ANGIOTENSIN-II BLOCKADE IN MITRAL REGURGITATION

描述（申请人的逐字描述）：背景：二尖瓣 反流（MR）是常见的，其患病率随着年龄的增长而增加， 人口。器质性二尖瓣返流，由于原发性瓣膜病变， 后果由其程度决定，左心室（LV）重塑 和功能障碍，左心房（LA）扩大，导致临床不良 结果。手术可以消除MR，但具有显著的风险， 适用于所有患者。因此，慢性降低MR，保护LV 血管活性治疗和LA是药物治疗的主要目标。然而，在这方面， 长期口服血管活性药物治疗MR的效果存在争议， 不确定的和最近的实践准则强调了这些知识差距 并且不推荐MR的血管活性治疗。因此， 需要有机MR。一项以死亡率-发病率为终点的大型试验是 可取但不成熟，不了解机械效应的大小 血管活性治疗。我们的试点研究表明， 二尖瓣返流的程度，左心室重塑和左心房扩大可以实现与组织 血管紧张素阻断。这些中间终点的改善， 与结果机械相关，可通过非侵入性定量 技术和形式的基础上，目前的临床试验建议。 假设：慢性组织血管紧张素阻滞治疗，使用 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（Ramiblide），称重 与安慰剂相比， 具体目标是治疗改善a）MR的程度（降低 抑制剂体积，主要终点），B）LV重构（降低LV 舒张末期容积指数，第二终点），和c）LA扩大（减少 LA体积，第三终点）与安慰剂相比。人群：患者 器质性二尖瓣返流（固有瓣膜疾病），孤立性（无其他瓣膜疾病），等同 中度或以上（返流量等于或大于30 mL/次）。方法：随机临床试验，安慰剂对照， 双盲，无交叉，1年口服强效组织 血管紧张素阻断（一组使用坎地沙坦，一组使用 拉米替尼）滴定至最大耐受剂量。审判之前， 急性研究以确定耐受性。通过以下方式测量终点： 使用多普勒超声心动图定量MR（血流容积） 3种同步方法（定量多普勒、二维 超声心动图、近端血流会聚）和 超声心动图和电子束计算机断层扫描测量LV和LA容积 测量.本单中心研究旨在招募总计135例患者。 分析将基于意向治疗，并比较 在给药后测量的左室舒张末期容积指数和左室容积 用活性药物或安慰剂治疗一年。的结果 临床试验应提供关于药物治疗的有力证据。 器质性MR患者，并确定未来的策略，以尽量减少死亡率， 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.