Executive Editor and Interim Editor in Chief, JAMA and the JAMA Network.
Executive Managing Editor, JAMA and the JAMA Network.
JAMA Neurol. 2021 Aug 1;78(8):1-3. doi: 10.1001/jamaneurol.2021.2135.
Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease.
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.
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.
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.
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.
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.
已假设酶诱导抗癫痫药物（eiASMs）与心血管疾病的长期风险有关。
量化和建模继发于 eiASM 使用的心血管疾病的潜在危害。
设计、设置和参与者：这项队列研究涵盖了 1990 年 1 月至 2019 年 3 月（中位数 [IQR] 随访时间，9 [4-15] 年）。该研究在英格兰国民保健系统医院的初级保健和医院电子健康记录之间建立了联系。在 1990 年 1 月 1 日之后被诊断患有癫痫的 18 岁或以上的人被纳入研究。所有符合条件的患者都被包括在内，且豁免同意。没有联系那些撤回同意的患者。分析于 2021 年 1 月开始，2021 年 8 月结束。
在成年后（年龄≥18 岁）诊断出癫痫后连续接受 4 种 eiASMs（卡马西平、依佐加滨、奥卡西平、苯巴比妥、苯妥英、普瑞巴林、鲁非酰胺或托吡酯）或在加权累积暴露模型中重复暴露。
孤立了三个队列，其中一个队列包含所有在 1990 年后被诊断出患有癫痫的成人（满足 1990 年后诊断出的癫痫病例的定义），另一个队列包含在 1998 年后（医院关联日期）诊断出的新发病例，另一个队列仅限于在 65 岁或以上被诊断为癫痫的成年人。结果是新发心血管疾病（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新发心血管疾病的风险。
在 10916166 名成年人中，有 50888 人（0.6%）被确定为患有时期流行病例（中位数 [IQR] 年龄，32 [19-50] 岁；16584 人[53%]为女性），其中 31479 人（62%）在 1990 年及之后被诊断出且在基线时无心血管疾病。在调整年龄、性别、基线社会经济状况和心血管危险因素的倾向匹配 Cox 比例风险模型中，接受 eiASMs 的患者新发心血管疾病的风险比为 1.21（95%CI，1.06-1.39）。累积风险的绝对差异在 10 年以上逐渐增加。对于那些持续接受 eiASMs 处方超过 4 次的患者，当 eiASM 的相对定义日剂量为 1 时，中位风险比从 1.54（1.28-1.79）增加到 2.38（1.52-3.56），当 eiASM 的相对定义日剂量为 2 时，在最长 25 年的随访期间，与未接受 eiASM 的患者相比。当将分析限制在新发病例或年龄大于 65 岁的患者时，风险会升高但会减弱。
接受 eiASMs 的患者新发心血管疾病的风险更高。这种关联是剂量依赖性的，风险的绝对差异似乎在首次暴露后约 10 年达到临床意义。
