Key result
P-gp/CYP3A4 inhibitors in NOAC-treated AF are linked to ~24% higher major bleeding and mortality.
Why the study?
The clinical relevance of common pharmacokinetic interactions with NOACs often remains unclear.
Does concomitant use of P-glycoprotein and CYP3A4-interacting drugs increase the risk of adverse clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants?
Cohort (n=193,072)
Yes
Does concomitant use of P-glycoprotein and CYP3A4-interacting drugs increase the risk of adverse clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants?
Hazard Ratio: 1.24 (95% CI 1.18–1.3)
Concomitant use of P-gp/CYP3A4 inhibitors with NOACs in atrial fibrillation patients increases the risk of major bleeding and mortality, while inducers increase the risk of stroke, highlighting the critical need for medication review during NOAC initiation.
Suggests higher major bleeding with NOAC plus P-gp/CYP3A4 inhibitors; leaves open need for RCT confirmation in AF.
AIMS: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. METHODS AND RESULTS: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality. CONCLUSION: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.
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Grymonprez et al. (2023) conducted a cohort in Atrial fibrillation (n=193,072). Concomitant use of P-glycoprotein (P-gp) and CYP3A4 inhibitors or inducers vs. NOAC users without concomitant P-gp/CYP3A4 interacting drugs was evaluated on Major bleeding (aHR 1.24, 95% CI 1.18-1.30). Concomitant use of P-gp/CYP3A4 inhibitors in NOAC-treated AF patients was associated with higher major bleeding (aHR 1.24; 95% CI 1.18-1.30) and all-cause mortality risks.
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