The VITAL Rhythm Study

描述(申请人提供)：房颤(房颤)是最常见的心律失常，发病率呈指数级增长，尤其是在老年人中。一旦确诊，房颤与显著的发病率和死亡率有关，而目前的治疗方案与有限的长期成功率和重大风险相关。在这项应用中，我们建议在NIH资助的大型临床试验--维生素D和omega-3试验(VITAL)的背景下，评估海洋omega-3脂肪酸(840毫克二十碳五烯酸[EPA]+二十二碳六烯酸[DHA])和维生素D3(2,000IU/天胆钙化醇)对房颤发病率的益处和风险。VITAL是一项随机、双盲、安慰剂对照的2x2因素试验，专门用于评估维生素D3和海洋omega-3脂肪酸补充剂在20000名男性(50岁以上)和女性(55岁以上)中对癌症和心血管疾病的一级预防效果。基于细胞、动物和人类研究的数据，这两种研究试剂都有可能影响总体的心律失常风险和特殊的房颤风险，无论是积极的还是消极的。然而，缺乏来自随机试验的明确数据，特别是在初级预防方面。在这项申请中，我们建议进行一项辅助研究，以确定和判断房颤的结局，主要目的是测试补充omega-3脂肪酸和/或维生素D3是否影响老年人群的房颤风险，因为在老年人群中，房颤的发病率正在大幅增长。房颤事件的病例验证将包括在年度研究问卷上系统地确定医生对房颤的诊断，辅之以CMS联系，然后从门诊和住院患者的医疗记录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事件的房颤事件。作为该提案的次要目标，还将在两年的治疗和随访后，在生命临床和翻译科学中心对1000名患者进行子队列评估，以评估补充维生素D3或omega-3是否以及在多大程度上可能影响作为心律紊乱中间表型的心电参数，并在基线和两年后再次获得心电图。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死亡机制的详细信息，以探讨对心律失常死亡的治疗效果， EPA/DHA和25(OH)维生素D水平将在基线血液样本中以嵌套病例队列设计进行测量，以探索基线水平是否会改变对房颤发病率的治疗效果。综上所述，我们提出了一种及时且经济有效的策略，该策略利用重要试验中巨大的资源和基础设施投资，提供关于这些药物在房颤发生率和其他心律失常终点上的益处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的风险，那么这些药物将代表着被证明对这种日益增长的病态疾病的一级预防有效的首批疗法之一。

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.