Medications and the Risk of Sudden Cardiac Death

描述（由申请人提供）：美国每年有超过40万例心脏性猝死，其中85%或更多是由室性心动过速引起的。药物是一个重要的可改变的危险因素，因为许多药物具有可引起致命性心律失常的作用。越来越多的人怀疑，在4类广泛使用的非心血管药物中，氟喹诺酮类和大环内酯类抗生素、抗精神病药和抗抑郁药会导致心律失常，从而增加心源性猝死的风险。我们发表的流行病学研究量化了老年抗精神病药物和抗抑郁药物以及口服红霉素所带来的风险。目前的项目将把这些研究扩展到美国大约20%的成年人使用的新药物，对替代标志物的研究表明，这些药物的促心律失常作用差异很大。特异性目的1检验了心源性猝死风险存在相应变异的假设。体内数据表明，研究药物与其他抑制其代谢的常用药物同时使用可显着增加药物浓度，从而增加心律失常的风险。特异性目标2验证了这些药代动力学相互作用（先验定义）增加心源性猝死风险的假设。常用的耗钾利尿剂引起的低钾血症可能会放大药物的促心律失常作用。特异性目的3验证了同时使用研究药物和这些利尿剂会增加心源性猝死风险的假设。我们将对田纳西州扩大的医疗补助计划TennCare进行回顾性队列研究。计算机化的TennCare文件与死亡证明相关联，提供必要的信息来定义队列，根据药物暴露和潜在混杂因素对随访进行分类，并使用我们开发的经过验证的计算机病例定义来识别心源性猝死病例。在500万人年的随访中，该队列将包括约80万人，其中15,000人死于心源性猝死，因此具有极好的风险估计能力。这项研究将为临床医生提供所需的数据，以最大限度地降低心源性猝死的风险，开出这些广泛使用的药物。

DESCRIPTION (provided by applicant): There are more than 400,000 sudden cardiac deaths annually in the U.S, of which 85% or more are caused by ventricular tachyarrhythmias. Medications are an important modifiable risk factor because many have effects that can provoke lethal arrhythmias. There is increasing suspicion that several drugs in 4 widely used classes of non-cardiovascular medications-fluoroquinolone and macrolide antibiotics, antipsychotics, and antidepressants- are pro-arrhythmic and thus increase the risk of sudden cardiac death. We have published epidemiologic studies that quantified the risk conferred by older antipsychotics and antidepressants as well as oral erythromycin. The current project will extend these studies to newer medications that are used by an estimated 20% of adults in the U.S. Studies of surrogate markers suggest that the pro-arrhythmic effects of these drugs vary markedly. Specific aim 1 tests the hypothesis that there is corresponding variation in risk of sudden cardiac death. In vivo data suggest that concurrent use of study drugs with other common medications that inhibit their metabolism could markedly increase drug concentrations, and thus risk of arrhythmias. Specific aim 2 tests the hypothesis that these pharmacokinetic interactions, defined a priori, increase risk of sudden cardiac death. The hypokalemia caused by the commonly used potassium-wasting diuretics may amplify the pro-arrhythmic effects of medications. Specific aim 3 tests the hypothesis that concurrent use of study drugs and these diuretics increases risk of sudden cardiac death. We will conduct a retrospective cohort study in TennCare, Tennessee's expanded Medicaid program. Computerized TennCare files, linked with death certificates, provide the information necessary to define the cohort, classify followup according to medication exposure and potential confounders, and identify cases of sudden cardiac death using a validated computer case definition we have developed. The cohort will include an estimated 800,000 persons with 15,000 sudden cardiac deaths during 5,000,000 person years of followup and thus will have excellent power for risk estimates. The study will provide data that clinicians need to prescribe these widely used medications in a way that minimizes the risk of sudden cardiac death.