Rizos Timolaos, Meid Andreas D, Huppertz Andrea, Dumschat Chris, Purrucker Jan, Foerster Kathrin I, Burhenne Jürgen, Czock David, Jenetzky Ekkehart, Ringleb Peter A, Haefeli Walter E
Department of Neurology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.
Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany.
J Stroke. 2022 Jan;24(1):88-97. doi: 10.5853/jos.2020.04952. Epub 2022 Jan 31.
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.
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.
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.
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.
在急性卒中患者中，入院时直接口服抗凝剂（DOAC）的血浆浓度只能很差地反映事件发生时的DOAC暴露情况或凝血状态。在此，我们评估了短暂性脑缺血发作（TIA）和缺血性卒中发生时的DOAC暴露和DOAC血浆浓度是否与其发生可能性相关。
前瞻性纳入连续的急性缺血性卒中或TIA的DOAC患者。通过超高效液相色谱 - 串联质谱法测量入院时的DOAC血浆浓度。个体DOAC暴露（曲线下面积）和事件发作时的DOAC浓度来自群体药代动力学分析。
在211例患者中成功建立了DOAC暴露模型（缺血性卒中74.4%，TIA 25.6%）。与已发表的值相比，63.0%的患者DOAC暴露相对较低，且他们比推荐剂量更常接受较低的DOAC剂量（比值比[OR]，2.125；95%置信区间[CI]，1.039至4.560；P = 0.044）。这些患者比TIA更易发生缺血性卒中（OR，2.411；95% CI，1.254至4.638；P = 0.008），且他们的卒中更严重（斜率，3.161；95% CI，0.741至5.58；P = 0.011）。事件发作时相对较低的DOAC浓度同样与缺血性卒中相关（OR，4.123；95% CI，1.834至9.268；P = 0.001），但与卒中严重程度无关（P = 0.272）。DOAC暴露对卒中严重程度的解释价值高于事件时的浓度。
低DOAC暴露与缺血性卒中和其严重程度密切相关。通过监测DOAC血浆浓度，可能识别出易发生缺血性卒中的患者。
