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Observational Study
. 2019 Jul;17(7):1064-1072.
doi: 10.1111/jth.14457. Epub 2019 May 26.

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

Sophie Testa  1 , Cristina Legnani  2 , Emilia Antonucci  2 , Oriana Paoletti  1 , Claudia Dellanoce  1 , Benilde Cosmi  3 , Vittorio Pengo  4 , Daniela Poli  5 , Rossella Morandini  1 , Roberto Testa  6 , Armando Tripodi  7 , Gualtiero Palareti  2 ; Coordinator of START2-Register
Affiliations
Observational Study

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

Sophie Testa et al. J Thromb Haemost. 2019 Jul.

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.

Background: Direct 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).

Methods: Five 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.

Results: Two 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.

Conclusions: Bleeding 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.

Keywords: atrial fibrillation; bleeds; direct oral anticoagulant; level; peak.

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Conflict of interest statement

S. Testa has received honoraria from Bayer Pharmaceuticals, Boehringer Ingelheim, Stago, Daiichi, BMS‐Pfizer, Sobi, CSL Behring, and Roche outside the submitted work; G. Palareti has sat on advisory boards for Alfasigma, Pfizer, BMS, and Roche and has received speaker's fees from Werfen, outside the submitted work. The other authors state that they have no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the study and included patients
Figure 2
Figure 2
Distribution of dabigatran, rivaroxaban, or apixaban plasma levels measured at peak into the four classes of drug levels, determined from the limit of quantification (LOQ) to the highest concentration. Filled and empty circles identify patients with bleeding events or none, respectively
Figure 3
Figure 3
Results of normalized anticoagulant median levels assessed at C‐trough and C‐peak times for all DOAC drug patients with/without bleeding complications. To make the observations for different DOACs comparable, the results obtained in patients treated with different drugs were divided for the median value calculated for the corresponding molecule. DOAC, direct oral anticoagulant
See this image and copyright information in PMC

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