Kawano Yohei, Nagata Masashi, Nakamura Saeko, Akagi Yuuki, Suzuki Tatsunori, Tsukada Emi, Hoshiko Mai, Kujirai Azusa, Nakamatsu Satoshi, Nishikawa Tomoki, Enomoto Aya, Negishi Kenichi, Shimada Shuji, Aoyama Takao, Mano Yasunari
Faculty of Pharmaceutical Sciences, Tokyo University of Science (TUS).
Department of Pharmacy, Medical Hospital, Tokyo Medical and Dental University (TMDU).
Biol Pharm Bull. 2021;44(5):611-619. doi: 10.1248/bpb.b20-00791.
Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41-0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33-0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84-12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.
口服抗凝剂（OACs）存在主要出血风险，其可能因合并用药而增加或降低。为探究影响OACs出血风险的药物，我们利用2005年1月至2017年6月的日本医疗保险数据库进行了一项巢式病例对照研究，纳入554例出血病例（华法林组327例；直接口服抗凝剂[DOACs]组227例）和1337例非出血对照（华法林组814例；DOACs组523例）。评估了事件/索引日期前30天内暴露于合并用药相关的主要出血风险，并使用逻辑回归分析计算调整后的比值比（aORs）。几种抗高血压药物，如氨氯地平和比索洛尔，与出血风险降低相关（华法林+氨氯地平[aOR，0.64；95%置信区间（CI）：0.41 - 0.98]，DOACs +比索洛尔[aOR，0.51；95% CI，0.33 - 0.80]）。由于高血压被认为是抗栓治疗中颅内出血的重要危险因素，抗高血压药物可能会抑制颅内出血。相比之下，广泛使用的抗高血压药物替米沙坦与出血风险增加相关[DOACs +替米沙坦（aOR，4.87；95% CI，1.84 - 12.91）]。由于替米沙坦是P - 糖蛋白（P - gp）抑制剂，阻碍了P - gp底物利伐沙班和阿哌沙班的消除，导致两种药物血药浓度升高，从而增加出血风险。总之，抗高血压药物可能会提高OACs的安全性，并且必须考虑DOACs基于药代动力学的药物相互作用。
