PAREPET II_Prediction of ARrhythnic Events with Positron Emission Tomography II

PAREPET II_正电子发射断层扫描 II 预测心律失常事件

基本信息

批准号：
10488053
负责人：
John M Canty
金额：
$ 72.1万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10488053
关键词：
Address Brain natriuretic peptide Cardiac Clinical Clinical Trials Coronary Arteriosclerosis Coronary heart disease Cyclotrons Data Defibrillators Devices EFRAC Event Exposure to Goals Guidelines Half-Life Heart Arrest Heart failure Hospitalization Image Infarction Isotopes Label Left Left Ventricular Dysfunction Medical Morbidity - disease rate Multivariate Analysis Myocardial Infarction Myocardium Norepinephrine Patients Positron-Emission Tomography Predictive Factor Primary Prevention Production Radiation exposure Research Subjects Risk Risk Assessment Risk Factors Signal Transduction Subgroup Testing Time Tracer United States National Institutes of Health Validation Ventricular End-Diastolic Volumes analog base clinical application clinical translation cohort cost cost effective improved indexing ischemic cardiomyopathy meta-hydroxyephedrine mortality patient subsets predictive modeling prospective public health relevance

项目摘要

DESCRIPTION (provided by applicant): Using current guidelines, only one-quarter of patients receiving an implantable cardiac defibrillator (ICD) for primary prevention of sudden cardiac arrest (SCA) receive appropriate ICD therapy within 5 years. PAREPET (Prediction of ARrhythmic Events with Positron Emission Tomography) identified four independent risk factors that predict SCA or ICD equivalent (SCAE) in subjects with ischemic cardiomyopathy. At optimized cut-points, the absence of these risk factors identified 38% of the cohort at very low risk of SCAE (<1%/yr). This is actually lower than the SCA rate for patients with coronary disease and mild left ventricular (LV) dysfunction (1.5-2%/yr) who are not candidates for an ICD. Thus, our goal is to prospectively determine whether these risk factors can identify a subgroup at low enough risk of SCAE to have an ICD safely withheld. PAREPET confirmed that denervated myocardium quantified with 11C-meta-hydroxyephedrine (HED) PET could predict time to SCAE. A post-hoc multivariate analysis subsequently determined that among those on optimal medical therapy, denervated myocardium, LV end-diastolic volume index (LVEDVI), and B-type natriuretic peptide (BNP) were the only independent predictors of SCAE. These parameters were independent of other PET, clinical, and demographic variables including infarct size, ejection fraction, and functional class. However, before proposing a very large clinical tria to test the potential for withholding ICD therapy among subjects predicted to be at low risk, a number of important details must be established. First, in PAREPET LVEDVI and BNP were found to be complementary to denervated myocardium based on a retrospective analysis. Thus, the independence and significance of these variables requires prospective validation. Second, HED uses a short half-life isotope that is ideal for limiting radiation exposure but requires local synthesis including a cyclotron. Clinical translation will therefore require a longer lived isotope that can be regionally produced. Finally, potentially withholding ICD therapy will require an approach for dynamic risk assessment in order to identify subsequent changes in risk. These issues will be addressed with the following Specific Aims: In subjects with ischemic cardiomyopathy on optimal medical therapy who receive an ICD for the primary prevention of SCA: Specific Aim #1 - prospectively validate whether LVEDVI and/or BNP are significant predictors of SCAE and are independent of denervated myocardium. Specific Aim #2 - determine if the 18F-labeled norepinephrine analog LMI1195 can reliably quantify denervated myocardium. Specific Aim #3 - determine whether repeat testing after a cardiac hospitalization predicts an increased risk of SCAE. This proposal will provide preliminary data for a prospective trial to test whether primary prevention ICDs can be safely withheld in subjects predicted to be at very low risk of SCAE, with cardiac hospitalizations expected provide a "warning signal" to reassess risk. Such a strategy would not only improve the alignment of device costs and complications with potential ICD benefit, but would almost certainly be cost-effective.

描述（由申请人提供）：根据现行指南，接受植入式心脏除颤器 (ICD) 进行心脏骤停 (SCA) 一级预防的患者中，只有四分之一在 5 年内接受适当的 ICD 治疗（心律失常事件预测）。正电子发射断层扫描）确定了四个独立的危险因素，可以预测缺血性心肌病受试者的 SCA 或 ICD 等效物（SCAE）。这些危险因素表明，38% 的人群发生 SCAE 的风险非常低（<1%/年），这实际上低于患有冠心病和轻度左心室 (LV) 功能障碍的患者的 SCA 发生率 (1.5-2%/年)。因此，我们的目标是前瞻性地确定这些风险因素是否可以识别 SCAE 风险足够低的亚组，以安全地保留 ICD 来确认去神经心肌。使用 11C-偏羟基麻黄碱 (HED) PET 进行量化可以预测 SCAE 的时间，随后的事后多变量分析确定，在接受最佳药物治疗的患者中，去神经心肌、左心室舒张末期容积指数 (LVEDVI) 和 B 型。利尿钠肽 (BNP) 是 SCAE 的唯一独立预测因子，这些参数独立于其他 PET、临床和人口统计学变量，包括梗塞面积、射血量。然而，在提出一项非常大的临床试验来测试预测为低风险受试者的 ICD 治疗的可能性之前，必须首先确定 PAREPET LVEDVI 和 BNP 中的一些重要细节。因此，这些变量的独立性和重要性需要前瞻性验证，其次，HED 使用短半衰期的同位素，该同位素是限制辐射暴露的理想选择，但需要局部治疗。因此，临床转化将需要寿命更长的同位素最后，可能停止 ICD 治疗将需要一种动态风险评估方法，以确定随后的风险变化，这些问题将通过以下具体目标得到解决：在接受最佳药物治疗的缺血性心肌病受试者中。接受 ICD 作为 SCA 的一级预防：具体目标 #1 - 前瞻性验证 LVEDVI 和/或 BNP 是否是 SCAE 的重要预测因素，并且与去神经心肌无关具体目标 #2 -。确定 18F 标记的去甲肾上腺素类似物 LMI1195 是否可以可靠地量化去神经心肌。具体目标 #3 - 确定心脏病住院后的重复测试是否可以预测 SCAE 风险增加。该提案将为前瞻性试验提供初步数据，以测试一级预防。对于预计 SCAE 风险极低的受试者，可以安全地停用 ICD，预计因心脏病住院治疗会提供重新评估风险的“警告信号”。不仅可以改善设备成本和并发症与潜在 ICD 益处的一致性，而且几乎肯定具有成本效益。