Date Published: February 3, 2017
Publisher: Public Library of Science
Author(s): Jun Young Chang, Seunguk Jung, Hyun Park, Moon-Ku Han, Jean-Claude Baron.
We investigated the association between the presence of major vessel occlusion (MVO) and the intensity of the International Normalized Ratio (INR) in cardioembolic high-risk patients taking warfarin. We also evaluated whether the presence of MVO could predict the subtherapeutic range of INR ≤1.7 ensuring safe administration of intravenous thrombolytics.
The medical records of 177 cardioembolic stroke patients who were taking warfarin between April, 2008 and March, 2015 were retrospectively analyzed. Logistic regression analysis was performed to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between vessel occlusion and intensity of INR. To predict INR ≤1.7, decision tree analysis was performed.
INR was inversely associated with MVO in an unadjusted model (OR, 0.36; 95% CI, 0.17–0.76), and in a model adjusted for initial NIHSS score and time from symptom onset to arrival (OR, 0.28; 95% CI, 0.11–0.73). Fifty-two of 58 (89.7%) patients with MVO had an INR ≤1.7, compared with 83 of 119 (69.7%) patients without MVO. Indication for anticoagulation agent use was dichotomized into NVAF and others, and applied to the subgroup of patients with MVO. All patients with NVAF (31/31, 100%) had INR ≤1.7, while 21 of 27 of the other patients (77.8%) had INR ≤1.7.
Low INR at presentation in cardioembolic stroke patients during anticoagulation treatment was associated with occurrence of major vessel occlusive stroke. Presence of MVO and indications for anticoagulation may be utilized to ensure the feasibility of administration of intravenous thrombolytics.
Cardioembolic stroke is a frequent event, constituting 14 to 30% of cases of acute ischemic stroke, and is the most lethal of stroke subtypes. [1, 2] Because of the increased prevalence of atrial fibrillation in the elderly population, warfarin use increased from 29% to 63% from 1992 to 2010.  Though anticoagulation therapy effectively reduces stroke recurrence by two-thirds and mortality by one-quarter in patients with nonvalvular atrial fibrillation,  long-term maintenance of an International Normalized Ratio (INR) within a therapeutic range as well as adherence to a warfarin regimen is difficult to attain. INR was outside the target range 32.1% of the time in warfarin-medicated patients, half of whom had INR <2.0.  Moreover, about one- quarter of atrial fibrillation patients who were prescribed warfarin quit taking the drug within 1 year.  As a result, the number of acute ischemic stroke patients taking oral anticoagulants is increasing in emergency departments. Current guidelines indicate the use of intravenous thrombolytic agents in patients with INR levels equal to or below 1.7 to avoid the risk of hemorrhagic complications.  When immediate thrombolysis is indicated, confirmation of coagulation-related laboratory results must be obtained in patients taking warfarin, which often delays the administration of recombinant tissue plasminogen activator (rtPA). No previous study has attempted to predict the subtherapeutic range of INR in patients with high cardioemobolic risk factors using oral anticoagulation agents. Knowledge of the relevant variables may be helpful in ensuring safe administration of intravenous thrombolytics. We retrospectively reviewed the medical records of the patients from a single hospital-based stroke registry. Patients with cardioembolic stroke taking warfarin who visited the institute within 24 hours from symptom onset between April, 2008 and March, 2015 were included in the analysis. Time from symptom onset was based on the first time the patient reported feeling abnormal or having symptoms. Cardioembolism was assigned when ischemic lesion were due to embolus of cardiac origin without any other embolic sources or significant stenosis at the relevant cerebral artery on angiographic studies. According to the TOAST classification, cardioembolic high risk includes mechanical prosthetic valve, mitral stenosis with atrial fibrillation, atrial fibrillation (other than lone atrial fibrillation), left atrial/atrial appendage thrombus, sick sinus syndrome, recent myocardial infarction (<4 weeks), left ventricular thrombus, dilated cardiomyopathy (ejection fraction <35%), akinetic left ventricular segment.  Besides the mentioned above, patients with patent foramen ovale (PFO) and a venous source of embolism, rheumatic mitral valve disease, atrial flutter were also indicated for anticoagulation and included in the analysis. Baseline demographics (age, sex), clinical characteristics (INR at presentation, initial NIHSS score, time from symptom onset to arrival, vascular risk factors, and cardioembolic risk factors) were collected from the registry. Institutional Review Board (IRB) of the study hospital approved the retrospective study. Of the 3,276 ischemic stroke patients who visited the institute within 24 hours of symptom onset during the study period, 951 (29%) were diagnosed with cardioembolic stroke according to the MAGIC algorithm.  Among them, 177 (5.4%) patients at high risk for cardioembolic stroke who were taking warfarin before the event fulfilled the inclusion criteria and were finally included in the analysis. The mean age of the study subjects was 73.2 years, and 48% were male. Thirty-two (18.1%) patients represented wake up stroke. The median from symptom onset to arrival based on last seen normal time was 218 minutes (interquartile range, 61–630). The median from symptom onset to arrival based on first abnormal time was 103 minutes (interquartile range, 45–276). The median baseline NIHSS score was 8 (interquartile range, 3–15), and hypertension (72.3%) was the most frequent risk factor. Major vessel occlusion was noted in 58 (32.8%) of the study subjects. Vessel occlusion site was as follows in order of frequency; M1 (20, 34.5%), M2 (15, 25.9%), intracranial ICA (12, 20.7%), extracranial ICA (3, 5.2%), ACA (2, 3.4%), BA (2, 3.4%), PCA (1, 1.7%), and VA (1, 1.7%). Nonvalvular atrial fibrillation (100, 56.5%) was the most frequent cause of anticoagulation among the study population, followed by vavular atrial fibrillation, and left atrial appendage thrombus (Table 1). The results of our study show that the initial level of INR during anticoagulation in high-risk cardioembolic stroke patients is inversely associated with major vessel occlusive stroke. Our study is unique in that, by utilizing factors such as presence of MVO and type of cardioembolic risk factor and conducting analysis by a decision tree method, we attempted to ensure the safety of intravenous thrombolysis. Maintenance of INR ≥2.0 during anticoagulation in patients with NVAF reduces stroke-related mortality as well as stroke recurrence.  A study from the Fukuoka Stroke Registry reported that baseline INR ≥2.0 was associated with less severe initial neurological deficits and favorable functional outcomes at discharge.  The mechanism of this result was assumed to be the consequence of smaller, more resolvable thrombi formation, thus leading to rapid, spontaneous recanalization of occluded arteries.  However, the vascular status of the subjects was not evaluated in the study. Intracranial large vessel occlusion in acute ischemic stroke was significantly associated with severe baseline NIHSS score and independent prognostic factors for poor outcomes.  The inverse correlation between intensity of INR and MVO demonstrated in our study could be the reason why preadmission INR ≥2.0 was more likely to cause stroke of reduced severity and lead to good outcomes. MVO represents not only an outcome predictor, but also an indicator for the need for urgent transfer to a higher care center for revascularization. Low INR in patients with anticoagulation was associated with occurrence of major vessel occlusive stroke. The presence of MVO and indications for anticoagulation may be utilized as clues to predict low INR in an effort to ensure the feasibility of administration of intravenous thrombolytics. However, the results of this study should be interpreted cautiously and regarded as hypothesis generating study which needs further prospective confirmation. Source: http://doi.org/10.1371/journal.pone.0170978