Low drug levels and thrombotic complications in high‐risk atrial fibrillation patients treated with direct oral anticoagulants

Abstract

Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15-25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA DS -VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3-6.3 versus 3.0 (95% CI 2.9-3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA DS -VASc score. Larger studies are warranted to confirm these preliminary observations.

A level‐headed approach to measuring direct oral anticoagulants: A 2‐year retrospective analysis of DOAC levels from a tertiary UK centre

“…This inter‐individual variability is even more pronounced in real‐world studies. For example, a recent Italian study measured trough DOAC levels in 565 patients at steady state . Although the median trough levels for DOAC were similar to that reported previously, the range of levels for apixaban and dabigatran was much wider than described .…”

“…For example, a recent Italian study measured trough DOAC levels in 565 patients at steady state . Although the median trough levels for DOAC were similar to that reported previously, the range of levels for apixaban and dabigatran was much wider than described . Similarly, extreme variability in the peak levels of DOAC have been observed in an observational study of 106 patients receiving either rivaroxaban or dabigatran for VTE prophylaxis following total hip replacement .…”

Changing the Approach to Anticoagulant Therapy in Older Patients with Multimorbidity Using a Precision Medicine Approach

“…The importance of this study for our purposes is highlighted by the evidence that high DOAC inter-individual variability cannot be explained by renal function alone. The potential clinical consequences of such large variability are highlighted by a more recent study involving 565 consecutive patients with atrial fibrillation receiving DOACs [24]. The results show that thromboembolic events occurred in 10 patients (1.8%) who had baseline concentration–trough levels in the lowest class of drug levels [24].…”

“…The potential clinical consequences of such large variability are highlighted by a more recent study involving 565 consecutive patients with atrial fibrillation receiving DOACs [24]. The results show that thromboembolic events occurred in 10 patients (1.8%) who had baseline concentration–trough levels in the lowest class of drug levels [24]. The incidence of thromboembolic events among patients with DOAC concentration trough results in the lowest level class was 2.4%, while it was 0% in the remaining groups [24].…”

“…The results show that thromboembolic events occurred in 10 patients (1.8%) who had baseline concentration–trough levels in the lowest class of drug levels [24]. The incidence of thromboembolic events among patients with DOAC concentration trough results in the lowest level class was 2.4%, while it was 0% in the remaining groups [24]. The patients with thrombotic complications also had a mean CHA 2 DS 2− VASc score, a composite score to assess of the risk of thromboembolic complications, higher than that of the total patient population: 5.3 (95% confidence interval 4.3–6.3) vs. 3.0 (95% confidence interval 2.9–3.1).…”