Hill Kevin, Sucha Ewa, Rhodes Emily, Bota Sarah, Hundemer Gregory L, Clark Edward G, Canney Mark, Harel Ziv, Wang Tzu-Fei, Carrier Marc, Wijeysundera Harindra C, Knoll Greg, Sood Manish M
Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Institute for Clinical Evaluative Sciences, Ottawa and London, Ontario, Canada.
CJC Open. 2021 Nov 13;4(3):315-323. doi: 10.1016/j.cjco.2021.11.002. eCollection 2022 Mar.
Routinely used cardiac medications, based on pharmacokinetics, are hypothesized to increase drug levels of direct oral anticoagulants (DOACs), with the potential to increase the risk of hemorrhage. We set out to compare the risk for hemorrhage following initiation of amiodarone, verapamil, or diltiazem (moderate cytochrome P450 3A4 and/or P-glycoprotein activity) vs metoprolol or amlodipine (weak or no activity), among older adults prescribed DOACs.
We conducted a population-based, retrospective cohort study of all adults (aged ≥ 66 years) on a DOAC (dabigatran, apixaban, rivaroxaban; = 295,038) who were newly prescribed amiodarone (n = 4872), verapamil (n = 1284), or diltiazem (n = 14,638), compared with metoprolol or amlodipine, from Ontario, Canada (2009-2016). The outcome was hospital admission or emergency room visit with a major hemorrhage (upper or lower gastrointestinal tract, intracranial), examined using weighted models.
A total of 1737 hemorrhage events occurred (amiodarone, 80 [1.6%] vs metoprolol 503 [2.3%]; verapamil, 32 [2.5%] vs amlodipine, 406 [1.6%]; diltiazem, 312 [2.1%] vs amlodipine, 404 [1.5%]). The weighted risk of major hemorrhage was not elevated with amiodarone, verapamil, or diltiazem initiation in DOAC users, compared to metoprolol or amlodipine, during the full follow-up period (hazard ratio [HR; 95% confidence interval]: amiodarone HR 0.77 [0.61-0.97]; verapamil HR 1.32 [0.88-1.98]; diltiazem HR 0.99 [0.85-1.15]). This finding was consistent with a broader definition of bleeding, adjusting for kidney function, by DOAC type or dosage.
Hemorrhage risk with amiodarone, verapamil, and diltiazem was similar to that with comparators, among DOAC users aged > 66 years.
基于药代动力学原理，常规使用的心脏药物被认为会提高直接口服抗凝剂（DOACs）的药物水平，从而有可能增加出血风险。我们旨在比较在使用DOACs的老年人中，开始使用胺碘酮、维拉帕米或地尔硫䓬（中等细胞色素P450 3A4和/或P-糖蛋白活性）与美托洛尔或氨氯地平（弱活性或无活性）后出血的风险。
我们对加拿大安大略省所有使用DOACs（达比加群、阿哌沙班、利伐沙班；n = 295,038）且年龄≥66岁的成年人进行了一项基于人群的回顾性队列研究，这些成年人新使用了胺碘酮（n = 4872）、维拉帕米（n = 1284）或地尔硫䓬（n = 14,638），并与美托洛尔或氨氯地平进行比较（2009 - 2016年）。结局是因大出血（上消化道或下消化道、颅内）住院或急诊就诊，使用加权模型进行分析。
共发生1737例出血事件（胺碘酮组80例[1.6%] vs美托洛尔组503例[2.3%]；维拉帕米组32例[2.5%] vs氨氯地平组406例[1.6%]；地尔硫䓬组312例[2.1%] vs氨氯地平组404例[1.5%]）。在整个随访期间，与美托洛尔或氨氯地平相比，DOACs使用者开始使用胺碘酮、维拉帕米或地尔硫䓬后，大出血的加权风险并未升高（风险比[HR；95%置信区间]：胺碘酮HR 0.77[0.61 - 0.97]；维拉帕米HR 1.32[0.88 - 1.98]；地尔硫䓬HR 0.99[0.85 - 1.15]）。这一发现与根据肾功能、DOAC类型或剂量对出血进行更宽泛定义的结果一致。
在年龄>66岁的DOACs使用者中，胺碘酮、维拉帕米和地尔硫䓬的出血风险与对照药物相似。
