Drug-Induced sudden death & ventricular arrhythmia

描述(申请人提供)：药物所致的心脏性猝死(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导致停用的药物比任何其他药物不良反应都多，并确定了100多种疑似高风险的非心脏药物。不幸的是，衡量与特定药物相关的风险的对照研究数量很少，可能是因为此类研究的复杂性以及研究这一结果所需的大量样本。即使是在“大型”数据库中的研究也缺乏足够的统计能力来进行关键的亚群分析。由于缺乏关于临床SD/VA的受控数据，因此有必要依赖非受控观察和QT间期延长等可能的风险标记物的研究。然而，不受控制的观察的效用总是受到质疑，这些假定的标记的有效性仍然未知。因此，临床医生、患者、监管机构和药品制造商在处理与药物引起的SD/VA相关的关键临床和公共卫生决策方面装备不足。这项研究将汇编一个庞大的新的药物流行病学数据库，其中包括来自五个大型医疗补助计划的医疗补助数据(与参加这两个计划的人的医疗保险数据相关联，以及与社会保障管理局死亡主文件相关联)。这将与英国普通实践研究数据库相结合。这个合并的数据库将用于进行一系列嵌套病例对照和病例交叉研究，以衡量与五种最受关注的最常用药物类别有关的全原因死亡率和SD/VA的绝对和相对比率：抗精神病药物、抗抑郁药物、阿片类止痛药、喹诺酮类抗生素和大环内酯类抗生素。将采用多阶段调查战略：第一阶段将汇编数据库，保证其质量，并复制已知的联系。阶段2a将在感兴趣的类别中比较药物。阶段2b将使用病例交叉设计来寻找控制稳定的患者因素的关联。阶段2c将检查剂量和药代动力学清除剂抑制剂的影响，药物动力学清除剂是大剂量使用的功能等价物。第三阶段将开发预测指数，以对接受高风险药物的患者亚组进行分层。这项研究将解决一个极其重要的公共卫生问题，通过提供关于死亡风险和SD/VA的迫切需要的比较数据，帮助临床和监管决策。此外，这项研究将提供临床结果数据，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使用。

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.