J Stroke.  2022 Jan;24(1):88-97. 10.5853/jos.2020.04952.

Low Exposure to Direct Oral Anticoagulants Is Associated with Ischemic Stroke and Its Severity

• Rizos T
• Meid AD
• Huppertz A
• Dumschat C
• Purrucker J
• Foerster KI
• Burhenne J
• Czock D
• Jenetzky E
• Ringleb PA
• Haefeli WE

• KMID: 2525334
• DOI: http://doi.org/10.5853/jos.2020.04952

Abstract

Background and purpose
In acute stroke patients, plasma concentrations of direct oral anticoagulants (DOAC) at hospital admission only poorly mirror DOAC exposure or the coagulation status at the time of the event. Here, we evaluated whether DOAC exposure and DOAC plasma concentration at the time of transient ischemic attacks (TIA) and ischemic strokes correlate with their likelihood of occurrence.
Methods
Prospectively, consecutive DOAC patients with acute ischemic stroke or TIA were included. Admission DOAC plasma concentrations were measured by ultraperformance liquid chromatography– tandem mass spectrometry. Individual DOAC exposure (area under the curve) and DOAC concentrations at event onset were derived from population pharmacokinetic analyses.
Results
DOAC exposure was successfully modeled in 211 patients (ischemic stroke 74.4%, TIA 25.6%). Compared to published values, 63.0% had relatively lower DOAC exposure and they more often received lower DOAC doses than recommended (odds ratio [OR], 2.125; 95% confidence interval [CI], 1.039 to 4.560; P=0.044). These patients more likely suffered ischemic strokes than TIA (OR, 2.411; 95% CI, 1.254 to 4.638; P=0.008) and their strokes were more severe (slope, 3.161; 95% CI, 0.741 to 5.58; P=0.011). Low relative DOAC concentrations at event onset were likewise associated with ischemic strokes (OR, 4.123; 95% CI, 1.834 to 9.268; P=0.001), but not to stroke severity (P=0.272). DOAC exposure had a higher explanatory value for stroke severity than concentrations at event.
Conclusions
Low DOAC exposure is strongly associated to ischemic stroke and its severity. By monitoring DOAC plasma concentrations, patients prone to ischemic stroke might be identified.

Keyword

Anticoagulants; Plasma; Tandem mass spectrometry; Ischemic stroke; Ischemic attack, transient

Figure

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  Figure 1. Model-based concentration-time profile of an exemplary patient treated with apixaban (red line). Shaded areas (purple) visualize the typical range of 95% virtual patients as predicted from the underlying population pharmacokinetic model for apixaban while accounting for available covariates of the particular patient or assuming median values [9]. Red dots represent the actual measurements in the particular patient and the red line shows the a posteriori estimates of the individual concentration-time profile based on individual pharmacokinetic parameters of the particular patient. The concentration at the time of event (+black cross) was directly derived from the profile.

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  Figure 2. Selection of the study population. DOAC, direct oral anticoagulant; TIA, transient ischemic attack; AUC, area under the curve; NA, non-adherence.

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  Figure 3. Box plots of the ratio of modeled area under the curve (AUC) and published figures corresponding to the respective doses with superimposed individual AUC values of all included patients. The broken line indicates the threshold between relatively higher and lower direct oral anticoagulant (DOAC) exposure than the published expected average. Each boxplot contains the median (horizontal line in the box), the upper quartile (75th percentile, top of box), the lower quartile (25th percentile, bottom of box). The whiskers plot the minimal and maximal DOAC exposure. Solid circles: Dot plots of categorized individual AUC results of all included patients (lower limit of quantification for ultraperformance liquid chromatography–tandem mass spectrometry 1 ng/mL). Open circles: non-adherent patients (concentration <1 ng/mL; n=19).

Reference

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