Association of Enzyme-Inducing Antiseizure Drug Use With Long-term Cardiovascular Disease
Association of Enzyme-Inducing Antiseizure Drug Use With Long-term Cardiovascular Disease
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DOI：
10.1001/jamaneurol.2021.3424
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发表时间：
2021-10-04
期刊：
影响因子：
29
通讯作者：
Keezer, Mark R.
中科院分区：
文献类型：
--
作者：
Josephson, Colin B.;Wiebe, Samuel;Keezer, Mark R.
酶诱导抗癫痫药物（eiasm）被假设与心血管疾病的长期风险相关。目的量化和建模使用eiASM继发心血管疾病的推定危险。设计、环境和参与者本队列研究涵盖1990年1月至2019年3月（中位[IQR]随访，9[4-15]年）。这项研究将英国国民健康服务医院的初级保健和医院电子健康记录联系起来。在1990年1月1日以后被诊断患有癫痫的18岁或以上的人也包括在内。所有符合条件的患者均在放弃同意的情况下纳入研究。没有患者撤回同意。分析开始于2021年1月，结束于2021年8月。在成人发病（年龄b> = 18岁）癫痫诊断或在加权累积暴露模型中重复暴露后，连续接受4次eim（卡马西平、埃斯卡巴西平、奥卡西平、苯巴比妥、苯妥英、普米酮、鲁非胺或托吡酯）。主要结局和测量方法三个队列被分离，其中1个队列包括所有符合1990年以后诊断的癫痫病例定义的成年人，1个队列包括1998年以后诊断的事件病例（医院联动日期），1个队列限于65岁或以上诊断为癫痫的成年人。结果是心血管疾病的发生（缺血性心脏病或缺血性或出血性中风）。使用调整后的倾向匹配生存分析和加权累积暴露模型评估心血管疾病发生的危险。结果在10916166名成年人中，50888人（0.6%）被确定为有月经期流行病例（中位[IQR]年龄，32[19-50]岁；16584人（53%）为女性），其中31479人（62%）在1990年或之后被诊断，基线时无心血管疾病。在调整了年龄、性别、基线社会经济地位和心血管危险因素的倾向匹配Cox比例风险模型中，接受eiasm的患者发生心血管疾病的风险比为1.21 （95% CI, 1.06-1.39）。累积危险度的绝对差值在10年后偏离大于1%。对于持续暴露超过4个处方的患者，在最长25年的随访期间，与未接受eiASM的患者相比，服用eiASM的相对限定日剂量为1时，中位风险比从1.54（1.28-1.79）增加到2.38(1.52-3.56)，相对限定日剂量为2。当将分析限制在事件病例或65岁以上诊断的病例时，风险升高，但降低。结论及相关性接受eiasm的患者发生心血管疾病的风险更高。这种关联是剂量依赖性的，危害的绝对差异似乎在第一次接触后大约10年达到临床意义。持续暴露于酶诱导抗癫痫药物（eiasm）后发生心血管疾病的风险是什么？结果：在31479例患者的队列研究中，在诊断时连续服用4次eiasm的患者发生心血管疾病的风险比高于未服用eiasm的患者。当随访期间持续服用eiASM时，在最长25年的随访期间，与未服用eiASM的患者相比，每日剂量较高的患者的中位风险与心血管疾病发生率增加相关。意义本研究发现与eiasm相关的心血管疾病发生风险呈剂量依赖性。本队列研究比较了心血管疾病患者使用酶诱导抗癫痫药物和非酶诱导抗癫痫药物的相关风险。
IMPORTANCE Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.OBJECTIVE To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use.DESIGN, SETTING, AND PARTICIPANTS This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021.EXPOSURES Receipt of 4 consecutive eiASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age >= 18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model.MAIN OUTCOMES AND MEASURES Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models.RESULTS Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years' follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years.CONCLUSIONS AND RELEVANCE The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.Question What is the risk of incident cardiovascular disease following persistent exposure to enzyme-inducing antiseizure medications (eiASMs)? Findings In this cohort study of 31 479 individuals, the hazard ratio of incident cardiovascular disease was higher for those receiving 4 consecutive prescriptions for eiASMs at diagnosis compared with non-eiASMs. When consistently taking eiASMs for the duration of follow-up, the median hazard was associated with an increase in incident cardiovascular disease for those with a higher defined daily dose compared with no eiASM throughout a maximum of 25 years follow-up. Meaning This study found a dose-dependent hazard of incident cardiovascular disease associated with eiASMs.This cohort study compares the risk associated with enzyme-inducing antiseizure medications and non-enzyme-inducing antiseizure medications in individuals with cardiovascular disease.