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Ankle-Brachial Index and Neurologic Deterioration in Acute Ischemic Stroke
Ankle-Brachial Index and Neurologic Deterioration in Acute Ischemic Stroke Kentaro Ishizuka, MD, Takao Hoshino, MD, and Shinichiro Uchiyama, MD, PhD
Background: Few studies have examined the relationship between abnormal anklebrachial index (ABI) and short-term outcome in patients with acute ischemic stroke (AIS). Methods: We included 209 consecutive patients with AIS admitted to our hospital and divided them into abnormal ABI (#.9) and normal ABI (..9) groups. We defined neurologic deterioration (ND) as an increase of 1 or more points in the National Institutes of Health Stroke Scale score within 7 days of stroke onset. Clinical characteristics were compared between the 2 groups. Then, we performed a multiple logistic regression analysis to identify independent predictors of ND. In the multivariate analysis, the ABI values were used separately as binary variables in different cutoff thresholds (.9, 1.0, and 1.1). Results: Of the 209 patients, 24 (11.5%) had an abnormal ABI. The patients in abnormal and normal ABI groups showed significant differences in carotid arterial stenosis (37.5% versus 18.9%; P 5 .040), intracranial artery stenosis (54.2% versus 18.9%; P , .001), and previous use of antiplatelet drugs (58.3% versus 29.2%; P 5 .004). According to the multivariate analysis, ABIs of .9 or less and 1.0 or less were positively associated with ND (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.03-2.89; P 5 .034 and OR, 1.63; 95% CI, 1.05-2.54; P 5 .027, respectively), whereas an ABI value of 1.1 or less was not an independent predictor of ND (OR, 1.17; 95% CI, 0.79-1.74; P 5 .43). Conclusions: Not only an ABI of .9 or less but also an ABI of 1.0 or less can be a predictor of ND in patients with AIS. Key Words: Acute ischemic stroke—anklebrachial index—atherosclerosis—neurologic deterioration—progressive stroke. Ó 2014 by National Stroke Association
Introduction The ankle-brachial index (ABI) is an easy and reliable tool for identifying patients with subclinical peripheral arterial disease (PAD) and is used as an indicator of generalized atherosclerosis.1-3 An abnormal ABI (#.9) is broadly used as an indicator of lower limb PAD4 and has been shown to predict all-cause mortality, vascularrelated deaths, and nonfatal cardiovascular events, even after adjusting for conventional vascular risk factors.1,3,5
From the Department of Neurology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan. Received October 14, 2013; revision received December 13, 2013; accepted December 16, 2013. Address correspondence to Kentaro Ishizuka, MD, Department of Neurology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.026
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Recent studies have suggested a high prevalence of low ABI among patients with acute ischemic stroke (AIS) or transient ischemic attack, with prevalence estimates ranging from 24%-51%.6-10 In patients with AIS, low ABI has been shown to be an independent predictor of subsequent stroke, myocardial infarction, or death.7,9,11 Furthermore, it was reported that low ABI may be a predictive factor of the initial severity and long-term functional outcomes of AIS.11-13 However, few data exist on the relationship between abnormal ABI and early neurologic deterioration (ND) during the acute phase of ischemic stroke. This study aimed to determine if the ABI predicted the risk of ND in patients with AIS, independently of other potential confounding factors.
Materials and Methods Study Protocol The ethics committee of our institution approved the study protocol. We conducted a hospital-based
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 10 (November-December), 2014: pp 2506-2510
ABI AND NEUROLOGIC DETERIORATION IN AIS
retrospective study involving 250 consecutive patients with AIS hospitalized in the Department of Neurology at the Tokyo Women’s Medical University Hospital between May 2009 and August 2012. The subjects were eligible if they (1) were recruited within 1 week of the onset of stroke and (2) underwent ABI measurement during hospitalization. Of 250 patients, 209 were eligible. Our hospital maintains a registry of all consecutive patients, and data were collected from a computerized observational database. We used a standardized case report form and abstracted several demographic and clinical variables, including date of the event, past medical history, risk factors for stroke, previous medications, findings of physiological examination, and neurologic symptoms. We also documented the results of all diagnostic tests and details of treatment performed during the hospitalization. The person imputing the data was blinded to the purpose of this study. AIS was defined as the sudden onset of acute neurologic deficits with evidence of acute infarction on brain computed tomography or magnetic resonance imaging. The severity of the event was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score. ND was defined as an increase of 1 or more points in the NIHSS score during the 7 days after admission. Stroke subtypes were classified on the basis of the Trial of ORG 10172 in Acute Stroke Treatment classification.14 Diagnosis of large artery atherosclerosis (LAA) required significant (.50%) stenosis of a large artery, which was relevant to the infarct lesion. Cardioembolism was diagnosed when a patient had at least 1 potential cardiac source of embolism that was based on the Trial of ORG 10172 in Acute Stroke Treatment classification. Small vessel occlusion was diagnosed when a patient presented with a classic lacunar syndrome, a small infarct lesion (,15 mm) in the perforating artery territory, no stenosis of large artery, and no potential cardiac sources of embolism and LAA.
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was calculated using the modification of diet in renal disease formula by the Japanese coefficient. Chronic kidney disease was defined as an estimated glomerular filtration rate less than 60 mL/minute$per 1.73 m2. Intracranial arterial stenosis of 50% or more on magnetic resonance angiography, 3-dimensional computed tomography angiography, or digital subtraction angiography was considered a significant finding. Findings of carotid artery ultrasonography were evaluated by appropriately trained neurologists, and stenosis of 50% or more was defined as significant extracranial arterial stenosis. Patients with either significant intra- or extracranial arterial stenosis were considered to have major artery lesions. Coronary artery disease was defined as a history of either angina pectoris or myocardial infarction, with or without coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Atrial fibrillation was diagnosed using the findings of at least 1 electrocardiogram (ECG) obtained before or during hospitalization. Routine cardiac tests included an initial 12-lead ECG, transthoracic echocardiography, and a Holter ECG; transesophageal echocardiography was also performed if indicated.
ABI Measurement ABI was measured using a noninvasive automatic pulse wave analyzer (Form PWV/ABI; Colin Co Ltd, Komaki, Japan) after a 5-minute rest in the supine position. According to the recommendations of the American Heart Association,15 ABI was calculated as the ratio of the systolic pressure in the posterior tibial artery and the highest systolic pressure in the 2 brachial arteries. After the individual calibration process, blood pressure was measured simultaneously using cuffs on both upper limbs (brachial arteries) and lower limbs (posterior tibial arteries). ABI was then calculated automatically and expressed as a ratio of systolic blood pressure in the ankle to that in the arm. An abnormal ABI was defined as ABI .9 or less than .9 on either the right or the left side.
Statistical Analysis Risk Factors Patients were diagnosed with a history of hypertension if they had evidence of systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more, or if they had received any antihypertensive medication. Diabetes mellitus was specified as fasting serum glucose of 126 mg/dL or more, serum glucose of 200 mg/dL or more on 2 random measurements, glycated hemoglobin (HbA1c) of 6.5% or more, or use of antidiabetic therapy (oral hypoglycemic agents or insulin). Dyslipidemia was diagnosed if the patient had low-density lipoprotein cholesterol of 140 mg/dL or more or total cholesterol of 220 mg/dL or more, or if the patient had been treated with lipid-lowering agents after diagnosis of dyslipidemia. Smoking status was defined as current use. The estimated glomerular filtration rate
Descriptive statistics were obtained using the JMP statistical software package (version 10; SAS Institute, Cary, NC). Statistical significance of intergroup differences was assessed by the c2 test for categorical variables and the Student t test or the Mann–Whitney U test for continuous variables. To identify predictors of ND, we performed the multiple logistic regression analysis. Mulvariate adjustments were done using following variables: age, sex, hypertention, diabetes mellitus, smoking status, AF, prior use of antithrombotic drugs, carotid aterial stenosis, intracranial arterial stenosis, and ABI value. ABI values were used as binary variables in different cutoff thresholds (.9, 1.0, and 1.1) separately (models A, B, and C, respectively). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In all analyses, P , .05 was considered significant.
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Results A total of 209 patients (mean age, 67.7 years; male, 68.4%) were enrolled in this study. The prevalence of abnormal ABI (#.9) was 11.5% (24 of 209 patients). In the comparisons of baseline characteristics (Table 1), patients in the abnormal ABI group presented more often with diabetes mellitus (58.3% versus 38.0%; P 5 .054), carotid artery stenosis (37.5% versus 18.9%; P 5 .040), intracranial artery stenosis (54.2% versus 18.9%; P , .001), and history of coronary artery disease (29.2% versus 15.1%; P 5 .083) than did those in the normal ABI group. A significantly higher number of patients underwent antiplatelet therapy before stroke in the abnormal ABI group than in the normal ABI group (58.3% versus 29.2%; P 5.004). NIHSS scores on admission were equivalent between the abnormal and normal ABI groups (5.5 versus 4; P 5.34). With regard to stroke subtypes, the percentage of LAA was significantly higher in the abnormal than the normal ABI group (58.3% versus 29.7%; P 5 .005), whereas there was no difference in the percentages of cardioembolism (16.7% versus 20.0%; P 5 .70) and small vessel occlusion (16.7% versus 30.8%; P 5 .15) between the groups. The proportion of cases of ND was significantly higher in the ABI of .9 or less group than greater than.9 group (37.5% versus 14.1%; P 5 .004), and in the ABI of 1.0 or less group than greater than 1.0 group (31.7% versus 13.1%; P 5 .004) (Fig 1). However, the proportion of ND cases was not significantly different be-
tween patients with ABI of 1.1 or less and greater than 1.1. Multivariate analysis showed that ABI values of .9 or less and 1.0 or less were positively associated with ND (OR, 1.74; 95% CI, 1.03-2.89; P 5 .034 and OR, 1.63; 95% CI, 1.05-2.54; P 5 .027, respectively); ABI of 1.1 or less was not an independent predictor of ND (OR, 1.17; 95% CI, 0.79-1.74; P 5 .43) (Table 2).
Discussion The present study indicated that a low ABI was strongly associated with ND in patients with AIS. Multivariate analysis showed that ABI values of .9 or less and 1.0 or less contributed to an 75% and 63% increase in risk of ND, respectively. These results suggest that the measurement of ABI in stroke patients during the acute phase may help identify high-risk patients who could potentially benefit from an intensified treatment. ABI has been used as a diagnostic and prognostic tool for the management of patients with PAD.15 Furthermore, several studies have indicated that an abnormal ABI can be a good predictor of initial or recurrent stroke.1,9,16,17 High prevalence of a low ABI in patients with ischemic stroke has been reported previously, with most studies indicating that the prevalence of low ABI ranges from 24%-51% among patients with AIS or transient ischemic attack.6-10 With respect to long-term stroke outcomes, Milionis et al11 showed that ABI of .9 or less was associated with 5-year mortality (OR, 3.36; 95% CI, 2.05-6.45;
Table 1. Baseline characteristics of patients with and without ABI # .9 Characteristic
All (N 5 209)
ABI # .9 (N 5 24)
ABI . .9 (N 5 185)
P value
Age, mean (SD), y Male Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Current smoking Atrial fibrillation Admission NIHSS score, median (IQR) Main arterial stenosis Carotid arterial stenosis Intracranial arterial stenosis History of coronary artery disease Previous use of antiplatelet drugs Previous use of anticoagulant Stroke subtype Large-artery atherosclerosis Cardioembolism Small vessel occlusion Other cause
67.7 (12.6) 143 (68.4) 153 (73.2) 84 (40.2) 106 (50.7) 55 (26.3) 35 (16.7) 20 (9.6) 4 (2-7) 79 (37.8) 44 (21.1) 48 (23.0) 35 (16.7) 68 (32.5) 15 (7.2)
71.3 (10.1) 18 (75.0) 17 (70.8) 14 (58.3) 9 (37.5) 10 (41.7) 5 (20.8) 2 (8.3) 5.5 (3-8.75) 17 (70.8) 9 (37.5) 13 (54.2) 7 (29.2) 14 (58.3) 1 (4.2)
67.3 (12.8) 125 (67.6) 136 (73.5) 70 (38.0) 97 (52.4) 45 (24.3) 30 (16.2) 18 (9.7) 4 (2-7) 62 (33.5) 35 (18.9) 35 (18.9) 28 (15.1) 54 (29.2) 14 (7.6)
.14 .46 .78 .054 .16 .070 .56 .83 .34 ,.001 .040 ,.001 .083 .004 .54
55 (29.7) 37 (20.0) 57 (30.8) 15 (8.1)
.005 .70 .15 .15
69 (33.0) 41 (19.6) 61 (29.2) 15 (7.2)
14 (58.3) 4 (16.7) 4 (16.7) 0 (0)
Abbreviations: ABI, ankle-brachial index; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. Unless otherwise indicated, figures expressed as n (%).
ABI AND NEUROLOGIC DETERIORATION IN AIS
Figure 1. The distributions of patients with and without neurologic deterioration for the different ABI value (ABI values were stratified as #.9, .9 , ABI # 1.0, 1.0 , ABI # 1.1, and .1.1). The proportion of cases of ND was significantly higher in the ABI of .9 or less group than greater than .9 group (37.5% versus 14.1%; P 5 .004), and in the ABI of 1.0 or less group than greater than 1.0 group (31.7% versus 13.1%; P 5 .004). However, there was no difference between patients in the ABI of 1.1or less and greater than 1.1 groups.
P , .001) and 5-year functional independence (OR, .40; 95% CI, .26-6.45; P , .001). To the best of our knowledge, the association between the low ABI and ND in patients with AIS has not been reported thus far, whereas brachial-ankle pulse wave velocity, which is widely applied to assess arteriosclerosis of lower limbs, was reported to be a possible predictor of progressive neurologic deficit in patients with AIS.18 Saji et al18 demonstrated that a high brachial-ankle pulse wave velocity (.18.24 m/s) increases the incidence of ND in AIS by approximately 8-fold. Table 2. Multiple logistic regression analysis for predictors of neurologic deterioration in acute ischemic stroke Model Model A Age Male Current smoking ABI # .9 Model B Age Current smoking ABI # 1.0 Model C Age ABI #1.1
OR (95% CI)
P value
1.02 (.99-1.07) .78 (.52-1.19) 1.40 (.84-2.27) 1.74 (1.03-2.89)
.13 .25 .18 .034
1.02 (.94-1.01) 1.40 (.88-2.39) 1.63 (1.05-2.54)
.18 .12 .027
1.03 (.99-1.07) 1.17 (.79-1.74)
.13 .43
Abbreviations: ABI, ankle-brachial index; CI, confidence interval; OR, odds ratio. ABI values were used as binary variables in different cutoff thresholds (.9, 1.0, and 1.1) separately (models A, B, and C, respectively).
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ABI of .9 or less was a useful cutoff value not only in detecting the PAD4 but also in estimating the risk of vascular events.1,3,5 Furthermore, an ABI value of .9-1.0 was associated with atherosclerosis in the coronary and cerebral arteries, risk of coronary events, and cardiovascular mortality.1 Therefore, this value is referred to as ‘‘borderline’’ ABI.19 In the present study, we demonstrated that patients with ABI value of 1.0 or less, including the abnormal and borderline ABI, had a significantly increased risk of ND. Several mechanisms may be responsible for the association between the low ABI and ND. Low ABI is associated with increased platelet aggregation, coagulatory activity, and arterial rigidity20-23; all these factors can cause expansion of infarct. In addition, vascular endothelial impairment, which is indicated by atherosclerosis,24,25 potentially causes blood–brain barrier failure and leads to cerebral parenchymal damage,26,27 possibly resulting in ND. The findings of the present study should be interpreted in the light of several limitations. First, this was a retrospective study conducted in a single hospital. We performed an analysis based on a computerized database created during the period of patient hospitalization and postdischarge follow-up. Because it was a hospitalbased study, the characteristics of the cohort may have differed from those of the general population. Furthermore, patients with mild neurologic symptoms, who did not require hospitalization, might have been excluded from the analysis. Second, we did not establish a unified treatment protocol for this study. Particularly, hypertension and hyperglycemia have been reported to worsen short-term outcomes in acute stroke,28,29 but the precise outcome data were not available because of the retrospective setting. However, the treatment policies during the acute phase were always decided by 2 or more board-certified stroke neurologists. All decisions were based on domestic guidelines. Although further studies with multicenter and larger cohorts are needed, our exploratory study may provide important and useful information regarding the management of patients with AIS.
References 1. Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality: a meta-analysis. JAMA 2008;300:197-208. 2. Greenland P, Abrams J, Aurigemma GP, et al. Prevention conference V. Beyond secondary prevention: identifying the high-risk patient for primary prevention. Noninvasive tests of atherosclerotic burden. Circulation 2000; 101:e16-e22. 3. Heald CL, Fowkes FG, Murray GD, et al. Risk of mortality and cardiovascular disease associated with the anklebrachial index: systematic review. Atherosclerosis 2006; 189:61-69.
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2510 4. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317-1324. 5. Criqui MH, Denenberg JO, Langer RD, et al. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med 1997; 2:221-226. 6. Agnelli G, Cimminiello C, Meneghetti G, et al. Low ankle-brachial index predicts an adverse 1-year outcome after acute coronary and cerebrovascular events. J Thromb Haemost 2006;4:2599-2606. 7. Busch MA, Lutz K, R€ ohl JE, et al. Low ankle-brachial index predicts cardiovascular risk after acute ischemic stroke or transient ischemic attack. Stroke 2009;40: 3700-3705. 8. Purroy F, Coll B, Or o M, et al. Predictive value of ankle brachial index in patients with acute ischaemic stroke. Eur J Neurol 2010;17:602-606. 9. Tsivgoulis G, Bogiatzi C, Heliopoulos I, et al. Low anklebrachial index predicts early risk of recurrent stroke in patients with acute cerebral ischemia. Atherosclerosis 2012;220:407-412. 10. Weimar C, Goertler M, R€ other J, et al. Predictive value of the Essen stroke risk score and ankle brachial index in acute ischaemic stroke patients from 85 German stroke units. J Neurol Neurosurg Psychiatry 2008;79:1339-1343. 11. Milionis H, Vemmou A, Ntaios G, et al. Ankle-brachial index long-term outcome after first-ever ischaemic stroke. Eur J Neurol 2013;20:1471-1478. 12. Lee DH, Kim J, Lee HS, et al. Low ankle-brachial index is a predictive factor for initial severity of acute ischaemic stroke. Eur J Neurol 2012;19:892-898. 13. Kim J, Lee DH, Cha MJ, et al. Low ankle-brachial index is an independent predictor of poor functional outcome in acute cerebral infarction. Atherosclerosis 2012;224: 113-117. 14. Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of ORG 10172 in acute stroke treatment. Stroke 1993;24:35-41. 15. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; Trans-
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Atlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-e654. Murabito JM, Evans JC, Larson MG, et al. The anklebrachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Arch Intern Med 2003;163:1939-1942. Abbott RD, Rodriguez BL, Petrovitch H, et al. Anklebrachial blood pressure in elderly men and the risk of stroke: the Honolulu Heart Program. J Clin Epidemiol 2001;54:973-978. Saji N, Kimura K, Kawarai T, et al. Arterial stiffness and progressive neurological deficit in patients with acute deep subcortical infarction. Stroke 2012;43:3088-3090. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;124: 2020-2045. Reininger CB, Graf J, Reininger AJ, et al. Increased platelet and coagulatory activity in peripheral atherosclerosis flow mediated platelet function is a sensitive and specific disease indicator. Int Angiol 1996;15:335-343. Iwashima Y, Horio T, Suzuki Y, et al. Adiponectin and inflammatory markers in peripheral arterial occlusive disease. Atherosclerosis 2006;188:384-390. Khaleghi M, Kullo IJ. Aortic augmentation index is associated with the ankle-brachial index: a community-based study. Atherosclerosis 2007;195:248-253. Weiss T, Fischer D, Hausmann D, et al. Endothelial function in patients with peripheral vascular disease: influence of prostaglandin E1. Prostaglandins Leukot Essent Fatty Acids 2002;67:277-281. Kim DH, Kim J, Kim JM, et al. Increased brachial-ankle pulse wave velocity is independently associated with risk of cerebral ischemic small vessel disease in elderly hypertensive patients. Clin Neurol Neurosurg 2008; 110:599-604. Saji N, Kimura K, Shimizu H, et al. Association between silent brain infarct and arterial stiffness indicated by brachial-ankle pulse wave velocity. Intern Med 2012; 51:1003-1008. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689-701. Wardlaw JM. Blood-brain barrier and cerebral small vessel disease. J Neurol Sci 2010;299:66-71. Keezer MR, Yu AY, Zhu B, et al. Blood pressure and antihypertensive theray as predictors of early outcome in acute ischemic stroke. Cerebrovasc Dis 2008;25:202-208. Tanaka R, Ueno Y, Miyamoto N, et al. Impact of diabetes and prediabetes on the short-term prognosis in patients with acute ischemic stroke. J Neurol Sci 2013;332:45-50.
Background: Few studies have examined the relationship between abnormal anklebrachial index (ABI) and short-term outcome in patients with acute ischemic stroke (AIS). Methods: We included 209 consecutive patients with AIS admitted to our hospital and divided them into abnormal ABI (#.9) and normal ABI (..9) groups. We defined neurologic deterioration (ND) as an increase of 1 or more points in the National Institutes of Health Stroke Scale score within 7 days of stroke onset. Clinical characteristics were compared between the 2 groups. Then, we performed a multiple logistic regression analysis to identify independent predictors of ND. In the multivariate analysis, the ABI values were used separately as binary variables in different cutoff thresholds (.9, 1.0, and 1.1). Results: Of the 209 patients, 24 (11.5%) had an abnormal ABI. The patients in abnormal and normal ABI groups showed significant differences in carotid arterial stenosis (37.5% versus 18.9%; P 5 .040), intracranial artery stenosis (54.2% versus 18.9%; P , .001), and previous use of antiplatelet drugs (58.3% versus 29.2%; P 5 .004). According to the multivariate analysis, ABIs of .9 or less and 1.0 or less were positively associated with ND (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.03-2.89; P 5 .034 and OR, 1.63; 95% CI, 1.05-2.54; P 5 .027, respectively), whereas an ABI value of 1.1 or less was not an independent predictor of ND (OR, 1.17; 95% CI, 0.79-1.74; P 5 .43). Conclusions: Not only an ABI of .9 or less but also an ABI of 1.0 or less can be a predictor of ND in patients with AIS. Key Words: Acute ischemic stroke—anklebrachial index—atherosclerosis—neurologic deterioration—progressive stroke. Ó 2014 by National Stroke Association
Introduction The ankle-brachial index (ABI) is an easy and reliable tool for identifying patients with subclinical peripheral arterial disease (PAD) and is used as an indicator of generalized atherosclerosis.1-3 An abnormal ABI (#.9) is broadly used as an indicator of lower limb PAD4 and has been shown to predict all-cause mortality, vascularrelated deaths, and nonfatal cardiovascular events, even after adjusting for conventional vascular risk factors.1,3,5
From the Department of Neurology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan. Received October 14, 2013; revision received December 13, 2013; accepted December 16, 2013. Address correspondence to Kentaro Ishizuka, MD, Department of Neurology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.026
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Recent studies have suggested a high prevalence of low ABI among patients with acute ischemic stroke (AIS) or transient ischemic attack, with prevalence estimates ranging from 24%-51%.6-10 In patients with AIS, low ABI has been shown to be an independent predictor of subsequent stroke, myocardial infarction, or death.7,9,11 Furthermore, it was reported that low ABI may be a predictive factor of the initial severity and long-term functional outcomes of AIS.11-13 However, few data exist on the relationship between abnormal ABI and early neurologic deterioration (ND) during the acute phase of ischemic stroke. This study aimed to determine if the ABI predicted the risk of ND in patients with AIS, independently of other potential confounding factors.
Materials and Methods Study Protocol The ethics committee of our institution approved the study protocol. We conducted a hospital-based
Journal of Stroke and Cerebrovascular Diseases, Vol. 23, No. 10 (November-December), 2014: pp 2506-2510
ABI AND NEUROLOGIC DETERIORATION IN AIS
retrospective study involving 250 consecutive patients with AIS hospitalized in the Department of Neurology at the Tokyo Women’s Medical University Hospital between May 2009 and August 2012. The subjects were eligible if they (1) were recruited within 1 week of the onset of stroke and (2) underwent ABI measurement during hospitalization. Of 250 patients, 209 were eligible. Our hospital maintains a registry of all consecutive patients, and data were collected from a computerized observational database. We used a standardized case report form and abstracted several demographic and clinical variables, including date of the event, past medical history, risk factors for stroke, previous medications, findings of physiological examination, and neurologic symptoms. We also documented the results of all diagnostic tests and details of treatment performed during the hospitalization. The person imputing the data was blinded to the purpose of this study. AIS was defined as the sudden onset of acute neurologic deficits with evidence of acute infarction on brain computed tomography or magnetic resonance imaging. The severity of the event was assessed according to the National Institutes of Health Stroke Scale (NIHSS) score. ND was defined as an increase of 1 or more points in the NIHSS score during the 7 days after admission. Stroke subtypes were classified on the basis of the Trial of ORG 10172 in Acute Stroke Treatment classification.14 Diagnosis of large artery atherosclerosis (LAA) required significant (.50%) stenosis of a large artery, which was relevant to the infarct lesion. Cardioembolism was diagnosed when a patient had at least 1 potential cardiac source of embolism that was based on the Trial of ORG 10172 in Acute Stroke Treatment classification. Small vessel occlusion was diagnosed when a patient presented with a classic lacunar syndrome, a small infarct lesion (,15 mm) in the perforating artery territory, no stenosis of large artery, and no potential cardiac sources of embolism and LAA.
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was calculated using the modification of diet in renal disease formula by the Japanese coefficient. Chronic kidney disease was defined as an estimated glomerular filtration rate less than 60 mL/minute$per 1.73 m2. Intracranial arterial stenosis of 50% or more on magnetic resonance angiography, 3-dimensional computed tomography angiography, or digital subtraction angiography was considered a significant finding. Findings of carotid artery ultrasonography were evaluated by appropriately trained neurologists, and stenosis of 50% or more was defined as significant extracranial arterial stenosis. Patients with either significant intra- or extracranial arterial stenosis were considered to have major artery lesions. Coronary artery disease was defined as a history of either angina pectoris or myocardial infarction, with or without coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Atrial fibrillation was diagnosed using the findings of at least 1 electrocardiogram (ECG) obtained before or during hospitalization. Routine cardiac tests included an initial 12-lead ECG, transthoracic echocardiography, and a Holter ECG; transesophageal echocardiography was also performed if indicated.
ABI Measurement ABI was measured using a noninvasive automatic pulse wave analyzer (Form PWV/ABI; Colin Co Ltd, Komaki, Japan) after a 5-minute rest in the supine position. According to the recommendations of the American Heart Association,15 ABI was calculated as the ratio of the systolic pressure in the posterior tibial artery and the highest systolic pressure in the 2 brachial arteries. After the individual calibration process, blood pressure was measured simultaneously using cuffs on both upper limbs (brachial arteries) and lower limbs (posterior tibial arteries). ABI was then calculated automatically and expressed as a ratio of systolic blood pressure in the ankle to that in the arm. An abnormal ABI was defined as ABI .9 or less than .9 on either the right or the left side.
Statistical Analysis Risk Factors Patients were diagnosed with a history of hypertension if they had evidence of systolic blood pressure of 140 mm Hg or more or diastolic blood pressure of 90 mm Hg or more, or if they had received any antihypertensive medication. Diabetes mellitus was specified as fasting serum glucose of 126 mg/dL or more, serum glucose of 200 mg/dL or more on 2 random measurements, glycated hemoglobin (HbA1c) of 6.5% or more, or use of antidiabetic therapy (oral hypoglycemic agents or insulin). Dyslipidemia was diagnosed if the patient had low-density lipoprotein cholesterol of 140 mg/dL or more or total cholesterol of 220 mg/dL or more, or if the patient had been treated with lipid-lowering agents after diagnosis of dyslipidemia. Smoking status was defined as current use. The estimated glomerular filtration rate
Descriptive statistics were obtained using the JMP statistical software package (version 10; SAS Institute, Cary, NC). Statistical significance of intergroup differences was assessed by the c2 test for categorical variables and the Student t test or the Mann–Whitney U test for continuous variables. To identify predictors of ND, we performed the multiple logistic regression analysis. Mulvariate adjustments were done using following variables: age, sex, hypertention, diabetes mellitus, smoking status, AF, prior use of antithrombotic drugs, carotid aterial stenosis, intracranial arterial stenosis, and ABI value. ABI values were used as binary variables in different cutoff thresholds (.9, 1.0, and 1.1) separately (models A, B, and C, respectively). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. In all analyses, P , .05 was considered significant.
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Results A total of 209 patients (mean age, 67.7 years; male, 68.4%) were enrolled in this study. The prevalence of abnormal ABI (#.9) was 11.5% (24 of 209 patients). In the comparisons of baseline characteristics (Table 1), patients in the abnormal ABI group presented more often with diabetes mellitus (58.3% versus 38.0%; P 5 .054), carotid artery stenosis (37.5% versus 18.9%; P 5 .040), intracranial artery stenosis (54.2% versus 18.9%; P , .001), and history of coronary artery disease (29.2% versus 15.1%; P 5 .083) than did those in the normal ABI group. A significantly higher number of patients underwent antiplatelet therapy before stroke in the abnormal ABI group than in the normal ABI group (58.3% versus 29.2%; P 5.004). NIHSS scores on admission were equivalent between the abnormal and normal ABI groups (5.5 versus 4; P 5.34). With regard to stroke subtypes, the percentage of LAA was significantly higher in the abnormal than the normal ABI group (58.3% versus 29.7%; P 5 .005), whereas there was no difference in the percentages of cardioembolism (16.7% versus 20.0%; P 5 .70) and small vessel occlusion (16.7% versus 30.8%; P 5 .15) between the groups. The proportion of cases of ND was significantly higher in the ABI of .9 or less group than greater than.9 group (37.5% versus 14.1%; P 5 .004), and in the ABI of 1.0 or less group than greater than 1.0 group (31.7% versus 13.1%; P 5 .004) (Fig 1). However, the proportion of ND cases was not significantly different be-
tween patients with ABI of 1.1 or less and greater than 1.1. Multivariate analysis showed that ABI values of .9 or less and 1.0 or less were positively associated with ND (OR, 1.74; 95% CI, 1.03-2.89; P 5 .034 and OR, 1.63; 95% CI, 1.05-2.54; P 5 .027, respectively); ABI of 1.1 or less was not an independent predictor of ND (OR, 1.17; 95% CI, 0.79-1.74; P 5 .43) (Table 2).
Discussion The present study indicated that a low ABI was strongly associated with ND in patients with AIS. Multivariate analysis showed that ABI values of .9 or less and 1.0 or less contributed to an 75% and 63% increase in risk of ND, respectively. These results suggest that the measurement of ABI in stroke patients during the acute phase may help identify high-risk patients who could potentially benefit from an intensified treatment. ABI has been used as a diagnostic and prognostic tool for the management of patients with PAD.15 Furthermore, several studies have indicated that an abnormal ABI can be a good predictor of initial or recurrent stroke.1,9,16,17 High prevalence of a low ABI in patients with ischemic stroke has been reported previously, with most studies indicating that the prevalence of low ABI ranges from 24%-51% among patients with AIS or transient ischemic attack.6-10 With respect to long-term stroke outcomes, Milionis et al11 showed that ABI of .9 or less was associated with 5-year mortality (OR, 3.36; 95% CI, 2.05-6.45;
Table 1. Baseline characteristics of patients with and without ABI # .9 Characteristic
All (N 5 209)
ABI # .9 (N 5 24)
ABI . .9 (N 5 185)
P value
Age, mean (SD), y Male Hypertension Diabetes mellitus Dyslipidemia Chronic kidney disease Current smoking Atrial fibrillation Admission NIHSS score, median (IQR) Main arterial stenosis Carotid arterial stenosis Intracranial arterial stenosis History of coronary artery disease Previous use of antiplatelet drugs Previous use of anticoagulant Stroke subtype Large-artery atherosclerosis Cardioembolism Small vessel occlusion Other cause
67.7 (12.6) 143 (68.4) 153 (73.2) 84 (40.2) 106 (50.7) 55 (26.3) 35 (16.7) 20 (9.6) 4 (2-7) 79 (37.8) 44 (21.1) 48 (23.0) 35 (16.7) 68 (32.5) 15 (7.2)
71.3 (10.1) 18 (75.0) 17 (70.8) 14 (58.3) 9 (37.5) 10 (41.7) 5 (20.8) 2 (8.3) 5.5 (3-8.75) 17 (70.8) 9 (37.5) 13 (54.2) 7 (29.2) 14 (58.3) 1 (4.2)
67.3 (12.8) 125 (67.6) 136 (73.5) 70 (38.0) 97 (52.4) 45 (24.3) 30 (16.2) 18 (9.7) 4 (2-7) 62 (33.5) 35 (18.9) 35 (18.9) 28 (15.1) 54 (29.2) 14 (7.6)
.14 .46 .78 .054 .16 .070 .56 .83 .34 ,.001 .040 ,.001 .083 .004 .54
55 (29.7) 37 (20.0) 57 (30.8) 15 (8.1)
.005 .70 .15 .15
69 (33.0) 41 (19.6) 61 (29.2) 15 (7.2)
14 (58.3) 4 (16.7) 4 (16.7) 0 (0)
Abbreviations: ABI, ankle-brachial index; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation. Unless otherwise indicated, figures expressed as n (%).
ABI AND NEUROLOGIC DETERIORATION IN AIS
Figure 1. The distributions of patients with and without neurologic deterioration for the different ABI value (ABI values were stratified as #.9, .9 , ABI # 1.0, 1.0 , ABI # 1.1, and .1.1). The proportion of cases of ND was significantly higher in the ABI of .9 or less group than greater than .9 group (37.5% versus 14.1%; P 5 .004), and in the ABI of 1.0 or less group than greater than 1.0 group (31.7% versus 13.1%; P 5 .004). However, there was no difference between patients in the ABI of 1.1or less and greater than 1.1 groups.
P , .001) and 5-year functional independence (OR, .40; 95% CI, .26-6.45; P , .001). To the best of our knowledge, the association between the low ABI and ND in patients with AIS has not been reported thus far, whereas brachial-ankle pulse wave velocity, which is widely applied to assess arteriosclerosis of lower limbs, was reported to be a possible predictor of progressive neurologic deficit in patients with AIS.18 Saji et al18 demonstrated that a high brachial-ankle pulse wave velocity (.18.24 m/s) increases the incidence of ND in AIS by approximately 8-fold. Table 2. Multiple logistic regression analysis for predictors of neurologic deterioration in acute ischemic stroke Model Model A Age Male Current smoking ABI # .9 Model B Age Current smoking ABI # 1.0 Model C Age ABI #1.1
OR (95% CI)
P value
1.02 (.99-1.07) .78 (.52-1.19) 1.40 (.84-2.27) 1.74 (1.03-2.89)
.13 .25 .18 .034
1.02 (.94-1.01) 1.40 (.88-2.39) 1.63 (1.05-2.54)
.18 .12 .027
1.03 (.99-1.07) 1.17 (.79-1.74)
.13 .43
Abbreviations: ABI, ankle-brachial index; CI, confidence interval; OR, odds ratio. ABI values were used as binary variables in different cutoff thresholds (.9, 1.0, and 1.1) separately (models A, B, and C, respectively).
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ABI of .9 or less was a useful cutoff value not only in detecting the PAD4 but also in estimating the risk of vascular events.1,3,5 Furthermore, an ABI value of .9-1.0 was associated with atherosclerosis in the coronary and cerebral arteries, risk of coronary events, and cardiovascular mortality.1 Therefore, this value is referred to as ‘‘borderline’’ ABI.19 In the present study, we demonstrated that patients with ABI value of 1.0 or less, including the abnormal and borderline ABI, had a significantly increased risk of ND. Several mechanisms may be responsible for the association between the low ABI and ND. Low ABI is associated with increased platelet aggregation, coagulatory activity, and arterial rigidity20-23; all these factors can cause expansion of infarct. In addition, vascular endothelial impairment, which is indicated by atherosclerosis,24,25 potentially causes blood–brain barrier failure and leads to cerebral parenchymal damage,26,27 possibly resulting in ND. The findings of the present study should be interpreted in the light of several limitations. First, this was a retrospective study conducted in a single hospital. We performed an analysis based on a computerized database created during the period of patient hospitalization and postdischarge follow-up. Because it was a hospitalbased study, the characteristics of the cohort may have differed from those of the general population. Furthermore, patients with mild neurologic symptoms, who did not require hospitalization, might have been excluded from the analysis. Second, we did not establish a unified treatment protocol for this study. Particularly, hypertension and hyperglycemia have been reported to worsen short-term outcomes in acute stroke,28,29 but the precise outcome data were not available because of the retrospective setting. However, the treatment policies during the acute phase were always decided by 2 or more board-certified stroke neurologists. All decisions were based on domestic guidelines. Although further studies with multicenter and larger cohorts are needed, our exploratory study may provide important and useful information regarding the management of patients with AIS.
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