Article

Letter to the Editor

Ann Lab Med 2024; 44(5): 459-462

Published online September 1, 2024 https://doi.org/10.3343/alm.2024.0036

Copyright © Korean Society for Laboratory Medicine.

Association Between Plasma Anti-Factor Xa Concentrations and Large Artery Occlusion in Patients With Acute Ischemic Stroke Taking Direct Oral Anticoagulants for Non-valvular Atrial Fibrillation

Dae-Hyun Kim, M.D.1 , Byung-Cheol Kwak, M.D.2 , Byeol-A Yoon, M.D.1 , Jae-Kwan Cha, M.D.1 , Jong-Sung Park, M.D.3 , Min-Sun Kwak, M.D.4 , Kwang-Sook Woo, M.D.4 , and Jin-Yeong Han, M.D., Ph.D.4

1Department of Neurology, Dong-A University College of Medicine, Busan, Korea; 2Department of Neurology, Pohang Stroke and Spine Hospital, Pohang, Korea; 3Department of Cardiology, Dong-A University College of Medicine, Busan, Korea; 4Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, Korea

Correspondence to: Jin-Yeong Han, M.D., Ph.D.
Department of Laboratory Medicine, Dong-A University College of Medicine, 26 Daesingongwon-ro, Seo-gu, Busan 49201, Korea
E-mail: jyhan@dau.ac.kr

Received: January 21, 2024; Revised: February 27, 2024; Accepted: April 12, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dear Editor,

Atrial fibrillation (AF), the leading cause of cardioembolic stroke, accounts for 20% of all acute ischemic stroke (AIS) cases [1]. AF-related AIS is likely to be more debilitating and fatal than other ischemic stroke subtypes [2]. Current guidelines recommend using direct oral anticoagulants (DOACs) for stroke prevention in patients with AF as the first choice over vitamin K antagonists, owing to their comparable efficacies and superior safety profiles [3-5]. However, whether the correlation between anticoagulation activity at onset and large artery occlusions (LAOs) applies to patients taking DOACs remains uncertain. We investigated the impact of the plasma anti-factor Xa concentration on the occurrence of LAOs in patients with AISs receiving factor Xa inhibitors.

We prospectively enrolled consecutive patients with non-valvular AF who developed AISs while taking apixaban, edoxaban, or rivaroxaban and presented within 24 hrs of symptom onset between March 2021 and January 2023. We included Korean patients who had confirmed ingesting DOAC within the last 24 hrs. Patients were excluded if their last DOAC dose was administered over 24 hrs before the index stroke or if the timing of their last DOAC dose was uncertain. AF was diagnosed based on a 12-lead electrocardiogram or 24 hrs of Holter monitoring. Non-valvular AF was defined as AF with no history of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve reconstruction [4, 5]. LAOs were defined as occlusions at the internal carotid artery, middle cerebral arteries (M1 and M2), basilar artery, anterior cerebral artery (A1), and posterior cerebral artery (P1). The presence of LAOs supplying the vascular territory of the ischemic lesion was determined using magnetic resonance angiography.

Peripheral blood specimens were collected with 3.2% sodium citrate VACUETTE blood collection tubes (Greiner Bio-One GmbH, Frickenhausen, Germany). Blood specimens were processed within 4 hrs of phlebotomy. Upon admission, plasma concentrations of specific DOACs were measured using anti-Xa-based heparin liquid-reagent technology (LRT) chromogenic assays (Hyphen BioMed, Neuville Sur Oise, France) with a Sysmex CS-5100 analyzer (Sysmex Corp., Kobe, Japan). The DOAC activities were categorized as “low” (<100 ng/mL) or “high” (≥100 ng/mL). A plasma DOAC concentration of ≤100 ng/mL was previously recommended as a threshold for using thrombolytics to treat AIS based on theoretical and pharmacological data [6, 7]. This study was approved by the Institutional Review Board of Dong-A University Hospital, Busan, Korea (approval number DAUHIRB-21- 019). The need for informed consent was waived because we used anonymous data and the residual samples after the intended tests were completed. All statistical analyses were performed using IBM SPSS (version 28.0; IBM Corp., Armonk, NY, USA).

The median age of the 66 patients enrolled in this study was 76.0 yrs (interquartile range [IQR], 68.5−82.0), and 41 (62.1%) patients were men. The median National Institute of Health Stroke Scale (NIHSS) score was 3 (IQR, 1.0–8.5). Major artery occlusions were observed in 25 patients (37.9%). DOACs were prescribed for 34 (51.5%) and 32 (48.5%) patients for primary and secondary stroke prevention, respectively. Twenty-eight (42.4%), 28 (42.4%), and 10 patients (15.2%) received apixaban, edoxaban, and rivaroxaban, respectively.

The characteristics of the two groups were compared according to the presence of LAOs (Table 1). The median DOAC plasma concentration on admission was 91.4 ng/mL (IQR, 43.5–178.4). DOAC concentrations were low (<100 ng/mL) in 37 (56.1%) patients and high (≥100 ng/mL) in 29 (43.9%) patients. The DOAC plasma concentrations among patients with LAOs were significantly lower than among patients without LAOs (63.1 ng/mL [IQR, 26.9–105.3] versus 136.6 ng/mL [61.9–200.0]; P=0.023). Multivariable analysis revealed low DOAC plasma concentrations as an independent LAO predictor (odds ratio, 4.86 [95% CI, 1.39–17.0]; P=0.013; Table 2).

Baseline characteristics and DOAC plasma concentrations in patients with or without LAO upon admission
ParametersWithout LAO (N=41)With LAO (N=25)P
Male sex, N (%)26 (63.4)15 (60.0)0.781
Age, yrs, median (range)77 (68.5−80.0)76 (68.5-84.0)0.731
Risk factors, N (%)
Hypertension25 (61.0)15 (60.0)0.937
Diabetes13 (31.7)11 (44.0)0.314
Dyslipidemia25 (61.0)15 (60.0)0.937
Current smoking7 (17.5)6 (24.0)0.524
Previous ischemic stroke23 (56.1)9 (36.0)0.113
Previous CAD13 (31.7)2 (8.0)0.034
NIHSS, median (IQR)2 (1.0−5.0)13 (2.0−19.0)<0.001
CHA2DS2-VASc score, median (IQR)4 (3.5−5.0)4 (2.0−5.0)0.083
Reduced-dose DOAC, N (%)5 (12.2)7 (28.0)0.106
DOAC, N (%)0.703
Apixaban19 (46.3)9 (36.0)
Edoxaban16 (39.0)12 (48.0)
Rivaroxaban6 (14.6)4 (16.0)
Laboratory findings, median (IQR)
PT, secs13 (12.5−15.9)12.4 (11.8−13.4)0.043
aPTT, secs27.2 (25.1−29.8)25.2 (23.4−27.3)0.028
Creatine clearance, mL/min50.9 (34.1−75.3)56.7 (46.8−77.3)0.479
Plasma concentration of DOACs, ng/mL136.6 (61.9−200.0)63.1 (26.9−105.3)0.023
Plasma concentration of DOACs, N (%)0.006
Low DOAC concentration (<100 ng/mL)18 (43.9)19 (76.0)
High DOAC concentration (≥100 ng/mL)23 (56.1)6 (24.0)
Concomitant medication, N (%)
Anti-platelet agent3 (7.3)4 (16.0)0.412
Statins27 (65.9)13 (52.0)0.264

Abbreviations: aPTT, activated partial thromboplastin time; CAD, coronary artery disease; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74, and sex category (female); DOAC, direct oral anticoagulant; IQR, interquartile range; LAO, large artery occlusion; N, number of samples; NIHSS, National Institute of Health Stroke Scale; PT, prothrombin time.



Multivariable-regression analysis of the independent factors associated with LAO upon admission
VariablesMultivariable-regression analysis
(low plasma DOAC concentration)
Odds ratio (95% CI)P
Age, yrs1.05 (0.97−1.13)0.265
Male sex0.68 (0.18−2.52)0.565
Previous ischemic stroke1.03 (0.23−4.74)0.967
Previous CAD0.20 (0.03−1.15)0.070
CHA2DS2-VASc score, median (IQR)0.61 (033−1.15)0.132
Reduced-dose DOAC2.98 (0.58−15.3)0.190
Low plasma DOAC concentration (<100 ng/mL)4.86 (1.39−17.0)0.013

Abbreviations: CAD, coronary artery disease; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age (65–74 yrs), and sex category (female); CI, confidence interval; DOAC, direct oral anticoagulant; IQR, interquartile range; LAO, large artery occlusion.



Whether DOAC concentrations are stable or variable between and within patients remains poorly understood. Low plasma DOAC concentrations were reportedly strongly associated with stroke severity and the presence of LAOs [6, 8]; however, these reports were obtained from Western countries. The median DOAC concentrations were 20%–25% lower in Asians than in non-Asians, resulting in lower anti-factor Xa activity in Asians [9]. Despite these racial differences, we observed an association between low DOAC blood concentrations (<100 ng/mL) and LAOs in patients receiving DOACs. Thus, monitoring plasma DOAC concentrations may help identify patients prone to severe stroke.

Reduced-dose DOAC refers to the administration of a DOAC at a lower-than-recommended DOAC dose. Theoretically, the use of reduced-dosed DOACs would be associated with lower plasma DOAC concentrations and LAOs in patients with AF. However, our current findings and previous data did not show such results [6], which might reflect the small sample size and low number of plasma DOAC-concentration measurements recorded at different times post-DOAC administration.

Our findings suggest that lower DOAC plasma concentrations are associated with an increased LAO risk in patients with AIS and AF receiving DOACs.

We thank Sysmex Korea Corp. for providing anti-Xa Heparin LRT reagents.

Kim DH, Park JS, and Han JY designed the study. Kim DH, Kwak BC, Yoon BA, Cha JK, and Park JS diagnosed patients as having AF and AIS, prescribed DOACs, and enrolled patients in this study. Kwak MS, Woo KS, and Han JY were responsible for performing the laboratory measurements for the coagulation tests. Kim DH and Kwak BC participated in the statistical analysis and data curation. Kim DH, Park JS, and Han JY helped prepare the manuscript. All the authors reviewed and accepted the contents of the manuscript before submission.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number 2022R1A2C1009739; JY Han).

  1. Kim BJ, Han MK, Park TH, Park SS, Lee KB, Lee BC, et al. Current status of acute stroke management in Korea: a report on a multicenter, comprehensive acute stroke registry. Int J Stroke 2014;9:514-8.
    Pubmed CrossRef
  2. McGrath ER, Kapral MK, Fang J, Eikelboom JW, Conghaile Aó, Canavan M, et al. Association of atrial fibrillation with mortality and disability after ischemic stroke. Neurology 2013;81:825-32.
    Pubmed CrossRef
  3. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021;23:1612-76.
    Pubmed CrossRef
  4. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021;42:373-498.
    Pubmed CrossRef
  5. Chao TF, Joung B, Takahashi Y, Lim TW, Choi EK, Chan YH, et al. 2021 focused update consensus guidelines of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation: executive summary. Thromb Haemost 2022;122:20-47.
    Pubmed KoreaMed CrossRef
  6. Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, et al. Cerebral ischemia in patients on direct oral anticoagulants. Stroke 2019;50:873-9.
    Pubmed CrossRef
  7. Siller T, Chandratheva A, Bucke P, Werring DJ, Seiffge D. Acute stroke treatment in an anticoagulant patient: when is thrombolysis as option?. Curr Treat Options Neurol 2021;23:41.
    CrossRef
  8. Rizos T, Meid AD, Huppertz A, Dumschat C, Purrucker J, Foerster KI, et al. Low exposure to direct oral anticoagulants is associated with ischemic stroke and its severity. J Stroke 2022;24:88-97.
    Pubmed KoreaMed CrossRef
  9. Chao TF, Chen SA, Ruff CT, Hamershock RA, Mercuri MF, Antman EM, et al. Clinical outcomes, edoxaban concentration, and anti-factor Xa activity of Asian patients with atrial fibrillation compared with non-Asians in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019;40:1518-27.
    Pubmed CrossRef