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Prevalence and Clinical Features of Asymptomatic Peripheral Artery Disease in Japanese Stroke Patients
Prevalence and Clinical Features of Asymptomatic Peripheral Artery Disease in Japanese Stroke Patients Haruhiko Hoshino, MD,* Yoshiaki Itoh, MD, PhD,† Satoshi Yamada, MD,† and Norihiro Suzuki, MD, PhD†
Background: A recent worldwide disease registration study has revealed a high prevalence of polyvascular diseases in stroke patients. However, although a poor clinical outcome of patients with polyvascular disease has been reported, there have been few reports on clinical features of peripheral artery disease (PAD) in stroke patients. We assessed the prevalence, demographics, characteristics, and risk factors of PAD in Japanese stroke patients. Methods: One hundred and one consecutive chronic stroke patients in an outpatient clinic underwent anklebrachial index (ABI) screening tests. PAD was diagnosed when the ABI was ,0.9. Results: Abnormal ABI was found in 19 patients (18.8%). Eleven patients were asymptomatic, and 8 patients had symptoms of intermittent claudication. Gender, prevalence of hypertension, and dyslipidemia and alcohol intake were not different between the patients with PAD and those without PAD. Prevalence of diabetes mellitus (63.6%) was higher in the patients with asymptomatic PAD. Among the clinical subtypes of stroke, the patients with atherothrombotic infarction had a higher prevalence of PAD. Conclusions: The prevalence of PAD in stroke patients was 18.8%. Approximately 60% of the patients had no symptoms related to PAD. Diabetes mellitus was associated with higher prevalence of asymptomatic PAD among Japanese stroke patients. Key Words: Ankle brachial pressure index— atherothrombotic infarction—diabetes mellitus—intermittent claudication— peripheral artery disease—polyvascular disease. Ó 2013 by National Stroke Association
Data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry have revealed that a high proportion of patients with cerebrovascular disease (CVD) also have polyvascular diseases, such as coronary artery disease (CAD) in 30.2%, peripheral artery disease (PAD) in 4.3%, and both in 5.8% of patients.1 However, despite the high risk of PAD in patients with
From the *Department of Neurology and Stroke Center, Tokyo Saiseikai Central Hospital; and the †Department of Neurology, Keio University School of Medicine, Tokyo, Japan. Received July 1, 2011; revision received August 24, 2011; accepted August 28, 2011. Address correspondence to Haruhiko Hoshino, MD, Department of Neurology and Stroke Center, Tokyo Saiseikai Central Hospital, 1-4-17 Mita, Minato, Tokyo, 108-0073, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.08.011
stroke, routine PAD screening is seldom undertaken and PAD is probably often missed. Measurement of the ankle-brachial index (ABI), which is the ratio of systolic pressure at the ankle to that in the arm, is a quick, easy, noninvasive method to establish the presence of PAD. A reduced ABI has been shown to identify patients at risk for cardiovascular events.2 In addition, the ABI is useful for identifying high-risk patients who might have no symptoms related to PAD.3 PAD is increasingly recognized as a clinically important marker of atherosclerotic disease because of its association with CVD incidence and mortality. The German Epidemiological Trial on Ankle-Brachial Index (getABI) revealed that the incidence of all stroke types, with the exception of hemorrhagic stroke, was approximately doubled in patients with PAD (defined as an ABI ,0.9), whether symptomatic or asymptomatic.4 The Japanese REACH Registry revealed that the event rates for nonfatal stroke, nonfatal myocardial infarction, and cardiovascular
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death were higher for patients with CVD and PAD than for patients with CVD and CAD. It also revealed that asymptomatic carotid stenosis $70% and ABI ,0.9 were significant predisposing factors for stroke.5 In acute stroke patients, an ABI ,0.9 is a clear predictor of increased stroke recurrence risk.6-9 However, although stroke patients with PAD seem to be one of the high-risk groups for cardiovascular events, many asymptomatic PAD patients are missed. In this study, we assess the prevalence and clinical features of asymptomatic PAD in Japanese stroke patients.
Patients and Methods In 2009, chronic stroke patients receiving care for secondary prevention regularly at the stroke outpatient clinic in Keio University Hospital were enrolled. We recruited the patients consecutively. The mean duration time from the last stroke was 76.8 6 71.0 months (median 48 months). The presence of comorbid conditions was based on the patients’ medical records. The presence of hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, smoking, history of stroke, and history of cardiovascular events including CAD was investigated. Hypertension was diagnosed if the patient’s blood pressure was $140/90 mm Hg or if the patient was receiving antihypertensive treatment. Dyslipidemia was defined according to the criteria established by the Japan Atherosclerosis Society (low-density lipoprotein $140 mg/dL, trigylcerides $150 mg/dL, and/or high-density lipoprotein ,40 mg/dL)10 in addition to a medical history of hypercholesterolemia. Diabetes mellitus was diagnosed according to the criteria defined by the Committee of the Japan Diabetes Society: a fasting plasma glucose (FPG) level of $126 mg/dL and/or a plasma glucose level at 2 hours after a 75-g oral glucose tolerance test (2hPG) of $200 mg/dL. A casual plasma glucose level .200 mg/dL and/or HbA1c $6.1% was also considered indicative of diabetes mellitus.11 In addition, patients with a history of treatment for diabetes mellitus were regarded as being diabetic. Atrial fibrillation was diagnosed when a previous electrocardiogram (ECG) or ECG monitoring performed on admission revealed atrial fibrillation. With regard to smoking habits, all patients were classified as current or noncurrent smokers. CAD was defined as either a history of angina pectoris or myocardial infarction, with or without coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Intracerebral hemorrhage was diagnosed based on the results of an initial computed tomographic (CT) scan. Ischemic stroke subtypes were determined using the Trial of Org 10172 in Acute Stroke Treatment classification12 for patients without atrial fibrillation and the criteria used in the analysis of Stroke Prevention in Atrial Fibrillation (SPAF)13 for patients with atrial fibrillation.
Figure 1. Results of ankle-brachial index examination. Distributions of the sides and symptoms in patients with ankle-brachial index ,0.9.
Brachial-ankle arterial blood pressures were simultaneously measured using a noninvasive automatic device (model BP-203RPE-III; Nihon Colin, Tokyo, Japan) after a 5-minute rest in the supine position. The ABI is defined as the ratio of the higher systolic blood pressure (SBP) in the ankle (dorsalis pedis and posterior tibial arteries) divided by the average SBP in the arm (brachial arteries) according to the recommendations of the American Heart Association.14 An ABI ,0.9 is considered diagnostic of PAD.15 PAD was defined as either symptomatic or asymptomatic. Asymptomatic PAD was defined as resting ABI ,0.9 with the absence of previous peripheral arterial events or clinical symptoms indicative of intermittent claudication. Symptomatic PAD was defined as intermittent claudication and/or history of peripheral vascular revascularization.
Statistical Analysis We evaluated the associations of PAD with comorbid conditions and clinical characteristics using the analysis of variance, the Fisher exact test, the Pearson Chi-square test, and the Wilcoxon rank-sum test for continuous and categorical variables, as appropriate. All analyses were performed using JMP (v 6.0; SAS, Inc., Cary, NC).
Ethics The data for the study were collected from our hospital’s prospective clinical protocols, which comply with the local ethics guidelines.
Results On ABI examination, 19 patients (18.8%) were diagnosed with PAD (Fig 1). Of those patients, 52.6% had abnormal ABI values on both sides, 15.8% on the right side only, and 31.6% on the left side only. Eleven patients (57.9%) among the patients with PAD had no intermittent claudication or other symptoms of leg ischemia (Fig 1).
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Table 1. Demographics, characteristics and risk factors of patients with symptomatic and asymptomatic peripheral artery disease Symptomatic
Asymptomatic
a:ABI ,0.9
b:ABI ,0.9
c:ABI $0.9
No. of cases
8
11
82
P value (b vs c)
P value (a 1 b vs c)
Gender (male %) Age (mean 6 SD) Hypertension Diabetes mellitus Dyslipidemia Smoking Atrial fibrillation CAD Previous stroke
62.5% 75.8 6 7.8 87.5% 62.5% 87.5% 0.0% 37.5% 14.3% 12.5%
90.9% 76.8 6 8.8 100.0% 63.6% 45.5% 0.0% 0.0% 0.0% 9.1%
80.5% 70.6 6 9.8 75.6% 25.6% 65.9% 11.0% 9.8% 11.4% 6.3%
.68 .05 .11 .02 .20 .59 .59 .59 .55
1.00 .02 .11 ,0.01 .80 .20 .43 .68 .62
Abbreviations: CAD, coronary artery disease; SD, standard deviation.
All 8 patients with symptomatic PAD had abnormal ABI examinations. Among the patients without PAD symptoms, demographics, characteristics, and risk factors were compared between the patients with ABI ,0.9 and those with ABI $0.9. Patients with ABI,0.9 were older (P 5 .0192) and had a higher prevalence of diabetes mellitus (P 5 .0028). There were no significant differences in the sex or in the prevalence of hypertension, dyslipidemia, current smoking, atrial fibrillation, coronary artery disease, or previous stroke between the patients with PAD and those without PAD (Table 1). The prevalences of PAD were higher in the patients with atherothrombotic infarction (28.2%), lacunar infarction (14.3%), cardioembolism (16.7%), and TIA (25.0%). The prevalence of asymptomatic PAD was high in the patients with atherothrombotic infarction (20.5%) and lacunar infarction (14.3%; Fig 2). The patients with other cerebral infarction or intracerebral hemorrhage had a lower prevalence of PAD.
52% in those .85 years of age.19 In the getABI study, the PAD prevalence in the total sample was 18.0%, with rates showing a sharp increase from 11% in the 65- to 70-year-olds to 39% in the $85-year-olds.20 Among stroke patients, the prevalence of PAD has been reported to be higher. In the getABI, the prevalence of ABI ,0.9 was 30.3% in 607 patients with a history of cerebrovascular disease.21 In the Polyvascular Atherothrombosis Observational Survey (PATHOS), an ABI #0.90 was found in 33.5% of 755 patients with acute cerebrovascular disease.8 In the Systemic Risk Score Evaluation in Ischemic Stroke Patients (SCALA), 51% of patients hospitalized with TIA/ischemic stroke had abnormal ABI values (#0.9).22 This higher prevalence may explained in part by the higher mean age and higher proportion of patients with atherosclerotic stroke in the SCALA study. In a study on 58 retrospectively selected Japanese patients with ischemic stroke, prevalence of ABI was a relatively low 17%.23 In the present study, we revealed that the
Discussion The ABI is a reliable, noninvasive screening tool for lower extremity ischemia and function.16 Measurement of ABI allows the identification of both symptomatic and asymptomatic patients with PAD. Therefore, ABI measurement is widely recommended for PAD screening.15 Many clinical studies have reported that PAD is highly prevalent in the general population of the United States and Europe. In the Cardiovascular Health Study, among the 5748 participants enrolled (mean age 73 6 6 years), 793 participants (13.8%) had ABI values of ,0.9.17 In the National Health and Nutrition Examination Survey (NHANES), which included 3947 men and women 60 years of age and older, the prevalence of PAD (defined as ABI ,0.9 in either leg) was 12.2%.18 PAD increases with age. In the Rotterdam Study, the prevalence of PAD increased from 7% in patients 55 to 59 years of age to
Figure 2. Prevalence of symptomatic and asymptomatic peripheral artery disease in subclasses of stroke.
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prevalence of abnormal PAD in a larger cohort of Japanese patients with chronic stroke was 18.8%, almost identical to the value in the previous report. In the present analysis, almost 60% of patients with PAD were asymptomatic. The prevalence of asymptomatic PAD patients can only be determined by using noninvasive screening tools. Asymptomatic patients have been found to have a reduced ABI with no claudication pain or other complaints.24 The NHANES reported that twothirds of subjects were asymptomatic.18 In the getABI study, among the total of 6821 patients 65 years of age or older, 1429 persons were categorized as PAD patients (21.0%), and 836 of these patients had asymptomatic PAD.4 In the SCALA study, symptomatic PAD was seen in only 10% of the patients compared with abnormal ABI in 51% of the patients.22 In the prospective, multicenter, Austrian, cross-sectional study (OECROSS), only 6.2% of the patients with acute ischemic stroke had a history of PAD, but an abnormal ABI of #0.9 was found in 44.9% of patients.25 In a prospective, longitudinal, hospital-based cohort study, asymptomatic PAD was detected by ABI measurement in 26% of the consecutive patients with stroke and patients with TIA.26 Busch et al9 reported that 31% of their acute ischemic stroke patients had a low ABI (#0.9), and the vast majority of these lowABI subjects (71%) were previously undiagnosed and asymptomatic. The high prevalence of asymptomatic PAD in our study may be explained by the lower walking activity because of the stroke disability. We showed that asymptomatic PAD stroke patients tended to be older and had a significantly higher prevalence of diabetes mellitus. In the getABI study, patients with PAD were older, had a higher mean systolic blood pressure, were more frequently current or previous smokers, and had a higher proportion of concomitant diseases (diabetes mellitus, arterial hypertension, or lipid disorders).20 In the NHANES study, current smoking, previous smoking, diabetes mellitus, low kidney function, mildly decreased kidney function, highsensitivity C-reactive protein .3.0 mg/dL, treated but not controlled hypertension, and untreated hypertension were all significantly associated with prevalent PAD.18 In a recent study on acute stroke patients, a low ABI was found in 63 patients (31%) and was associated with older age, current smoking, hypertension, peripheral arterial disease, and cervical or intracranial stenosis.9 In our study, only diabetes mellitus was significantly different, and all other risk factors were statistically similar between patients with and without PAD. The reason for this finding was that all stroke patients in this study already had many atherosclerotic risk factors. Only diabetes mellitus was significantly more prevalent in the asymptomatic PAD patients. This means that the patients with diabetes mellitus tended not to have ischemic symptoms in their legs. With respect to silent coronary ischemia in patients with diabetes mellitus,27
one of the possible explanations is comorbid diabetic autonomic sensory neuropathy.28 In the present work, we found that the prevalence of PAD was different among clinical subtypes of stroke patients. Asymptomatic PAD was higher in patients with atherothrombotic infarction and TIA. Busch et al9 reported that an ABI #0.9 was found in 18 of 46 (39.1%) atherosclerotic, in 19 of 61 (31.1%) cardioembolic, in 15 of 57 (26.3%) lacunar infarction, and in 11 of 40 (27.5%) other or undetermined stroke patients.9 Sawayama et al29 reported that PAD was present in 81 of 101 patients (80.2%) with acute ischemic stroke admitted to 1 hospital, including 57 of 73 (78.1%) with small artery occlusion, 11 of 13 (84.6%) with large artery occlusion, and 13 of 15 (86.7%) with cardiogenic embolism. In 42 of these 81 patients (51.9%), PAD was asymptomatic. The reason for their high prevalence ratios of PAD seemed to be that they defined PAD as being present when either lower extremity MRA or ultrasonography revealed severe stenosis or occlusion or when at least 2 out of 3 clinical factors (ABI ,0.9, a pulseless artery, and symptoms) were positive. However, the prevalence of PAD has varied in previous studies depending on the age distribution of the subjects, the presence or absence of underlying disease, and the diagnostic criteria used for diagnosing PAD.29 PAD has been correlated with intracranial stenosis.23 In the OECROSS study, the prevalence of abnormal ABI was 95 of 183 (51.9%) in large artery atherosclerosis, 74 of 170 (43.5%) in cardioembolism, and 97 of 202 (48.0%) in small vessel disease.25 It is reasonable that the prevalence of PAD was high in patients with atherothrombotic infarction or TIA, most of whom had advanced systemic atherosclerosis. The reason for the high prevalence of PAD in the patients with cardioembolism was that these patients also had atherosclerotic risk factors. There were some limitations in this study. First, the subjects came from only a single university clinic and the size of the sample was small. Second, only ABI at rest was used for diagnosing PAD. It is possible that more stroke patients with asymptomatic PAD could be found by using diagnostic criteria that included the results of an exercise loading examination.30 Summarizing these data, the prevalence of PAD defined as an ABI ,0.9 among stable stroke patients was about 20%. About two-thirds of patients with PAD were asymptomatic. Asymptomatic PAD patients had a significantly higher prevalence of diabetes mellitus. Because stroke patients with PAD were expected to be at high risk of cardiovascular events, a PAD screening examination must be considered in patients with stroke.
References 1. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk
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factors in outpatients with atherothrombosis. JAMA 2006;295:180-189. Heald CL, Fowkes FG, Murray GD, et al. Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review. Atherosclerosis 2006;189:61-69. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001;286:1317-1324. Meves SH, Diehm C, Berger K, et al. Peripheral arterial disease as an independent predictor for excess stroke morbidity and mortality in primary-care patients: 5-year results of the getABI study. Cerebrovasc Dis 2010;29:546-554. Uchiyama S, Goto S, Matsumoto M, et al. Cardiovascular event rates in patients with cerebrovascular disease and atherothrombosis at other vascular locations: Results from 1-year outcomes in the japanese reach registry. J Neurol Sci 2009;287:45-51. Purroy F, Coll B, Oro M, et al. Predictive value of ankle brachial index in patients with acute ischaemic stroke. Eur J Neurol 2010;17:602-606. Weimar C, Goertler M, Rother 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. 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. Busch MA, Lutz K, Rohl JE, et al. Low ankle-brachial index predicts cardiovascular risk after acute ischemic stroke or transient ischemic attack. Stroke 2009;40:3700-3705. Teramoto T, Sasaki J, Ueshima H, et al. Diagnostic criteria for dyslipidemia. Executive summary of Japan Atherosclerosis Society (JAS) guideline for diagnosis and prevention of atherosclerotic cardiovascular diseases for Japanese. J Atheroscler Thromb 2007;14:155-158. Kuzuya T, Nakagawa S, Satoh J, et al. Report of the Committee on the classification and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract 2002;55:65-85. 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. Hart RG, Pearce LA, Miller VT, et al. Cardioembolic vs. noncardioembolic strokes in atrial fibrillation: Frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies. Cerebrovasc Dis 2000; 10:39-43. Orchard TJ, Strandness DE Jr. Assessment of peripheral vascular disease in diabetes. Report and recommendations of an international workshop sponsored by the American Diabetes Association and the American Heart Association September 18-20, 1992 New Orleans, Louisiana. Circulation 1993;88:819-828. 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
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259 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; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. Circulation 2006;113:e463-e654. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: The walking and leg circulation study. Ann Intern Med 2002;136:873-883. O’Hare AM, Katz R, Shlipak MG, et al. Mortality and cardiovascular risk across the ankle-arm index spectrum: Results from the cardiovascular health study. Circulation 2006;113:388-393. Ostchega Y, Paulose-Ram R, Dillon CF, et al. Prevalence of peripheral arterial disease and risk factors in persons aged 60 and older: Data from the national health and nutrition examination survey 1999-2004. J Am Geriatr Soc 2007;55:583-589. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: The rotterdam study. Arterioscler Thromb Vasc Biol 1998;18:185-192. Diehm C, Lange S, Darius H, et al. Association of low ankle brachial index with high mortality in primary care. Eur Heart J 2006;27:1743-1749. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: Cross-sectional study. Atherosclerosis 2004;172:95-105. Weimar C, Goertler M, Rother J, et al. Systemic risk score evaluation in ischemic stroke patients (scala): A prospective cross sectional study in 85 german stroke units. J Neurol 2007;254:1562-1568. Nakano T, Ohkuma H, Suzuki S. Measurement of ankle brachial index for assessment of atherosclerosis in patients with stroke. Cerebrovasc Dis 2004;17:212-217. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: Associated clinical characteristics and functional impairment. JAMA 2001;286: 1599-1606. Topakian R, Nanz S, Rohrbacher B, et al. High prevalence of peripheral arterial disease in patients with acute ischaemic stroke. Cerebrovasc Dis 2010;29:248-254. Sen S, Lynch DR Jr, Kaltsas E, et al. Association of asymptomatic peripheral arterial disease with vascular events in patients with stroke or transient ischemic attack. Stroke 2009;40:3472-3477. Coronado BE, Pope JH, Griffith JL, et al. Clinical features, triage, and outcome of patients presenting to the ED with suspected acute coronary syndromes but without pain: A multicenter study. Am J Emerg Med 2004;22:568-574. Niakan E, Harati Y, Rolak LA, et al. Silent myocardial infarction and diabetic cardiovascular autonomic neuropathy. Arch Intern Med 1986;146:2229-2230. Sawayama Y, Hamada M, Otaguro S, et al. The impact of peripheral arterial disease and acute ischemic stroke. Fukuoka Acta Med 2006;97:293-301. Stein R, Hriljac I, Halperin JL, et al. Limitation of the resting ankle-brachial index in symptomatic patients with peripheral arterial disease. Vasc Med 2006;11:29-33.
Background: A recent worldwide disease registration study has revealed a high prevalence of polyvascular diseases in stroke patients. However, although a poor clinical outcome of patients with polyvascular disease has been reported, there have been few reports on clinical features of peripheral artery disease (PAD) in stroke patients. We assessed the prevalence, demographics, characteristics, and risk factors of PAD in Japanese stroke patients. Methods: One hundred and one consecutive chronic stroke patients in an outpatient clinic underwent anklebrachial index (ABI) screening tests. PAD was diagnosed when the ABI was ,0.9. Results: Abnormal ABI was found in 19 patients (18.8%). Eleven patients were asymptomatic, and 8 patients had symptoms of intermittent claudication. Gender, prevalence of hypertension, and dyslipidemia and alcohol intake were not different between the patients with PAD and those without PAD. Prevalence of diabetes mellitus (63.6%) was higher in the patients with asymptomatic PAD. Among the clinical subtypes of stroke, the patients with atherothrombotic infarction had a higher prevalence of PAD. Conclusions: The prevalence of PAD in stroke patients was 18.8%. Approximately 60% of the patients had no symptoms related to PAD. Diabetes mellitus was associated with higher prevalence of asymptomatic PAD among Japanese stroke patients. Key Words: Ankle brachial pressure index— atherothrombotic infarction—diabetes mellitus—intermittent claudication— peripheral artery disease—polyvascular disease. Ó 2013 by National Stroke Association
Data from the Reduction of Atherothrombosis for Continued Health (REACH) Registry have revealed that a high proportion of patients with cerebrovascular disease (CVD) also have polyvascular diseases, such as coronary artery disease (CAD) in 30.2%, peripheral artery disease (PAD) in 4.3%, and both in 5.8% of patients.1 However, despite the high risk of PAD in patients with
From the *Department of Neurology and Stroke Center, Tokyo Saiseikai Central Hospital; and the †Department of Neurology, Keio University School of Medicine, Tokyo, Japan. Received July 1, 2011; revision received August 24, 2011; accepted August 28, 2011. Address correspondence to Haruhiko Hoshino, MD, Department of Neurology and Stroke Center, Tokyo Saiseikai Central Hospital, 1-4-17 Mita, Minato, Tokyo, 108-0073, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association doi:10.1016/j.jstrokecerebrovasdis.2011.08.011
stroke, routine PAD screening is seldom undertaken and PAD is probably often missed. Measurement of the ankle-brachial index (ABI), which is the ratio of systolic pressure at the ankle to that in the arm, is a quick, easy, noninvasive method to establish the presence of PAD. A reduced ABI has been shown to identify patients at risk for cardiovascular events.2 In addition, the ABI is useful for identifying high-risk patients who might have no symptoms related to PAD.3 PAD is increasingly recognized as a clinically important marker of atherosclerotic disease because of its association with CVD incidence and mortality. The German Epidemiological Trial on Ankle-Brachial Index (getABI) revealed that the incidence of all stroke types, with the exception of hemorrhagic stroke, was approximately doubled in patients with PAD (defined as an ABI ,0.9), whether symptomatic or asymptomatic.4 The Japanese REACH Registry revealed that the event rates for nonfatal stroke, nonfatal myocardial infarction, and cardiovascular
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death were higher for patients with CVD and PAD than for patients with CVD and CAD. It also revealed that asymptomatic carotid stenosis $70% and ABI ,0.9 were significant predisposing factors for stroke.5 In acute stroke patients, an ABI ,0.9 is a clear predictor of increased stroke recurrence risk.6-9 However, although stroke patients with PAD seem to be one of the high-risk groups for cardiovascular events, many asymptomatic PAD patients are missed. In this study, we assess the prevalence and clinical features of asymptomatic PAD in Japanese stroke patients.
Patients and Methods In 2009, chronic stroke patients receiving care for secondary prevention regularly at the stroke outpatient clinic in Keio University Hospital were enrolled. We recruited the patients consecutively. The mean duration time from the last stroke was 76.8 6 71.0 months (median 48 months). The presence of comorbid conditions was based on the patients’ medical records. The presence of hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, smoking, history of stroke, and history of cardiovascular events including CAD was investigated. Hypertension was diagnosed if the patient’s blood pressure was $140/90 mm Hg or if the patient was receiving antihypertensive treatment. Dyslipidemia was defined according to the criteria established by the Japan Atherosclerosis Society (low-density lipoprotein $140 mg/dL, trigylcerides $150 mg/dL, and/or high-density lipoprotein ,40 mg/dL)10 in addition to a medical history of hypercholesterolemia. Diabetes mellitus was diagnosed according to the criteria defined by the Committee of the Japan Diabetes Society: a fasting plasma glucose (FPG) level of $126 mg/dL and/or a plasma glucose level at 2 hours after a 75-g oral glucose tolerance test (2hPG) of $200 mg/dL. A casual plasma glucose level .200 mg/dL and/or HbA1c $6.1% was also considered indicative of diabetes mellitus.11 In addition, patients with a history of treatment for diabetes mellitus were regarded as being diabetic. Atrial fibrillation was diagnosed when a previous electrocardiogram (ECG) or ECG monitoring performed on admission revealed atrial fibrillation. With regard to smoking habits, all patients were classified as current or noncurrent smokers. CAD was defined as either a history of angina pectoris or myocardial infarction, with or without coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Intracerebral hemorrhage was diagnosed based on the results of an initial computed tomographic (CT) scan. Ischemic stroke subtypes were determined using the Trial of Org 10172 in Acute Stroke Treatment classification12 for patients without atrial fibrillation and the criteria used in the analysis of Stroke Prevention in Atrial Fibrillation (SPAF)13 for patients with atrial fibrillation.
Figure 1. Results of ankle-brachial index examination. Distributions of the sides and symptoms in patients with ankle-brachial index ,0.9.
Brachial-ankle arterial blood pressures were simultaneously measured using a noninvasive automatic device (model BP-203RPE-III; Nihon Colin, Tokyo, Japan) after a 5-minute rest in the supine position. The ABI is defined as the ratio of the higher systolic blood pressure (SBP) in the ankle (dorsalis pedis and posterior tibial arteries) divided by the average SBP in the arm (brachial arteries) according to the recommendations of the American Heart Association.14 An ABI ,0.9 is considered diagnostic of PAD.15 PAD was defined as either symptomatic or asymptomatic. Asymptomatic PAD was defined as resting ABI ,0.9 with the absence of previous peripheral arterial events or clinical symptoms indicative of intermittent claudication. Symptomatic PAD was defined as intermittent claudication and/or history of peripheral vascular revascularization.
Statistical Analysis We evaluated the associations of PAD with comorbid conditions and clinical characteristics using the analysis of variance, the Fisher exact test, the Pearson Chi-square test, and the Wilcoxon rank-sum test for continuous and categorical variables, as appropriate. All analyses were performed using JMP (v 6.0; SAS, Inc., Cary, NC).
Ethics The data for the study were collected from our hospital’s prospective clinical protocols, which comply with the local ethics guidelines.
Results On ABI examination, 19 patients (18.8%) were diagnosed with PAD (Fig 1). Of those patients, 52.6% had abnormal ABI values on both sides, 15.8% on the right side only, and 31.6% on the left side only. Eleven patients (57.9%) among the patients with PAD had no intermittent claudication or other symptoms of leg ischemia (Fig 1).
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Table 1. Demographics, characteristics and risk factors of patients with symptomatic and asymptomatic peripheral artery disease Symptomatic
Asymptomatic
a:ABI ,0.9
b:ABI ,0.9
c:ABI $0.9
No. of cases
8
11
82
P value (b vs c)
P value (a 1 b vs c)
Gender (male %) Age (mean 6 SD) Hypertension Diabetes mellitus Dyslipidemia Smoking Atrial fibrillation CAD Previous stroke
62.5% 75.8 6 7.8 87.5% 62.5% 87.5% 0.0% 37.5% 14.3% 12.5%
90.9% 76.8 6 8.8 100.0% 63.6% 45.5% 0.0% 0.0% 0.0% 9.1%
80.5% 70.6 6 9.8 75.6% 25.6% 65.9% 11.0% 9.8% 11.4% 6.3%
.68 .05 .11 .02 .20 .59 .59 .59 .55
1.00 .02 .11 ,0.01 .80 .20 .43 .68 .62
Abbreviations: CAD, coronary artery disease; SD, standard deviation.
All 8 patients with symptomatic PAD had abnormal ABI examinations. Among the patients without PAD symptoms, demographics, characteristics, and risk factors were compared between the patients with ABI ,0.9 and those with ABI $0.9. Patients with ABI,0.9 were older (P 5 .0192) and had a higher prevalence of diabetes mellitus (P 5 .0028). There were no significant differences in the sex or in the prevalence of hypertension, dyslipidemia, current smoking, atrial fibrillation, coronary artery disease, or previous stroke between the patients with PAD and those without PAD (Table 1). The prevalences of PAD were higher in the patients with atherothrombotic infarction (28.2%), lacunar infarction (14.3%), cardioembolism (16.7%), and TIA (25.0%). The prevalence of asymptomatic PAD was high in the patients with atherothrombotic infarction (20.5%) and lacunar infarction (14.3%; Fig 2). The patients with other cerebral infarction or intracerebral hemorrhage had a lower prevalence of PAD.
52% in those .85 years of age.19 In the getABI study, the PAD prevalence in the total sample was 18.0%, with rates showing a sharp increase from 11% in the 65- to 70-year-olds to 39% in the $85-year-olds.20 Among stroke patients, the prevalence of PAD has been reported to be higher. In the getABI, the prevalence of ABI ,0.9 was 30.3% in 607 patients with a history of cerebrovascular disease.21 In the Polyvascular Atherothrombosis Observational Survey (PATHOS), an ABI #0.90 was found in 33.5% of 755 patients with acute cerebrovascular disease.8 In the Systemic Risk Score Evaluation in Ischemic Stroke Patients (SCALA), 51% of patients hospitalized with TIA/ischemic stroke had abnormal ABI values (#0.9).22 This higher prevalence may explained in part by the higher mean age and higher proportion of patients with atherosclerotic stroke in the SCALA study. In a study on 58 retrospectively selected Japanese patients with ischemic stroke, prevalence of ABI was a relatively low 17%.23 In the present study, we revealed that the
Discussion The ABI is a reliable, noninvasive screening tool for lower extremity ischemia and function.16 Measurement of ABI allows the identification of both symptomatic and asymptomatic patients with PAD. Therefore, ABI measurement is widely recommended for PAD screening.15 Many clinical studies have reported that PAD is highly prevalent in the general population of the United States and Europe. In the Cardiovascular Health Study, among the 5748 participants enrolled (mean age 73 6 6 years), 793 participants (13.8%) had ABI values of ,0.9.17 In the National Health and Nutrition Examination Survey (NHANES), which included 3947 men and women 60 years of age and older, the prevalence of PAD (defined as ABI ,0.9 in either leg) was 12.2%.18 PAD increases with age. In the Rotterdam Study, the prevalence of PAD increased from 7% in patients 55 to 59 years of age to
Figure 2. Prevalence of symptomatic and asymptomatic peripheral artery disease in subclasses of stroke.
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prevalence of abnormal PAD in a larger cohort of Japanese patients with chronic stroke was 18.8%, almost identical to the value in the previous report. In the present analysis, almost 60% of patients with PAD were asymptomatic. The prevalence of asymptomatic PAD patients can only be determined by using noninvasive screening tools. Asymptomatic patients have been found to have a reduced ABI with no claudication pain or other complaints.24 The NHANES reported that twothirds of subjects were asymptomatic.18 In the getABI study, among the total of 6821 patients 65 years of age or older, 1429 persons were categorized as PAD patients (21.0%), and 836 of these patients had asymptomatic PAD.4 In the SCALA study, symptomatic PAD was seen in only 10% of the patients compared with abnormal ABI in 51% of the patients.22 In the prospective, multicenter, Austrian, cross-sectional study (OECROSS), only 6.2% of the patients with acute ischemic stroke had a history of PAD, but an abnormal ABI of #0.9 was found in 44.9% of patients.25 In a prospective, longitudinal, hospital-based cohort study, asymptomatic PAD was detected by ABI measurement in 26% of the consecutive patients with stroke and patients with TIA.26 Busch et al9 reported that 31% of their acute ischemic stroke patients had a low ABI (#0.9), and the vast majority of these lowABI subjects (71%) were previously undiagnosed and asymptomatic. The high prevalence of asymptomatic PAD in our study may be explained by the lower walking activity because of the stroke disability. We showed that asymptomatic PAD stroke patients tended to be older and had a significantly higher prevalence of diabetes mellitus. In the getABI study, patients with PAD were older, had a higher mean systolic blood pressure, were more frequently current or previous smokers, and had a higher proportion of concomitant diseases (diabetes mellitus, arterial hypertension, or lipid disorders).20 In the NHANES study, current smoking, previous smoking, diabetes mellitus, low kidney function, mildly decreased kidney function, highsensitivity C-reactive protein .3.0 mg/dL, treated but not controlled hypertension, and untreated hypertension were all significantly associated with prevalent PAD.18 In a recent study on acute stroke patients, a low ABI was found in 63 patients (31%) and was associated with older age, current smoking, hypertension, peripheral arterial disease, and cervical or intracranial stenosis.9 In our study, only diabetes mellitus was significantly different, and all other risk factors were statistically similar between patients with and without PAD. The reason for this finding was that all stroke patients in this study already had many atherosclerotic risk factors. Only diabetes mellitus was significantly more prevalent in the asymptomatic PAD patients. This means that the patients with diabetes mellitus tended not to have ischemic symptoms in their legs. With respect to silent coronary ischemia in patients with diabetes mellitus,27
one of the possible explanations is comorbid diabetic autonomic sensory neuropathy.28 In the present work, we found that the prevalence of PAD was different among clinical subtypes of stroke patients. Asymptomatic PAD was higher in patients with atherothrombotic infarction and TIA. Busch et al9 reported that an ABI #0.9 was found in 18 of 46 (39.1%) atherosclerotic, in 19 of 61 (31.1%) cardioembolic, in 15 of 57 (26.3%) lacunar infarction, and in 11 of 40 (27.5%) other or undetermined stroke patients.9 Sawayama et al29 reported that PAD was present in 81 of 101 patients (80.2%) with acute ischemic stroke admitted to 1 hospital, including 57 of 73 (78.1%) with small artery occlusion, 11 of 13 (84.6%) with large artery occlusion, and 13 of 15 (86.7%) with cardiogenic embolism. In 42 of these 81 patients (51.9%), PAD was asymptomatic. The reason for their high prevalence ratios of PAD seemed to be that they defined PAD as being present when either lower extremity MRA or ultrasonography revealed severe stenosis or occlusion or when at least 2 out of 3 clinical factors (ABI ,0.9, a pulseless artery, and symptoms) were positive. However, the prevalence of PAD has varied in previous studies depending on the age distribution of the subjects, the presence or absence of underlying disease, and the diagnostic criteria used for diagnosing PAD.29 PAD has been correlated with intracranial stenosis.23 In the OECROSS study, the prevalence of abnormal ABI was 95 of 183 (51.9%) in large artery atherosclerosis, 74 of 170 (43.5%) in cardioembolism, and 97 of 202 (48.0%) in small vessel disease.25 It is reasonable that the prevalence of PAD was high in patients with atherothrombotic infarction or TIA, most of whom had advanced systemic atherosclerosis. The reason for the high prevalence of PAD in the patients with cardioembolism was that these patients also had atherosclerotic risk factors. There were some limitations in this study. First, the subjects came from only a single university clinic and the size of the sample was small. Second, only ABI at rest was used for diagnosing PAD. It is possible that more stroke patients with asymptomatic PAD could be found by using diagnostic criteria that included the results of an exercise loading examination.30 Summarizing these data, the prevalence of PAD defined as an ABI ,0.9 among stable stroke patients was about 20%. About two-thirds of patients with PAD were asymptomatic. Asymptomatic PAD patients had a significantly higher prevalence of diabetes mellitus. Because stroke patients with PAD were expected to be at high risk of cardiovascular events, a PAD screening examination must be considered in patients with stroke.
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