Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non‐valvular atrial fibrillation

Abstract

BackgroundDabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated.MethodsChanges in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI.ResultsThe average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types.ConclusionsPPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered.

Proton Pump Inhibitors and Dabigatran Therapy: Impact on Gastric Bleeding and Dabigatran Plasma Levels

“…In this study, there were no significant differences between the PPIs in dabigatran trough (62. 20 showed in patients with AF on DT no significant differences in trough and peak dabigatran plasma levels among three different PPIs (lansoprazole, rabeprazole, and esomeprazole). Thus, currently available data suggest that the PPI-dabigatran interaction is rather a "class" than "drug" effect, and that there are no significant differences in this interaction among different PPIs.…”

“…Comparing those with and without PPI, dabigatran trough and peak levels were significantly lower in individuals receiving PPI. Moreover, in an open-label, randomized, two-period crossover study in Japanese AF patients, 20 the authors demonstrated (►Table 3) significantly lower dabigatran trough and peak levels in those with PPI compared with those without PPI. Therefore, PPI administrated together with DT in patients with AF significantly reduced dabigatran on treatment plasma levels in two postmarketing clinical studies 19,20 ; most probably through the effect on gastric pH.…”

“…Moreover, in an open-label, randomized, two-period crossover study in Japanese AF patients, 20 the authors demonstrated (►Table 3) significantly lower dabigatran trough and peak levels in those with PPI compared with those without PPI. Therefore, PPI administrated together with DT in patients with AF significantly reduced dabigatran on treatment plasma levels in two postmarketing clinical studies 19,20 ; most probably through the effect on gastric pH. However, there are differences in PPI pharmacokinetics (►Table 1), such as in half-life, bioavailability, and metabolism, which may translate into differences in interaction.…”

“…PPI could have a direct protective effect on gastric mucosa, 25 or the gastroprotection could be due to a reduction in dabigatran plasma levels. 19,20,22,23 Considering above-mentioned facts regarding the impact of PPI on dabigatran plasma levels, and that the incidence of bleeding events on DT correlate positively with dabigatran plasma levels, 24 it seems that the reduction of dabigatran levels in patients receiving PPI could be, at least in part, responsible for the reduction of gastric bleeds in patients on long-term DT. 12 However, further studies regarding this issue would be needed to resolve the question.…”

Clinical Guidelines for Drug-Related Peptic Ulcer, 2020 Revised Edition

“… 131 , 134 , 135 However, the interaction of PPIs and the direct thrombin inhibitor dabigatran was reported (low on-treatment level of dabigatran) from recently published studies. 136 - 138 Potential adverse events related to the long-term use of PPIs is another concern. Therefore, balancing the risk-benefit approach is still necessary before the co-prescription of anticoagulants and acid suppressants.…”