variceal hemorrhage are a direct consequence of portal hypertension and account in large part for the high mortality of cirrhosis. Non-selective beta- adrenergic blockers decrease portal pressure and have been shown to prevent the first variceal hemorrhage in patients with cirrhosis and varices. Early portal hypotensive therapy, before the patients develop varices, would be beneficial not only because it may prevent or delay the formation of varices (and variceal hemorrhage) but because it may prevent or delay the development of other complications of portal hypertension, such a ascites. This ongoing multi-center, prospective, randomized, placebo-controlled, double-blind trial was designed with the primary aim of investigating if early therapy with timolol, a non- selective beta-adrenergic blocker, can prevent or delay the development of varices in patients with cirrhosis and portal hypertension. Secondary aims will examine whether timolol prevents or delays other complications of portal hypertension such as ascites and porto-systemic encephalopathy, as well as liver transplantation or death. Patients with cirrhosis, without varices on endoscopy and with portal hypertension (portal pressure greater than 6 mmHg) are included in the study. This grant application was funded in April of 1993 and patient randomization began in August of 1993. Patient accrual took longer than originally estimated, however it is now certain that the number of 190 patients required for the study will have been randomized by the end of the current funding period (March 1998), since at the writing of this proposal 158 patients had already been randomized. In calculating sample size, we assumed a rate of development of varices of 50 percent at 4 years in the control arm, to be reduced to 30 percent in the timolol arm. So far our observed rates for development of varices are consistent with our planned estimates. However, we have now estimated that a minimum follow-up of 4 years (after last patient is recruited) is necessary to ensure high statistical power (80 percent at the 2-sided 0.05 level). The trial is highly significant for the promise it holds for the treatment of cirrhosis of all etiologies and for an understanding of the natural history of the disease. The four centers involved are widely renown for their studies in this area and have collaborated productively in the past, including the only published double-blind trial of propranolol in the prevention of first variceal hemorrhage in patients with cirrhosis and varices.

肝硬化是美国第五大死亡原因 65岁以下的个人，即生命的生产力年龄。 它 平等地影响男性和女性，并影响所有种族和社会 经济水平。 门静脉高压症是其主要并发症 肝硬化，无论病因如何。胃食管静脉曲张和静脉曲张 出血是门静脉高压症的直接后果 很大程度上是因为肝硬化的高死亡率。 非选择性β- 肾上腺素能阻滞剂可降低门静脉压力，并已被证明可以 预防肝硬化患者首次静脉曲张出血 静脉曲张。 在患者出现病情之前进行早期门脉低血压治疗 静脉曲张，将是有益的，不仅因为它可以预防或延迟 静脉曲张的形成（和静脉曲张出血），但因为它可能 预防或延缓门静脉其他并发症的发生 高血压，腹水之类的。这项正在进行的多中心、前瞻性、 随机、安慰剂对照、双盲试验的设计 主要目的是调查是否早期使用噻吗洛尔（一种非 选择性β-肾上腺素能阻滞剂，可以预防或延缓发展 肝硬化和门脉高压患者的静脉曲张。中学 目标将检查噻吗洛尔是否可以预防或延迟其他并发症 门静脉高压症，如腹水和门体系统性 脑病，以及肝移植或死亡。 患者 患有肝硬化，内窥镜检查无静脉曲张且有门脉 高血压（门静脉压力大于6毫米汞柱）包括在 学习。 该拨款申请于 1993 年 4 月资助，患者 随机化开始于 1993 年 8 月。患者累积花费的时间比 最初是估计的，但现在可以肯定的是，这个数字是 190 该研究所需的患者将在年底前被随机分配 当前的资助期（1998 年 3 月），自撰写本报告时起 提议 158 名患者已被随机分组​​。 在计算中 对于样本量，我们假设静脉曲张的发生率为 50% 在控制臂中使用 4 年，在控制臂中将减少至 30% 噻吗洛尔臂。 到目前为止，我们观察到的静脉曲张发生率是 与我们计划的估计一致。 然而，我们现在估计 至少随访 4 年（招募最后一位患者后） 是确保高统计功效所必需的（80% 在 2 边 0.05级）。 该试验因其所带来的承诺而具有非常重要的意义 用于治疗所有病因的肝硬化并 了解疾病的自然史。四个中心 所涉及的人员在该领域的研究中享有盛誉，并且 过去曾进行过富有成效的合作，包括唯一发表的 普萘洛尔预防首次静脉曲张的双盲试验 肝硬化和静脉曲张患者的出血。