Medications and the Risk of Sudden Cardiac Death

描述(申请人提供)：美国每年有超过40万例心脏性猝死，其中85%或更多是由室性快速性心律失常引起的。药物是一个重要的可改变的风险因素，因为许多药物都有可能引发致命的心律失常。越来越多的人怀疑，在4类广泛使用的非心血管药物中，有几种药物-氟喹诺酮和大环内酯类抗生素、抗精神病药物和抗抑郁药-是促心律失常的，因此增加了心源性猝死的风险。我们已经发表了流行病学研究，量化了较老的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估计有20%的成年人使用的较新的药物。对替代标志物的研究表明，这些药物的促心律失常作用明显不同。特定目标1检验了心源性猝死风险存在相应变化的假设。体内数据表明，将研究药物与其他抑制其代谢的常见药物同时使用，可能会显著增加药物浓度，从而增加心律失常的风险。特定目标2测试了这样的假设，即这些先验定义的药代动力学相互作用会增加心源性猝死的风险。通常使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。特定目标3测试了同时使用研究药物和这些利尿剂会增加心脏性猝死风险的假设。我们将在田纳西州扩大的医疗补助计划TennCare中进行一项回溯性队列研究。与死亡证书链接的计算机化TennCare文件提供了定义队列所需的信息，根据药物暴露和潜在的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脏性猝死病例。该队列将包括在500万人年的随访中估计有80万人和1.5万人心脏性猝死，因此将具有出色的风险估计能力。这项研究将提供数据，表明临床医生需要以将心脏性猝死的风险降至最低的方式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.