Medications and the Risk of Sudden Cardiac Death

描述（由申请人提供）：处方药可增加心源性猝死的风险，这是工业化国家最常见的死亡原因之一。因此，一个重要的预防策略是识别增加心脏性猝死风险的药物，并使用这些信息来指导临床实践。识别高风险药物的常用方法是研究心律失常风险的电生理标志物和尖端扭转型室性心动过速的病例报告。然而，虽然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确定几种常用处方药（包括口服红霉素、周期性抗抑郁药和抗精神病药）的重要但意外的心源性猝死风险增加。我们建议利用这种方法来研究美国超过1100万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，但证据不确定：当代抗抑郁药，美沙酮，以及同时使用抗精神病药物和可能抑制其代谢的药物。 尖端扭转型室性心动过速的电生理学研究和病例报告表明，四种广泛使用的抗抑郁药-氟西汀，西酞普兰，依他普仑和曲唑酮-可能增加心源性猝死的风险。现在最常用于治疗慢性疼痛的m-阿片激动剂美沙酮，抑制心脏复极，并可引起尖端扭转型室性心动过速，这表明它可能增加心源性猝死的风险。抗精神病药物常用的几种药物，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，我们提出了一系列的控制流行病学研究在田纳西州医疗补助有三个具体目标：1。检验以下假设：心源性猝死风险因抗抑郁药而异，而氟西汀、西酞普兰、依他普仑和曲唑酮这四种药物会增加风险。2.检验以下假设：在接受慢性疼痛治疗的患者中，美沙酮使用者的心源性猝死风险大于可比阿片类镇痛药。3.检验以下假设：与不使用代谢抑制剂相比，同时使用抗精神病药物和代谢抑制剂会增加心源性猝死的风险。这些研究将提供的新的定量数据对于优化临床实践至关重要，因为它们将使药物选择更安全，特别是对于基线心血管风险高的患者。 公共卫生相关性：我们将量化心源性猝死的风险，心源性猝死是死亡的主要原因，对于特定的当代抗抑郁药，美沙酮和抗精神病药与代谢抑制剂。由此产生的数据将使临床医生能够做出更安全的药物选择，特别是对于基线心血管风险高的患者。

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. PUBLIC HEALTH RELEVANCE: We will quantify risk of sudden cardiac death, a leading cause of death, for specific contemporary antidepressants, methadone, and antipsychotics with metabolic inhibitors. The resulting data will enable clinicians to make safer drug choices, particularly for patients with high baseline cardiovascular risk.