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Archives of cardiovascular diseases
Volume 102, n° 8-9
pages 625-631 (août 2009)
Doi : 10.1016/j.acvd.2009.05.004
Received : 24 February 2009 ;  accepted : 18 May 2009
Prevalence of unknown peripheral arterial disease in patients with coronary artery disease: Data in primary care from the IPSILON study
Prévalence de l’artériopathie oblitérante des membres inférieurs méconnue chez les patients coronariens : données de l’étude IPSILON en médecine générale
 

Serge Kownator a, , Jean-Pierre Cambou b, Patrice Cacoub c, d, Philippe Léger e, François Luizy f, Marie-Annick Herrmann g, Pascal Priollet h
a 1, allée Raymond-Poincaré, 57100 Thionville, France 
b Rangueil Hospital, University of Medicine, Toulouse, France 
c CNRS UMR 7087, Pierre-et-Marie-Curie (Paris 6) University, Paris, France 
d Department of Internal Medicine, Pitié-Salpêtrière Hospital, AP–HP, Paris, France 
e Department of Cardiology, Pasteur Clinic, Toulouse, France 
f Paris, France 
g Bristol-Myers Squibb, Rueil-Malmaison, France 
h Department of Vascular Medicine, Saint-Joseph Hospital, Paris, France 

Corresponding author. Fax: +33 3 82 53 39 71.
Summary
Background

Peripheral arterial disease (PAD) is a marker of increased risk of cardiovascular events and of poor prognosis in patients with coronary artery disease (CAD). The prevalence of unknown PAD among patients with CAD varies between studies according to the mode of diagnosis.

Aims

To evaluate the prevalence of unknown PAD, diagnosed using the ankle-brachial index (ABI), in patients from the IPSILON study with a CAD diagnosis; to assess the profile of these patients; and to determine predictors of PAD.

Methods

IPSILON was an observational, cross-sectional study. General practitioners measured ABI in 5679 consecutive adults aged 55 years or over with signs or symptoms suggestive of PAD (21.3%), a history of an atherothrombotic event (42.1%) or two or more cardiovascular risk factors (36.6%). This analysis focuses on the subgroup of patients with CAD and no other known overt atherothrombotic disease.

Results

A total of 1340 patients presented with isolated CAD. PAD (ABI<0.90) was diagnosed in 26.6% of these patients; 16.2% were asymptomatic. Older age, symptoms suggestive of PAD and cardiovascular risk factors were found to be independent predictors of PAD in multivariable analysis.

Conclusion

Over 26% of patients with CAD present with unknown PAD, as diagnosed using ABI measurement. More than half of these patients are asymptomatic. Screening for PAD in patients with CAD will allow detection of a subpopulation at particularly high cardiovascular risk. An aggressive medical treatment strategy could help to improve their outcome.

The full text of this article is available in PDF format.
Résumé
Justification

L’artériopathie oblitérante des membres inférieurs (Aomi) est un indicateur connu de risque accru d’événements cardiovasculaires et un marqueur de mauvais pronostic chez les patients coronariens. La prévalence des Aomi méconnues chez les coronariens varie selon la méthode diagnostique employée dans les différentes études.

Objectifs

Évaluer la prévalence de l’Aomi méconnue diagnostiquée par mesure de l’index de pression systolique (IPS) chez les patients coronariens de l’étude Ipsilon ; décrire le profil de ces patients ; et déterminer les facteurs prédictifs d’Aomi chez ces patients.

Méthodes

Ipsilon était une étude observationnelle et transversale. L’IPS a été mesuré par des médecins généralistes chez 5679 adultes consécutifs, d’âge supérieur ou égale à 55 ans : 21,3 % avec signes cliniques évocateurs d’Aomi, 42,1 % avec antécédents de manifestation athéromateuse, et 36,6 % avec au moins deux facteurs de risque cardiovasculaire associés. La présente analyse a été menée dans le sous-groupe de patients coronariens sans aucune autre atteinte connue de maladie athéromateuse.

Résultats

Mille trois cent quarante patients présentaient une maladie coronarienne isolée. Une Aomi (définie par un IPS inférieur à 0,90) a été diagnostiquée chez 26,6 % d’entre eux ; 16,2 % étaient asymptomatiques. En analyse multivariée, l’âge élevé, la présence de tout symptôme évocateur d’Aomi et celle de facteurs de risque cardiovasculaire étaient des facteurs indépendants associés à l’Aomi.

Conclusion

La mesure de l’IPS a permis de détecter une Aomi chez 26,6 % des patients coronariens. L’Aomi était asymptomatique dans plus de la moitié des cas. Le dépistage de l’Aomi permettra d’identifier une sous-population à risque cardiovasculaire particulièrement élevé. Une prise en charge thérapeutique spécifique pourrait améliorer le pronostic de ces patients.

The full text of this article is available in PDF format.

Keywords : Peripheral arterial disease, Coronary artery disease, Ankle-brachial index, Primary care, Prevalence, Predictors

Mots clés : Artériopathie oblitérante des membres inférieurs, Atteinte coronarienne, Index de pression systolique, Médecine générale, Prévalence, Facteurs prédictifs


Abbreviations

ABI : Ankle-brachial index
CAD : Coronary artery disease
CI : Confidence interval
HDL : High-density lipoprotein
LDL : Low-density lipoprotein
PAD : Peripheral arterial disease
SBP : Systolic blood pressure

Background

Cardiovascular diseases are the leading causes of death in industrialized countries. Prevention of cardiovascular diseases in clinical practice usually focuses on risk factor management of coronary heart disease, stroke or transient ischaemic attack. PAD remains too often ignored, although it has the same underlying cause as cardiovascular disease and is a strong predictor of cardiovascular events and mortality, even when asymptomatic [1, 2, 3, 4, 5]. The ratio between symptomatic and asymptomatic patients varies from 1:1 to 1:6 [4], meaning that a huge number of patients present with a high level of risk but without any symptoms. The PARTNERS study [6] emphasized how often PAD is ignored by patients and physicians in the USA. This is also true in France, as shown in the ATTEST study [7].

CAD is the most prevalent manifestation of cardiovascular disease and is associated with high mortality and morbidity rates. With CAD, as with other atherosclerotic arterial diseases, the cardiovascular event rate is amplified in cases of multiple and/or overlapping locations. Patients with polyvascular disease account for over 20% of vascular patients [8, 9]. In patients with established atherosclerotic arterial disease from the REACH Registry [10], the one-year rate of cardiovascular death/myocardial infarction/stroke/hospitalization for atherothrombotic event(s) (transient ischaemic attack, unstable angina or worsening of PAD) was 13.0% for patients with isolated CAD, 17.4% for patients with isolated PAD and 23.1% for patients with CAD plus PAD. This rate was even higher (26.3%) in cases of CAD plus PAD plus cerebrovascular disease. In the PATHOS study, PAD was found in one third of patients hospitalized for acute coronary or cerebrovascular events and was a predictor of one-year fatal and non-fatal cardiovascular events [11]. Other studies showed that PAD increases the mortality rate in cases of acute CAD [12, 13], including a long-term evaluation [14].

Considering the increased level of risk in patients presenting with both CAD and PAD, and the frequency with which PAD is ignored, we sought to determine the incidence of unknown PAD in a cohort of patients with CAD. The IPSILON study was carried out to evaluate the current prevalence and predictors of PAD using the ABI in 5679 patients considered to be at high risk in primary care [15]. This study included patients presenting with leg pain, history of cardiovascular disease (CAD, cerebrovascular disease or PAD) or two or more conventional risk factors. Our current investigation examines the prevalence of unknown PAD among patients from the IPSILON study with a CAD diagnosis.

Methods

IPSILON was a cross-sectional study. General practitioners selected randomly from a national database were invited to participate. Those who agreed received specific training in the measurement of ABI under standardized conditions. Training was carried out by experienced angiologists and cardiologists in dedicated workshops.

Patients

General practitioners recruited the first five consecutive patients aged 55 years or over into the IPSILON study if they were considered to be at high risk of PAD, irrespective of the reason for seeing the general practitioner. Three clinical, mutually exclusive, high-risk subgroups were predefined as follows:

Group 1 had one or more signs or symptoms suggestive of PAD (first evidence of intermittent claudication, atypical pain in a leg muscle [calf, thigh, or buttock] while walking, pulseless lower limb artery [dorsalis pedis, posterior tibial, popliteal or femoral], iliac or femoral bruits and/or lower limb ulcer or gangrene);
Group 2 (secondary prevention) had a history of at least one atherothrombotic event (myocardial infarction [Q wave or non-Q wave], angina pectoris [stable or unstable], ischaemic stroke, previously established symptomatic PAD [Leriche-Fontaine stage II or higher] and/or carotid, coronary or lower limb artery revascularization [bypass graft or angioplasty]);
Group 3 (primary prevention) had two or more cardiovascular risk factors (history of smoking, hypercholesterolaemia, diabetes and/or hypertension) and no history of an atherothrombotic event.

For the present analysis, we studied patients with isolated CAD from Group 2. Isolated CAD was defined as a history of myocardial infarction (Q wave or non-Q wave), angina pectoris (stable or unstable) or coronary revascularization (bypass graft or angioplasty), without cerebrovascular disease or a known history of PAD.

Data

Patients’ demographic characteristics, body weight and height, signs or symptoms suggestive of PAD and cardiovascular medical and surgical histories were determined by physical examination, questioning and from medical records. Smoking history was established in patients currently or formerly (cessation ≤1year) smoking at least one cigarette per day. History of hypercholesterolaemia was defined as a fasting LDL cholesterol concentration of greater than or equal to 130mg/dL (3.4mmol/L) on two occasions within the past year. The most recent concentrations of total, LDL and HDL cholesterol were also retrieved. Diabetes was defined, regardless of whether it was type 1 or type 2, as a fasting glycaemia of greater than or equal to 126mg/dL on two occasions and/or use of diabetes medication. Hypertension was defined as an SBP of greater than or equal to 140mmHg, a diastolic blood pressure of greater than or equal to 90mmHg on two occasions and/or use of treatment.

Outcome measure

The primary outcome was the prevalence of PAD, defined as ABI less than 0.90 [16]. ABI provides objective data easily and is now the recommended standard for diagnosing PAD [4]. Blood pressure measurements were performed under standardized conditions by the general practitioners. A Doppler ultrasonic pen device (8mHz, Mini Dopplex® D900/EZ8, Huntleigh Healthcare Inc., Eatontown, NJ, USA) was used with a standard sphygmomanometer at each site. We chose the most sensitive method for calculating ABI, i.e. division of the lowest of the four ankle systolic pressures (posterior tibial and dorsalis pedis arteries) by the brachial systolic pressure [17].

Statistical analysis

Standard descriptive statistics were provided for all variables; 95% CIs were calculated when appropriate. Proportions were calculated taking into account missing data in the denominator. Groups were compared using the chi2 test. Factors predictive of PAD were investigated by multivariable logistic regression with stepwise backward procedure (at the 0.20 level), regardless of the univariate analyses results. The following variables were entered into the initial model:

patients’ characteristics (age and signs or symptoms suggestive of PAD);
cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, smoking status, brachial SBP at the visit and latest measurement of LDL cholesterol);
abdominal aortic aneurysm.

The corresponding odds ratios and their 95% CIs were calculated. Statistical significance was accepted at the two-sided 0.05 level. Data were analysed using SAS® 8.02 (SAS Institute Inc., Cary, NC, USA).

Results
Patient characteristics

Between 2nd May 2005 and 15th February 2006, 1219 general practitioners throughout France enrolled 5679 high-risk patients aged 55 years or over in the IPSILON study. History of atherothrombotic events was recorded in 2393 patients; of these, 1340 (56.0%) patients had isolated CAD, 364 (15.2%) had CAD plus cerebrovascular disease and/or a known history of PAD and 689 (28.8%) had no history of CAD. PAD was already known in 79 patients with CAD. Table 1 summarizes the main characteristics of the 1340 patients with isolated CAD, who comprise the study population.

Prevalence of unknown PAD in CAD patients (univariate analyses)

The prevalence of unknown PAD in patients with isolated CAD was 26.6% (n =357; 95% CI 24.3–29.1). Severity of PAD was moderate in most patients, with an ABI less than 0.5 in three (0.8%) cases only, between 0.5 and less than 0.75 in 138 (38.7%) cases and between 0.75 and less than 0.9 in 216 (60.5%) cases.

Univariate analyses in the 357 patients with CAD and PAD (Table 2) showed an increased prevalence of unknown PAD with older age, higher number of cardiovascular risk factors, higher SBP at the visit and increased LDL cholesterol at the latest measurement. In patients with signs or symptoms suggestive of PAD, PAD was found in 43.2%, which was approximately twice as frequent as in asymptomatic patients. The prevalence of PAD was also higher in patients with hypertension, diabetes and angina pectoris, and in smokers (or patients who had stopped smoking in the past year).

Factors associated with PAD in CAD patients (multivariate analyses)

The independent variables significantly associated with the diagnosis of PAD in patients with isolated CAD are displayed in Table 3. The statistical model retained the following variables as risk factors for PAD:

older age;
any symptom suggestive of PAD;
cardiovascular risk factors (smoking, diabetes, uncontrolled arterial hypertension and elevated LDL cholesterol).

Discussion

In the primary care setting, ABI measurement enabled the detection of PAD in 26.6% of 1340 patients with CAD and no other known location of atherothrombotic disease; 16.2% of CAD patients presented with asymptomatic PAD. Prevalence of unknown PAD was increased significantly in patients with diabetes mellitus, whereas myocardial infarction and coronary surgery or angioplasty was not associated with a higher rate of PAD. Independent factors predictive of PAD were identified, such as older age and current or former smoking.

Our study has an observational design, without any study-specific intervention apart from ABI measurement. The data provide a unique, up-to-date picture of PAD screening among CAD patients in France. A weakness may be the subgroup analysis, which resulted in the statistical analysis being less powerful and a lack of certain information that would have been of interest in the context of CAD. To our knowledge, however, little recent information on PAD in CAD patients is available, especially on unknown PAD.

The overall prevalence of PAD was 27.8% in the whole IPSILON cohort. Prevalence of PAD ranged from 10.4% in patients with a high-risk cardiovascular profile only to approximately 38% in patients with symptoms suggestive of PAD [15]. We found here a high prevalence (26.6%) of unknown PAD in CAD patients. This is in line with previous estimations where ABI measurement was used (30–40%) [11, 18, 19] and, as expected, is higher than estimations based on clinical findings only (<10%) [14, 20, 21]. Furthermore, 16.2% of our CAD patients (i.e. more than half of the patients with CAD plus PAD) presented with asymptomatic PAD. Prevalence of PAD was increased in diabetic patients with CAD (34.7%) in univariate analyses. Finally, we identified independent predictors of PAD in CAD patients, as follows: older age, any symptom suggestive of PAD, smoking, diabetes, uncontrolled arterial hypertension and elevated LDL cholesterol.

Our results confirm that widespread use of ABI measurement would enable the detection of a subgroup of patients at a particularly high level of risk. Indeed, an adverse one-year outcome occurs more often in CAD patients with PAD than in those without PAD [11, 22]. We must emphasize the fact that, in the literature, PAD in CAD patients is associated with an increased severity of the disease at the different stages of the disease course [10]. The patients have a multivessel disease more frequently, they experience more events after acute coronary syndrome [23] but also in cases of stable angina, and they have a higher rate of death after percutaneous coronary intervention and after coronary artery bypass grafting [24]. Altogether, these results suggest that diagnosis and control of risk factors in PAD patients need to be improved. This subgroup of patients should achieve tighter risk reduction and could benefit from specific treatment targets. For example, an LDL cholesterol goal of less than 70mg/dL could be a therapeutic option [4].

In conclusion, unknown PAD was diagnosed by ABI measurement in 26.6% of CAD patients with no other known location of atherothrombotic disease, and PAD was asymptomatic in 16.2% of CAD patients. Screening with ABI would allow the identification of a subgroup of CAD patients at particularly high risk and who could benefit from an aggressive medical treatment strategy. Our results should be confirmed in further studies.

Conflicts of interest

Prs/Drs Kownator, Cambou, Cacoub, Léger, Luizy and Priollet have received consulting fees/honoraria/research grants from Sanofi-Aventis France and Bristol-Myers Squibb. Dr Kownator has also received consulting fees/honoraria/research grants from Pfizer and AstraZeneca, Pr Cacoub from Servier, AstraZeneca, Schering-Plough, Roche and Gilead, Dr Léger from Leo Pharma and Dr Priollet from Actelion. Dr Herrmann is an employee of a sponsor.


Acknowledgements

The IPSILON survey was supported by an unrestricted grant from Bristol-Myers Squibb and Sanofi-Aventis France. Bristol-Myers Squibb and Sanofi-Aventis France supported data collection, central analysis and data disposition and publication of the findings. Each of the authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prs/Drs Kownator, Cambou, Cacoub, Léger, Luizy and Priollet (the study’s Scientific Committee) helped to design the study and analyse the data. M. H. Barlet (Winner Pharma, France) helped with field monitoring. F. Bugnard (Mapi-Naxis, France) and N. Schmidely (Bristol-Myers Squibb, France) helped to analyse the data. Dr M. Varastet (ClinSearch, France) and all authors helped to prepare the manuscript. The authors wish to thank all general practitioners who participated in the study.

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