Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD.
Division of Nephrology Geisinger Health System Danville PA.
J Am Heart Assoc. 2022 Jul 19;11(14):e025723. doi: 10.1161/JAHA.122.025723. Epub 2022 Jul 5.
Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m) ( for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.
地尔硫䓬是一种中度细胞色素 P450 3A4 同工酶/ P-糖蛋白抑制剂，通过药代动力学相互作用可能会增加直接口服抗凝剂（DOACs）的出血风险。我们评估了地尔硫䓬与 DOACs 联合使用与不同程度肾功能的房颤患者出血之间的相关性。
我们在 2010 年至 2019 年间在 Geisinger Health 中确定了 4544 名开始使用利伐沙班（n=1583）、阿哌沙班（n=2373）或达比加群（n=588）的房颤患者，平均年龄为 72 岁，估算肾小球滤过率为 70ml/min/1.73m²。在开始使用 DOAC 时，15%的患者正在服用地尔硫䓬，另有 5%的患者在随访期间开始服用地尔硫䓬。在 DOAC 使用者中，与单独使用 DOAC 相比，同时使用地尔硫䓬（地尔硫䓬联合 DOACs）与任何出血相关住院治疗的风险增加相关（未调整的风险差异为 2.4；95%CI，0.6-4.2 事件/100 人年；调整后的危险比，1.56，95%CI，1.15-2.12），以及大出血（未调整的风险差异为 1.4[95%CI，0.1-2.6 事件/100 人年]；调整后的危险比，1.84[95%CI，1.18-2.85]）。在有和没有 CKD（估算肾小球滤过率<60ml/min/1.73m²）的患者中均观察到地尔硫䓬使用与任何/主要出血风险增加（对于交互检验=0.524 和 0.629）。在 13179 名华法林使用者（阴性对照）中，同时使用地尔硫䓬与出血无关。
在房颤患者中，与 DOACs 同时使用地尔硫䓬与更高的出血风险相关，在慢性肾脏病和非慢性肾脏病亚组中均一致。对于 DOAC 使用者，只有当益处超过风险时，才应开处方同时使用地尔硫䓬，并密切监测出血迹象。
