Comprehensive exploration of medications that affect the bleeding risk of oral anticoagulant users

Yohei Kawano, Masashi Nagata, Saeko Nakamura, Yuuki Akagi, Tatsunori Suzuki, Emi Tsukada, Mai Hoshiko, Azusa Kujirai, Satoshi Nakamatsu, Tomoki Nishikawa, Aya Enomoto, Kenichi Negishi, Shuji Shimada, Takao Aoyama, Yasunari Mano

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 30d 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.

Original languageEnglish
Pages (from-to)611-619
Number of pages9
JournalBiological and Pharmaceutical Bulletin
Volume44
Issue number5
DOIs
Publication statusPublished - May 2021

Keywords

  • Bleeding risk
  • Comprehensive analysis
  • Direct oral anticoagulant
  • Drug–drug interaction
  • Oral anticoagulant
  • Warfarin

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