Højlund Mikkel, Andersen Kjeld, Ernst Martin T, Correll Christoph U, Hallas Jesper
Department of Public Health, Clinical Pharmacology, Pharmacy and Environmental Medicine, University of Southern Denmark, Odense, Denmark.
Department of Psychiatry Aabenraa, Mental Health Services in the Region of Southern Denmark, Aabenraa, Denmark.
World Psychiatry. 2022 Oct;21(3):444-451. doi: 10.1002/wps.21010.
At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides, to-tal cholesterol and low-density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off-label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low-dose quetiapine compared to use of Z-drug hypnotics in a nationwide, active comparator-controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18-85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non-fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low-dose quetiapine users with 454,567 Z-drug users, followed for 890,198 person-years in intent-to-treat analysis, and 330,334 person-years in as-treated analysis. In intention-to-treat analysis, low-dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02-1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11-1.43, p<0.001). In as-treated analysis, continuous low-dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35-1.70, p<0.001), non-fatal ischemic stroke (aHR=1.37, 95% CI: 1.13-1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64-2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low-dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non-fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low-dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off-label low-dose quetiapine for sedative or hypnotic purposes should be discouraged.
在用于治疗精神分裂症或双相情感障碍的标准剂量下，喹硫平与体重增加以及甘油三酯、总胆固醇和低密度脂蛋白（LDL）胆固醇水平升高有关，而这些都是心血管疾病发病和死亡的危险因素。然而，这种药物也常用于低剂量的非适应证用药，用于抗焦虑或催眠目的，其在这些剂量下的心血管安全性尚不清楚。我们旨在通过一项全国性的、活性对照队列研究，评估与使用Z类药物催眠药相比，使用低剂量喹硫平发生主要不良心血管事件的风险。该队列包括2003年至2017年丹麦年龄在18 - 85岁之间、无缺血性中风、心肌梗死、癌症和严重精神疾病病史的这两种药物的新使用者。主要结局是发生主要不良心血管事件，定义为非致命性心肌梗死或缺血性中风，或心血管原因导致的死亡。在敏感性分析中，选择性5-羟色胺再摄取抑制剂（SSRIs）被用作替代对照。总共，我们将60566名低剂量喹硫平使用者与454567名Z类药物使用者进行了比较，在意向性分析中随访了890198人年，在实际治疗分析中随访了330334人年。在意向性分析中，低剂量喹硫平与主要不良心血管事件风险增加相关（调整后风险比，aHR = 1.13，95%置信区间：1.02 - 1.24，p = 0.014）以及心血管死亡风险增加相关（aHR = 1.26，95%置信区间：1.11 - 1.43，p < 0.001）。在实际治疗分析中，持续使用低剂量喹硫平与主要不良心血管事件风险增加相关（aHR = 1.52，95%置信区间：1.35 - 1.70，p < 0.001）、非致命性缺血性中风风险增加相关（aHR = 1.37，95%置信区间：1.13 - 1.68，p = 0.002）以及心血管死亡风险增加相关（aHR = 1.90，95%置信区间：1.64 - 2.19，p < 0.001）。主要不良心血管事件风险在女性中更高（aHR = 1.28，p = 0.02）以及在开始用药时年龄≥65岁的人群中更高（aHR = 1.24，p < 0.001）。与SSRIs相比，使用低剂量喹硫平与主要不良心血管事件风险增加相关（aHR = 1.42，p < 0.001）、非致命性缺血性中风风险增加相关（aHR = 1.27，p = 0.0028）以及心血管死亡风险增加相关（aHR = 1.72，p < 0.001）。因此，我们得出结论，使用低剂量喹硫平与主要不良心血管事件风险增加相关，尤其是在女性和老年人中。基于这些发现，我们建议不鼓励将低剂量喹硫平用于非适应证的镇静或催眠目的。
