ANGIOTENSIN-II BLOCKADE IN MITRAL REGURGITATION

血管紧张素 II 阻断治疗二尖瓣反流

• 批准号: 6537825
• 负责人: MAURICE ENRIQUEZ-SARANO
• 金额: $ 61.04万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537825
• 关键词: ACE inhibitors; angiotensin II; angiotensin receptor; antihypertensive agents; computed axial tomography; drug screening /evaluation; echocardiography; heart disorder chemotherapy; heart enlargement; human subject; human therapy evaluation; intracardiac volume; mitral valve insufficiency; patient oriented research

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.

描述（申请人的逐字描述）：背景：二尖瓣 反流（MR）很常见，并且其患病率随着年龄的增长而增加 人口。器质性 MR，由于原发性瓣膜病变有严重的 后果取决于其程度，即左心室 (LV) 重塑 和功能障碍，左心房（LA）扩大，导致临床效果不佳 结果。手术可以消除 MR，但会带来显着的风险，因此不可行 适用于所有患者。因此，长期降低 MR，保护 LV 和血管活性治疗的 LA 是药物治疗的主要目标。然而， 慢性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指南强调了这些知识差距 且不推荐对MR进行血管活性治疗。于是，尝试治疗 需要有机MR。一项具有死亡率-发病率终点的大型试验是 理想但不成熟，不了解机械效应的程度 的血管活性治疗。我们的试点研究表明，持续改进 通过组织可以实现 MR、LV 重塑和 LA 扩大程度 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测量 技术并构成当前临床试验提案的基础。 假设：慢性组织血管紧张素阻断疗法使用 血管紧张素-II 受体阻滞剂（Candesartan Cilexetil）或组织 两只手臂的血管紧张素转换酶抑制剂（雷米普利），称重 与安慰剂相比，有机药物的后果持续减少 先生。具体目标是治疗改善 a) MR 程度（降低 反流量，主要终点），b) LV 重塑（降低 LV） 舒张末期容积指数，第二个终点），以及 c) LA 扩大（减少 LA 体积，第三个终点）与安慰剂相比。人群：患者 MR 器质性（内在瓣膜疾病），孤立性（无其他瓣膜疾病），同等 至或大于中等（反流量等于或大于 30 毫升/次）。方法：一项随机临床试验，安慰剂对照， 双盲、无交叉、为期 1 年的口服强效组织治疗 血管紧张素阻断（一只手臂使用坎地沙坦，另一只手臂使用 雷米普利）滴定至最大耐受剂量。审判之前有一个 急性研究以确定耐受性。终点通过以下方式测量 使用多普勒超声心动图定量 MR（反流量） 3 种同时方法的组合（定量多普勒、二维 超声心动图、近端血流汇聚）和组合 超声心动图和电子束计算机断层扫描检查 LV 和 LA 体积 测量。这项单中心研究总共招募了 135 名患者。 分析将基于治疗和比较变化的意图 返流容量、左心室舒张末期容量指数和左心室容量 使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药物治疗的有力证据 患有器质性 MR 的患者，并制定未来策略以尽量减少死亡率和 器质性MR的发病率。