Poor concordance among drug compendia for proposed interactions between enzyme‐inducing antiepileptic drugs and direct oral anticoagulants

Abstract

Purpose To assess concordance regarding proposed interactions between enzyme‐inducing antiepileptic drugs (EI‐AEDs) and direct oral anticoagulants (DOACs) in leading, international drug compendia. Methods We measured consistency of interaction reporting for each DOAC with a group of potent EI‐AEDs among eight provider and consumer‐focused drug compendia. Discrepant severity ranking systems were consolidated on a 0 to 4 scale. Percent agreement (PA) and Scott/Fleiss' Kappa (к) were used to quantify inter‐compendia agreement on interaction listings, with linear weighting when consolidated severity rankings were taken into account (wPA and wк, respectively). Results For dabigatran, rivaroxaban, apixaban, and edoxaban, poor inter‐compendia concordance was observed for interaction listings with EI‐AEDs, with and without accounting for severity rankings (wPA: 0.54‐0.72/wк: −0.08‐0.03, and PA 0.47‐0.79/к: −0.09‐0.09, respectively). Conversely, betrixaban was consistently listed as not interacting with EI‐AEDs in almost all assessed compendia, despite overlap in P‐glycoprotein‐based transport with other DOACs. Only 6/20 (30%) EI‐AED/DOAC interactions were listed in all eight databases, and even in these six cases, severity rankings were universally discordant. Extreme inconsistencies in interaction reporting (some compendia assigning the highest possible severity ranking, while others reported no interactions) were observed in half of the individually examined interactions (10/20). Conclusions Drug compendia are highly inconsistent in the inclusion and reported severity of interactions between EI‐AEDs and DOACs. Generation of high‐quality, real‐world evidence from large‐scale outcome studies is imperative to resolve discordance and provide clarity for clinical guidelines.

Potential Drug interactions with Drugs used for Bipolar Disorder: A Comparison of 6 Drug Interaction Database Programs

“…The overall interrater reliability was slight, and only moderate for potential DDI in the severe (contraindicated) category. Poor agreement between drug interaction database programs is well documented [58][59][60], including in studies of psychiatric and antiepileptic drugs that involve potential DDI rated major or severe [32,[61][62][63][64]. Potential DDI are challenging to define and detect [5][6][7]14], and both polypharmacy and biologics further increase the methodological complexity [65][66][67].…”

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

“…Other reports have also suggested that DOAC treatment failure is associated with low DOAC concentrations [6-9, 13, 15, 17]. However, there is poor concordance among drug compendia regarding the clinical significance of DOAC-EI-ASM interactions [36], indicating the need for real-world evidence and quality data [37].…”

A review of pharmacokinetic drug interactions between antimicrobial and antiseizure medications in children

“…Other sources of concern in the field of pharmacokinetic interactions are derived from the literature. In the case of several drugs, discrepancies in reporting and evaluating severity of interactions have been noted between different compendia [62]. Most often, inconsistences are noted between the effect of a drug on oxidative metabolism or membrane proteins, as described in the SPC and for DDIs reported in the compendia [7].…”