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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）：使用现行指南，只有四分之一的植入式心脏除颤器（ICD）用于心脏骤停（SCA）一级预防的患者在5年内接受了适当的ICD治疗。PAREPET（用正电子发射断层扫描预测心律失常事件）确定了四个独立的风险因素，可预测缺血性心肌病受试者的SCA或ICD等效（SCAE）。在优化的临界点，这些风险因素的缺乏确定了38%的队列中SCAE的风险非常低（<1%/年）。这实际上低于冠心病和轻度左心室（LV）功能障碍患者的SCA发生率（1.5-2%/年），这些患者不适合ICD。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出SCAE风险足够低的亚组，以安全地保留ICD。 PAREPET证实，用11 C-间羟麻黄碱（HED）PET定量的失神经支配心肌可以预测SCAE的时间。事后多变量分析随后确定，在接受最佳药物治疗的患者中，去神经支配心肌、LV舒张末期容积指数（LVEDVI）和B型利钠肽（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，包括梗死面积、射血分数和功能分级。然而，在提议进行一项非常大规模的临床试验来测试预测低风险受试者暂停ICD治疗的可能性之前，必须确定一些重要的细节。首先，在PAREPET中，基于回顾性分析，发现LVEDVI和BNP与去神经心肌互补。因此，这些变量的独立性和重要性需要前瞻性验证。其次，HED使用半衰期短的同位素，这对于限制辐射暴露是理想的，但需要局部的放射性。包括回旋加速器的合成。因此，临床转化将需要寿命更长的同位素可以在当地生产。最后，可能暂停ICD治疗将需要一种动态风险评估方法，以识别随后的风险变化。这些问题将通过以下具体目标来解决：在接受最佳药物治疗并接受ICD作为SCA一级预防的缺血性心肌病受试者中：具体目标#1 -前瞻性验证LVEDVI和/或BNP是否是SCAE的重要预测因子，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LMI 1195是否可以可靠地量化去神经心肌。具体目标#3 -确定心脏病住院后重复检测是否可预测SCAE风险增加。该提案将为一项前瞻性试验提供初步数据，以测试在预计SCAE风险极低的受试者中是否可以安全地停用一级预防ICD，预计心脏病住院治疗将提供重新评估风险的“警告信号”。这样的策略不仅可以改善设备成本和并发症与ICD潜在受益的一致性，而且几乎肯定是成本效益。