Biomarker guided therapies in Stage A/B Heart Failure

描述（由申请人提供）：即使在今天，临床心力衰竭（HF）的发病也与不良预后相关，不幸的是，预计未来几十年心力衰竭的发病率将继续增加。因此，美国心脏病学会（ACC）和美国心脏协会（AHA）等组织已经确定预防心衰是一项主要需求，因此已经开始努力预防心衰。早期的倡议包括一种新的心衰分类系统，将“高危”个体划分为a期（有高血压和糖尿病等危险因素的人）或B期（有一些心肌结构性改变（如左心室肥厚）但没有明显心衰的人）。然而，这样的分类系统将大多数（~65-75%）的中年人群确定为a期或b期。最近，我们已经表明，使用一种新的高灵敏度测定法（hs-cTnT）和n端前b型利钠肽（NT-proBNP）测量心脏肌钙蛋白T可以改善HF风险预测。此外，hs-cTnT似乎可以在有HF危险因素（如高血压）的人群中识别出高风险个体。在初步结果中，我们已经表明收缩压为120- 129毫米汞柱且hs-cTnT升高的个体比收缩压为150-159毫米汞柱且hs-cTnT检测不到的个体有更高的HF发生率。因此，我们相信，通过使用hs-cTnT来估计HF风险，我们可以识别出那些积极改变风险因素（如高血压）将与有利的风险-收益比相关的个体。因此，我们的目标/具体目的是评估A期或B期患者的治疗效果

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.