Medications and the Risk of Sudden Cardiac Death

描述(由申请人提供)：处方药会增加心源性猝死的风险，这是工业化国家最常见的单一死亡原因之一。因此，预防的一个重要策略是识别增加心源性猝死风险的药物，并利用这些信息指导临床实践。识别高危药物的主流方法是研究心律失常风险的电生理标记物和尖端扭曲症的病例报告。然而，尽管这些方法可以识别极端风险，但它们往往是不确定的。我们利用田纳西州医疗补助自动化数据库来识别几种常用处方药的重要但意想不到的心脏性猝死风险增加，包括口服红霉素、环状抗抑郁药和抗精神病药物。我们建议利用这种方法来研究美国1100多万患者服用的其他药物，这些药物有强烈的信号表明心脏性猝死的风险增加，但没有确凿证据：当代抗抑郁药、美沙酮，以及与可能抑制其代谢的药物同时使用的抗精神病药物。电生理学研究和尖端扭曲症的病例报告表明，四种广泛使用的特定抗抑郁药--氟西汀、西酞普兰、艾司匹兰和曲唑酮--可能会增加心源性猝死的风险。M-阿片激动剂美沙酮现在最常用于慢性疼痛，它会延长心脏复极，并可能导致尖端扭矩，这表明它可能会增加心脏性猝死的风险。几种常用的抗精神病药物，如氟西汀和环丙沙星，明显抑制抗精神病药物的代谢，这可能会增加抗精神病药物的有效剂量，从而增加心源性猝死的风险。为了更好地确定这些广泛使用的药物的心脏风险，我们在田纳西州医疗补助计划中提出了一系列受控流行病学研究，目的有三：1.检验以下假设：个别抗抑郁药的心脏性猝死风险不同，以及四种药物--氟西汀、西酞普兰、艾司匹兰和曲唑酮--增加风险。2.检验这样一种假设，即在接受慢性疼痛治疗的患者中，美沙酮使用者发生心脏性猝死的风险高于类似的阿片类止痛药。3.与没有代谢抑制剂的抗精神病药物同时使用会增加心源性猝死的风险，这一假设得到了验证。这些研究将提供的新的量化数据对最佳临床实践至关重要，因为它们将使药物选择更加安全，特别是对于具有高基线心血管风险的患者。

DESCRIPTION (provided by applicant): Prescribed medications can increase the risk of sudden cardiac death, one of the single most common causes of death in industrialized countries. Thus, an important strategy for prevention is identifying medications that increase the risk of sudden cardiac death and using this information to guide clinical practice. The prevailing approach to identification of high-risk medications has been study of electrophysiologic markers of arrhythmia risk and case reports of torsade de pointes. However, while these methods can identify extreme risks, they often are inconclusive. We have utilized the Tennessee Medicaid automated database to identify important, yet unexpected, increased risks of sudden cardiac death for several commonly prescribed medications, including oral erythromycin, cyclic antidepressants, and antipsychotics. We propose to utilize this methodology to study other medications taken by more than 11 million patients in the U.S. with a strong signal suggesting increased risk for sudden cardiac death, but inconclusive evidence: contemporary antidepressants, methadone, and concurrent use of antipsychotics with drugs likely to inhibit their metabolism. Electrophysiologic studies and case reports of torsade de pointes suggest four specific widely used antidepressants--fluoxetine, citalopram, escitalopram, and trazodone--may increase risk of sudden cardiac death. The m-opioid agonist methadone, now most commonly used for chronic pain, prolongs cardiac repolarization and can cause torsade de pointes, suggesting it may increase the risk of sudden cardiac death. Several medications commonly prescribed with antipsychotics, such as fluoxetine and ciprofloxacin, markedly inhibit antipsychotic metabolism, which may increase antipsychotic effective dose and thus the risk of sudden cardiac death. To better define the cardiac risks of these widely used drugs, we propose a series of controlled epidemiologic studies in Tennessee Medicaid with three specific aims: 1. Test the hypothesis that sudden cardiac death risk varies for individual antidepressants and that four drugs--fluoxetine, citalopram, escitalopram, and trazodone--increase risk. 2. Test the hypothesis that in patients treated for chronic pain, the risk of sudden cardiac death in methadone users is greater than that for comparable opioid analgesics. 3. Test the hypothesis that concurrent antipsychotic use with strong inhibitors of their metabolism increases the risk of sudden cardiac death relative to such use without metabolic inhibitors. The novel quantitative data these studies will provide are critical for optimal clinical practice, as they will enable safer drug choices, particularly for patients with high baseline cardiovascular risk.