Biomarker guided therapies in Stage A/B Heart Failure

A/B 期心力衰竭的生物标志物引导治疗

• 批准号: 8736435
• 负责人: VIJAY NAMBI
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8736435
• 关键词: Adrenergic beta-Antagonists; Aldosterone Antagonists; American; American Heart Association; Antihypertensive Agents; Biological Assay; Biological Markers; Blinded; Blood Pressure; Blood Tests; Blood Vessels; Brain natriuretic peptide; Cardiac; Cardiology; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Caring; Classification; Clinical; Clinical Trials; Data; Demographic Factors; Development; Diabetes Mellitus; Early identification; Heart failure; High Prevalence; Hospitalization; Hypertension; Hypotension; Image; Incidence; Individual; Laboratories; Left Ventricular Hypertrophy; Measures; Medical; Modeling; Modification; Myocardial; N-terminal; Pharmaceutical Preparations; Population; Prevalence; Prevention; Prevention strategy; Randomized; Randomized Clinical Trials; Reporting; Risk; Risk Factors; Spironolactone; Staging; Staging System; Surrogate Markers; System; Testing; Troponin T; Ultrasonography; Veterans; aged; blood pressure reduction; blood pressure regulation; cardiovascular risk factor; carvedilol; college; cost; design; high risk; improved; middle age; myocardial damage; novel; open label; outcome forecast; prevent; prognostic; prospective; public health relevance; risk benefit ratio; sound; treatment as usual

DESCRIPTION (provided by applicant): The onset of clinical heart failure (HF) is associated with poor prognosis even today, and unfortunately the incidence of HF is projected to continue to increase in the coming decades. Therefore, organizations such as the American College of Cardiology (ACC) and American Heart Association (AHA) have identified the prevention of HF as a major need and therefore have commenced efforts aimed at preventing HF. Early initiatives included a new system of HF classification which identified "at risk" individuals as Stage A (those with risk factors such as hypertension and diabetes) or Stage B (those with some structural myocardial changes [for example, left ventricular hypertrophy] but without manifest HF). However, such systems of classification identified the majority (~65-75%) of a middle-aged population as Stage A or B. Recently we have shown that HF risk prediction can be improved using cardiac troponin T measured with a novel high-sensitivity assay (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Furthermore, hs-cTnT seems to identify individuals at higher risk among those with established risk factors (such as hypertension) for HF. In preliminary results, we have shown that individuals with systolic blood pressure of 120- 129 mm Hg and elevated hs-cTnT have a higher rate of incident HF than those with systolic blood pressure of 150-159 mm Hg and undetectable hs-cTnT. Therefore, we believe that by using hs-cTnT to estimate HF risk we can identify individuals in whom aggressive modification of risk factors such as high blood pressure will be associated with a favorable risk-benefit ratio. Our objective/specific aim therefore is to evaluate if treatment of selected subjects with Stage A or B HF (i.e., those with hs-cTnT >5 ng/L and an estimated 10-year HF hospitalization risk of >5%) who have reasonably well- controlled blood pressure with antihypertensive agents (carvedilol or spironolactone) will be associated with improvement of surrogate markers associated with incident HF (i.e., speckle-tracked cardiac and vascular strain). Carvedilol and spironolactone were chosen for the following reasons: a) they are not routinely used as first-line antihypertensive agents; b) beta-blockade was associated with decreases in hs-cTnT in our preliminary analysis of subjects with established HF; and c) the mechanism of actions of carvedilol and spironolactone provide a sound scientific rationale for use in prevention of HF. Using a prospective open-label blinded end point (PROBE) design, we propose to randomize 210 subjects aged >40 years with systolic blood pressure between 125-150 mm Hg, cardiac troponin T (measured with a novel high- sensitivity assay) level >5 ng/L, and 10-year HF risk >5% (estimated using a validated laboratory model including demographic factors, NT-proBNP, and hs-cTnT) to receive carvedilol (nonselective beta-blocker), spironolactone (aldosterone antagonist), or usual care for 18 months. The primary end point will be change in global longitudinal systolic myocardial strain estimated using 2D speckle tracking. Additionally, changes in vascular strain and biomarkers will be evaluated. This study will help us identify whether both or either of the medications can be further tested in large randomized clinical trials to prevent the incidence of HF.

描述（由申请人提供）：即使在今天，临床心力衰竭（HF）的发作也与不良预后相关，不幸的是，预计HF的发病率在未来几十年将继续增加。因此，诸如美国心脏病学会（ACC）和美国心脏协会（AHA）的组织已经将预防HF确定为主要需求，并且因此已经开始旨在预防HF的努力。早期的倡议包括一个新的HF分类系统，该系统将“高危”个体确定为A期（具有高血压和糖尿病等风险因素的个体）或B期（具有一些结构性心肌变化[例如，左心室肥大]但没有明显HF的个体）。然而，这种分类系统将大多数（约65-75%）中年人群确定为A期或B期。最近，我们发现，使用新型高灵敏度测定（hs-cTnT）和N-末端B型利钠肽前体（NT-proBNP）测量心肌肌钙蛋白T可以改善HF风险预测。此外，hs-cTnT似乎可以在具有已确定的HF风险因素（如高血压）的人群中识别出风险较高的个体。在初步结果中，我们已经表明，收缩压为120- 129 mm Hg和hs-cTnT升高的个体比收缩压为150-159 mm Hg和检测不到hs-cTnT的个体具有更高的HF发生率。因此，我们认为，通过使用hs-cTnT来估计HF风险，我们可以识别出对风险因素（如高血压）进行积极调整的个体，这些个体将与有利的风险-获益比相关。因此，我们的目标/具体目的是评价所选A期或B期受试者的治疗是否 HF（即，hs-cTnT >5 ng/L和估计的10年HF住院风险>5%的患者）使用抗高血压药（卡维地洛或螺内酯）合理良好地控制血压将与改善与事件HF相关的替代标志物（即，斑点追踪的心脏和血管应变）。选择卡维地洛和螺内酯的原因如下：a）它们不是常规用作一线抗高血压药物; B）在我们对确诊HF受试者的初步分析中，β受体阻滞剂与hs-cTnT降低相关; c）卡维地洛和螺内酯的作用机制为预防HF提供了合理的科学依据。采用前瞻性开放盲法终点（PROBE）设计，我们建议随机选择210名年龄>40岁的受试者，收缩压在125-150 mm Hg之间，心肌肌钙蛋白T（cTnT）在125-150 mm Hg之间，（用一种新的高灵敏度测定法测量）水平>5 ng/L，10年HF风险>5%（使用经验证的实验室模型估计，包括人口统计学因素、NT-proBNP和hs-cTnT）接受卡维地洛（非选择性β受体阻滞剂）、螺内酯（醛固酮拮抗剂）或常规护理18个月。主要终点将是使用2D斑点追踪估计的整体纵向收缩心肌应变的变化。此外，还将评价血管应变和生物标志物的变化。这项研究将帮助我们确定是否两种或任何一种药物可以在大型随机临床试验中进一步测试 以防止HF的发生。