Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants

Abstract

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring.Direct oral anticoagulant‐specific measurements were performed at trough and peak.Patients who developed bleeding events showed higher DOAC plasma levels at peak.This study suggests the need of a more accurate DOAC dose assessment. BackgroundDirect oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C‐trough or C‐peak plasma levels and bleeding complications in patients with non‐valvular atrial fibrillation (NVAF).MethodsFive hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C‐trough and at C‐peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non‐major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1 year of follow‐up after blood sampling, were recorded. For each DOAC, interval of C‐trough and C‐peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated.ResultsTwo hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1‐[qqqdeletezzz] year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C‐peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C‐peak levels were higher in patients with bleeding than in those without bleeding.ConclusionsBleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C‐peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C‐trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Apixaban and rivaroxaban anti-Xa level utilization and associated bleeding events within an academic health system

“…Several other reports have attempted to describe the association between anti-Xa levels and clinical outcomes in a real-world setting. One study examined 411 C-peak anti-Xa levels for patients taking apixaban, rivaroxaban, and dabigatran for atrial fibrillation [ 28 ]. In a multivariate regression analysis, higher C-peak plasma concentrations were significantly associated with development of bleeding events (OR = 2.7, 95% CI = 1.3–5.4) [ 28 ].…”

“…One study examined 411 C-peak anti-Xa levels for patients taking apixaban, rivaroxaban, and dabigatran for atrial fibrillation [ 28 ]. In a multivariate regression analysis, higher C-peak plasma concentrations were significantly associated with development of bleeding events (OR = 2.7, 95% CI = 1.3–5.4) [ 28 ]. Likewise, Japanese patients taking rivaroxaban for atrial fibrillation who experienced a major ( n = 3) or non-major ( n = 19) bleed had higher peak anti-Xa levels (2.40 IU/mL vs. 1.85 IU/mL, p = 0.001) and lower baseline creatinine clearance (46.2 mL/min vs. 58.8 mL/min, p = 0.024) [ 29 ].…”

Direct oral anticoagulant plasma levels’ striking increase in severe COVID‐19 respiratory syndrome patients treated with antiviral agents: The Cremona experience

“…3 At present DOACs are administered at fixed dose without indications for dose adjustment based on laboratory testing, 3,4 even if a high inter-individual variability in drug blood levels was shown and an association between DOAC plasma levels and thrombotic and bleeding complications was observed. [5][6][7][8][9][10][11][12] Patients treated with DOACs should receive multiple drug treatment during hospitalization for severe COVID-19 respiratory syndrome that may include antiviral therapies (lopinavir/ritonavir, darunavir), tocilizumab (humanized monoclonal antibody against the interleukin-6 receptor), chloroquine or hydroxychloroquine, antibiotics, steroids, nonsteroidal anti-inflammatory drugs, bronchodilators, and immunosuppressive drugs. [13][14][15][16] As previously reported, antiviral therapies strongly interact with DOACs, because both are substrates of the P-glycoprotein and/or cytochrome P450-based metabolic pathways.…”

Drug–Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review

“…In particular, coadministration of dabigatran and rifampicin, via P-gp induction, has been documented to lower dabigatran concentration by more than 60%; coadministration of rivaroxaban with ketoconazole or ritonavir has instead been shown to raise rivaroxaban concentrations by more than 150%, via CYP3A4 and P-gp/BCRP (ABCG2) inhibition [ 6 , 7 ]. At present, there is no accepted threshold for a change in DOAC concentrations that defines clinical significance; however, the anticoagulant effect of DOACs is concentration-dependent, and significant changes in DOAC concentrations likely affects clinical outcomes [ 8 ].…”