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

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 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 Pglycoprotein (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.

Gastrointestinal Bleeding Due to NOACs Use: Exploring the Molecular Mechanisms

“…A large study by Kawano et al [46] used Japanese insurance data to consider the bleeding risk for the combination of NOACs and antihypertensive medications. Particularly, patients under those antihypertensive drugs not acting on P-gp had a reduced bleeding risk.…”

The Influence of EGCG on the Pharmacokinetics and Pharmacodynamics of Bisoprolol and a New Method for Simultaneous Determination of EGCG and Bisoprolol in Rat Plasma

“…Therefore any drugs or herbs that induce the activity of CYP3A4 and CYP2D6 can accelerate the metabolic clearance of bisoprolol and result in drug interactions. Furthermore, the absorption and excretion of bisoprolol is closely related to the activity of OATP1A2 and P-gP ( 11 ). Therefore, any concomitant drug that affects the activity of CYP3A4, CYP2D6, P-gP or OATP1A2 may lead to changes in the plasma concentration of bisoprolol, which may be the molecular basis for the pharmacokinetic interactions between other drugs or herbs and bisoprolol.…”