CNS Drugs ( IF 7.4 ) Pub Date : 2022-11-24 , DOI: 10.1007/s40263-022-00971-9 Bonaventure Y Ip 1 , Ho Ko 1, 2 , Grace Lh Wong 1, 3 , Terry Cf Yip 1, 3 , Louis Hs Lau 1 , Alexander Yl Lau 1 , Xinyi Leng 1 , Howan Leung 1 , Howard Hw Chan 1 , Helen Yf Chan 1 , Vincent Ct Mok 1, 2 , Yannie Oy Soo 1 , Thomas W Leung 1
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Background and Objective
Drug–drug interactions between direct oral anticoagulants (DOAC) and antiseizure medications via the cytochrome P450 (CYP) or the P-glycoprotein (P-gp) systems may lead to under-anticoagulation. The clinical relevance of these interactions is unclear. We aimed to elucidate the risk of thromboembolism with concurrent DOAC and CYP/P-gp modulating antiseizure medications.
Methods
In this propensity score-weighted population-based retrospective cohort study, we used competing risk regression analyses to determine the risks of ischemic stroke, venous thromboembolism, and death in DOAC recipients taking CYP/P-gp-modulating antiseizure medications (phenytoin, valproate, levetiracetam, carbamazepine, or phenobarbital) versus those taking CYP/P-gp-neutral antiseizure medications (pregabalin, gabapentin, or clobazam). We also performed secondary analyses for the epilepsy and atrial fibrillation subgroups.
Results
Among DOAC users, CYP/P-gp-modulating antiseizure medications were collectively associated with an increased risk of ischemic stroke (adjusted hazard ratio 1.28, 95% confidence interval 1.05–1.57, p = 0.017). In addition, phenytoin (adjusted hazard ratio 1.34, 95% confidence interval 1.07–1.68, p = 0.011) and valproate (adjusted hazard ratio 1.38, 95% confidence interval 1.10–1.74, p = 0.006) were associated with increased mortality. In the epilepsy subgroup, the risk of ischemic stroke and venous thromboembolism did not differ between CYP/P-gp-modulating and CYP/P-gp-neutral antiseizure medications.
Conclusions
Although CYP/P-gp-modulating antiseizure medications were associated with an increased risk of ischemic stroke when paired with DOAC in the primary analysis, such a phenomenon was not found among patients with epilepsy who took phenytoin, valproate, or levetiracetam with DOAC. Therefore, these antiseizure medication options among patients with epilepsy with concurrent DOAC should not be restricted solely based on their potential drug–drug interactions. Yet, the increased mortality during concurrent use of DOAC with phenytoin or valproate might call for caution.
中文翻译：
同时使用直接口服抗凝剂和抗惊厥药物的血栓栓塞风险：一项基于人群的分析
背景和目标
直接口服抗凝剂 (DOAC) 和通过细胞色素 P450 (CYP) 或 P-糖蛋白 (P-gp) 系统进行的抗癫痫药物之间的药物相互作用可能导致抗凝不足。这些相互作用的临床相关性尚不清楚。我们的目的是阐明同时使用 DOAC 和 CYP/P-gp 调节抗癫痫药物的血栓栓塞风险。
方法
在这项基于人群的倾向评分加权回顾性队列研究中，我们使用竞争风险回归分析来确定服用 CYP/P-gp 调节抗癫痫药物（苯妥英钠、丙戊酸钠、左乙拉西坦、卡马西平或苯巴比妥）与服用 CYP/P-gp 中性抗癫痫药物（普瑞巴林、加巴喷丁或氯巴占）的患者。我们还对癫痫和房颤亚组进行了二次分析。
结果
在 DOAC 使用者中，CYP/P-gp 调节抗惊厥药物与缺血性卒中风险增加相关（调整后风险比 1.28，95% 置信区间 1.05–1.57，p = 0.017）。此外，苯妥英（调整后风险比 1.34，95% 置信区间 1.07–1.68，p = 0.011）和丙戊酸钠（调整后风险比 1.38，95% 置信区间 1.10–1.74，p = 0.006）与死亡率增加相关。在癫痫亚组中，缺血性卒中和静脉血栓栓塞的风险在 CYP/P-gp 调节剂和 CYP/P-gp 中性抗癫痫药物之间没有差异。
结论
尽管在初步分析中，CYP/P-gp 调节抗惊厥药物与 DOAC 联合使用会增加缺血性卒中的风险，但在同时服用苯妥英、丙戊酸钠或左乙拉西坦和 DOAC 的癫痫患者中并未发现这种现象。因此，并发 DOAC 的癫痫患者的这些抗癫痫药物选择不应仅基于潜在的药物相互作用而受到限制。然而，DOAC 与苯妥英或丙戊酸盐同时使用期间死亡率增加可能需要谨慎。
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