Ischemic stroke in patients with intermittent ...

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Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases Adrià Arboix, Marc Tarruella, Lluis García-Eroles, Montserrat Oliveres, Carles Miquel, Miquel Balcells and Cecilia Targa Vasc Med 2004 9: 13 DOI: 10.1191/1358863x04vm523oa The online version of this article can be found at: http://vmj.sagepub.com/content/9/1/13

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V ascular M edicine 2004; 9: 13¡17

Ischemic stroke in patients with intermittent claudication: a clinical study of 142 cases Adria` Arboixa , Marc Tarruellaa , Lluis GarcOá-Erolesb , Montserrat Oliveresa, Carles Miquelc , Miquel Balcellsa and Cecilia Targaa Abstract: The clinical features, risk factors, neuroimaging ndings, and outcome of acute ischemic stroke were assessed in patients with intermittent claudication. Data from 142 patients with ischemic stroke and intermittent claudication were collected from a prospective hospitalbased stroke registry in which 2500 consecutive acute stroke patients attended over a 12-year period. Ischemic stroke in patients with intermittent claudication accounted for 7.7% of all ischemic strokes (n ˆ 1840). Ischemic stroke with and without intermittent claudication showed a similar in-hospital mortality rate (16% vs 14%) and absence of functional limitation at hospital discharge (20.5% vs 18.5%). Ischemic stroke patients with intermittent claudication showed a signi cantly shorter length of stay than patients without symptomatic peripheral arterial disease (14.6 vs 18.8 days, p < 0.05). Ischemic heart disease, transient ischemic attack (TIA), renal dysfunction, and watershed infarct were signi cant independent predictors of ischemic stroke in patients with intermittent claudication. Although cerebral infarction in patients with intermittent claudication showed a clinical pro le suggestive of poor outcome, the prognosis was similar to that of ischemic stroke without intermittent claudication. Key words: arterial occlusive diseases; brain infarction; cerebrovascular accident; intermittent claudication; ischemic stroke

Introduction

Methods

Studies assessing ischemic stroke in symptomatic atherosclerosis peripheral artery disease or intermittent claudication have been relatively small. Intermittent claudication is not only a symptom of leg artery occlusive disease, but also an indicator of generalized atherosclerosis and is associated with a greatly increased cardiovascular and cerebrovascular morbidity and mortality rate.1¡3 Patients with intermittent claudication have a high risk of death from premature ischemic heart disease and stroke.4 H owever, little is known about the clinical features, risk factor pro les, and prognosis of cerebral infarction in patients with intermittent claudication. On the other hand, it seems plausible to consider that this subset of patients may present, (a) a risk factor pro le and clinical features different from those of the remaining patients with cerebral infarct and (b) a poor early outcome compared with ischemic stroke patients without symptomatic peripheral arterial disease. In order to con rm these hypotheses, we assessed clinical features, risk factors, neuroimaging ndings, and outcome of acute ischemic stroke in patients with intermittent claudication collected from a prospective hospital-based stroke registry. A comparison was made with the remaining patients with ischemic stroke without symptomatic peripheral arterial disease.

Between January 1986 and December 1995, data from 2500 acute stroke patients admitted consecutively to the Department of Neurology of the Sagrat Cor H ospital (an acute-care 350-bed teaching hospital in the city of Barcelona, Spain) were collected prospectively in a stroke registry.5 Patients with transient ischemic attack (TIA) (n ˆ 328), intracerebral hemorrhage (n ˆ 270), subarachnoid hemorrhage (n ˆ 35), and spontaneous subdural hematoma (n ˆ 27) were excluded. The study population consisted of 1840 patients with acute ischemic stroke. Subtypes of stroke were classi ed according to the Cerebrovascular Study G roup of the Spanish Neurological Society,6 which is similar to the National Institute of Neurological Disorders and Stroke Classi cation,7 and are those used by our group in previous studies.8,9 Subtypes of stroke included atherothrombotic infarct (n ˆ 553), lacunar infarction (n ˆ 484), cardioembolic infarction (n ˆ 468), infarction of undetermined origin (n ˆ 248), and infarction of unusual etiology (n ˆ 87). De nitions of cerebrovascular risk factors were those used in previous studies.8,9 Patients included in the study had a history of intermittent claudication as de ned by the WH O classi cation,10 that is, effort-induced pain which forced the patient to stop walking, but which disappeared within 10 min of rest. The presence of leg artery occlusive disease was con rmed by an ankle¡brachial pressure index 0.90.11 This index was calculated by dividing the ankle pressure by the brachial pressure. Patients who had undergone reconstructive vascular surgery to relieve the symptoms of intermittent claudication, or amputation, were also eligible for inclusion in the study.

a

Acute Stroke Unit, Department of Neurology, b Intensive Care Unit, and c Department of Vascular Surgery, Hospital del Sagrat Cor, Barcelona, Spain Address for correspondence: Adria` Arboix, Acute Stroke Unit, Department of Neurology, H ospital del Sagrat Cor, Viladomat 288, E-08029 Barcelona, Spain. Tel: + 34 93 4948940; F ax: + 34 93 4948906; E-mail: [email protected].


© Arnold 2004

10.1191/ 1358863x04vm523oa

14

A A rboix et al

F or the purpose of this hospital-based prospective study, 142 patients with ischemic stroke and intermittent claudication secondary to symptomatic atherosclerotic peripheral arterial disease were selected. All patients were admitted to the hospital within 48 h of the onset of symptoms. On admission, demographic characteristics, salient features of clinical and neurological examination and results of routine laboratory tests (blood cell count, biochemical pro le, serum electrolytes, urinalysis), chest radiography, and 12 lead electrocardiography were recorded. Neurological examination was performed every day after admission to the hospital. In all patients, a brain computed tomography (CT) scan was performed within the rst week of hospital admission. Other investigations included magnetic resonance imaging (MR I) or angio-MR I in 22% of patients, arterial digital subtraction angiography in 16%, B-mode echocardiography in 28%, carotid duplex scan in 59%, and immunological study in 7.7%. As in previous studies,5,8,9 demographic variables included age and sex. Anamnestic ndings were dichotomized as present versus absent and included history of hypertension, diabetes, ischemic heart disease, rheumatic heart disease, congestive heart failure, atrial brillation, smoking habit (> 20 cigarettes=day), alcohol abuse ( > 80 g=day), previous TIA, previous cerebral infarction, hyperlipidemia, renal dysfunction (clinically signi cant impaired renal function with serum creatinine concen200 mmol=l), cirrhosis or chronic liver disease, tration chronic obstructive pulmonary disease (COPD), and age 85 years or older. Patients were excluded if they were already receiving dialysis for chronic renal failure. Clinical variables were also dichotomized as present versus absent and included sudden onset of symptoms (minutes), headache, dizziness, seizures, nausea or vomiting, altered consciousness (drowsy, stuporous, comatose), limb weakness (hemiparesis or hemiplegia, Babinski’s sign not mandatory), sensory symptoms, hemianopia, aphasia or dysarthria, ataxia, cranial nerve palsy, presence of lacunar syndrome, and cranial nerve palsy. Neuroimaging variables, also dichotomized as present versus absent, included middle cerebral artery topography, anterior cerebral artery, posterior cerebral artery, watershed cerebral infarct, and vertebral and basilar artery topography. The presence of thrombotic arterial vascular occlusion was also analyzed. Outcome variables also dichotomized as present versus absent included in-hospital mortality, absence of functional limitation at hospital discharge, and length of hospital stay. Statistical methods A comparative analysis of demographic characteristics, vascular risk factors, clinical variables, topography, and outcome data between ischemic stroke in patients with and without intermittent claudication was performed using the Student’s t-test for continuous variables and the chi-squared (c2) test (with Yate’s correction when necessary) for categorical data. Statistical signi cance was set at p < 0.05. Variables related to ischemic stroke in patients with intermittent claudication in the univariate analysis plus age (used as a continuous variable with a constant odds ratio for each year) were studied in two logistic regression models and forward stepwise selection

if p < 0.10. The rst predictive model was based on demographic variables and cardiovascular risk factors, with a total of seven variables, and the second predictive model was based on demographic variables, cardiovascular risk factors, and neuroimaging data, with a total of 10 variables. Ischemic stroke with intermittent claudication, coded as absent ˆ 0, present ˆ 1, was the dependent variable. The level of signi cance to remain in the models was 0.15. The tolerance level was established as 0.0001. The maximum likelihood approach was used to estimate weights of the logistic parameters.12 Odds ratios (OR ) and 95% con dence intervals (CI) were calculated from the beta coef cients and standard errors. The hypothesis that the logistic model adequately t the data was tested by means of the goodness of t c2 test.13 The SPSS-PC ‡ 14 and BM DP15 computer programs were used for statistical analyses.

Results Ischemic stroke in patients with intermittent claudication accounted for 7.7% of all ischemic stroke patients (142 out of 1840). There were 96 men and 46 women with a mean (SD) age of 74.1 (9.1) years. Main vascular risk factors included hypertension that was present in 58% of patients, ischemic heart disease in 29.6%, atrial brillation in 29.6%, and diabetes in 27.5%. TIA prior to ischemic stroke was recorded in 18.3% of patients. Renal dysfunction was present in 5.6% of patients. Main clinical ndings included limb weakness in 80.3% of patients, speech disturbances in 50.7%, and sensory symptoms in 35.9%. In relation to subtypes of stroke, atherothrombotic infarction occurred in 48.6% of patients, lacunar infarct in 27.5%, cardioembolic infarct in 20.4%, infarct of undetermined cause in 2.1%, and infarct of unusual etiology in 1.4%. The main vascular topography was the middle cerebral artery in 48.6% of cases, basilar artery in 8.5%, and cerebral posterior artery in 5.5%. Watershed infarct was observed in 4.4% of cases. A total of 23 patients died, with an in-hospital mortality rate of 16.2%. Absence of de cit at discharge was observed in only 20.5% of the patients. The mean (SD) length of stay was 14.6 (9) days. In the comparison of ischemic stroke that occurred in patients with and without intermittent claudication (Table 1), it was found that in the group with intermittent claudication there was a higher frequency of male gender, diabetes, ischemic heart disease, previous TIA, renal dysfunction, watershed infarct, thrombotic occlusion, and atherothrombotic infarction, as well as a lower frequency of patients aged 85 years or older, cerebral posterior topography, infarction of undetermined etiology, and mean length of hospital stay. Differences regarding other stroke subtypes, including lacunar infarct, cardioembolic infarct, and infarct of unknown cause, were not found. The overall in-hospital mortality rate, the in-hospital mortality rate in patients older than 85 years of age, and the percentage of patients with absence of functional de cit at discharge were also similar. On the other hand, the mean [SD] length of stay of patients with cerebral infarction and intermittent claudication who died was not signi cantly different from that of patients with cerebral infarction without intermittent claudication (15.14 [11.55] days vs 18.8 [22.75] days).


V ascular M edicine 2004; 9: 13–17

Ischemic stroke in patients with intermittent claudication 15

Table 1 Comparison of demographic features, vascular risk factors, clinical variables, and outcome between patients with ischemic stroke with and without intermittent claudication. Data

Ischemic stroke and intermittent claudication n ˆ 142

Ischemic stroke without intermittent claudication n ˆ 1698

p-value

Male sex Age, years, mean (SD) Age, 85 years or older Vascular risk factors Hypertension Ischemic heart disease Atrial brillation Diabetes mellitus Valvular heart disease Congestive heart disease Previous TIA Previous cerebral infarction Renal dysfunction Alcohol abuse ( > 80 g=day) Cigarette smoking ( > 20=day) Hyperlipidemia Chronic obstructive pulmonary disease

96 (67.7) 74.1 (9.1) 15 (10.6)

830 (48.9) 73.9 (12.4) 288 (17)

< 0.001 NS < 0.05

Clinical and neuroimaging variables Headache Seizures Nausea, vomiting Altered consciousness Limb weakness Sensory symptoms Hemianopia Ataxia Cerebral cranial palsy Aphasia, dysarthria Lacunar syndrome Cerebral posterior artery topography Watershed cerebral infarct Thrombotic occlusion Stroke subtypes Atherothrombotic infarct, n ˆ 553 Lacunar infarct, n ˆ 484 Cardioembolic infarction, n ˆ 468 Infarct of undetermined cause, n ˆ 248 Infarct of unusual etiology, n ˆ 87 Outcome Absence of de cit at discharge Length of stay, days, mean (SD) In-hospital mortality, all patients In patients aged 85 years or older

82 42 42 39 12 8 26 30 8 4 19 21 13

(57.7) (29.6) (29.6) (27.5) (8.4) (5.6) (18.3) (21.1) (5.6) (2.8) (13.4) (14.8) (9.1)

11 2 8 22 114 51 23 11 4 72 49 8 6 30

(7.7) (1.4) (5.5) (15.5) (80.3) (35.9) (16.2) (7.7) (2.8) (50.7) (34.5) (5.5) (4.2) (21.1)

69 39 29 3 2

(48.6) (27.5) (20.4) (2.1) (1.4)

896 224 503 354 118 98 202 270 43 44 176 309 113

(52.8) (13.2) (29.6) (20.8) (6.9) (5.8) (11.9) (15.9) (2.5) (2.6) (10.4) (18.2) (6.6)

NS < 0.01 NS < 0.05 NS NS < 0.05 NS < 0.05 NS NS NS NS

197 (11.6) 32 (1.9) 116 (7) 308 (18.1) 1302 (76.7) 693 (40.8) 327 (19.2) 94 (5.5) 8 (0.5) 900 (53.0) 501 (29.5) 172 (10.1) 26 (1.5) 248 (14.6)

NS NS NS NS NS NS NS NS NS NS NS < 0.05 < 0.05 < 0.05

484 445 439 245 85

29 (20.5) 14.6 (9) 23 (16.2) 4 (26.7)

(28.5) (26.2) (25.9) (14.4) (5.0)

< 0.001 NS NS < 0.001 NS

314 (18.5) 18.8 (22.7) 238 (14.0) 75 (26.0)

NS < 0.05 NS NS

Data given as number and percentage in parenthesis unless otherwise stated. NS, not signi cant.

In the multivariate analysis (Table 2), ischemic heart disease (OR ˆ 2.83), watershed infarct (OR ˆ 2.57), renal dysfunction (OR ˆ 2.22), and previous TIA (OR ˆ 1.76) were the only independent predictors of ischemic stroke in patients with intermittent claudication.

Discussion This study shows that 7.7% of patients with ischemic stroke had symptomatic peripheral arterial disease. This percentage is similar to a prevalence of intermittent claudication of 5.6% reported by Liu et al16 and of 6.9% reported by Gracia et al.17 As expected, the number of atherothrombotic strokes was higher in patients with

intermittent claudication. H owever, this study shows that ischemic stroke patients with intermittent claudication may also suffer from other subtypes of stroke, particularly lacunar infarction and cardioembolic stroke. The present ndings con rm the rst hypothesis of differences in the risk factor pro les between ischemic stroke patients with and without intermittent claudication. On the other hand, in the multivariate analysis, three clinical variables (previous TIA, ischemic heart disease, and renal dysfunction) and one neuroimaging variable (watershed infarct) were independently associated with ischemic stroke in patients with intermittent claudication. The comparison of risk factor differences between the study of Liu et al16 and this study shows similar frequencies of hypertension (59.4% vs 57.7%), diabetes



16

A A rboix et al

Table 2 Independent predictive value of different variables on ischemic stroke in patients with intermittent claudication. Logistic regression models

b

SE (b)

Odds ratio (95% CI)

Demographic and vascular risk factorsa Ischemic heart disease Transient ischemic attack

1.0411 0.5643

0.1983 0.2323

2.83 (1.92 to 4.18) 1.76 (1.12 to 2.77)

Demographic, vascular risk factors, and neuroimaging datab Ischemic heart disease Watershed infarct Renal dysfunction Transient ischemic attack

1.0111 0.9454 0.7974 0.5629

0.1995 0.4707 0.4037 0.2330

2.75 (1.86 to 2.57 (1.02 to 2.22 (1.01 to 1.76 (1.11 to

4.06) 6.47) 4.90) 2.77)

a

b ˆ ¡2.7801, SE (b ) ˆ 0.1127, goodness of t c2 ˆ 0.0013, df ˆ 1, p ˆ 0.9715. Area under the ROC curve ˆ 0.606, sensitivity 76%, speci city 43.6%, correct classi cation 73.6%. b b ˆ ¡2.8296, SE (b ) ˆ 0.1155, goodness of t c2 ˆ 0.0825, df ˆ 1, p ˆ 0.7740. Area under the ROC curve ˆ 0.623, sensitivity 73.3%, speci city 49.3%, correct classi cation 71.5%.

(23.3% vs 27.5%), and prior TIAs (17.8% vs 18.3%). However, the occurrence of hyperlipidemia is lower in our study (14.8% vs 37%), a plausible observation in accordance with the bene cial effect of the components (olive oil, fruits, vegetables) of the Mediterranean diet in our patients. Internal carotid artery disease was a risk factor in the study of Liu et al,16 which is consistent with atherothrombotic stroke being the most frequent stroke subtype in our study. On the other hand, the higher occurrence of TIA in ischemic infarction with intermittent claudication may be explained by the greater occurrence of TIA in atherothrombotic stroke. In our study, the prevalence of atherothrombotic stroke in patients with intermittent claudication was signi cantly higher than in patients without intermittent claudication (48.6% vs 28.5%). By contrast, cerebral infarcts of undetermined etiology were more frequent in ischemic stroke patients without intermittent claudication, which is similar to that observed in the study of Liu et al.16 These ndings are consistent with the results of a study in which the frequency of TIA associated with large ischemic infarction in the area of the middle cerebral artery (mainly due to atherothrombotic infarcts) was signi cantly higher than that of TIA associated with lacunar infarcts (38% vs 17.5%).18 Moreover, in a recent study,19 TIA was an independent predictor only for atherothrombotic infarction, which is in agreement with the study of Whisnant et al20 in which TIA was mostly a marker of large artery disease. On the other hand, the higher frequency of ischemic heart disease in cerebral infarcts with intermittent claudication is consistent with previous observations of an increased occurrence of coronary events in claudicants.2,21,22 In the study of Liu et al,16 cardiac ischemia was signi cantly more frequent in stroke with intermittent claudication than in stroke without intermittent claudication. R enal dysfunction was observed in 2.7% of our patients, which is similar to 3.2% in the study of MacWalter et al.23 However, the frequency of renal dysfunction in claudicants (5.6%) was signi cantly higher than in nonclaudicants (2.5%). Serum creatinine acts as a marker for generalized vascular disease. Renal dysfunction may represent the in uence of generalized vascular disease on the kidney24 or seems more likely to be a marker for the severity or duration of hypertension.23,25 The higher frequency of watershed infarcts may be explained because watershed infarcts are more common

in severe stenosis or occlusion of large extracranial arteries,26,27 a fact that is more frequent in ischemic stroke in patients with intermittent claudication. By contrast, the second hypothesis regarding a poor early outcome with ischemic stroke patients without symptomatic peripheral arterial disease was not con rmed given that the immediate prognosis of ischemic stroke patients with intermittent claudication is not worse than the outcome of patients without intermittent claudication, without statistically signi cant differences between both groups. Although peripheral arterial disease is rarely fatal, coronary heart disease and symptomatic peripheral arterial disease tend to be associated.21,22 The general prognosis for patients with symptomatic peripheral arterial disease is particularly negative.28 In the general population, symptomatic peripheral atherosclerosis is a strong predictor of cardiovascular disease and death.3,29,30 Survival following onset of intermittent claudication is only two-thirds of that of the general population: after 10 years, 60% died. In addition, in the study of Bowling et al,31 intermittent claudication, angina pectoris, advancing age, male gender, and computed tomographic evidence of any cerebral infarct especially a watershed infarct or white matter hypodensity ¡ factors that were all present and associated with ischemic stroke in patients with intermittent claudication in our study ¡ were independent risk factors for major vascular events (stroke, myocardial infarction, or vascular death) in patients with a recent TIA or minor stroke. In another study,23 renal dysfunction was a signi cant predictor of increased mortality in acute stroke patients in both the short- and long-term. In the present study, the early prognosis of patients with ischemic stroke with and without claudication was similar, with no differences in the percentages of in-hospital mortality (16% vs 14%) and absence of functional limitation at hospital discharge (20.5% vs 18.5%). In addition, patients with intermittent claudication showed a signi cantly shorter length of stay than those without intermittent claudication (14.6 vs 18.8 days). It has been shown that the short duration of ischemic episodes reduces cerebral damage originating from a later persistent ischemia in experimental32 and clinical studies.33,34 In animal models of focal cerebral ischemia, a brief sublethal ischemic event (a process called ischemic preconditioning) protects tissue from subsequent more severe ischemic injury (ischemic tolerance).35 There is already clinical evidence to support the phenomenon of



Ischemic stroke in patients with intermittent claudication 17

ischemic tolerance in the human heart.36 In a recent study, Moncayo et al37 analysed the outcome of 2490 patients with cerebral infarction and showed that patients with previous TIAs (n ˆ 293) had a signi cantly more favourable outcome that those without TIAs. In that study,37 after adjustment for confounding variables, TIAs lasting 10¡20 min were still signi cantly associated with a favourable outcome. The authors conclude that ischemic tolerance may play a role in patients with TIAs before cerebral infarction, allowing a better recovery from a subsequent ischemic stroke. In summary, although cerebral infarction in patients with intermittent claudication showed a clinical pro le suggestive of poor outcome, including history of TIA, ischemic heart disease, renal dysfunction, and watershed infarction, the prognosis was similar to that of ischemic stroke without intermittent claudication.

Acknowledgements We thank Dr O Aguado from the Department of Internal Medicine and Dr J M assons and Dr E Comes from the Department of N eurology for their valuable scienti c contribution, and Marta Pulido for editing the manuscript and editorial assistance.

References 1 Kannel WB, Skinner JJ Jr, Schwartz MJ, Shurtleff D. Intermittent claudication. Incidence in the Framingham Study. Circulation 1970; 41: 875¡83. 2 Balkau B, Vray M, Eschwege E. Epidemiology of peripheral arterial disease. J Cardiovasc Pharmacol 1994; 23 (suppl 3): S8-S16. 3 Leng GC, Lee AJ, Fowkes FG et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172¡81. 4 Smith FB, Rumley A, Lee AJ, Leng GC, Fowkes FG, Lowe GD. Haemostatic factors and prediction of ischaemic heart disease and stroke in claudicants. Br J Haematol 1998; 100: 758¡63. 5 Arboix A, Vericat MC, Pujades R, Massons J, Garcia-Eroles L, Oliveres M. Cardioembolic infarction in the Sagrat Cor-Alianza Hospital of Barcelona Stroke Registry. Acta Neurol Scand 1997; 96: 407¡12. 6 Arboix A, Alvarez-Sabin J, Soler L for the Cerebrovascular Study Group of the Spanish Society of Neurology. Nomenclatura de las enfermedades cerebrales [Article in Spanish]. Neurologia 1998; 13 (suppl 3): 1¡10. 7 Special Report from the National Institute of Neurological Disorders and Stroke. Classi cation of cerebrovascular diseases III. Stroke 1990; 21: 637¡76. 8 Arboix A, Padilla I, Massons J, Garcia-Eroles L, Comes E, Targa C. Clinical study of 222 patients with pure motor stroke. J Neurol Neurosurg Psychiatry 2001; 71: 239¡42. 9 Arboix A, Massons J, Garcia-Eroles L, Oliveres M, Targa C. Diabetes is an independent risk factor for in-hospital mortality from acute spontaneous intracerebral hemorrhage. Diabetes Care 2000; 23: 1527¡32. 10 Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular survey methods. Geneva: World Health Organization, 1982. 11 Carter SA. Indirect systolic pressures and pulse waves in arterial occlusive diseases of the lower extremities. Circulation 1968; 37: 624¡37. 12 Hosmer DW, Lemershow S. Applied logistic regression. New York: Wiley, 1989: 25¡37.

13 Hosmer DW, Lemershow S. Goodness of t tests for the multiple logistic regression model. Commun Stat 1980; A9: 1043¡69. 14 Norusis MJ. SPSS advanced statistics student guide. Chicago: SPSS, 1990. 15 Dixon WJ. BM DP statistical software manual. Berkeley: University of California Press, 1990: 330¡44. 16 Liu XF, van Melle G, Bogousslavsky J. Heart and carotid artery disease in stroke patients with intermittent claudication. Eur J Neurol 2000; 7: 459¡63. 17 Gracia J, Monteagudo S, Escalante S, Mej‡ás B, Fuentes B, D‡éz-Tejedor E. Symptomatic peripheral vascular and brain ischemic. J Neurol 2002; 249 (suppl 1): 183. 18 Arboix A, Mart‡´-Vilalta JL. Transient ischemic attacks in lacunar infarcts. Cerebrovasc Dis 1991; 1: 20¡24. 19 Arboix A, Morcillo C, Garcia-Eroles L, Oliveres M, Massons J, Targa C. Different vascular risk factor pro les in ischemic stroke subtypes: a study from the ‘Sagrat Cor Hospital of Barcelona Stroke Registry’. Acta Neurol Scand 2000; 102: 264¡70. 20 Whisnant JP, Wiebers DO, O’Fallon WM, Sicks JD , Frye RL. A population-based model of risk factors for ischemic stroke: Rochester, Minnesota. Neurology 1996; 47: 1420¡28. 21 Janzon L, Bergqvist D, Boberg J et al. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. J Intern M ed 1990; 227: 301¡308. 22 Skalkidis Y, Katsouyanni K, Petridou E, Sehas M, Trichopoulos D. Risk factors of peripheral arterial occlusive disease: a case¡control study in Greece. Int J Epidemiol 1989; 18: 614¡18. 23 MacWalter RS, Wong SY, Wong KY et al. Does renal dysfunction predict mortality after acute stroke? A 7-year follow-up study. Stroke 2002; 33: 1630¡35. 24 Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke 1997; 28: 557¡63. 25 Manolio TA, Kronmal RA, Burke GL, O’Leary DH, Price TR for the CHS Collaborative Research Group. Short-term predictors of incident stroke in older adults. The Cardiovascular Health Study. Stroke 1996; 27: 1479¡86. 26 Marti-Vilalta JL, Arboix A, Garc‡á JH. Brain infarcts in the arterial border zones: a clinical pathological correlations. J Stroke Cerebrovasc Dis 1994; 4: 114¡20. 27 Bogousslavsky J, Regli F. Borderzone infarctions distal to internal carotid artery occlusion: prognostic implications. Ann Neurol 1986; 20: 346¡50. 28 Dormandy JA, Murray GD. The fate of the claudicant¡A prospective study in 1969 claudicants. Eur J Vasc Surg 1991; 5: 131¡33. 29 Kannel WB. The demographics of claudication and the aging of the American population. Vasc M ed 1996; 1: 60¡64. 30 Verhaeghe R. Epidemiology and prognosis of peripheral obliterative arteriopathy. Drugs 1998; 56 (suppl 3): 1¡10. 31 Bowling SJ, Medalie JH , Flocke SA, Zyzansku SJ, Yaari S, Goldbourt U. Intermittent claudication in 8343 men and 21-year speci c mortality follow-up. Ann Epidemiol 1997; 7: 180¡87. 32 The Dutch TIA Trial Study Group. Predictors of major vascular events in patients with a transient ischemic attack or nondisabling stroke. Stroke 1993; 24: 527¡31. 33 Hakim AM. Could transient ischemic attacks have a cerebroprotective role? Stroke 1994; 25: 715¡16. 34 Petrov I, Petrova V, Barbov I. Transient ischemic attack (TIA): a clinical model of ischemic tolerance. J Neurol 2002; 249 (suppl 1): 126. 35 Kirino T. Ischemic tolerance. J Cereb Blood Flow M etab 2002; 22: 1283¡96. 36 Tomai F, Crea F, Chiariello L, Gioffre PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation 1999; 100: 559¡63. 37 Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology 2000; 54: 2089¡94.

