Thrombotic events associated with low baseline direct oral anticoagulant levels in atrial fibrillation: the MAS study

Abstract

Although effective and safe, treatment with direct oral anticoagulants (DOAC) in atrial fibrillation (AF) is still associated with thrombotic complications. Whether the measurement of DOAC levels may improve treatment efficacy is an open issue. We carried out the observational, prospective, multicenter Measure and See (MAS) study. Blood was collected 15 to 30 days after starting DOAC treatment in patients with AF who were followed-up for 1 year. Plasma samples were centralized for DOAC level measurement. Patients' DOAC levels were converted into drug/dosage standardized values to allow a pooled analysis in a time-dependent, competitive-risk model. The measured values were transformed into standardized values (representing the distance of each value from the overall mean) by subtracting the DOAC-specific mean value from the original values and dividing by the standard deviation. Trough and peak DOAC levels were assessed in 1657 and 1303 patients, respectively. In total, 21 thrombotic complications were recorded during 1606 years of follow-up (incidence of 1.31% of patients per year). Of 21 thrombotic events, 17 occurred in patients whose standardized activity levels were below the mean of each DOAC (0); the incidence was the highest (4.82% of patients per year) in patients whose standardized values were in the lowest class (-1.00 or less). Early measurement of DOAC levels in patients with AF allowed us to identify most of the patients who, having low baseline DOAC levels, subsequently developed thrombotic complications. Further studies are warranted to assess whether thrombotic complications may be reduced by measuring baseline DOAC levels and modifying treatment when indicated. This trial was registered at www.ClinicalTrials.gov as #NCT03803579.

Graphical abstract

Figure 1.

Flowchart of the study. NVAF, nonvalvular atrial fibrillation; VKA, vitamin K antagonist.

Figure 2.

Measured C-trough DOAC levels assessed at steady-state in atrial fibrillation patients who experienced thrombotic outcomes within 1 year follow-up. Blue dots represent the values and dotted lines represent the mean values of each drug.

Figure 3.

Cumulative event rates for thrombotic outcomes. The Kaplan-Meier cumulative event rates for the thrombotic outcomes in patients with DOAC levels in the standardized class of −1.00 or less (continuous line) and in patients with DOAC levels in the standardized classes of more than −1.00 (dotted line) at C-trough. HR, hazard ratio.