J Public Health (2009) 17:127–135DOI 10.1007/s10389-008-0223-8 Presentation and medical management of peripheral arterialdisease in general practice: rationale, aims, designand baseline results of the PACE-PAD Study Anja Neumann & Rebecca Jahn & Curt Diehm &Elke Driller & Franz Hessel & Gerald Lux &Oliver Ommen & Holger Pfaff & Uwe Siebert &Jürgen Wasem &on behalf of the Patient Care Evaluation-PeripheralArterial Disease (PACE-PAD) Study Investigators Received: 24 April 2008 / Accepted: 5 August 2008 / Published online: 10 September 2008 diagnostic and therapeutic management (including referral Background Peripheral arterial disease (PAD) is highly to specialists), and medium-term outcomes.
prevalent among individuals of higher age or those with Methods This was a multicentre, prospective, observational one or more cardiovascular risk factors. Screening for PAD cohort study with a cross-sectional and a longitudinal part.
is recommended, since it is often linked to atherothrombotic A total of 2,781 general practitioners across Germany were manifestations in the coronary or carotid circulation and cluster randomised to document five consecutive patients associated with a substantial increase in all-cause and each in one of the strata: (1) patients with intermittent cardiovascular mortality. We aimed to assess patients with claudication (IC) or other typical PAD-related complaints newly diagnosed, suspected and confirmed PAD in the (group A) or (2) patients >55 years of age with one or more primary care setting with regards to clinical characteristics, risk factors (group B) for PAD (current smoking, diabetes,previous myocardial infection and/or previous stroke).
Patients with confirmed PAD will be followed up for The study group was supported by an advisory board founded in 2003 diagnostic procedures, therapy and vascular events over with the following members: Hans Jürgen Ahrens, Curt Diehm, Leonhard Hansen (until 2004), Klaus-Dieter Kossow.
Results In group A, a total of 2,131 patients with suspected A. Neumann R. Jahn F. Hessel G. Lux J. Wasem (*) PAD (80.1% confirmed, 75.9% with referral to specialists) Alfried Krupp von Bohlen und Halbach-Stiftungslehrstuhl für and in group B 9,921 patients were included (44.6% Medizin-Management, Universität Duisburg-Essen, confirmed, 54.6% referral). The ankle-brachial index was calculated in 41.3% and 33.5% only. Mean age was 45127, Essen, Germanye-mail: [email protected] 66.6 years (group A) and 68.4 years (group B), respective-ly. Vascular risk factors were prevalent in both groups, in particular smoking (group A 44.6%, group B 44.4%), hypertension (73.2 and 78.1%), hypercholesterolaemia (64.6 and 70.6%) and diabetes mellitus (41.7 and 60.6%).
Concomitant atherothrombotic morbidities were frequent in Zentrum für Versorgungsforschung, Universität zu Köln, both groups. In patients with the respective diseases, antihypertensive, antidiabetic, lipid-lowering and antith- rombotic therapies were prescribed in group A in 96.6, 96.0, 91.1 and 89.7% and in group B in 98.3, 97.4, 94.1 Medical Decision Making and Health Technology Assessment, Conclusion The cross-sectional part of the study indicates a Medical Informatics and Technology,Hall, Austria substantial burden of disease in PAD patients in primary care. Treatment rates appear to have improved compared to earlier surveys. In the follow-up period, outcomes of thesepatients and their association with disease stages, guideline- oriented treatment or patient compliance and disease-copingstrategies, among other factors, will be determined.
The primary aim of the study is the description of themanagement (diagnostics and therapy) of patients with Keywords Peripheral arterial disease . Management .
newly diagnosed, suspected or confirmed PAD, with Vascular risk factors . Observational study .
particular focus on the interaction between general physi- cian and specialist care, depending on patient-relatedfactors such as compliance with therapy and activity(coping with disease).
Secondary study aims are the investigation of the outcomes of guideline-oriented therapy on the incidence Atherosclerotic cardiovascular disease remains the most of cardiovascular, cerebrovascular or peripheral vascular common single cause of death in Germany and other events in patients with newly diagnosed PAD, depending Western countries (Statistisches Bundesamt Its three on patient-related factors such as compliance and activity.
main manifestations comprise coronary heart disease The following hypotheses will be tested: The cumulative (CDH), cerebrovascular disease (CVD) and peripheral incidence of cardiac, cerebrovascular and peripheral vascu- arterial disease (PAD). The latter condition has been found lar events during the follow-up period is lower: to be highly prevalent in the general population and in 1. In PAD patients with guideline-oriented management primary care, respectively. For example, the getABI study compared to PAD patients without such management in 6,880 patients aged 65 years and above found asymp- 2. In PAD patients with high compliance compared with tomatic PAD as evidenced by a low ankle-brachial index (ABI) in 12.1%, and symptomatic PAD in 8.7% of patients 3. In PAD patients who are actively coping with their (Diehm et al. ). Thus, only half of patients who present disease compared with patients who do not with objective evidence of PAD have clinically significantlimb symptoms, such as walking impairment, intermittentclaudication, ischaemic rest pain or non-healing wounds (Hirsch et al. ). The main medical problem of the PADpatient is not losing the lower extremity due to amputation, PACE-PAD is a multicentre, observational, non-interventional but rather to suffer a myocardial infarction or stroke (Heald prospective study with pretest and pilot study periods, and in et al. ). In view of the high disease burden of PAD with the main study, a cross-sectional part (all patients) and a its associated risk of poor ischaemic outcomes, appropriate longitudinal part with three visits over 18 months (for screening and intervention measures—including aggressive confirmed PAD patients in Fontaine stage I-IV only, see treatment of the common atherosclerotic risk factors—have Fig. ). Patients were assigned to two strata (symptomatic been suggested repeatedly (Belch et al. ; Hirsch et al.
patients and patients with risk factors, both with suspected While the necessity of such measures is widely undis- A representative sample of ca. 43,500 physicians were puted, the situation and management of PAD patients in contacted (general physicians or internists in primary care) primary care has been less well investigated. It may well throughout Germany. The “total design method” (Dillman differ between primary care setting across health care ) for mail surveys was used with elements to ensure systems and countries (Hirsch et al. ; Khan et al.
high acceptance rates. Basic elements include: minimisation ), and therefore extrapolation may not be possible. The of the burden on the respondent by designing question- primary care setting is of particular interest from a public naires that are attractive in appearance and easy to health perspective, because the general physician serves as complete, printing mail questionnaires in booklet format, gatekeeper (Grumbach et al. with an important role placing personal questions at the end, creating a vertical in the case finding for PAD, referral to specialists to flow of questions and creating sections of questions based confirm or reject the suspected diagnosis and in the long- on their content; constructing a persuasive letter and using term management of these risk patients.
personalised communication; essential follow-up contacts Against this background, the Patient Care Evaluation- of non-respondents (Dillman ). The questionnaire was Peripheral Arterial Disease (PACE-PAD) Study was initiated.
pretested in terms of comprehensibility and feasibility with The present article describes the rationale, aims and methods 12 randomly chosen physicians applying think aloud and of the study and the key findings of the cross-sectional part.
At inclusion the initials, birth date and gender of thepatients were recorded. Further, type of insurance (privateor general) and participation at a disease managementprogram (diabetes mellitus type 1 or 2, coronary heartdisease or other) were noted. Besides weight, height,systolic and diastolic blood pressure (method according tophysician discretion), presence of complaints possiblyassociated with PAD (gluteal or leg pain when walking,reduced walk distance, ulceration or problems with legwound healing), presence of risk factors for PAD (smoking,type 1 or 2 diabetes, arterial hypertension, hypercholester-olaemia and previously diagnosed carotid stenosis) wererecorded, as were previous ischaemic manifestations [tran-sient ischaemic attack (TIA) or prolonged reversibleischaemic neurological deficit (PRIND), stable or unstableangina pectoris, including myocardial infarction] or inter-ventions [percutaneous transluminal coronary angioplasty(PTCA) with or without stenting, coronary artery bypasssurgery (CABG), carotid revascularisation or stenting].
The general health state of the patient was rated by the physician on a 10-point numerical scale (1=extremely poor,10=excellent). Similarly, compliance with therapy (1=extremely poor, 10=excellent) as well as coping withdisease (1=passive, 10=active) were assessed.
The following diagnostic procedures for PAD were recorded (by extremity, if applicable): leg pulse status at Physicians were assigned to one of two patient strata by arteria (a.) femoralis, a. tibialis posterior, a. dorsalis pedis means of cluster randomisation using a computer-generated (normal, pathological, not assessed), auscultation of arter- randomisation list. They were requested to include consec- ies, Ratschow test, measurement of walking distance, tiptoe utively up to five eligible patients in the assigned stratum.
exercise testing, Doppler-based measurement of the ABI, The study was conducted according to the principles of PAD stage according to Fontaine stage (if confirmed: I: “good epidemiological practice” (Arbeitsgruppe Epidemio- asymptomatic, IIa: mild claudication, IIb: moderate-severe logische Methoden der Deutschen Arbeitsgemeinschaft claudication, III: ischaemic rest pain, IV: ulceration or Epidemiologie, DAE). Protection of patient and centre data gangrene), alternatively differential diagnosis of PAD or was ensured. According to a statement of the legal exclusion of PAD diagnosis in the office. Referrals were department of the University Duisburg-Essen, for this non- recorded, too (angiology, vascular surgery, neurology, interventional study a formal approval was not necessary.
orthopaedics, phlebology, radiology, other). In the case ofreferral to a vascular specialist, his/her diagnoses (PAD yes/ no, Fontaine stage, ABI and therapy) were recorded, too.
The following therapeutic measures were recorded: Patients were eligible for inclusion in group A if they had newly specific exercise, drug therapy [prostaglandins, rheologic occurring intermittent claudication (IC) or claudication-like agents (pentoxifylline, naftidrofuryl) or other] and planned vascular surgery (revascularisation, peripheral bypass sur- Patients with suspected PAD were eligible for inclusion gery). Further detailed assessment of risk factor manage- in group B if they were aged 55 years or above and had (1) ment was performed: smoking cessation, antithrombotic previous myocardial infarction and/or (2) previous ischae- therapy (aspirin, ticlopidine, clopidogrel, other), anticoagu- mic stroke and/or (3) manifest type 1 or type 2 diabetes lation (unfractionated heparins, low molecular weight mellitus and/or (4) current smoking (for more than heparins, heparinoids, vitamin K antagonists, other), lipid- lowering measures (diet, statins, fibrates, other), antihyper- Patients were not eligible if they had PAD which had tensive treatment (salt restriction, diuretics, calcium channel blockers, beta blockers, alpha1 blockers, AT1 receptor antagonists, other), antidiabetic therapy (diet, insulin, oral group B. Compared to those patients aged ≥ 55 years, the antidiabetic drugs) or other and unspecified measures used younger patients in group A were less frequently current smokers, but included higher proportions of diabetic andhypercholesterolaemic individuals.
Longitudinal study: endpoints at follow-up visits Diagnostics In group A, 80.1% of all included patients The following endpoints will be recorded: myocardial were finally assigned a PAD diagnosis and in group B infarction, stroke or minor/major amputation due to PAD.
44.6% (Table While the great majority of physiciansreported that they applied basic diagnostic measures such asinspection, auscultation and leg pulse status (usually at three levels and on both sides), walking distance (57.3% ingroup A), tiptoe exercise testing (55.9% in group A) and The sample size was calculated based on the assumption Ratschow test (33.7% in group A) were done less that the cumulative incidence of vascular events after frequently. The ABI was determined in 41.3 (group A) 18 months is 6.8% in PAD patients with guideline-oriented therapy vs 9.8% in other PAD patients. Guideline-orientedtherapy was defined by quality indicators that were Referrals While in group A three quarters were also seen determined by a standardised questionnaire. A sample of by one or more specialists for further diagnostics or therapy, 3,483 symptomatic patients (of whom at least 85% were the proportion was much lower (only 54.6%) in group B assumed to have diagnosed PAD) and of 20,485 patients (Table ). If referred, patients in both groups were seen with risk factors (of whom at least 10% were assumed to mostly by angiologists or vascular specialists.
have diagnosed PAD) is required to obtain a power of 80%at a significance level of 5%.
Health status, coping, compliance The majority of patients Using cross tables, frequency distributions and descriptive were reported to be at an intermediate level of health status statistics, the distributions of variables between the two patient (ca. 60% in level 4–7 on the 10-point scale; Table About strata were compared. Additionally, a subgroup analysis of a quarter of patients (27.8% in group A and 23.5% in patients aged ≥55 years was performed. Throughout all group B) were reported to be passive. Compliance with analyses, a two-sided or the chi-square p value <0.05 (to diagnostics and therapy was predominantly intermediate or evaluate differences between proportions for two or more than two groups) was considered to denote statisticalsignificance. All analyses were performed with SPSS version Management Table shows the patient management for 13 for Windows (SPSS Inc, Chicago, IL, USA).
diabetes, hypertension, hypercholesterolaemia and smokingin both strata. General advice about smoking cessation incurrent smokers and dietary advice in patients with elevated blood cholesterol level was frequent in both groups.
Treatment rates with blood pressure-lowering therapy in Characteristics Table provides an overview of demograph- hypertensive patients were 96.6% in group A and 98.3% in ic and clinical patient characteristics at inclusion. Mean patient group B. Likewise, treatment rates were also similar in both age was somewhat lower in group A compared to group B groups for diabetic patients (antidiabetic therapy in 96.0% (66.6 vs 68.4 years), as per definition in the latter group only in group A and 97.4% in group B), as well as for lipid- patients aged 55 years and above were eligible. Male patients lowering therapy in hyperlipidaemic patients (91.1% in constituted about two thirds of the cohorts. While smoking was recorded in both groups with equal frequency, the otherindex risk factors current smoking, diabetes, hypertension and PAD The great majority of the PAD patients in both groups hypercholesterolaemia were more prevalent in group B, received antithrombotics or anticoagulants (89.7% of group mostly with a long disease history. Previous ischaemic events A and 91.2% of group B; Table ). Pain medication was (myocardial infarctions, stroke etc.), related interventions and prescribed in a quarter of group A and group B patients.
current atherothrombotic manifestations (angina pectoris) While there was a substantially lower proportion of training were noted substantially more frequently in group B, but advice in group A (66.1 vs 71.4% in group B), in this group more prescriptions of rheologic agents (35.0 vs 31.1% in Table subdivides the patients in group A into those group B) and more planned vascular surgery interventions aged below 55 years and those aged 55 years and above, in (23.3 vs 20.6% of group B) were reported. Both groups order to enable direct comparison with the age-matched showed similar prescription prevalences of prostaglandins, Table 1 Patient characteristics in the two strata at inclusion Percutaneous transluminal coronary angioplasty (PTCA) Values indicate % (n)a Carotid stenosis excluded Table 2 Vascular risk factors (age ≥ or <55 years) Values indicate % (n)a Carotid stenosis excluded Table 3 Diagnostics to confirm or reject the PAD diagnosis in the Table 5 Health status, compliance and coping in the two strata Values indicate % (n); 10-point scales with 0=worst and 10=best Table 6 Prescription prevalences for diabetes, hypertension, hyper- a A. femoralis, a. tibialis posterior, a. dorsalis pedis, both legs eachb recommended bed rest, recommended posture of legs, Fontaine stages In group B, there were significantly more asymptomatic PAD patients than in group A, while there were significantly more PAD patients in group A in higher identifiable risk factors. A substantial proportion of patientsin both groups was referred to specialists for differential diagnosis as indicated in the guidelines (e.g. exclusion of spinal claudication, venous claudication, nerve root com- pression or symptomatic Bakers’s cyst (Hirsch et al. Patients with previous CHD, CVD events or PAD had, across vascular beds, remarkably consistent risk factors.
This finding is in line with the “Reduction of Atherothrom- ) or the global observation of survivors of myocardial infarction in the INTERHEART study (Yusuf et al. ).
Both groups in PACE-PAD showed high rates of vascular risk factors and atherothrombotic manifestations; the respective proportions were even higher in group B owing to the inclusion criteria. It was interesting to note that physicians in order to confirm the suspected PAD diagnosis regularly applied the recommended elements of physical examination (inspection, auscultation, pulse palpi- tation at different levels) and did additional non-invasivetests. However, the ABI, which is the most suitable non- invasive screening test for PAD, was infrequently used toconfirm the diagnosis. Compared to angiography, an ABI less than 0.9 is 90% sensitive and 98% specific for astenosis of 50% or more in leg arteries (Criqui et al. ; The present cross-sectional study provides detailed insights Yao et al. ) and, among well-trained operators, the test- into the characteristics, diagnostic procedures and thera- retest reliability is excellent (Holland-Letz et al. ; peutic management of patients with suspected PAD on the Kaiser et al. A large series of studies has confirmed basis of symptoms (group A) or one or more cardiovascular the prognostic value of a low ABI to predict future risk factors that are often associated with PAD (group B).
cardiovascular and cerebrovascular events (Heald et al.
The study is open and non-controlled, which may lead to ; Holland-Letz et al. While this diagnostic tool bias. In contrast to randomised controlled trials, the present is recommended in the major international and national study was performed in health service research. In this PAD guidelines, including those of the USA or Germany context, a blinded design was not practical.
(Diehm et al. Hirsch et al. ; Norgren et al. The suspicion of PAD on the basis of IC was verified it is still underused as PACE-PAD confirms. However, as with further diagnostic procedures by the treating physician this study relies on self-reporting of the physicians, in 80.1% of patients and in about half of the patients (44.6%) with risk factors. This confirms that patients at Regarding management, the data in our study suggest high risk can be easily identified on the basis of clinical that treatment intensity in IC patients as well as in patients symptoms or by the presence of one or more of four easily with risk factors has improved. The current PAD guidelinesunivocally agree that asymptomatic and symptomatic PADpatients should be treated with the same intensity as other manifestations of atherosclerosis, particularly coronaryheart disease. Besides the advice to stop smoking as the central PAD risk factor, concomitant diabetes mellitus, arterial hypertension and dyslipidaemia must be aggres- sively treated (Hirsch and Gotto Hirsch et al. ; Norgren et al. ). The benefit of antiplatelet therapy [acetylic salicylic acid and clopidogrel; )] has been shown in many randomised controlled studies and a meta- analysis of the Antithrombotic Trialists’ Collaboration (Antithrombotic Trialists’ Collaboration Statins have been shown to reduce coronary death in PAD patients irrespective of their initial cholesterol value (Heart Protection Study Collaborative Group and similarly, the ACE The authors confirm that there are no relevant inhibitor ramipril (Yusuf et al. ) has been shown to associations that might pose a conflict of interest.
prevent coronary death in PAD patients with subclinical orclinical disease (Ostergren et al. ). Applying these drug treatments systematically to PAD patients would lead to a25–30% mortality reduction (Feringa et al. ). The large (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) CAPRIE Steering majority of patients in our study received recommendations on how to improve lifestyle (smoking cessation, diet, Antithrombotic Trialists’ Collaboration (2002) Collaborative meta- exercise), and compared to previous screening studies on analysis of randomised trials of antiplatelet therapy for prevention PAD, for example getABI in Germany (Pittrow et al. ), of death, myocardial infarction, and stroke in high risk patients.
BMJ 324:71–86 or PARTNERS in the USA (Hirsch et al. treatment Arbeitsgruppe Epidemiologische Methoden der Deutschen Arbeitsge- rates seem to have improved. The large contemporary meinschaft Epidemiologie (DAE) Leitlinien und Empfehlungen zur REACH registry reported in patients with manifest PAD Sicherung von Guter Epidemiologischer Praxis (GEP). Available and the respective concomitant disease or condition drug treatment rates of 92% for hypertension, 86% for diabetes, Belch JJF, Topol EJ, Agnelli G, Bertrand M, Califf RM, Clement DL, 70% for hyperlipidaemia and 82% for antiplatelet use (Bhatt Creager MA, Easton JD, Gavin I, James R, Greenland P, Hankey et al. While at first glance these rates appear G, Hanrath P, Hirsch AT, Meyer J, Smith SC, Sullivan F, Weber satisfactory, in that registry only a minority of patients were MA (2003) Critical issues in peripheral arterial disease detectionand management: a call to action. Arch Intern Med 163:884–892 at target goals for blood pressure, glucose, cholesterol, body Bhatt DL, Steg PG, Ohman EM, Hirsch AT, Ikeda Y, Mas J-L, Goto S, weight and non-use of tobacco (Bhatt et al. ).
Liau C-S, Richard AJ, Rother J, Wilson PWF, REACH Registry The clinical health status of the majority of IC (Liles et Investigators (2006) International prevalence, recognition, and al. and of vascular risk patients is reduced, which is treatment of cardiovascular risk factors in outpatients withatherothrombosis. JAMA 295:180–189 also confirmed by our findings. Further, various disease- Criqui MH, Denenberg JO, Bird CE, Fronek A, Klauber MR, Langer RD coping strategies [such as “approach or avoidance” in (1996) The correlation between symptoms and non-invasive test patients with CHD (van Elderen et al. have been results in patients referred for peripheral arterial disease testing.
described. The present study will provide an opportunity Diehm C, Heidrich H, Schulte K, Spengel FA, Theiss W, für Deutsche to assess the association between these factors and PAD Gesellschaft für Angiologie, Gesellschaft für Gefäßmedizin (2001) Leitlinien zur Diagnostik und Therapie der arteriellen Verschlus-skrankheit der Becken-Beinarterien. VASA 30(Suppl 57):1–20 Diehm C, Schuster A, Allenberg H, Darius H, Haberl R, Lange S, Pittrow D, von Stritzky B, Tepohl G, Trampisch H (2004) High prevalence of peripheral arterial disease and co-morbidity in 6880primary care patients: cross-sectional study. Atherosclerosis A substantial number of PAD patients in general practice are identified on the basis of IC symptoms or typical risk Dillman D (1991) The design and administration of mail surveys.
factors. Increased use of the ABI would help to make the Feringa HH, van Waning VH, Bax JJ, Elhendy A, Boersma E, diagnostic process more efficient. PAD patients carry a Schouten O, Galal W, Vidakovic RV, Tangelder MJ, Poldermans substantial burden of disease (complaints, comorbidities).
D (2006) Cardioprotective medication is associated with im- Their outcomes will be followed prospectively in the proved survival in patients with peripheral arterial disease. J AmColl Cardiol 47:1182–1187 Grumbach K, Selby JV, Damberg C, Bindman AB, Quesenberry C Jr, AN, JW, FH and RD participated in study conception Truman A, Uratsu C (1999) Resolving the gatekeeper conun- and design, acquisition of data, analysis and interpretation drum: what patients value in primary care and referrals to of data, funding acquisition, and drafting and critical Heald CL, Fowkes FG, Murray GD, Price JF (2006) Risk of mortality revision of the paper for important intellectual content.
and cardiovascular disease associated with the ankle-brachial HP, ED, OO and CD advised on the study design and index: systematic review. Atherosclerosis 189:61–69 focussed especially on patients’ compliance and coping Heart Protection Study Collaborative Group (2002) MRC/BHF Heart with disease. US did the sample size calculations and GL Protection Study of cholesterol lowering with simvastatin in20,536 high-risk individuals: a randomised placebo-controlled the baseline statistical calculations. All authors accept responsibility for the scientific content of the paper.
Hirsch AT, Gotto AM Jr (2002) Undertreatment of dyslipidemia in peripheral arterial disease and other high-risk populations: an The study is supported by an unrestricted opportunity for cardiovascular disease reduction. Vasc Med educational grant from Sanofi-Aventis Pharma. We thank Anja Neumann for her a strong commitment in the project office. Further, Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, we appreciate the help of the participating GPs for collecting the data Olin JW, Krook SH, Hunninghake DB, Comerota AJ, Walsh ME, for the study and their practice staff for their assistance.
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assessed by vascular experts, family physicians and nurses. Vasc Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G (2000) Kaiser V, Kester A, Stoffers H, Kitslaar P, Knottnerus J (1999) The Effects of an angiotensin-converting-enzyme inhibitor, ramipril, influence of experience on the reproducibility of the ankle- on cardiovascular events in high-risk patients. The Heart Out- brachial systolic pressure ratio in peripheral arterial occlusive comes Prevention Evaluation Study Investigators. N Engl J Med disease. Eur J Vasc Endovasc Surg 18:25–29 Khan S, Flather M, Mister R, Delahunty N, Fowkes G, Bradbury A, Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, Stansby G (2007) Characteristics and treatments of patients with McQueen M, Budaj A, Pais P, Varigos J, Lisheng L, INTER- peripheral arterial disease referred to UK vascular clinics: results HEART Study Investigators (2004) Effect of potentially modifi- of a prospective registry. Eur J Vasc Endovasc Surg 33:442–450 able risk factors associated with myocardial infarction in 52 Liles DR, Kallen MA, Petersen LA, Bush RL (2006) Quality of life countries (the INTERHEART study): case-control study. Lancet and peripheral arterial disease. J Surg Res 136:294–301



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