ANGIOTENSIN-II BLOCKADE IN MITRAL REGURGITATION

描述(申请人逐字描述)：背景：二尖瓣 反流(MR)是一种常见的疾病，其患病率随着年龄的增长而增加。 人口数量。器质性磁共振，由于原发瓣膜病变 左心室(LV)重塑的后果取决于其程度 和功能障碍，左房(LA)扩大，导致临床不良 结果。手术可以消除MR，但有显著的风险，而且不是 适用于所有患者。因此，慢性降低MR，保护LV 血管活性治疗的LA是内科治疗的主要目标。然而， 慢性口服血管活性治疗对MR的影响存在争议 不确定的和最近的实践指导方针强调了这些知识上的差距 并不建议对先生进行血管活性治疗，因此进行了治疗试验 需要有机MR。一项关于死亡率和发病率终点的大型试验是 可取但为时过早，不知道机械效应的大小 血管活性治疗。我们的初步研究表明，持续的改善 不同程度的MR、LV重塑和左房扩大可以通过组织来实现 血管紧张素受体阻滞剂。这些中间端点的改进， 与结果机械地联系在一起，可通过非侵入性定量测量 技术和构成本临床试验提案的基础。 假设：慢性组织血管紧张素受体阻滞剂治疗 血管紧张素-II受体阻滞剂(坎地沙坦酯)或组织 双臂血管紧张素转换酶抑制药(雷米普利)，称量 反对安慰剂可持续减少有机药物的后果 先生的具体目标是治疗改善(减少)程度的MR 返流体积，主要终点)，b)LV重构(减少LV 舒张末容量指数，第二个终点)，以及c)左房扩大(减少 LA体积，第三个终点)与安慰剂相比。人口：患有癌症的患者 MR器质性(固有瓣膜病)，隔离(无其他瓣膜病)，相等 达到或大于中等(返流量等于或大于30 毫升/次)。方法：随机临床试验，安慰剂对照， 使用强效组织进行为期一年的双盲、无交叉口服治疗 血管紧张素受体阻滞剂(一只手臂用坎地沙坦，一只手臂用坎地沙坦 雷米普利)滴定到最大耐受量。在审判之前，有一个 敏锐的研究，以确定耐受性。端点通过以下方式进行测量 多普勒超声心动图定量反流容积的研究 3种同步方法的组合(定量多普勒、二维 超声心动图，近端血流会聚)和组合 超声心动图和电子束CT测量左、右室容积 测量。这项单中心研究旨在招募总共135名患者。 分析将基于治疗和比较变化的意图 术后测量返流容量、左室舒张末期容量指数和左房容量 用活性药物或安慰剂治疗一年。这样做的结果 临床试验应提供有关该病治疗的有力证据。 并确定未来的策略，以最大限度地减少死亡率和 器质性MR的发病率

DESCRIPTION (the applicant's description verbatim): Background: Mitral regurgitation (MR) is frequent and its prevalence is increasing with aging of the population. Organic MR, due to primary valvular lesions has severe consequences determined by its degree, with left ventricular (LV) remodeling and dysfunction, left atrial (LA) enlargement, leading to poor clinical outcome. Surgery can eliminate MR, but carries notable risks and is not applicable to all patients. Therefore, chronically decreasing MR, protecting LV and LA with vasoactive treatment are major goals of medical therapy. However, effects of chronic oral vasoactive treatment of MR are controversial and uncertain and recent practice guidelines underscored these gaps in knowledge and did not recommend vasoactive treatment of MR. Hence, a trial of treatment of organic MR is needed. A large trial with mortality-morbidity end-points is desirable but premature without knowledge of magnitude of mechanistic effects of vasoactive treatment. Our pilot studies suggest that sustained improvement of degree of' MR, LV remodeling and LA enlargement can be achieved with tissue angiotensin blockade. The improvement of these intermediate endpoints, mechanistically linked to outcome, is measurable with non-invasive quantitative techniques and forms the basis of the present clinical trial proposal. Hypothesis: Chronic tissue angiotensin blockade therapy using either angiotensin-II receptor blocker (Candesartan Cilexetil) or tissue angiotensin-converting enzyme inhibition (Ramipril) in two arms, weighed against placebo produces a sustained reduction of the consequences of organic MR. Specific aims are that treatment improves a) degree of MR (decreases regurgitant volume, primary end-point), b) LV remodeling (decreases LV end-diastolic volume index, second end-point), and c) LA enlargement (decreases LA volume, third end-point) as compared to placebo. Population: Patients with MR organic (intrinsic valve disease), isolated (no other valve disease), equal to or greater than moderate (regurgitant volume equal to or greater than 30 mL/beat). Methods: A randomized clinical trial, placebo controlled, double-blind, without crossover, of 1 year oral treatment with potent tissue angiotensin blockade (with one arm using Candesartan and one arm using Ramipril) titrated to the maximally tolerated dose. The trial is preceded by an acute study to determine tolerance. End-points are measured by Doppler-Echocardiography for quantitation of MR (regurgitant volume) using combination of 3 simultaneous methods (quantitative Doppler, two-dimensional echocardiography, proximal flow convergence) and combination of echocardiography and electron beam computed tomography for LV and LA volume measurement. This single center study seeks to enroll a total of 135 patients. The analysis will be based on intention to treat and compare changes in regurgitant volume, LV end-diastolic volume index and LA volume measured after one year of treatment with active drugs or placebo. The results of this clinical trial should provide strong evidence regarding medical treatment of patients with organic MR and define future strategies to minimize mortality and morbidity of organic MR.