Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients

Abstract

Data are limited on the effects of drug interactions on direct-acting oral anticoagulant (DOAC) levels. We evaluated the effects of the use of interacting drugs on DOAC levels in patients with atrial fibrillation (AF). We reviewed data of AF patients tested for DOAC levels in 2013-2017. The primary outcomes were drug levels exceeding the expected steady-state range, and in the highest quartile. A multivariate analysis was performed to evaluate the correlation of treatment by the use of interacting drugs, CYP3A4 and P-glycoprotein (P-gp) inhibitors, with the primary outcomes. Overall, 147 patients underwent DOAC level measurement [dabigatran (n = 31), rivaroxaban (n = 29), apixaban (n = 87)]. Thirty-three (22.4%) had drug levels exceeding the expected range. Seventy-nine (53.7%) patients were treated with at least one interacting drug. In multivariate analysis, the concomitant use of interacting drugs was an independent predictor for drug levels exceeding the expected range (OR 3.3, 95% CI 1.20-9.05). The defined daily dose of the interacting drug correlated positively with DOAC levels (r = 0.29, P = 0.001). Co-treatment with interacting drugs was associated with extremely high levels of dabigatran, (OR 16.6, 95% CI 1.29-215.18) but not of the other DOAC examined. Concomitant use of interacting drugs is associated with high DOAC levels in patients with AF. Further investigation is warranted to establish the differences between specific DOAC, evaluate the effect on patient outcomes, and characterize the role of DOAC monitoring in this setting.

Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study

“…Our current findings support our previous study, which reported that the use of moderate CYP3A inhibitors was correlated with higher DOAC concentrations [38]. The concordance between the previous [38] and current data regarding the effect of enzyme inhibitors on DOAC concentrations may also validate the data used in the current analyses and our findings on the effect of EI-ASMs on DOAC concentrations.…”

<p>Real-World Analysis of Potential Pharmacokinetic and Pharmacodynamic Drug Interactions with Apixaban in Patients with Non-Valvular Atrial Fibrillation</p>

“…Our findings showed that 611 (48.1%) of our patients were receiving at least one interacting medication with apixaban, which is consistent with previous studies that showed that the prevalence of drug interactions with DOACs ranges between (37–78%). 11 – 15 It is important to highlight that the prevalence of drug interactions with apixaban remains high and is consistent with other studies. One explanation of this high percentage could be due to polypharmacy in patients with atrial fibrillation.…”

Drug-drug interactions with direct oral anticoagulants associated with adverse events in the real world: A systematic review

“…Although fewer in number than warfarin [ 1 , 2 , 8 ], the clinical importance of pharmacokinetic DOAC DDIs is increased as the lack of an “INR-equivalent” results in less testing and monitoring – thus such interactions are likely to remain unnoticed until a complication occurs since DOAC levels are not routinely monitored. Currently, pharmacokinetic studies, case reports, and guidance documents based on these reports in the literature propose several pharmacokinetic DDIs for DOACs demonstrated by significant alterations in plasma DOAC concentrations [ [9] , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] ] but some occur in the absence of adverse clinical events [ [19] , [20] , [21] , [22] ]. While the ability of P-gp and/or CYP3A4 modifiers to alter DOAC drug levels is well-established, given the wider therapeutic index of the DOACs relative to a narrow therapeutic index drug like warfarin, it is unknown if these pharmacokinetic alterations are sufficient to contribute to clinical adverse events.…”