Comprehensive Exploration of Medications That Affect the Bleeding Risk of Oral Anticoagulant Users

• Published in: Biological & pharmaceutical bulletin 2021/05/01, Vol.44(5), pp.611-619
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Anticoagulants; Antihypertensives; Bleeding; bleeding risk; Blood levels; comprehensive analysis; direct oral anticoagulant; Drugs; drug–drug interaction; Hemorrhage; oral anticoagulant; P-Glycoprotein; Pharmacokinetics; Risk factors; Warfarin
• ISSN: 0918-6158; 1347-5215
• 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.