Drug-Induced sudden death & ventricular arrhythmia

描述（由申请人提供）：药物诱导的心源性猝死（也称为猝死，SD）和室性心律失常（VA）在过去十年中已成为主要的公共卫生问题。近年来，SD/VA导致的停药数量超过任何其他药物不良反应，并确定了100多种疑似高风险的非心脏药物。不幸的是，测量与特定药物相关的风险的对照研究数量很少，可能是因为这些研究的复杂性和研究这一结果所需的大量样本。即使是在“大型”数据库中进行的研究，也缺乏足够的统计能力来进行关键的亚组分析。由于缺乏临床SD/VA的对照数据，因此必须依赖非对照观察结果和假定风险标志物（如QTc延长）的研究。然而，非受控观察的效用总是受到质疑，这些假定的标记物的有效性仍然未知。因此，临床医生、患者、监管机构和药品生产商都没有能力做出关于药物诱导SD/VA的关键临床和公共卫生决策。这项研究将汇编一个庞大的新药物流行病学数据库的医疗补助数据（与医疗保险数据的那些参加了这两个计划，并与社会保障管理局死亡主文件）从五个大型医疗补助计划。这将与英国全科医学研究数据库相结合。该合并数据库将用于进行一系列巢式病例对照和病例交叉研究，以测量与最受关注的五种最常用药物类别相关的全因死亡和SD/VA的绝对和相对发生率：抗精神病药、抗抑郁药、阿片类镇痛药、喹诺酮类抗生素和大环内酯类抗生素。将采用多阶段的调查策略：第一阶段将编制数据库，确保其质量，并复制已知的关联。阶段2a将比较感兴趣类别中的药物。阶段2b将使用病例交叉设计来寻找控制稳定患者因素的关联。阶段2c将检查剂量和药代动力学清除抑制剂的影响，高剂量使用的功能等效物。第3阶段将开发预测指数，对接受高风险药物的患者亚组进行分层。本研究将解决一个极其重要的公共卫生问题，通过提供急需的死亡风险和SD/VA的比较数据来帮助临床和监管决策。此外，本研究将提供临床结局数据，有助于阐明广泛使用的标志物与临床风险之间的关系。最后，该项目将创建一个有价值的和持久的药物流行病学数据资源，可以在未来的药物安全性研究中发挥作用。

DESCRIPTION (provided by applicant): Drug-induced sudden cardiac death (also called sudden death, SD) and ventricular arrhythmia (VA) have arisen as major public health concerns in the last decade. SD/VA has resulted in the withdrawal of more drugs in recent years than any other adverse drug reaction, and the identification of over 100 non-cardiac drugs as suspected of being high-risk. Unfortunately, controlled studies measuring the risks associated with specific drugs are very few in number, presumably because of the complexity of such studies and the massive sample sizes needed to study this outcome. Even studies in "large" databases have lacked adequate statistical power for crucial subgroup analyses. This lack of controlled data on clinical SD/VA has necessitated reliance on uncontrolled observations and on studies of putative markers of risk such as QTc prolongation. However, the utility of uncontrolled observations is always subject to question, and the validity of these putative markers remains unknown. As a result, clinicians, patients, regulators, and drug manufacturers are ill-equipped to address the critical clinical and public health decisions concerning drug-induced SD/VA. This study will compile a massive new pharmacoepidemiologic database of Medicaid data (linked with Medicare data for those enrolled in both programs, and with the Social Security Administration Death Masterfile) from five large Medicaid programs. This will be combined with the UK General Practice Research Database. This combined database will be used to conduct a series of nested case-control and case-crossover studies to measure the absolute and relative rate of all-cause death and SD/VA associated with five of the most commonly used drug classes of greatest concern: antipsychotics, antidepressants, opioid analgesics, quinolone antibiotics, and macrolide antibiotics. A multi-stage investigative strategy will be used: Stage 1 will compile the database, assure its quality, and reproduce known associations. Stage 2a will compare drugs among the classes of interest. Stage 2b will use the case-crossover design to look for associations controlling for stable patient factors. Stage 2c will examine the effect of dose and inhibitors of pharmacokinetic clearance, the functional equivalent of high-dose use. Stage 3 will develop predictive indices to stratify patient subgroups receiving high-risk drugs. This study will address an extremely important public health concern, aiding clinical and regulatory decision making by providing critically needed comparative data on the risk of death and SD/VA. In addition, this study will provide clinical outcome data that will help to elucidate the relationship between widely used markers and clinical risk. Finally, this project will create a valuable and lasting pharmacoepidemiologic data resource that can be brought to bear in future drug safety studies.