Zhu et al. BMC Neurology (2018) 18:194 https://doi.org/10.1186/s12883-018-1200-7 RESEARCH ARTICLE Open Access Pre-stroke warfarin enhancement of collateralization in acute ischemic stroke: a retrospective study Jiaying Zhu1,2†, Mengmeng Ma1†, Yijia Guo1, Muke Zhou1, Jian Guo1 and Li He1* Abstract Background: Warfarin therapies not only are used to prevent stroke in patients with high risk of cardioembolism such as patients with atrial fibrillation (AF) and rheumatic heart disease (RHD), but also was associated with lower stroke severity and more favorable functional outcomes in patients with acute ischemic stroke due to middle cerebral artery occlusion. It was speculated that pre-stroke warfarin may promote collateralization and result in reduced stroke severity. This study aimed to investigate the association between pre-stroke warfarin use and leptomeningeal collaterals in patients with acute ischemic stroke due to occlusion of the middle cerebral artery. Methods: We enrolled consecutive acute ischemic stroke patients (occlusion of the middle cerebral artery within 24 h) with known history of AF and/or RHD at the neurology department of the West China Hospital from May 2011 to April 2017. Computed tomography angiography (CTA) before treatment was used to detect the thrombus. Regional leptomeningeal collateral (rLMC) score based on CTA images was used to assess collateral circulation. Prior use of warfarin was recorded. Univariate and multivariate analyses were performed to detect the association of prior warfarin use with the collateral circulation. Results: A total of 120 patients were included; 29 (24.2%) were taking warfarin before stroke. The international normalized ratio (INR) in patients with prior warfarin use was 1.53 ± 1.00, compared with 1.02 ± 0.09 in patients without prior warfarin use (P < 0.001). Prior oral warfarin therapy was inversely associated with poor rLMC (OR=0. 07, 95%CI 0.01–0.44, P = 0.005). There were no associations between prior warfarin use and initial stroke severity or functional outcomes at 3 months. Conclusion: Warfarin use seems improve collateralization in patients with acute stroke. However, clinical controlled studies should be used to verify this claim. Keywords: Warfarin, Acute ischemic stroke, Collateral circulation Background outcome in acute ischemic stroke [3–6]. Collateral blood Leptomeningeal collaterals are pre-existing anasto- vessels could be a therapeutic target in acute ischemic moses of distal regions of intracerebral small blood stroke [2]. However, preexisting collaterals depend on car- vessels [1, 2]. Collaterals provide the brain tissue with diac and pulmonary illnesses, metabolic syndrome, hyper- supplementary blood flow in the case of occlusion of uricemia, aging, and genetic factors [2, 4, 7, 8]. Although primary intracranial arteries to protect brain tissue there are no pharmacologic treatments proven to promote against irreversible damage [2]. Patients with good cerebral collateralization currently, some conventional leptomeningeal collaterals usually have lower severity stroke treatments may be available to enhance the collat- of stroke, better response to therapy, and better clinical eral circulation [6]. Statins, which have modest antithrom- botic pleiotropic effects, have been shown to be associated * Correspondence: [email protected] with the presence of better collaterals in patients with †Jia Ying Zhu and Mengmeng Ma contributed equally to this work. 1Department of Neurology, West China Hospital, Sichuan University, acute stroke [9]. Chengdu, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhu et al. BMC Neurology (2018) 18:194 Page 2 of 7 In addition, numerous studies have demonstrated that Maximum-intensity projection images (20 mm) were oral anticoagulants (such as warfarin) reduced the risk reconstructed in the axial, sagittal, and coronal planes. of ischemic stroke [10]. Warfarin was also associated with lower stroke severity and more favorable func- Leptomeningeal collateral flow assessment tional outcomes when stroke occurs [11–13]. Although We assessed the degree of leptomeningeal collateral flow the mechanism for pre-stroke warfarin lowering stroke using the regional leptomeningeal collateral (rLMC) score severity and improving functional outcomes was not (20 points) [3]. The rLMC score is based on scoring the very clear, two hypothesizes have been suggested. First, pial and lenticulostriate arteries in six MCA regions pre-stroke warfarin use may prevent thrombus forma- (M1-M6) and in the anterior cerebral artery region and tion and reduce the size of thrombi. Smaller thrombi the basal ganglia (0 = no; 1 = less; 2 = equal or more prom- cause distal infarctions and lower stroke severity and a inent compared with a matching region in the pial artery more favorable clinical outcome [14, 15]. Secondly, of the contralateral hemisphere). The arteries in the Syl- pre-stroke warfarin use may promote collateralization vian sulcus are given a higher score: 0 = not seen; 2 = less; since that the patients who used warfarin before stroke 4 = same or more prominent compared with the opposite had lower stroke severity comparing with not using Sylvian sulcus. An rLMC score of 0–10 was defined as warfarin even though the patients of two groups had poor collateral flow, 11–16 was defined as moderate col- the similar thrombi and arterial occlusion site [16, 17]. lateral flow, and 17–20 was defined as good collateral flow Then it was speculated that pre-stroke warfarin may [3]. The assessment was performed by four radiologists promote collateralization and result in reduced stroke with extensive experience in acute stroke imaging. The severity. However, whether the association exit between average score was used as the final score for the analyses. pre-stroke warfarin use and collaterals still needs to be clarified. In this study, we aimed to evaluate the associ- Data collection ation between pre-stroke warfarin use and collaterals in Clinical variables (age, gender, stroke risk factors, ad- acute ischemic stroke patients presenting with occlu- mission examinations, previous medications, thrombo- sion of the middle cerebral artery. lytic therapy, and hemorrhagic transformation) were collected for each patient from the stroke database. All Methods biochemical indexes were measured within 24 h of ad- Study population mission. The patient was considered to be using war- We performed a retrospective analysis of demographic, farin if they had been using it for at least 3 months clinical, and radiographic data in consecutive patients prior to stroke and were still using warfarin when at the Neurology Department of West China Hospital stroke occurred. Neurological severity was assessed by between May 2011 and April 2017. The inclusion cri- trained neurologists using the National Institutes of teria were: (1) ≥18 years of age; (2) history of AF and/or Health Stroke Scale (NIHSS, < 5 was defined as mild RHD; (3) available computed tomography angiography stroke, 5–14 as moderate stroke, and > 14 as severe (CTA) images within 24h of symptom onset; and (4) stroke) [11, 18]. Intracerebral hemorrhage (ICH) was CTA detection of acute infarction due to occlusion of diagnosed according to the European Cooperative the M1 or M2 middle cerebral artery (MCA), with or Acute Stroke Study (ECASS) criteria. All patients were without occlusion of the internal carotid artery (ICA). managed optimally according to the current guidelines, The exclusion criteria were: (1) pre-stroke modified physicians’ experience, and patients’ comorbidities. Rankin Scale (mRS) score > 2; (2) severe extracranial Follow-up mRS at 3-month after discharge was used to vascular stenosis detected by CTA; or (3) < 90 days of assess the functional outcome. All data collectors were follow-up. blind to the baseline collateral status. Admission CT Statistical analysis All patients underwent non-contrast computed tomog- Statistical analysis was performed using SPSS 22.0 for raphy (NCCT) and CTA. Imaging was conducted on a Windows (IBM, Armonk, NY, USA). The patients were 128-slice Siemens SOMATOM Definition Flash double grouped as warfarin users vs. non-warfarin users. The source CT scanner. NCCT helical scans were potential determinants of collaterals evaluated based performed form the skull base to the vertex using the on previous reports in the literature were age, blood following parameters: 70 kV, 150 mA, and 5-mm colli- pressure, total cholesterol (treated as continuous vari- mation. CTA was performed using: 42 ml of contrast at ables), high-density lipoprotein cholesterol (HDL-C), 6 ml/s, 3 to 5 s delay from injection to scanning, 70 kV, and low-density lipoprotein cholesterol (LDL-C), and 150 mA, 0.5 s/rotation, and 1.25-mm thick slice. The history of stroke, TIA, hypertension, diabetes, hyper- CTA scan covered the carotid bifurcation to the vertex. cholesterolemia, and pre-stroke statin