Investigating the comparative cardiac safety of selective serotonin reuptake inhibitors in the hemodialysis population

项目摘要/摘要 25%至40%的血液透析患者患有抑郁症，其患病率高于一般人。 人口增加了7到12倍。这种已经很高的流行率可能还会增加。2018年，一个新的中心 Medicare&Medicaid Services(CMS)临床质量测量要求透析机构报告抑郁症 每年对CMS的筛查率和治疗计划。这种高度的关注无疑将增加 抑郁症的诊断和治疗，需要更好地了解抗抑郁药物的安全性 在血液透析人群中。选择性5-羟色胺再摄取抑制剂(SSRIs)值得特别考虑 由于它们作为一线抑郁症治疗药物的作用和导致致命心血管疾病的不同倾向 副作用。尽管37%的美国血液透析患者使用SSRI进行治疗，但人们对 SSRs的相对心脏安全性是这一脆弱人群的心脏安全性。SSRI的一个不受欢迎的属性是它们的能力 延迟心室复极，在心电图上表现为QT间期延长 (心电图)。这种传导异常创造了有利于发育的电生理环境 导致快速致命性心律失常。心电图数据显示，所有六种SSRI在治疗时都具有延长QT的能力 剂量。然而，西酞普兰和艾司匹兰最大程度地延长了QT间期，超出了美国。 食品和药物管理局的监管关注门槛。因此，使用西酞普兰或艾司匹兰治疗 (与其他SSRI相比)可能会增加心脏性猝死的风险。血液透析患者可能是唯一的易感人群 由于结构性心脏病的巨大负担，西酞普兰和埃西妥普兰引发的心律失常， 在透析治疗期间每周三次暴露在电解质变化中，并广泛使用能够 增强SSRIs延长QT的作用。具体地说，已知某些血液透析治疗条件 可能会导致QT延长，例如暴露在更宽(与更窄)的电解质血液到透析液的梯度中 放大西酞普兰和埃西妥普兰的促心律失常作用。虽然临床试验已经证明 SSRI在血液透析人群中是有效的抗抑郁药物，其小样本量排除了 充分的安全评估。利用美国肾脏数据系统链接的行政索赔数据 有了来自美国一家大型透析提供商的详细电子病历数据，我们将使用现代流行病学 研究设计和分析方法：1)调查心脏性猝死的比较1年风险 在启动SSRI的血液透析患者中，高剂量(西酞普兰或艾司匹兰)与低剂量(氟西汀， 氟伏沙明、帕罗西汀或舍曲林)QT延长潜伏期；以及2)调查突发事件的近期风险。 同时暴露于QT延长电位较高(与较低)的SSRIs和 血液透析治疗期间更宽(与更窄)的电解质从血液到透析液的梯度。这项研究将 提供有关SSRIs在血液透析中的心脏安全性的临床可操作知识 最终导致更多知情的SSRI处方。

PROJECT SUMMARY/ABSTRACT Between 25% and 40% of hemodialysis patients have depression, a prevalence that exceeds that of the general population by 7- to 12-fold. This already high prevalence is primed to increase. In 2018, a new Centers for Medicare & Medicaid Services (CMS) clinical quality measure mandated that dialysis facilities report depression screening rates and treatment plans to CMS annually. This heightened focus will undoubtedly increase depression diagnosis and treatment, necessitating a better understanding of anti-depressant medication safety in the hemodialysis population. Selective serotonin reuptake inhibitors (SSRIs) warrant special consideration due to their role as a first-line depression treatment and differential propensity to cause lethal cardiovascular side effects. Even though 37% of U.S. hemodialysis patients are treated with an SSRI, little is known about the comparative cardiac safety of SSRIs this vulnerable population. An undesirable property of SSRIs is their ability to delay ventricular repolarization, an effect that manifests as QT interval prolongation on an electrocardiogram (ECG). Such a conduction abnormality creates an electrophysiologic environment that favors the development of rapidly fatal arrhythmias. ECG data indicate that all six SSRIs have QT prolonging capabilities at therapeutic doses. However, citalopram and escitalopram prolong the QT interval to the greatest extent, beyond the U.S. Food and Drug Administration’s threshold of regulatory concern. Thus, treatment with citalopram or escitalopram (vs. other SSRIs) may increase sudden cardiac death risk. Hemodialysis patients may be uniquely susceptible to citalopram- and escitalopram-triggered arrythmias due to their tremendous burden of structural heart disease, thrice-weekly exposure to electrolyte shifts during dialysis treatments, and extensive use of medications that can enhance the QT prolonging effects of SSRIs. Specifically, certain hemodialysis treatment conditions known to induce QT prolongation, such as exposure to wider (vs. narrower) electrolyte blood-to-dialysate gradients, likely amplify citalopram’s and escitalopram’s pro-arrhythmic effects. While clinical trials have demonstrated that SSRIs are efficacious anti-depressants in the hemodialysis population, their small sample sizes precluded adequate safety assessments. Leveraging administrative claims data from the U.S. Renal Data System linked with detailed electronic medical record data from a large U.S. dialysis provider, we will use modern epidemiologic study designs and analytic methods to: 1) investigate the comparative 1-year risk of sudden cardiac death between hemodialysis patients initiating SSRIs with higher (citalopram or escitalopram) vs. lower (fluoxetine, fluvoxamine, paroxetine or sertraline) QT prolonging potential; and 2) investigate the near-term risk of sudden cardiac death associated with concurrent exposure to SSRIs with higher (vs. lower) QT prolonging potential and wider (vs. narrower) electrolyte blood-to-dialysate gradients during hemodialysis treatments. This study will provide clinically-actionable knowledge about the comparative cardiac safety of SSRIs in the hemodialysis population, ultimately leading to more informed SSRI prescribing.