March 26, 2019Circulation Journal31 citationsOpen Access

Rivaroxaban or Apixaban for Non-Valvular Atrial Fibrillation　― Efficacy and Safety of Off-Label Under-Dosing According to Plasma Concentration ―

MSMichihiro Suwa IMIsao Morii MKMasaya Kino

Structured PICO

Does peak plasma concentration-guided off-label under-dosing of rivaroxaban or apixaban prevent bleeding without increasing thromboembolic events in patients with non-valvular atrial fibrillation?

Population

348 outpatients with non-valvular atrial fibrillation (NVAF) undergoing treatment with rivaroxaban or apixaban (219 men, 129 women; age range 40-89 years) at a single center in Japan.

Intervention

Off-label under-dosing of rivaroxaban (10 mg once daily) or apixaban (2.5 mg twice daily) guided by peak plasma concentration monitoring (anti-Xa chromogenic assay) 3 hours post-dose.

Comparator

Standard labeled dosing of rivaroxaban (15 mg once daily) or apixaban (5 mg twice daily), or labeled lower dosing based on standard clinical criteria.

Outcome

Bleeding events (major and non-major clinically relevant) and thromboembolic events, and their correlation with peak plasma concentration cut-offs.safety

Anticoagulation monitoring using peak plasma concentration can identify patients with non-valvular atrial fibrillation who may safely benefit from off-label under-dosing of rivaroxaban or apixaban to prevent bleeding.

Limitations

Single institution
Small sample size (≤200 per drug)
Plasma concentration measured only a few times
Lower limit of acceptable PC may be underestimated
Inter-individual variation in peak time (3h may not reflect actual peak)

Abstract

BACKGROUND: Practice-based investigations on direct oral anticoagulant (DOAC) treatment for non-valvular atrial fibrillation (NVAF) have shown that off-label under-dosing is increasingly becoming an issue. Here, we investigate the significance of drug monitoring to prevent undesirable under-dosing with DOAC. METHODS AND RESULTS: In 255 outpatients with NVAF undergoing treatment with rivaroxaban or apixaban we estimated the cut-offs for bleeding events using drug plasma concentration (PC) data 3 h after drug treatment, that is, at the peak level. Furthermore, we evaluated the appropriateness of labeled and off-label dosing implemented for 348 patients using the obtainable PC threshold. A total of 73 off-label under-dose users of rivaroxaban (37% of all users and 63% of lower dose users) had acceptable peak PC (155-400 ng/mL). Additionally, 46 off-label under-dose users of apixaban (31% of all users and 55% of lower dose users) received appropriate doses according to peak PC threshold (90-386.4 ng/mL). These off-label under-dose users reported no bleeding or thromboembolic events during follow-up. CONCLUSIONS: Anticoagulation monitoring enables personalized and appropriate off-label under-dosing in NVAF patients on rivaroxaban or apixaban through the measurement of peak PC during DOAC use.

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