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

• 批准号: 9644068
• 负责人: John M Canty
• 金额: $ 70.72万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9644068
• 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

 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)：按照目前的指导方针，在5年内接受用于心脏骤停(SCA)一级预防的植入式心脏除颤器(ICD)的患者中，只有四分之一得到了适当的ICD治疗。PAREPET(用正电子发射断层扫描预测心律失常事件)确定了四个独立的危险因素，预测缺血性心肌病患者的SCA或ICD等效性(SCAE)。在优化的临界点上，缺乏这些危险因素的队列中38%的人患有SCAE的风险非常低(1%/年)。这实际上低于不适合ICD的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)。因此，我们的目标是前瞻性地确定这些危险因素是否能够识别出SCAE风险足够低的亚组，从而安全地保留ICD。PAREPET证实，11C-偏羟基麻黄碱(Hed)PET定量的失神经心肌可以预测SCAE的发生时间。随后的多因素分析表明，在接受最佳药物治疗的患者中，去神经心肌、左室舒张末容量指数(LVEDVI)和B型利钠肽(BNP)是唯一独立预测SCAE的因素。这些参数独立于其他正电子发射计算机断层扫描、临床和人口统计学变量，包括梗塞面积、射血分数和功能分级。然而，在提出一个非常大的临床试验来测试在预测为低风险的受试者中停止ICD治疗的可能性之前，必须确定一些重要的细节。首先，通过回顾分析发现，在PAREPET中，LVEDVI和BNP与失神经心肌是互补的。因此，这些变量的独立性和重要性需要前瞻性验证。其次，HED使用的是一种半衰期短的同位素，这是限制辐射暴露的理想选择，但需要局部 包括回旋加速器的合成。因此，临床翻译需要使用寿命更长的同位素。 可以按地区生产。最后，可能停止ICD治疗将需要一种动态风险评估的方法，以便确定随后的风险变化。这些问题的解决将有以下具体目标：在接受ICD作为SCA一级预防的最佳药物治疗的缺血性心肌病患者中：具体目标1-前瞻性验证LVEDVI和/或BNP是否为SCAE的重要预测因素，并且独立于失神经心肌。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失神经心肌。具体目标#3-确定心脏住院后的重复测试是否预示着SCAE风险的增加。这项建议将为一项前瞻性试验提供初步数据，以测试是否可以在预测为SCAE风险非常低的受试者中安全地保留一级预防ICD，预计心脏住院将提供重新评估风险的“警告信号”。这样的战略不仅将改善设备成本和并发症与ICD潜在好处的一致性，而且几乎肯定是具有成本效益的。