Department of Neurology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.
Department of Neurology, Military University Hospital Prague, Prague, Czech Republic.
Am J Ther. 2024;31(4):e362-e371. doi: 10.1097/MJT.0000000000001710. Epub 2024 Mar 20.
Dabigatran directly inhibits thrombin and is used in primary and secondary stroke prevention in individuals with nonvalvular atrial fibrillation. The prodrug dabigatran etexilate is absorbed by enteral P-glycoprotein (ABCB1) and then activated by hepatic and intestinal carboxylesterases (CES1) to produce active metabolites. Variations in dabigatran metabolism because of genetics may affect concentration levels and clinical outcomes.
We conducted a study to assess how polymorphisms in the CES1 (rs2244613) and ABCB1 (rs4148738) genes affect the through plasma level (c min ) of dabigatran and its correlation to clinical outcomes.
Retrospective multicentric study of consecutive patients on dabigatran therapy. Examination of CES1 rs2244613 and ABCB1 rs4148738 polymorphisms, c min 12 hours after administration, clinical follow-up (ischemic stroke, major or clinically relevant hemorrhage, myocardial infarction, other thromboembolism, and death).
A total of 432 patients received treatment for an average of 19.78 months (SD of 20.165). The sex distribution of the patients was 56.5% male, and the average age was 67.56 years (SD of 14.7). The ABCB1 variant genotype was present in 67.8% of patients, whereas 37.5% carried the CES1 polymorphism.
Compared with wild-type patients, patients with the CES1 variant had significantly lower dabigatran plasma levels (with a mean difference of 16.986; 95% confidence interval, 5.794-28.178 ng/mL, P = 0.003). We also found a significant risk of major bleeding in patients carrying the ABCB1 rs4148738 allele (hazard ratio = 1.99, confidence interval 95% 1.10 to 3.59, P = 0.024).
The CES1 variant genotype rs2244613 is closely linked with reduced c min of dabigatran. Carriers of the ABCB1 rs4148738 polymorphism exhibit a tendency toward higher plasma levels of dabigatran, which leads to a significantly increased risk of bleeding.
达比加群直接抑制凝血酶，用于非瓣膜性心房颤动患者的一级和二级卒中预防。前体药物达比加群酯通过肠 P-糖蛋白（ABCB1）吸收，然后被肝和肠羧酸酯酶（CES1）激活，产生活性代谢物。由于遗传因素导致的达比加群代谢差异可能会影响浓度水平和临床结局。
我们进行了一项研究，以评估 CES1（rs2244613）和 ABCB1（rs4148738）基因的多态性如何影响达比加群的血浆水平（c min）及其与临床结局的相关性。
对接受达比加群治疗的连续患者进行回顾性多中心研究。检测 CES1 rs2244613 和 ABCB1 rs4148738 多态性，给药后 12 小时 c min，临床随访（缺血性卒中、主要或临床相关出血、心肌梗死、其他血栓栓塞和死亡）。
共有 432 例患者接受了平均 19.78 个月（20.165 标准差）的治疗。患者的性别分布为 56.5%为男性，平均年龄为 67.56 岁（14.7 标准差）。ABCB1 变异基因型在 67.8%的患者中存在，而 37.5%的患者携带 CES1 多态性。
与野生型患者相比，携带 CES1 变异的患者达比加群的血浆水平显著降低（平均差异为 16.986；95%置信区间，5.794-28.178ng/mL，P=0.003）。我们还发现携带 ABCB1 rs4148738 等位基因的患者发生大出血的风险显著增加（风险比=1.99，95%置信区间 1.10-3.59，P=0.024）。
CES1 变异基因型 rs2244613 与达比加群 c min 降低密切相关。携带 ABCB1 rs4148738 多态性的患者达比加群的血浆水平有升高的趋势，导致出血风险显著增加。
