Abstract：
BACKGROUND: Direct oral anticoagulants (DOACs) are commonly co-prescribed with amiodarone/diltiazem/verapamil, but whether there is a drug interaction between these drugs is unclear.
OBJECTIVE: The purpose of this study was to investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil.
METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011, to December 31, 2019. We used a cohort design to estimate hazard ratios for ischemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality, comparing DOACs + amiodarone/diltiazem/verapamil users and DOACs + beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window vs referent window within an individual also was conducted.
RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs + amiodarone/diltiazem/verapamil users vs DOACs + beta-blocker users in the cohort design. However, in the case-crossover design, we observed an odds ratio (OR) of 2.09 (99% confidence interval [CI] 1.37-3.18) for all-cause mortality associated with initiation of a DOAC while taking amiodarone, which was greater than that observed for DOAC monotherapy (OR 1.30; 99% CI 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem.
CONCLUSIONS: Our study showed no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem, or verapamil. Elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.
OBJECTIVE: The purpose of this study was to investigate the risk of clinical outcomes associated with concomitant use of DOACs and amiodarone/diltiazem/verapamil.
METHODS: We identified DOAC users in the Clinical Practice Research Datalink Aurum from January 1, 2011, to December 31, 2019. We used a cohort design to estimate hazard ratios for ischemic stroke, myocardial infarction, venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, other bleeding, cardiovascular mortality, and all-cause mortality, comparing DOACs + amiodarone/diltiazem/verapamil users and DOACs + beta-blocker users. A case-crossover design comparing odds of exposure to different drug initiation patterns for all outcomes in hazard window vs referent window within an individual also was conducted.
RESULTS: Of 397,459 DOAC users, we included 9075 co-prescribed amiodarone, 9612 co-prescribed diltiazem, and 2907 co-prescribed verapamil. There was no difference in risk of any outcomes between DOACs + amiodarone/diltiazem/verapamil users vs DOACs + beta-blocker users in the cohort design. However, in the case-crossover design, we observed an odds ratio (OR) of 2.09 (99% confidence interval [CI] 1.37-3.18) for all-cause mortality associated with initiation of a DOAC while taking amiodarone, which was greater than that observed for DOAC monotherapy (OR 1.30; 99% CI 1.25-1.35). Similar findings were observed for cardiovascular mortality and all-cause mortality respectively with diltiazem.
CONCLUSIONS: Our study showed no evidence of higher bleeding or cardiovascular risk associated with co-prescribed DOACs and amiodarone, diltiazem, or verapamil. Elevated risks of cardiovascular and all-cause mortality were only observed during DOAC initiation when diltiazem/amiodarone were being taken.
摘要：
背景：直接口服抗凝剂（DOAC）通常与胺碘酮/地尔硫卓/维拉帕米共同处方，但是这些药物之间是否存在药物相互作用尚不清楚。
目的：探讨联合使用DOAC和胺碘酮/地尔硫/维拉帕米的临床结局风险。
方法：我们从1/1/2011-31/12/2019确定了临床实践研究数据链Aurum中的DOAC用户。我们使用队列设计来估计缺血性卒中的风险比，心肌梗塞,静脉血栓栓塞,颅内出血,消化道出血,其他出血,心血管死亡率，和全因死亡率比较DOAC+胺碘酮/地尔硫卓/维拉帕米使用者，分别和DOACs+β受体阻滞剂使用者。还进行了病例交叉设计，比较了个体中危险窗口与参考窗口中所有结果暴露于不同药物起始模式的几率。
结果：在397,459个DOAC用户中，我们包括9075共同处方的胺碘酮，9612共同处方地尔硫，和2907共同处方的维拉帕米。DOACs+胺碘酮/地尔硫卓/维拉帕米使用者的任何结局的风险没有差异，队列设计中分别与DOACs+β受体阻滞剂使用者的比较。然而,在案例交叉设计中，我们观察到与服用胺碘酮时开始DOAC相关的全因死亡率比值比(OR)为2.09(99CI:1.37~3.18),高于DOAC单药治疗的比值比(OR:1.30;99CI:1.25~1.35).地尔硫卓的心血管死亡率和全因死亡率分别观察到类似的发现。
结论：我们的研究表明，没有证据表明与共同处方DOAC和胺碘酮相关的出血或心血管风险更高，地尔硫卓或维拉帕米分别。仅在服用地尔硫卓/胺碘酮的DOAC开始期间观察到心血管和全因死亡率的升高风险。
目的：探讨联合使用DOAC和胺碘酮/地尔硫/维拉帕米的临床结局风险。
方法：我们从1/1/2011-31/12/2019确定了临床实践研究数据链Aurum中的DOAC用户。我们使用队列设计来估计缺血性卒中的风险比，心肌梗塞,静脉血栓栓塞,颅内出血,消化道出血,其他出血,心血管死亡率，和全因死亡率比较DOAC+胺碘酮/地尔硫卓/维拉帕米使用者，分别和DOACs+β受体阻滞剂使用者。还进行了病例交叉设计，比较了个体中危险窗口与参考窗口中所有结果暴露于不同药物起始模式的几率。
结果：在397,459个DOAC用户中，我们包括9075共同处方的胺碘酮，9612共同处方地尔硫，和2907共同处方的维拉帕米。DOACs+胺碘酮/地尔硫卓/维拉帕米使用者的任何结局的风险没有差异，队列设计中分别与DOACs+β受体阻滞剂使用者的比较。然而,在案例交叉设计中，我们观察到与服用胺碘酮时开始DOAC相关的全因死亡率比值比(OR)为2.09(99CI:1.37~3.18),高于DOAC单药治疗的比值比(OR:1.30;99CI:1.25~1.35).地尔硫卓的心血管死亡率和全因死亡率分别观察到类似的发现。
结论：我们的研究表明，没有证据表明与共同处方DOAC和胺碘酮相关的出血或心血管风险更高，地尔硫卓或维拉帕米分别。仅在服用地尔硫卓/胺碘酮的DOAC开始期间观察到心血管和全因死亡率的升高风险。
