Prevalence, risk factors and cardiovascular comorbidity of symptomatic peripheral arterial disease in Italy

Atherosclerosis 175 (2004) 131 138 Prevalence, risk factors and cardiovascular comorbidity of symptomatic peripheral arterial disease in Italy Gregorio Brevetti a,, Gabriella Oliva a, Antonio Silvestro a, Francesco Scopacasa b, Massimo Chiariello a, Peripheral Arteriopathy and Cardiovascular Events (PACE) Study Group a Departments of Clinical Medicine and Cardiovascular and Immunological Sciences, Via G. Iannelli 45/A, Napoli 80313, Italy b Department of Laboratory Medicine, University Federico II, Naples, Italy Received 1 December 2003; received in revised form 8 March 2004; accepted 17 March 2004 Available online 7 May 2004 Abstract The epidemiology of peripheral arterial disease (PAD) has been studied almost exclusively in northern European and northern American populations. We report the first survey in Italy to describe the prevalence of symptomatic PAD and clinical correlates. From the lists of seven general practitioners, all subjects aged 40 80 years (n = 4352) received a Rose Questionnaire (RQ). In those reporting pain in the leg while walking, which did not disappear while continuing to walk (n = 760), Doppler examination was performed. PAD was defined by ankle/brachial index 0.90, or reduced flow velocity. The prevalence of symptomatic PAD was 1.6% (2.4% in men, 0.9% in women). For each PAD patient, three controls matched for sex and age were randomly selected. At the multivariate analysis, smoking, diabetes and hypertension were significantly associated with PAD. A coexistent cardiovascular disease was found in 34% of patients and 11% of controls (P <0.001). Only PAD was shown to be independently associated with a previous cardiovascular event. Although symptomatic, 45% of the patients were unaware of their condition. In conclusion, prevalence and cardiovascular comorbidity of symptomatic PAD in Italy seem to be lower than in other western countries. The finding that PAD was unrecognised in about 50% of affected individuals implies that a large proportion of PAD population is not given preventive therapy, so remaining at high cardiovascular risk. Thus, there is need to alert general practitioners to this topic. 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Peripheral arterial disease; Epidemiology; Risk factors; Cardiovascular comorbidity 1. Introduction Peripheral arterial disease (PAD), one of the most common clinical manifestations of atherosclerosis, affects a significant number of individuals, represents an important cause of disability and is associated with elevated cardiovascular morbidity and mortality [1]. Thus, PAD places a great burden on health care system and on society as a whole, and the concept that this condition merits great attention from the physicians and public health authorities is widely shared [2,3]. However, our knowledge about the epidemiology of Corresponding author. Tel.: +39-081-7462240; fax: +39-081-7462240. E-mail address: brevetti@unina.it (G. Brevetti). PAD is derived from studies carried out almost exclusively in northern European and northern American populations [4 8], and, thus, it is unclear what is the magnitude of the problem in other countries. The epidemiology of atherosclerotic disease is influenced by a number of factors, such as genetics, ethnicity, diet, environment genetic interactions, lifestyle and others, that may vary from one population to another. Therefore, the distribution and natural history of PAD in a southern European country could be different from that observed in northern European communities. We report on the first survey in Italy to describe the prevalence of symptomatic PAD in the general population and its relationship with cardiovascular risk factors and other diseases. Our intention is to follow-up this population during subsequent years to study the natural history of PAD in a Mediterranean population. 0021-9150/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.03.009

132 G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 2. Methods 2.1. Study population and general design The study area included five villages, located in a predominantly urban territory of Irpinia, a well-defined area of the region Campania in Southern Italy. Every citizen in Italy is registered in a general practice and, thus, the population of a general practice is a segment of the general population. Seven out 21 general practitioners were randomly selected and accepted to participate to the study. From their lists all subjects were identified who were aged 40 80 years. General practitioners reviewed lists of their patients and excluded those unfit to participate (e.g. due to severe mental illness or terminal disease), those who had moved from the practices and those who had died. A Rose Questionnaire (RQ) [9] for identifying leg symptoms while walking was posted to each subject with an explanatory letter. After 1 month, each non-responder was interviewed by telephone or visited at home by his (her) general practitioner. Subjects who reported pain in the calf that began while walking and did not disappear while continuing to walk, and those with other complaints of the calf, foot, thigh or buttock (not of the knee) showing the ischaemic pattern described above, were included in the definition of possible symptomatic PAD. These subjects underwent Doppler examination with measurement of ankle/brachial index (ABI) and flow velocity in the femoral and posterior tibial arteries for confirmation of PAD diagnosis. Subjects were also questioned about lower extremity vascular interventions and amputations. Patients who did not attend were offered another appointment. 2.2. Data collection Data regarding demographic characteristics, smoking habit, established cardiovascular risk factors, presence of coronary artery disease (CAD), cerebrovascular disease (CVD), previous vascular interventions and current pharmacological treatments were obtained from the subjects electronic medical records. Furthermore, the general practitioner filled the cumulative illness rating scale (CIRS) [10], an instrument which explores the presence and the severity of 14 diseases (these data will be presented separately). The subsequent medical examination, performed by four trained physicians, included the administration of the Walking Impairment Questionnaire (WIQ) [11], the collection of a venous blood sample (after 12 h of fasting), and the measurement of ABI and flow velocity. Systolic blood pressure was taken with an 8-MHz Doppler probe and a random zero sphygmomanometer, in the supine position, after 5 min of rest. For each leg, a single blood pressure reading was taken. The ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the arm (ABI) was calculated for each leg. 2.3. Diagnostic criteria and definitions PAD was defined by ABI < 0.90, or reduced flow velocity in at least one leg. Femoral peak forward flows 20 cm/s and posterior tibial peak forward flows 10 cm/s are considered to be abnormal when accompanied by delayed pulse decays or reduced deceleration [12]. Hypertension was diagnosed if systolic arterial pressure exceeded 140 mmhg and/or diastolic arterial pressure exceeded 90 mmhg, or if the patient used antihypertensive drugs. Hyperlipidemia was diagnosed if plasma total cholesterol exceeded 200 mg/dl or plasma triglycerides exceeded 200 mg/dl or HDL cholesterol was lower than 35 mg/dl, or if the patient used lipid-lowering drugs. Diabetes mellitus was diagnosed if plasma fasting glucose exceeded 120 mg/dl or if the patient used hypoglycaemic drugs. Smokers were defined as former or current smokers. The coexistence of CAD (stable and unstable angina, myocardial infarction, bypass grafting and percutaneous transluminal coronary angioplasty) and CVD (transitory ischaemia attack, stroke and carotid surgery) was assessed by the general practitioners on the basis of data from hospital records. A history of angina pectoris not documented by a medical report was assessed by the World Health Organization Questionnaire [9], at the time of the vascular visit. 2.4. Inflammatory markers Plasma CRP was determined with highly sensitive assay (Dade Behring Diagnostics, Marburg, Germany). Clottable fibrinogen was estimated according to a functional assay (Clauss) on a Behring BCS coagulation analyzer with Multifibren U (Dade Behring Diagnostics). 2.5. Control subjects For each patient identified as having symptomatic PAD, three controls negative to the RQ, matched for sex and age (±2 years), were selected randomly from the alphabetical listing for each general practice. These subjects underwent similar investigations as PAD patients. Six (3.3%) of them presented an ABI < 0.90 and were excluded from the analysis. Patients and controls gave their informed consent to the study, which was approved by the ethics committee at our institution. 2.6. Statistical analysis For PAD the age and sex-specific prevalence rates were calculated with exact 95% confidence interval (CI). In both PAD patients and controls, the prevalence of risk factors and other comorbid conditions, and the corresponding crude odds ratio (cor) with 95% CI were estimated. Stepwise logistic regression analysis, including variables identified as statistically significant at the univariate analysis, was used to assess the independence of the association with PAD.

G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 133 Continuous variables were expressed as mean ± S.D. and compared by t-test for unpaired samples. 3. Results 3.1. PAD prevalence Fig. 1 shows the study profile. Of the 4352 subjects aged 40 80 years included in the lists of the general practitioners, 3865 (89%) filled the RQ. Their work status was as follows: executive/professional, 12.7%; administrative/small business, 21.8%; blue collar, 18.3%; and retired, 47.2%. Non participation had various reasons: subjects had died, had moved or were absent due to protracted admission to a hospital, or showed no interest. Seven hundred and sixty (329 males, 431 females) were positive to the RQ according to the criteria indicated above. Of these, 12 died before the vascular examination, 65 moved and 89 refused to participate. These 166 individuals did not differ appreciably from those who received vascular examination for age, sex, risk factors and prevalence of coexistent cardiovascular disease. Thus, the prevalence of symptomatic PAD was calculated in 3699 subjects (1713 males, 1986 females). Among these, the prevalence of symptomatic PAD was 1.6% (95% CI 1.2; 2.0), 2.4% (95% CI 1.7; 3.1) in males and 1.0% (95% CI 0.5; 1.4) in females. It is of note that typical intermittent claudication, as defined by strict Rose criteria, was present in only 0.8% (95% CI 0.5; 1.1) of the population. Statistical analysis did not show differences between patients with typical and those with atypical claudication with respect to risk factors and cardiovascular comorbidity. As shown in Fig. 2, the prevalence of symptomatic PAD increased with increasing age. 3.2. Risk factors Table 1 reports the prevalence and the corresponding crude OR of cardiovascular risk factors. Smoking, diabetes, hypertension and CRP plasma levels > 3 mg/l were significantly associated with PAD. In stepwise logistic regression analysis, smoking, diabetes and hypertension remained associated with PAD, while the association of CRP approached the statistical significance (Table 2). Interestingly, more than three classic and novel risk factors were present in 65.3% of PAD patients, and in 39.9% of controls (P = 0.003). 3.3. Cardiovascular comorbidity As shown in Table 3, 34% of PAD patients and only 11% of controls (P <0.001) had a coexistent cardiovascular disease. In particular, CAD was present in 32% of patients and 9% of controls (P <0.001); for CVD the corresponding Fig. 1. Flow diagram of the study. See PAD prevalence in the Section 3.

134 G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 Fig. 2. Age- and sex-specific prevalence of symptomatic peripheral arterial disease (and 95% CI) according to age for men (white bars) and women (grey bars). Table 1 Prevalence and crude odds ratio (cor) of cardiovascular risk factors PAD (n = 60) Controls (n = 174) cor (95% CI) P Smoking (%) 65 44 2.03 (1.1 3.8) 0.029 Hypercholesterolemia (%) 71 72 0.94 (0.5 1.9) 0.860 HDL < 35 mg/dl (%) 50 37 1.73 (0.8 3.6) 0.180 Hypertriglyceridemia (%) 43 53 0.66 (0.3 1.2) 0.240 Hypertension (%) 80 61 2.59 (1.3 5.2) 0.007 Diabetes mellitus (%) 47 22 3.17 (1.7 5.9) 0.001 Fibrinogen > 350 mg/dl (%) 31 24 1.40 (0.7 2.9) 0.710 CRP > 3 mg/l (%) 60 41 2.14 (1.1 15) 0.025 PAD, peripheral arterial disease; MI, myocardial infarction; HDL, high-density lipoprotein; CRP, C reactive protein. figures were 10 and 3% (P = 0.035). In a multivariate analysis including risk factors and presence of PAD, only PAD was significantly associated with a previous cardiovascular event (OR 3.72, 95% CI 1.51 9.15; P = 0.004). Table 2 Risk factors associated with peripheral arterial disease at the multivariate analysis OR (95% CI) Diabetes mellitus 4.08 (1.9 8.7) 0.001 Smoking 3.55 (1.6 7.8) 0.002 Hypertension 3.04 (1.3 7.3) 0.012 CRP > 3 mg/l 2.02 (0.97 4.2) 0.061 CRP, C reactive protein. P 3.4. PAD severity Distribution of ABI values and WIQ percent scores in PAD patients are shown in Fig. 3 and Table 4, respectively. No relationship was observed between ABI and WIQ percent scores. Table 5 shows the distribution by age of patients with more severe PAD. Overall, 22% of PAD patients had an ABI < 0.50, 25% were unable to walk a distance as short as 100 m and 14% were unable to climb one flight of stairs. In 58% of the cases, PAD was bilateral. 3.5. Awareness of symptomatic PAD Although symptomatic on the basis of the RQ, 44% of the patients did not know they were affected by PAD. These

G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 135 Table 3 Cardiovascular comorbidity: univariate analysis Events PAD (n = 60) Controls (n = 176) OR (95% CI) P At least a previous cardiovascular event (%) 34 11 4.85 (2.2 10.9) 0.001 Cardiac At least a previous coronary event (%) 32 9 4.47 (2.1 9.4) 0.001 Angina (%) 20 7 3.29 (1.4 7.8) 0.007 Previous MI (%) 12 4 3.46 (1.1 10.7) 0.046 Coronary revascularisation (%) 15 4 4.61 (1.6 13.5) 0.005 Cerebrovascular At least a previous cerebrovascular event (%) 10 3 3.73 (1.0 12.7) 0.035 Stroke (%) 5 2 2.86 (0.6 14.6) 0.189 Carotid surgery (%) 7 2 4.05 (0.88 18.6) 0.073 PAD, peripheral arterial disease; MI, myocardial infarction. Fig. 3. Distribution of the ankle/brachial index in PAD patients. Table 4 Patient distribution (%) according to percent scores of the four sections of the Walking Impairment Questionnaire (WIQ) WIQ percent scores a <25 25 < 50 50 < 75 75 Claudication pain 18 (30) 13 (22) 13 (22) 16 (26) Walking distance 32 (54) 9 (15) 4 (7) 15 (24) Walking speed 39 (67) 13 (21) 6 (9) 2 (3) Stairs climb 23 (39) 12 (20) 18 (32) 17 (9) a The lower the percent score, the greater the difficulty experienced by the patient. Table 5 Distribution of patients with more severe PAD by age 40 59 (n = 6) Age groups 60 69 (n = 24) 70 80 (n = 30) ABI < 0.50 2 (33%) 4 (17%) 7 (23%) Very severe pain while 1 (17%) 1 (4%) 5 (17%) walking at WIQ Unable to walk 100 m at WIQ 1 (17%) 4 (17%) 10 (33%) Unable to climb one flight 1 (17%) 3 (12%) 4 (13%) of stairs at WIQ Bilateral PAD 2 (33%) 4 (17%) 7 (23%) WIQ, Walking Impairment Questionnaire.

136 G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 patients tended to have a less severe PAD. Actually, compared to the known cases, they had a higher ABI (0.67±0.2 versus 0.72 ± 0.2) and a lower prevalence of ABI < 0.50 (29% versus 12%), although these differences were not statistically significant. Furthermore, typical intermittent claudication, according to the classic Rose criteria, was found in 46% of known cases and 32% of unknown cases. This difference was not statistically significant. 3.6. Treatments Compared to controls, a higher number of patients took antiplatelet medication (16.4% versus 59.3%, P<0.001), statins (8.2% versus 20.3%, P = 0.016) and nitrates (4.7% versus 24.1%, P<0.001). Conversely, no group difference was observed for ACE inhibitors (35.3% versus 43.1%). It is noteworthy, that among the known cases, antiplatelet therapy was assumed by 53% of those without, and 71% of those with coexistent coronary or cerebrovascular disease. The difference, however, was not statistically significant. 4. Discussion In this Italian study, the prevalence of symptomatic PAD was 1.6%, varying from 0% in women aged 40 49 years to 6.4% in men aged 70 80 years. Previous studies carried out in northern Europe reported the prevalence of symptomatic PAD to range from 1.6 to 7.7% [4 8], depending on age and sex distribution of the screened population and the method used to assess the presence of the disease. A survey in rural Finland found a prevalence of 7.7% in men aged 55 74 years [4]. In the Edinburgh study [6], which assessed the presence of PAD by measuring ABI and changes in ankle systolic pressure during reactive hyperemia, the prevalence of intermittent claudication was 4.6%. In the United Kingdom, a lower prevalence (2.2%) was found by Hughson et al. [5], who, however, screened a younger population. In the Netherlands, the Limburg study [7], which defined PAD by an ABI < 0.95 and intermittent claudication by criteria similar to those adopted in the present study, found a prevalence of 3.8%, in a population aged 40 78 years (a range similar to that of our population). Another Dutch survey, the Rotterdam study [8], reported a prevalence of intermittent claudication as low as 1.6% in individuals aged 55 years and over. However, the Rotterdam study defined intermittent claudication using strict Rose criteria. This may imply an underestimation of symptomatic PAD, because exertional leg symptoms other than intermittent claudication are common in PAD [13]. To avoid an under-recognition of the disease, we used broader criteria. According to previous epidemiologic studies [2,7,14,15] we defined possible symptomatic PAD as pain in the calf that began while walking and did not disappear while continuing to walk, regardless of whether the remaining Rose criteria for claudication were met. Furthermore, other complaints of the calf, and complaints of foot, thigh or buttock (not of the knee) showing the ischaemic pattern described above were included in the definition of possible PAD. Using these criteria to select patients for Doppler examination, we found that the prevalence of symptomatic PAD was 1.6%, (i.e. about half than that in the Limburg study) [7]. When strict Rose criteria were used, the prevalence of typical intermittent claudication was 0.8%, (i.e. about half than that in the Rotterdam study) [8]. From these figures, one may cautiously conclude that the prevalence of symptomatic PAD in Italy is lower than that reported in northern Europe countries. The less aggressive nature of PAD in the Italian population seems to be confirmed by data on cardiovascular comorbidity. Actually, the coexistence of ischaemic heart disease was present in 32% of our patients, in 71% of claudicants in the Edinburgh study [6] and 43.5% of patients with symptomatic PAD in the Limburg study [7]. The Rotterdam study [8] reported the prevalence of cardiovascular comorbidity in all subjects with ABI < 0.90, that is, also in those with asymptomatic disease. However, considering that in asymptomatic PAD the prevalence of cardiovascular comorbidity is similar or even lower than that in symptomatic PAD [16], the prevalence rates of 21.5% for a previous myocardial infarction and of 8.6% for a previous stroke observed in the Rotterdam study [8], appear to be markedly higher than the corresponding figures of 12.0 and 5.0% observed in our population. The hypothesis that the Italian population is less susceptible to PAD and other atherosclerotic diseases usually associated to PAD is consistent with the finding that in countries bordering the Mediterranean, the cardiovascular risk is lower than in northern Europe [17]. Among the numerous factors that may account for such a reduced risk, major emphasis was placed on a more healthy dietary pattern [18]. Indeed, the risk of developing PAD is increased by higher intake of saturated fatty acids [19], very common in northern Europe [20], and reduced by higher intake of cereal fiber and Vitamin E, and wine consumption [19,21 23], which are typical components of the so-called Mediterranean diet [20]. It is noteworthy that, at least in patients with type 2 diabetes, a high score Mediterranean dietary pattern is associated with a reduced risk of PAD [24]. We did not collect dietary information, however, the present study was carried out in Campania, a region of southern Italy where the use of Mediterranean diet is widely diffused. Smoking, diabetes mellitus and hypertension, but not hypercholesterolemia, were significantly associated with PAD. These results are similar to those reported in the Limburg study for symptomatic PAD [7]. With respect to the inflammatory markers, CRP > 3 mg/l, but not fibrinogen > 350 mg/dl, was significantly associated with symptomatic PAD, although, for CRP, the relationship only approached statistical significance at the multivariate analysis. The observation that, compared to controls, a higher number of PAD patients had plasma levels of CRP > 3 mg/l is in keeping with a previous study showing that elevated plasma levels of CRP are associated with the risk of developing symptomatic

G. Brevetti et al. / Atherosclerosis 175 (2004) 131 138 137 PAD among apparently healthy men [25]. Conversely, the lack of association between fibrinogen and PAD is in contrast with the results of the already cited surveys carried out in northern Europe [5,26,27]. The reasons for this discrepancy are unclear, however, a study comparing haemostatic parameters in elderly men in Italy and in the Netherlands found that the Dutch men had higher levels of fibrinogen [28]. An important finding of this survey is that about half of the PAD patients, although positive to RQ, and, thus, symptomatic, were unaware of being affected by such disease. Although no significant group differences were observed, unknown cases tended to be affected by less severe PAD and to have a more frequent atypical claudication. Thus, the under-recognition of symptomatic PAD could be attributed to the fact that patients and physicians underestimate mild, atypical leg symptoms and/or attribute them to other diseases very common in the elderly (e.g. muscle skeletal diseases). It is worth noting that, under-recognition of symptomatic PAD, which is a relatively frequent feature also in other western countries [2,5,7], implies that a large proportion of PAD population is not given preventive therapy, so remaining at high cardiovascular risk. Therefore, when history and vascular examination yield ambiguous results, non invasive testing should be performed. 5. Conclusion This is the first study specifically aimed at assessing the prevalence of symptomatic PAD in Italy. Although it is difficult to compare studies because of differences in study populations and tests used, our figure of 1.6% is lower than that reported in northern Europe countries [4 9]. We cannot exclude that the prevalence rate, as in any epidemiological survey, may be prone to some bias. However, the fact that cardiovascular comorbidity also was lower in our population suggests that, with respect to PAD and its clinical correlates, the differences between the Italian and northern European populations are probably due to a different severity of the atherosclerotic process. This, which is supported by the finding that the coronary risk is lower in southern than in northern Europe [17] could be the result of a complex interplay of biological, social and cultural factors. The findings that although symptomatic, about 50% of the cases were unaware of being affected by PAD, and that among the known cases only 53% received antiplatelet treatment, confirm that also in Italy PAD is an under-recognised and under-treated condition, as observed in other countries [2,5,7]. 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