Original Paper. Cerebrovasc Dis 2010;29: DOI: /

Transcription

1 Origial Paper DOI: / Received: October 9, 2009 Accepted: Jauary 18, 2010 Published olie: April 8, 2010 Peripheral Arterial Disease as a Idepedet Predictor for Excess Stroke Morbidity ad Mortality i Primary-Care Patiets: 5-Year Results of the getabi Study Saskia H. Meves a Curt Diehm c Klaus Berger d David Pittrow e Has-Joachim Trampisch b Ia Burghaus b Gerhart Tepohl f Jes-Raier Alleberg h Heiz G. Edres b Markus Schwertfeger i Harald Darius j Roma L. Haberl g for the getabi Study Group a Departmet for Neurology, St. Josef Hospital ad b Departmet of Medical Iformatics, Biometry ad Epidemiology, Ruhr Uiversity of Bochum, Bochum, c Departmet of Iteral Medicie/Vascular Medicie, SRH-Cliic, Karlsbad-Lagesteibach, d Istitute of Epidemiology ad Social Medicie of the Uiversity Hospital Müster, Müster, e Istitute for Cliical Pharmacology, Techical Uiversity Dresde, Dresde, f Iterist/Vascular Medicie, Gefässzetrum Mücher Freiheit ad g Cliic for Neurology, Kliikum Harlachig, Städtisches Kliikum Müche GmbH, Muich, h Departmet of Vascular Surgery, Uiversity of Heidelberg, Heidelberg, i Medical Departmet, Saofi-Avetis Pharma GmbH, ad j Medical Cliic I, Vivates Neukoell Medical Ceter, Berli, Germay Key Words Peripheral arterial disease Stroke mortality Stroke morbidity Akle-brachial idex Primary care Abstract Backgroud: There is cotroversial evidece with regard to the sigificace of peripheral arterial disease (PAD) as a idicator for future stroke risk. We aimed to quatify the risk icrease for mortality ad morbidity associated with PAD. Methods: I a ope, prospective, oitervetioal cohort study i the primary care settig, a total of 6,880 uselected patiets 6 65 years were categorized accordig to the presece or absece of PAD ad followed up for vascular evets or deaths over 5 years. PAD was defied as akle-brachial idex (ABI)! 0.9 or history of previous peripheral revascularizatio ad/or limb amputatio ad/or itermittet claudicatio. Associatios betwee kow cardiovascular risk factors icludig PAD ad cerebrovascular mortality/evets were aalyzed i a multivariate Cox regressio model. Re- sults: Durig the 5-year follow-up [29,915 patiet-years (PY)], 183 patiets had a stroke (icidece per 1,000 PY: 6.1 cases). I patiets with PAD ( = 1,429) compared to those without PAD ( = 5,392), the icidece of all stroke types stadardized per 1,000 PY, with the exceptio of hemorrhagic stroke, was about doubled (for fatal stroke tripled). The correspodig adjusted hazard ratios were 1.6 (95% cofidece iterval, CI, ) for total stroke, 1.7 (95% CI ) for ischemic stroke, 0.7 (95% CI ) for hemorrhagic stroke, 2.5 (95% CI ) for fatal stroke ad 1.4 (95% CI ) for ofatal stroke. Lower ABI categories were associated with higher stroke rates. Besides high age, previous stroke ad diabetes mellitus, PAD was a sigificat idepedet predictor for ischemic stroke. Coclusios: The risk of stroke is substatially icreased i PAD patiets, ad PAD is a strog idepedet predictor for stroke. Copyright 2010 S. Karger AG, Basel These results were preseted by R.L.H. at the Iteratioal Stroke Coferece i Sa Diego, Calif., USA, February 18 20, Fax karger@karger.ch S. Karger AG, Basel /10/ $26.00/0 Accessible olie at: Prof. Dr. Roma L. Haberl, Kliik für Neurologie ud Neurologische Itesivmedizi, Neurologische Frührehabilitatio, Neurophysiologie ud Stroke Uit, Kliikum Harlachig, Städtisches Kliikum Müche GmbH Saatoriumsplatz 2, DE Müche (Germay), Tel Fax , kliikum-mueche.de

2 Backgroud It is well kow that idividuals with peripheral arterial disease (PAD) of the lower extremities are amog the highest-risk vascular patiets [1, 2]. The presece of PAD is widely accepted as a idicator for geeralized atherosclerosis, ad the associatio betwee PAD ad cardiovascular mortality ad morbidity ca be regarded as cofirmed [3 8]. Patiets with stroke or trasiet ischemic attack ofte have PAD [9, 10]. However, it is still uclear whether PAD is also a good predictor for future cerebrovascular disease (CVD). A umber of previous studies have reported coflictig results [11 14], ad epidemiological data i the primary-care settig are limited. Such studies are eeded, as the geeral physicia holds a gatekeeper role i the diagosis ad maagemet of PAD patiets. Thus, the aim of the preset study was to quatify the CVD (stroke) risk of PAD patiets compared to those without PAD i a typical primary-care sample of uselected elderly patiets. For the idetificatio of PAD, the akle-brachial idex (ABI) was used which is the ratio of aterior/posterior akle systolic blood pressure to brachial systolic blood pressure. The ABI is i essece a screeig-level assessmet for PAD i the legs [15, 16]. Whe 0.9 or lower, it is very sesitive ad specific for obstructio compared with the gold stadard agiography [17] or compared with a full vascular laboratory evaluatio [18]. Methods Patiets ad Study Evaluatios The methods ad desig of the Germa Epidemiological Trial o Akle-Brachial Idex (getabi) have bee described elsewhere i greater detail [19, 20]. Briefly, the study is a ope, oitervetioal prospective cohort study that is moitored. A total of 344 geeral physicias (GPs) across Germay, who were traied ad supervised by 34 vascular physicias i their viciity, performed the study. A prevalece assessmet of primary-care attedees, irrespective of their reaso for seeig the doctor, was coducted withi a prespecified week i October I each practice, the geder ad age category of all patiets attedig the practice ad seeig the doctor were recorded i a log file for each day of the week. The oly exclusio criterio was life expectacy ^ 6 moths. A total of 20 (i exceptioal cases up to 25) eligible patiets fulfillig the iclusio criteria (age 6 65 years, patiet beig legally competet ad able to cooperate appropriately ad providig writte iformed coset) were recruited, preferably as evely as possible over this week i order to avoid selectio bias. The sex ad age distributio of this elderly cohort ( = 6,880) was very similar to oe of the geeral populatio ( 6 65 years) i Germay, with a slight uderrepresetatio of the very old [19]. The protocol was approved by the ethics committee of the Ruprecht- Karls Uiversity Heidelberg, ad all patiets provided iformed coset. As the study is purely observatioal, o recommedatio was give to physicias o how to maage their patiets, irrespective of PAD status. Examiatios at Baselie A short physical examiatio was performed at baselie. Medical history assessmet icluded the followig coditios: (a) history of revascularizatio (coroary/at carotids) or myocardial ifarctio [myocardial ifarctio, coroary revascularizatio procedures, revascularizatio procedures o the carotid arteries (ad o stroke)], (b) history of stroke, (c) history of peripheral revascularizatio or amputatio (due to PAD), i.e. a history of revascularizatio procedures o the peripheral arteries, or amputatio (mior ad major form) of the lower extremities o accout of PAD, (d) itermittet claudicatio (i.e. pai i the calf muscles while walkig or durig other exertio ad disappearig withi 10 mi at rest), (e) risk factors, e.g. systolic blood pressure, diabetes, lipid disorders or smokig. Subjects were defied as havig diabetes mellitus (i) if they had bee assiged the cliical diagosis by their physicia ad/or (ii) if their HbA 1c was 6 6.5% (criterio used i 94 cases) ad/or (iii) if they were receivig ay oral atidiabetic drug ad/or isuli at baselie. The 6 6.5% HbA 1c value is above the typically used upper referece value of 6.0% ad is highly specific for diabetes [21, 22]. Subjects were defied as takig hypertesio medicatio, if they were receivig AT 1 receptor atag oists ad/or ACE ihibitors ad/or diuretics at baselie. As -blockers ad calcium chael blockers are ofte used i idicatios other tha hypertesio (e.g. coroary heart disease, heart failure), we excluded them from the defiitio of hypertesio. Subjects were defied as havig lipid disorders (i) if they had bee assiged the cliical diagosis by their physicia ad/or (ii) if they were receivig statis ad/or fibrates ad/or (iii) if their total cholesterol was mg/dl at baselie ad/or (iv) if their triglyceride value was mg/dl at baselie. All laboratory examiatios were performed cetrally. A cigarette smokig history was take from all study subjects (ever, curret, past). Iformatio o atrial fibrillatio was retrieved for stroke patiets from patiet charts ad physicia letters. PAD Defiitio GPs were specifically traied by vascular physicias to perform ABI measuremets uder stadardized coditios o the restig patiet. Doppler measuremets were doe with the Krazbühler 8-MHz device, Geeral Electrics, Solige, Germay. Blood pressure measuremets ad ABI calculatios were performed accordig to the recommedatios of the America Heart Associatio [23, 24]. The ABI was calculated separately for each leg by dividig the higher of the 2 systolic pressures (tibial posterior ad aterior artery) above the akle, by the average of the right ad left brachial artery pressures. If there was a discrepacy 6 10 mm Hg i blood pressure values betwee the two arms, the higher readig was used for the ABI. The lower of the two ABI values was used for aalyses. PAD was defied as either symptomatic or asymptomatic PAD. Asymptomatic PAD was defied as restig ABI! 0.90 [1, 2, 24], with absece of prior peripheral arterial evets or cliical symptoms idicative of itermittet claudicatio. Symptomatic PAD as a Idepedet Predictor for Excess Stroke Morbidity ad Mortality 547

3 PAD was defied as itermittet claudicatio ad/or history of peripheral vascular revascularizatio ad/or limb amputatio due to PAD. Fifty-ie patiets with icompressible arteries (Möckeberg sclerosis) as idicated by a ABI were excluded (52.5% of these were diabetic), as i other studies, to avoid misclassificatio [25, 26], for a total of 6,821 patiets i the aalyses. Cases with missig ABI values ( = 8) ad o past peripheral evets or itermittet claudicatio were classified as patiets without PAD. Defiitio of Stroke Evets durig Follow-Up Iformatio o patiets deaths ad vascular evets was obtaied from the participatig GPs i regular prespecified itervals (at 6 moths, ad at 1, 3 ad 5 years) o case record forms detailig the evet. At the 5-year-follow-up visit, GPs were requested to fill i the case record form, which specifically asked for occurrece of strokes, or hospitalizatios because of a cerebrovascular evet, ad death because of a cerebrovascular evet (other vascular evets were also assessed). Afterwards GPs were asked to supply all available iformatio about these evets (e.g. hospital discharge letter) to the study ceter where two experieced eurologists tried to verify whether there was ideed a stroke. If ecessary, the GPs ad the hospitals were cotacted ad a fial decisio was made. Evets qualified as stroke if commo focal symptoms lasted loger tha 24 h or a defiite ew focal lesio i brai imagig was visualized. Partly due to imprecise or uspecific symptom descriptio of trasiet ischemic attacks, these were excluded from further aalysis. The followig cerebrovascular evets were categorized: total strokes; ischemic ad hemorrhagic strokes; fatal ad ofatal strokes. All strokes were further verified ad adjudicated by two eurologists idepedetly (S.M. ad K.B.), who were uaware of PAD status of patiets. I case of deviatig opiios [27], cosesus was reached by discussio. Particular attetio was paid to the categorizatio of stroke evets ito hemorrhagic ad ischemic [28]. Statistical Aalyses Uivariate ad multivariate Cox regressio aalyses were performed, ad the correspodig hazard ratios (HR, ad their 95% cofidece itervals, CI) were calculated to assess associatios betwee PAD (ad other risk factors) ad 5-year CVD mortality/ morbidity. I additio to PAD (yes/o), or PAD (symptomatic/ asymptomatic) or ABI categories, respectively, the followig variables were icluded i all multivariate statistical models (each yes or o, if ot idicated otherwise): age (above/below media), geder (male/female), smokig status (ever/ever), BMI (above/below 30), history of revascularizatio (coroary/at carotids) or myocardial ifarctio, history of stroke, presece of diabetes, systolic blood pressure per 10 mm Hg (cotiuous), hypertesio medicatio, lipid disorders ad homocysteie (below/above 4th quitile, 19.1 mol/l). For calculatig the icidece rates, oly the first evet was take ito accout. To illustrate possible liear relatios betwee low ABI values ad the risk of CVD deaths or evets, the ABI was categorized accordig to the cutoff poits 1.1, 0.9, 0.7 ad 0.5. Patiets with a history of peripheral revascularizatio or amputatio due to PAD at baselie were icluded as a separate category. Time-to-evet distributios i the idividual categories were summarized with Kapla-Meier curves. Statistical sigificace was accepted at the two-sided 0.05 level, ad all cofidece itervals were computed at the 95% level. Statistical aalyses were performed with SAS versio 9.1 (SAS Istitute Ic., Cary, N.C., USA). Patiet Dispositio at Follow-Up At 5 years, the survival status (dead/alive) of all but 4 of the 6,880 patiets was kow ( %). I 5,032 of 6,049 patiets still alive, a cliical examiatio at study ed could be performed, whereas i 273 cases iformatio could be obtaied oly idirectly, e.g. via telephoe. From the 309 patiets with potetial strokes reported by the GPs (233 ofatal strokes, 76 deaths because of a cerebrovascular evet), 185 were cofirmed as stroke (150 ofatal strokes, 35 deaths because of a cerebrovascular evet). Two strokes (1 ischemic) occurred i the 59 patiets with ABI 1 1.5; oe of the patiets was diabetic. Patiets lost to follow-up were icluded i the correspodig time-to-evet aalyses with cesorig at the date of last iformatio. R e s u l t s Baselie Characteristics A total of 6,821 patiets aged 65 years or older were icluded i the aalyses. Table 1 shows the baselie characteristics of the 5,392 idividuals without PAD ad the 1,429 persos categorized as PAD patiets (21.0%), of whom 836 had asymptomatic PAD (12.3%) ad 593 symptomatic PAD (8.7%). A total of 311 patiets, i.e. 113 (7.9%) i the PAD group ad 198 (3.7%) i patiets without PAD, had a history of stroke. PAD patiets were somewhat older tha patiets without PAD, were more commoly curret or past smokers, ad had a higher burde of cocomitat diseases, i particular diabetes mellitus. Stroke Mortality ad Morbidity by PAD Status Durig the 5-year follow-up (29,915 patiet-years, PY), 183 patiets had a stroke (icl. fatal; 6.1 cases per 1,000 PY; 95% CI ). For compariso, the icidece per 1,000 PY for a myocardial ifarctio, a coroary revascularizatio ad/or death because of a cardiovascular evet was 17.7 (95% CI ). O the left, figure 1 shows the PY ad umbers of stroke evets, by type (ischemic vs. hemorrhagic), ad outcomes (ofatal vs. fatal). Fatal strokes (35 cases) were much less frequet tha ofatal strokes (149 cases). I patiets with PAD, the raw icidece of all stroke types per 1,000 PY, with the exceptio of hemorrhagic stroke, was about doubled (for fatal stroke tripled). The correspodig uadjusted HR were 2.1 (95% CI ) for total stroke, 2.4 (95% CI ) for ischemic stroke, 0.9 (95% CI ) for hemorrhagic stroke, 3.4 (95% CI ) for fatal stroke ad 1.9 (95% CI ) for ofatal stroke. 548 Meves et al.

4 Table 1. Patiet characteristics at iclusio, i the total cohort ad by PAD status All patiets No/ukow PAD P AD % or mea 8 SD % or mea 8 SD % or mea 8 SD All 6,821 5,392 1,429 Age 6, , , Geder Female 3, , Male 2, , Smokig status Never 3, , Past 2, , Curret BMI 6, , , Diabetes mellitus No/ukow 5, , Yes 1, , Hypertesio medicatio No/ukow 3, , Yes 3, , Lipid disorders No/ukow 1, Yes 5, , , History of stroke No/ukow 6, , , Yes History of revascularizatio (coroary/at carotids) or myocardial ifarctio No/ukow 5, , , Yes Systolic blood pressure 6, , , A total of 59 patiets with ABI >1.5 were excluded from the aalyses. For defiitio of PAD, diabetes mellitus, lipid disorders etc., see Methods sectio. The icreased risk of PAD patiets for stroke remaied sigificat for total stroke, ischemic stroke ad fatal stroke (but ot for hemorrhagic stroke or ofatal stroke) after adjustmet for age, history of stroke evets, atihypertesive medicatio, geder ad kow stroke risk factors as show i figure 1, o the right. Risk icreases after adjustmet were betwee 1.4 (ofatal stroke) ad 2.5 (fatal stroke). Excludig patiets with previous strokes from aalysis, there is o substatial chage i the progostic effect of PAD for ischemic stroke [1.8 ( ) vs. 1.7 ( )]. Figure 2 illustrates the compariso of asymptomatic ad symptomatic PAD patiets for ischemic stroke. Compared to patiets without PAD, the risk icrease was somewhat higher i asymptomatic PAD patiets tha i symptomatic PAD patiets. Differeces for all stroke types did ot reach sigificace (data ot show). Stroke Morbidity ad Mortality by ABI Category I the aalysis of ischemic strokes by ABI category, patiets with ABI (3.8 evets) ad (4.4 evets) had the lowest evet rate per 1,000 PY, while with decreasig ABI evet rates icreased substatially ( fig. 2 ). This fidig is illustrated with evet-free survival over time by ABI category, i figure 3. Similar outcomes were foud for total stroke, ad for ofatal ad fatal stroke. Associatio of Risk Factors ad Icidet Ischemic Stroke I the multivariate aalysis of cardiovascular risk factors ( fig. 4 ), statistically sigificat predictors for ischemic stroke were higher age (defied as above the media of 72 years: HR 2.0), history of stroke (HR 1.9), PAD (HR 1.9), diabetes mellitus (HR 1.5) ad systolic blood pressure (per 10 mm Hg: HR 1.1). Coversely, history of re- PAD as a Idepedet Predictor for Excess Stroke Morbidity ad Mortality 549

5 PY Evets Icidece /1,000 PY HR (adjusted) Strokes total PAD o/ukow 1 24, ( ) PAD 2 5, ( ) Ischemic strokes PAD o/ukow 24, ( ) PAD 5, ( ) Hemorrhagic strokes PAD o/ukow 24, ( ) PAD 5, (0 1.4) Fatal strokes PAD o/ukow 26, ( ) PAD 6, ( ) Nofatal strokes PAD o/ukow 24, ( ) PAD 5, ( ) 1.57 ( ) 1.73 ( ) 0.70 ( ) ( ) 1.41 ( ) Fig. 1. Stroke evets durig 5-year follow-up accordig to various defiitios ad respective adjusted HR i patiets with ad without PAD. F igures i paretheses are 95% CI. A total of 59 patiets with ABI >1.5 were excluded from the aalyses. Oe patiet had a fatal ad a ofatal stroke ad was couted i both subgroups. For the aalysis, oly the first evet was take ito accout. HR as a result of a Cox regressio aalysis: adjusted for diabetes mellitus, hypertesio medicatio, systolic blood pressure per 10 mm Hg, lipid disorders, age (>media), sex, BMI ( 30), smokig (ever), history of revascularizatio (coroary/at carotids) or myo cardial ifarctio, history of stroke ad homocysteie (>4th quitile, 19.1 μmol/l) at baselie. For defiitios, see Methods sectio. 1 Referece, = 5, = 1, Not adjusted for history of revascularizatio (coroary/at carotids) or myocardial ifarctio because of lack of evets. vascularizatio (at carotids/coroary) or myocardial ifarctio was ot foud to be associated with icidet ischemic strokes, or was lipid disorders. The prevalece of atrial fibrillatio, as documeted i patiet charts ad physicia letters, did ot sigificatly differ i stroke patiets without PAD (35 patiets, 28.9%) versus stroke patiets with PAD (15 patiets, 24.2%, p = 0.5 i 2 test). Discussio We have recetly reported a substatially icreased risk of all-cause ad cardiovascular mortality after 3-year ad 5-year follow-ups associated with a low ABI i this cohort [7, 20]. The preset aalysis idicates that such PAD patiets also carry a substatially elevated risk for ischemic stroke, which is about doubled compared to idividuals without PAD. Previously, a series of major commuity studies of at least 3 years duratio ivestigated the relative risk icrease i icidet stroke evets i patiets with a low ABI! 0.9 compared to patiets without PAD. I the Cardiovascular Health Study (5,888 Medicare patiets 665 years), the uadjusted relative risk (RR) associated with a low ABI was 1.9 (95% CI ), ad the adjusted RR was 1.1 (95% CI ) [20, 29]. I the Hoolulu Heart Program (2,767 me aged years of Japaese acestry), the uadjusted RR was 2.1 (95% CI ), ad the adjusted RR was 2.0 (95% CI ) [30]. I the ARIC study (14,839 me ad wome aged years i 4 US commuities), the uadjusted RR was 3.3 (95% CI ), ad the adjusted RR was 1.9 (95% CI ) [31]. Two other studies that used a slightly differet ABI cutoff for the PAD diagosis ( ^ 0.9), amely the Ediburgh Artery Study (55- to 74-year-old primary-care patiets) with a adjusted RR of 2.0 (95% CI ) [11], ad a small Swedish study of 68-year-old me i a commuity sample (adjusted RR 2.0; 95% CI ) [12] came to similar coclusios. Take together, all these studies foud before adjustmet a doubled or tripled stroke risk i patiets with low ABI, ad the risk icrease i the majority 550 Meves et al.

6 Patiets PY Evets Icidece of ischemic strokes /1,000 PY HR (adjusted) All 6,821 29, ( ) PAD o/ukow 5,392 24, ( ) referece PAD total 1,429 5, ( ) 1.73 ( ) PAD asymptomatic 836 3, ( ) 1.91 ( ) PAD symptomatic 893 2, ( ) 1.51 ( ) PAD symptomatic vs. PAD asymptomatic 0.82 ( ) ABI category Missig (.a.) 1.5 ABI 1.1 2,172 9, ( ) referece 1.1 > ABI 0.9 3,414 15, ( ) 1.13 ( ) 0.9 > ABI , ( ) 1.54 ( ) 0.7 > ABI ( ) 2.32 ( ) ABI < (.a.) 2.53 ( ) History of peripheral revascularizatio or amputatio (due to PAD) at baselie ( ) 1.42 ( ) Fig. 2. Ischemic stroke accordig to presece/absece of PAD or accordig to ABI category. F igures i paretheses are 95% CI;.a. = ot assessed. A total of 59 patiets with ABI >1.5 were excluded from the aalyses. HR as a result of a Cox regressio aalysis: adjusted for diabetes mellitus, hypertesio medicatio, systolic blood pressure per 10 mm Hg, lipid disorders, age (>media), sex, BMI ( 30), smokig (ever), history of revascularizatio (coroary/at carotids) or myocardial ifarctio, history of stroke ad homocysteie (>4th quitile, 19.1 μmol/l) at baselie. For defiitios, see Methods sectio Color versio available olie Evet-free survival ABI ABI < ABI < ABI < 0.7 ABI <0.5 Previous peripheral revascularizatio or amputatio due to PAD Fig. 3. Risk of ischemic stroke by ABI category. Evet-free survival refers to the ooccurrece of ischemic strokes Time after baselie (years) 4 5 PAD as a Idepedet Predictor for Excess Stroke Morbidity ad Mortality 551

7 Patiets PY Evets Icidece of ischemic strokes /1,000 PY HR (adjusted) PAD o/ukow 5,392 24, ( ) yes 1,429 5, ( ) Diabetes mellitus o/ukow 5,090 22, ( ) yes 1,731 7, ( ) Age (>media) o 3,696 16, ( ) yes 3,125 13, ( ) Homocysteie (>4th o/ukow 5,488 24, ( ) quitile; 19.1 μmol/l) yes 1,333 5, ( ) Male sex o 3,959 17, ( ) yes 2,862 12, ( ) Smoker (ever) o 3,687 16, ( ) yes 3,134 13, ( ) BMI ( 30) o/ukow 5,246 23, ( ) yes 1,575 6, ( ) History of revasculari- o/ukow 5,975 26, ( ) zatio (coroary/ yes 846 3, ( ) at carotids) or myocardial ifarctio History of stroke o/ukow 6,510 28, ( ) yes 311 1, ( ) Lipid disorders o/ukow 1,158 4, ( ) yes 5,663 24, ( ) Hypertesio o/ukow 3,311 14, ( ) medicatio yes 3,510 15, ( ) Systolic blood pressure cotiuous per 10 mm Hg 1.73 ( ) 1.54 ( ) 2.03 ( ) 1.08 ( ) 1.14 ( ) 1.13 ( ) 1.15 ( ) 1.16 ( ) 1.86 ( ) 0.77 ( ) 1.12 ( ) 1.13 ( ) Fig. 4. Factors associated with icidet ischemic stroke evets. F igures i paretheses are 95% CI. A total of 59 patiets with ABI >1.5 were excluded from the aalyses. HR as a result of a Cox regressio aalysis: adjusted for diabetes, hypertesio medicatio, systolic blood pressure per 10 mm Hg, lipid disorders, age (>media), sex, BMI ( 30), smokig (ever), history of revascularizatio (coroary/at carotids) or myocardial ifarctio, history of stroke ad homocysteie (>4th quitile, 19.1 μmol/l) at baselie. For defiitios, see Methods sectio. of these studies, but ot all, remaied sigificat after adjustmet for other risk factors. Our study is oe of the largest with a relatively high umber of stroke evets. It should be oted that i terms of cardiovascular risk, populatio-based studies as well as our study were uequivocal, cofirmig that a low ABI is a idepedet predictor of future cardiovascular evets [8, 20]. The preset study documets a liear icrease i risk (lowest i ABI ) to the category. I the category of patiets with a ABI ( = 59), the umber of strokes (2) was too low to assess whether there is a higher risk of these patiets with calcified arteries, as has bee suggested i two previous studies [32, 33], who foud a U-shaped risk curve related to the ABI. I our aalysis of associatios betwee various kow cardiovascular risk factors ad ischemic stroke, there was o sigificat differece i terms of comorbid atrial fibrillatio i PAD patiets versus o-pad patiets who had suffered a stroke. However, the differece i the PAD emerged as oe of the sigificat factors, similarly to previous aalyses that documeted the lik betwee PAD ad death due to coroary artery disease [7]. This result clearly cotrasts with the Rotterdam study, i which a low ABI lost its predictive ability after adjustmet for other cardiovascular risk factors [34]. Notably, while previous stroke evets predicted icidet (recurret) strokes, we did ot fid a relatio betwee prior revascularizatios (at carotids or coroaries) as idicators of less severe vascular evets. I cotrast to validated scores ad their al- 552 Meves et al.

8 gorithms for the predictio of recurret strokes i the log term such as the Stroke Progosis Istrumet I II [35] or the Esse Stroke Risk Score [36], previous myocardial ifarctio did ot predict strokes. Lipid disorders i our study were mostly characterized by the itake of statis, which might explai the protective effect of the coditio i the multivariate model. Our study has stregths i terms of represetativeess for the primary care settig, high data quality due to osite moitorig of ceters, very low attritio rates ad early complete follow-ups cocerig life status. However, some limitatios have to be cosidered. While stroke diagoses take from hospital or GP records were verified cetrally to the best extet possible, misclassificatios of evets caot be etirely excluded [28]. However, such misclassificatios would occur i both groups, ad our results are cosistet with the fidigs of previous smaller studies as described above. Secod, data o medicatio use were oly recorded at baselie, but ot durig the follow-up. It is coceivable that physicias icreased the itesity of atihypertesive, lipid-lowerig ad/or atiplatelet treatmet i the ewly diagosed PAD patiets i the absece of blidig, leadig to cofoudig due to medical care [37]. This could have led to a uderestimatio of the risk associated with PAD, but would ot alter the coclusios draw from the study. It is more likely that GPs did ot itesify treatmet i PAD patiets, as udertreatmet seems to be the rule rather tha a exceptio i these patiets [1, 2]. Summig up, primary-care patiets with (asymptomatic or symptomatic) PAD have a substatially icreased risk of stroke, which was sigificat for the all-cause, ischemic ad fatal stroke categories. I the cotext of other studies, our fidigs cofirm the value of PAD (ad a low ABI) for the predictio of icidet vascular evets. Elderly patiets i the primary-care settig should be screeed for PAD to eable striget treatmet of modifiable cardiovascular risk factors to reduce the risk of ischemic stroke ad other vascular evets. Ackowledgmets This study was supported by a urestricted educatioal grat by Saofi-Avetis, Berli, Germay ( ), ad the Germa Federal Miistry of Educatio ad Research (sice 2007). D i s c l o s u r e Dr. Schwertfeger is a full-time employee of Saofi-Avetis Pharma, which is oe of the sposors of the study. Refereces 1 Hirsch AT, Haskal ZJ, Hertzer NR, et al: ACC/AHA 2005 practice guidelies for the maagemet of patiets with peripheral arterial disease (lower extremity, real, meseteric, ad abdomial aortic): a collaborative report from the America Associatio for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Agiography ad Itervetios, Society for Vascular Medicie ad Biology, Society of Itervetioal Radiology, ad the ACC/AHA Task Force o Practice Guidelies (Writig Committee to Develop Guidelies for the Maagemet of Patiets with Peripheral Arterial Disease): edorsed by the America Associatio of Cardiovascular ad Pulmoary Rehabilitatio, Natioal Heart, Lug ad Blood Istitute, Society for Vascular Nursig, Trasatlatic Iter-Society Cosesus ad Vascular Disease Foudatio. Circulatio 2006; 113:e463 e Norgre L, Hiatt W, Dormady J, Nehler M, Harris K, Fowkes F: Iter-society cosesus for the maagemet of peripheral arterial disease (TASC II). Eur J Vasc Edovasc Surg 2007; 33(suppl 1):S1 S75. 3 Criqui MH, Lager RD, Froek A, et al: Mortality over a period of 10 years i patiets with peripheral arterial disease. N Egl J Med 1992; 326: Newma AB, Sutto-Tyrrell K, Vogt MT, Kuller LH: Morbidity ad mortality i hypertesive adults with a low akle/arm blood pressure idex. JAMA 1993; 270: Lee AJ, Price JF, Russell MJ, Smith FB, va Wijk MCW, Fowkes FGR: Improved predictio of fatal myocardial ifarctio usig the akle brachial idex i additio to covetioal risk factors: the Ediburgh Artery Study. Circulatio 2004; 110: Hooi JD, Kester AD, Stoffers HE, Rikes PE, Kotterus JA, va Ree JW: Asymptomatic peripheral arterial occlusive disease predicted cardiovascular morbidity ad mortality i a 7-year follow-up study. J Cli Epidemiol 2004; 57: Diehm C, Lage S, Darius H, et al: Associatio of low akle brachial idex with high mortality i primary care. Eur Heart J 2006; 27: Doobay AV, Aad SS: Sesitivity ad specificity of the akle-brachial idex to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol 2005; 25: Topakia R, Naz S, Rohrbacher B, Koppesteier R, Aicher FT: High prevalece of peripheral arterial disease i patiets with acute ischaemic stroke. Cerebrovasc Dis 2009; 29: Rother J, Alberts MJ, Touze E, et al: Risk factor profile ad maagemet of cerebrovascular patiets i the REACH Registry. Cerebrovasc Dis 2008; 25: Leg GC, Fowkes FG, Lee AJ, Dubar J, Housley E, Ruckley CV: Use of akle brachial pressure idex to predict cardiovascular evets ad death: a cohort study. BMJ 1996; 313: PAD as a Idepedet Predictor for Excess Stroke Morbidity ad Mortality 553

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