The VITAL Rhythm Study

描述（由申请人提供）：房颤（AF）是最常见的心律失常，其发病率呈指数级增长，尤其是在老年人中。一旦确定，AF与显著的发病率和死亡率相关，目前的治疗选择与有限的长期成功率和显著风险相关。在本申请中，我们建议在NIH资助的大规模临床试验Vitamin D and OmegA-3 TriaL（VITAL）中评估海洋omega-3脂肪酸（840 mg二十碳五烯酸[EPA] +二十二碳六烯酸[DHA]）和维生素D3（2，000 IU/天胆钙化醇）对AF发病率的益处和风险平衡。VITAL是一项随机、双盲、安慰剂对照、2x2析因试验，专门设计用于评估维生素D3和海洋omega-3脂肪酸补充剂在20，000名男性（50岁以上）和女性（55岁以上）中癌症和心血管疾病一级预防的疗效。基于细胞、动物和人体研究的数据，两种研究药物都有可能影响一般的药物风险，特别是AF风险，无论是正面还是负面。然而，缺乏来自随机试验的确切数据，特别是在初级预防方面。在本申请中，我们提出了一项辅助研究，以确定和裁定AF结局，主要目的是测试补充omega-3脂肪酸和/或维生素D3是否会影响AF发病率大幅增长的老年人群的AF风险。房颤事件的病例确认将涉及系统性确定医生对年度研究问卷的房颤诊断，并辅以CMS链接，然后从门诊和住院病历中收集详细的诊断信息。由心脏病专家组成的终点委员会将根据病历审查确认新发AF事件。作为该提案的次要目的，还将在VITAL临床和转化科学中心评估的1000名患者的子队列中获得基线心电图，并在治疗和随访两年后再次获得心电图，以评估维生素D3或omega-3补充剂是否以及在多大程度上可能影响心电图参数，这些参数可作为心脏节律疾病的中间表型。为了解决第三个目标，还将在整个队列中收集关于死亡时间和机制的详细信息，以探索对药物性死亡的治疗效果， 和EPA/DHA沿着25（OH）维生素D水平将在巢式病例队列设计中在基线血液样本中测量，以探索基线水平是否改变对AF发病率的治疗效果。总之，我们提出了一种及时且具有成本效益的策略，该策略利用VITAL试验中资源和基础设施的巨大投资，提供了这些药物对AF发生率以及其他药物终点的获益和风险总和的急需数据。如果任何一种药物都能显著降低房颤风险，那么这些药物将成为首批被证明对这种日益严重的疾病的一级预防有效的疗法之一。

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common heart rhythm disturbance and the incidence is growing exponentially especially among older individuals. Once established, AF is associated with significant morbidity and mortality, and current treatment options are associated with limited long term success rates and significant risks. In this application, we propose to evaluate the balance of benefits and risks of marine omega-3 fatty acid (840 mg eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and vitamin D3 (2,000 IU/day cholecalciferol) on AF incidence in the setting of an NIH-funded large-scale clinical trial, the Vitamin D and OmegA-3 TriaL (VITAL). VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial specifically designed to evaluate the efficacy of vitamin D3 and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease among 20,000 men (aged 50+ years) and women (aged 55+ years). Based upon data in cellular, animal, and human studies, both of the study agents have the potential to influence arrhythmic risk in general and AF risk specifically, both positively and negatively. However, definitive data from randomized trials are lacking, particularly with respect to primary prevention. In this application, we propose an ancillary study to ascertain and adjudicate AF outcomes for the primary aim of testing whether omega-3 fatty acid and/or vitamin D3 supplementation influences AF risk in an older population, where the incidence of AF is growing substantially. Case validation of incident AF will involve systematic ascertainment of physician diagnoses of AF on annual study questionnaires supplemented by CMS linkage followed by collection of detailed diagnostic information from outpatient and inpatient medical records. An endpoint committee composed of cardiologists will confirm incident AF events based on medical record review. As a secondary aim of the proposal, electrocardiograms will also be obtained at baseline and again after two years of treatment and follow-up among a sub-cohort of 1000 patients evaluated at the VITAL Clinical and Translational Science Center to assess whether and to what extent vitamin D3 or omega-3 supplementation might impact electrocardiographic parameters, which could serve as intermediate phenotypes for heart rhythm disorders. To address tertiary aims, detailed information on timing and mechanism of death will also be collected in the entire cohort to explore treatment effects on arrhythmic death, and EPA/DHA along with 25(OH) vitamin D levels will be measured in baseline blood samples in a nested case-cohort design to explore if baseline levels modify treatment effects on AF incidence. In summary, we propose a timely and cost-effective strategy that takes advantage of the enormous investment of resources and infrastructure in the VITAL trial to provide much needed data on the summation of benefits and risks of these agents on AF incidence as well as other arrhythmic endpoints. If either agent significantly lowers AF risk, then these agents would represent one of the first therapies proven effective for the primary prevention of this growing morbid disease.