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Insufficient Warfarin Therapy Is Associated With Higher Severity of Stroke Than No Anticoagulation in Patients With Atrial Fibrillation and Acute Anterior-Circulation Stroke

Background: Insufficient anticoagulant intensity on admission is common in stroke patients with atrial fibrillation (AF) on vitamin K antagonist (VKA) therapy. Nevertheless, the effects of VKA under-treatment on stroke severity or arterial occlusion are not well known. The aim of the present study was to investigate the relationship between insufficient VKA therapy and stroke severity, or the site of arterial occlusion in patients with acute ischemic stroke (AIS) and AF. Methods and Results: From March 2011 through July 2016, 446 consecutive patients with AF and AIS were recruited. Of the 446 patients, 364 (167 women; median age, 79 years; IQR, 71–86 years) with anterior-circulation stroke were assessed to investigate the effects of insufficient VKA. Of these, 281 were on no anticoagulant, 53 were undertreated with a VKA, and 30 were sufficiently treated with VKA on admission (PT-INR ≥ 2.0 for patients <70 years and PT-INR ≥ 1.6 for ≥ 70 years old). On multivariate analysis, insufficient VKA was independently associated with severe stroke (i.e., initial NIHSS score ≥ 10; OR, 2.70, P=0.022) and higher prevalence of proximal artery occlusion (OR, 1.91; P=0.039) compared with no anticoagulant therapy. Conclusions: Insufficient VKA therapy on admission was associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke compared with no anticoagulant medication.

stroke. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Routine blood biochemistry was analyzed on admission.

Neuroimaging
Magnetic resonance imaging (MRI) including diffusionweighted imaging (DWI) and time-of-flight MR angiography (MRA) were performed on admission using a commercially available echo planar instrument operating at 1.5 T (Echelon Oval, Hitachi Medical Systems, Tokyo, Japan). DWI was obtained using the following parameters: TR/TE, 6,000/65 ms; b-values, 0 and 1,000 s/mm 2 ; field of view, 24 cm; acquisition matrix, 128×128; and slice thickness, 4.5 mm, with a 2.5-mm intersection gap. The site of arterial occlusion was determined on initial MRA. Major artery occlusion was defined as internal carotid artery (ICA), middle cerebral artery (MCA) horizontal segment (M1), or basilar artery occlusion. When analyzing patients with anterior-circulation stroke, the site of arterial occlusion was divided into 4 categories based on initial MRA: at the ICA; at the M1; at the MCA insular segment (M2); and occlusion at another site or no identifiable occlusion. Although almost all (97%) of the patients were evaluated on MRI on admission, patients with a contraindication to MRI were evaluated on computed tomography angiography or conventional angiography. with prior insufficient VKA therapy and those with no anticoagulation or sufficient VKA therapy, patients pretreated with direct oral anticoagulants (DOAC) were excluded from the present study. This study was approved by the institutional ethics committee. Written, informed consent was obtained from all patients or their next-of-kin.

Clinical Characteristics
Clinical background characteristics, including sex, age, cardiovascular risk factors, and past medical history, were recorded on admission. Cardiovascular risk factors were defined as follows: (1) hypertension, history of anti-hypertensive agents, systolic blood pressure ≥140 mmHg, or diastolic blood pressure ≥90 mmHg before or ≥2 weeks after stroke onset; (2) hyperlipidemia, use of anti-hyperlipidemic agents, or serum total cholesterol ≥220 mg/dL; (3) diabetes mellitus, use of hypoglycemic agents, random glucose ≥200 mg/dL, or glycosylated hemoglobin ≥6.5% on admission; and (4) current smoker. Pre-stroke CHADS2 or CHA2DS2-VASc score was calculated for each patient based on the published guideline. 18 Aortic plaque, however, was not assessed as a component of the score, because transesophageal echocardiography was performed for only approximately one-quarter of the present patients. The index stroke was not counted in the history of ischemic

Insufficient Warfarin Leads to Severe Stroke
PT-INR ≥1.6 for patients ≥70 years old). The cut-off for sufficient VKA anticoagulation was based on previous studies in Japan 17, 19 and on a domestic guideline. 20 Renal function was assessed using estimated glomerular filtration rate (eGFR) instead of creatinine clearance on admission. First, univariate analysis was performed for all included patients using the chi-squared test, Fisher's exact test, or the Kruskal-Wallis test, as appropriate. The data are given as median (IQR) or n (%). Next, the independent variables   were on sufficient VKA on admission. Table 1 lists the patient clinical background characteristics. The proportions of patients with a history of dyslipidemia (P=0.009), congestive heart failure (P=0.011), and prior embolism (P<0.001); CHADS2 (P<0.001), CHA2DS2-VASc (P<0.001), and pre-admission modified Rankin scale (mRS, P=0.005) scores; and aPTT (P<0.001), PT-INR (P<0.001), eGFR (P=0.037), and D-dimer (P=0.031) were significantly different between the 3 groups. Although the initial NIHSS score was also significantly different between groups (median 9 in patients with no anticoagulation; 14 in insufficient VKA; and 7 in sufficient VKA; P=0.035, Table 1), on multivariate logistic regression analysis with backward stepwise selection there was no independent relationship between anticoagulant status on admission and severe stroke (anticoagulant status had been removed from the regression model after backward stepwise selection; Table 2).
Of the included patients, 364 (82%) had ischemic lesions in the anterior-circulation territory (167 women; median age, 79 years; IQR, 71-86 years; n=289, 79% ≥70 years old; median NIHSS score, 12; IQR, 3-22; median onset to arrival, 4.0 h; IQR, 2.0-12.0 h). Table 3 lists the clinical background characteristics of these patients. Prevalence of history of dyslipidemia (P=0.021), congestive heart failure (P=0.007), prior embolism (P<0.001), vascular disease (P=0.042), and pre-admission antiplatelet use (P=0.038), and the CHADS2 (P<0.001) and CHA2DS2-VASc (P=0.001) scores, pre-admission mRS (P=0.011) score, site of arterial occlusion on admission (P=0.010, Figure), and aPTT (P<0.001) and PT-INR (P<0.001) were significantly different between the 3 groups: stroke patients with insufficient VKA on admission tended to have a higher prevalence of for severe stroke (i.e., initial NIHSS score ≥10) 21 were assessed on multivariate logistic regression analysis with a backward stepwise selection procedure. Then, the same analyses were performed for those with anterior-circulation stroke (developed in the anterior and middle cerebral artery territories). Variables available on admission (except for CHADS2 and CHA2DS2-VASc scores, activated partial thromboplastin time [aPTT], and PT-INR) were included in the models ( Table 1). Backward selection was carried out using P>0.1 of the likelihood ratio test for exclusion. The relative risks of severe stroke are expressed as OR with 95% CI. Finally, multivariate ordinal logistic regression analysis was performed to identify independent factors associated with higher prevalence of proximal arterial occlusion in patients with anterior-circulation stroke. This model allows the outcome variable to have >2 categories and estimates proportional OR for each predictor of shifting to a more proximal arterial occlusion category (e.g., no occlusion vs. M2, M1, and ICA occlusion; no and M2 occlusion vs. M1 and ICA occlusion; and no, M2, and M1 occlusion vs. ICA occlusion). Sex, age, and all clinical characteristics identified on univariate analysis at P<0.1 were entered into the model. In the multivariate ordinal regression model, CHADS2 and CHA2DS2-VASc scores were excluded due to duplication of variables, and initial NIHSS score was also excluded, because this parameter is a consequence of, rather than a factor associated with, arterial occlusion. All statistical analysis was performed using PASW for Windows version 17.0 (SPSS, Chicago, IL, USA). Results were considered significant at P<0.05.

Results
Overall, 489 consecutive patients with AF and AIS were admitted to the stroke center during the study period. Of these, 43 patients were excluded due to prior DOAC treatment. Finally, 446 patients (189 women; median age, 79 stroke severity in patients with AIS and AF compared with no anticoagulant therapy. 5-7 There have been few reports, however, on the effects of insufficient VKA on stroke severity or the site of arterial occlusion, especially in the setting of a relatively lower PT-INR target (≥1.6 for patients ≥70 years old). 20 Insufficient VKA treatment was independently associated with higher severity of stroke and higher prevalence of proximal artery occlusion in the present study, and this seems pharmacokinetically plausible: the functional activity of protein C -the protein that has the anticoagulant effect -is decreased even in the subtherapeutic PT-INR range. 22 Insufficient VKA therapy may lead to larger thrombus formation than in those without anticoagulant medication through insufficient suppression of coagulation factors plus suppression of functional activity of protein C, and it may be associated with more severe stroke via proximal artery occlusion. This association was found only in patients with anterior-circulation stroke, probably because the relationship between vessel occlusion and NIHSS score in posteriorcirculation stroke patients was relatively weaker than in anterior-circulation stroke. 23 The present results are compatible with past reports showing that AF treated with warfarin and PT-INR <1.6 or ≤1.7 was associated with more severe stroke, 11 larger infarct volume, 11,12 and more frequent arterial occlusion 10 compared with no anticoagulant congestive heart failure, prior embolism, and ICA occlusion and higher CHADS2 or CHA2DS2-VASc scores on admission than those without anticoagulant therapy. The initial NIHSS scores were different (median 11 in patients with no anticoagulation; 18 in insufficient VKA; and 7 in sufficient VKA; P=0.022, Table 3; Figure), and on multivariate logistic regression analysis insufficient VKA at admission was independently associated with severe stroke (OR, 2.70; 95% CI: 1.15-6.34, P=0.022, Table 4), compared with no anticoagulation. Moreover, on multivariate ordinal logistic regression analysis of variables identified on univariate analysis at P<0.1 (Table S1), insufficient VKA was independently related to higher prevalence of proximal artery occlusion when no anticoagulant therapy prior to the index event was set as a reference in this model (OR, 1.92; 95% CI: 1.06-3.48, P=0.031; Table 5; Figure).

Discussion
The present study showed that insufficient VKA on admission was independently associated with higher severity of stroke and higher prevalence of proximal artery occlusion in patients with AF and acute anterior-circulation stroke, compared with no anticoagulation before the index stroke.
Sufficient VKA on admission has been shown to reduce  Advance Publication by-J-STAGE