Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Versus Warfarin in Patients with Atrial Fibrillation Using P-gp and/or CYP450-Interacting Drugs: a Systematic Review and Meta-analysis

Abstract

Purpose: Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although less drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically-interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs.Methods: Using Pubmed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs, were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method.Results: Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with Pgp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15,)) than VKAs. Conclusion:The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using Pgp/CYP3A4 inhibitors, including amiodarone.

Major bleeding in patients with atrial fibrillation treated with apixaban versus warfarin in combination with amiodarone: nationwide cohort study

“… 13 14 The findings also align with reports from systematic reviews which included data from both observational studies and subgroup analysis of direct oral anticoagulant (DOAC) trials. 16 However, in a subgroup analysis of the ARISTOTLE trial, specifically comparing apixaban versus warfarin in patients treated with concomitant amiodarone, apixaban was associated with lower rates of major bleeding (HR: 0.61; 95% CI: 0.39 to 0.96). 10 The differences in the findings from our study and the subgroup analysis from the ARISTOTLE trial might be explained by the difference in study design, the diverse definitions of major bleeding implemented by different studies and the larger sample size and the inclusion of real-life non-selected patients in the current study.…”

“… 10 In contrast to the current study, earlier studies have reported higher rates of gastrointestinal bleeding with DOACs other than apixaban compared with warfarin. 16 18 19 One possible explanation for this disparity could be the lower sensitivity associated with ICD codes for gastrointestinal bleeding (82.6%) compared with other bleeding outcomes. 14 …”

Clinical outcomes in patients with atrial fibrillation and a history of falls using non-vitamin K antagonist oral anticoagulants: A nationwide cohort study

“…Fall prevention is essential, which should include strength, balance and gait training, use of walking aids, correction of environmental hazards, correction of footwear or structural impairments of the feet, vision assessment and treatment, and supplementation of vitamin D and calcium [11] , [31] , [32] , [33] . Likewise, a thorough medication review as part of a comprehensive geriatric assessment [34] should be performed, to switch or discontinue unnecessary, interacting or contraindicated comedication (e.g., fall-risk-increasing drugs) [11] , [30] , [35] , [36] , [37] . Lastly, therapy adherence should be optimized [7] .…”

Drug-drug interactions with oral anticoagulants: information consistency assessment of three commonly used online drug interactions databases in Switzerland

“…They frequently present conflicting advice, varying severity classifications, and significant differences in sensitivity and specificity for detecting DDIs ( Abarca et al, 2006 ; Clauson et al, 2007 ; Vonbach et al, 2008 ; Sweidan et al, 2009 ; Reis and Cassiani, 2010 ; Kongsholm et al, 2015 ; Roblek et al, 2015 ). Understanding the risk associated with DDIs involving oral anticoagulants is of major importance to minimize the risk of hemorrhages or thromboses ( Ufer, 2005 ; Vazquez, 2018 ; Hanigan et al, 2020 ; Li et al, 2020 ; Gronich et al, 2021 ; Holm et al, 2021 ; Grymonprez et al, 2023 ). While several databases list DDIs associated with oral anticoagulants, none specialize exclusively in this category.…”