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PAD
Thrombosis Research 106 (2002) V295 – V301
PAD Epidemiology and pathophysiology C. Cimminiello Divisione Medicina II, Ospedale Vimercate, Milano, Italy
Abstract The real prevalence of Peripheral Arterial Disease (PAD) is considerably underestimated if only symptomatic patients (i.e those with Intermittent Claudication) are taken into account instead of subjects with instrumental abnormalities such as a low Ankle – Branchial Index (ABI). The risk of both—fatal and non-fatal—cardiovascular events is particularly high in these patients either presenting with symptoms or asymptomatic. On the contrary the tendency to local worsening (need of revascularization or amputation of leg) is reduced. PAD is markedly prevailing in elderly, with a peak of incidence after the fifth decade of life. Owing to this, Owing to this, the prevalence is not significantly different in men compared to women. The risk factors related to PAD are the same as those observed in the other locations of atherosclerosis but cigarette smoking and diabetes seem to be more often associated to PAD than the remaining factors. D 2002 Elsevier Science Ltd. All rights reserved. Keywords: Peripheral Arterial Disease; Intermittent Claudication; Ankle – Branchial Index; Atherosclerosis; Risk factors; Cardiovascular events
1. Introduction The term peripheral arterial disease (PAD) is widely used to refer to chronic arterial disease of the legs of atherosclerotic origin. Atherosclerosis is by far the most common cause—more than 90%—of arterial problems in the legs. In terms of frequency, other causes such as cardiogenic or arterio-arterial emboli, or inflammatory/autoimmune vasculitis causing necrosis of the vessel wall, are virtually negligible. The atherosclerotic plaque in the leg arteries develops the same way as in other districts. It usually grows slowly and insidiously, often causing no bother whatsoever for years, or at most a very mild symptomatology. This helps explain why the clinical symptoms of the disease tend to be more evident in the elderly. However, the size of the vessel involved—in the macro- or microcirculation, or both—influences the severity of the disease and its rate of progression. In clinical terms, PAD is divided into Fontaine et al.’s [1] four stages, set out in Table 1. A new classification has now been proposed by Rutherford et al. [2]. It comprises six clinical categories (Table 2), and its use is recommended by the Trans-Atlantic InterE-mail address: [email protected] (C. Cimminiello).
Society Consensus (TASC) Working Group for the diagnosis and assessment of the progression of PAD. Figures on the prevalence of the disease closely reflect the methods used to detect it. Early epidemiological studies were based on clinical records, and the most widespread, earliest clinical manifestation of PAD is intermittent claudication (IC). This is due to pain during walking, caused by ischemia in a group of functionally related muscles. IC can take the form of cramp-like pain, or weakness in the muscle area involved. The threshold for ischemia, hence, for symptoms, is constant, and when the patient stops walking and remains standing, the pain disappears within 1– 5 min. The location of pain gives a broad indication of the extent of vascular involvement. Atherosclerosis in the aortoiliac district causes symptoms from the buttocks down through the thigh to the calf. If the superficial femoral artery is affected, symptoms will be restricted to the calf—this being the most frequent finding. Ischemic pain in the foot during exercise points to infrapopliteal arterial involvement. Therefore, the arterial district involved is clearly a major factor in the ischemia, but others are the degree of stenosis caused by the atherosclerotic lesions and the viscosity of blood circulating there. Blood flow regulation is governed by Poiseuille’s law: F ¼ Pr4 =VL
0049-3848/01/$ - see front matter D 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 9 - 3 8 4 8 ( 0 1 ) 0 0 4 0 0 - 5
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Table 1 Fontaine’s classification Stage I Stage II IIa
IIb Stage III IIIa IIIb Stage IV IVa IVb
Asymptomatic arteriopathy Exercise-induced ischemia Intermittent claudication, pain during walking Relief of symptoms when standing Compensated disease: walking distance > 100 m Decompensated disease: walking distance < 100 m Ischemia-driven symptoms at rest Ankle Pressure Index z 50 mm Hg Ankle Pressure Index < 50 mm Hg Trophic ulcers and gangrene Limited gangrene Extensive gangrene
These initial observations clearly indicate the discrepancy between the presence of symptoms like IC and instrumental detection of PAD, as the latter method finds the disease in up to three times as many subjects. Subsequent studies (Table 3) confirmed this ratio, showing that a large majority of PAD patients have no symptoms. Stoffers et al. [7], investigating the prevalence of asymptomatic PAD in a population of 18,884 people between 45 and 74 years old, found that although the disease had been diagnosed in 6.9%, only 22% of these had symptoms. Other epidemiological features of PAD brought to light by the various studies include: (a) The prevalence appears lower among women, but the gap seems to narrow after 70 years [13]. Data on this point are, however, discordant. The Framingham study, for instance, sustains the difference remains at all ages [14]. (b) Elderly people are the most affected, especially after the age of 60. In people around 50, the frequency of IC is 1 –2%, but after age 50, respectively 0.4% and 0.7% of new cases of IC are recorded for women and men, every 2 years [14]. (c) The overall age-adjusted prevalence of PAD diagnosed on the basis of the ABI is around 12%, and the figure for IC is much lower—1 –2%—up to age 50 but rises considerably—between 5% and 7%—from the seventh decade onwards [15,16].
where F = flow, P = pressure, r = radius of the vessel, V = viscosity and L = length of the vessel. Since PAD is basically due to acute or chronic ischemia of the legs, it is clear how the above factors affect the clinical picture, which may involve no symptoms at all, pain when walking, or even ‘‘critical limb ischemia,’’ which causes pain at rest and trophic skin lesions.
2. Incidence and prevalence Early epidemiological studies of prevalence were, as noted above, based on recording claudication. In a study of four areas of Finland, conducted between 1966 and 1972, Reunanen et al. [3] interviewed 5738 men and 5224 women aged from 30 to 59 years; the prevalence of symptoms was 2.1% for the men and 1.8% for women. Other evidence brought to light in this study has since been widely confirmed and now forms a fundamental part of our knowledge of PAD:
IC was more frequent among diabetics or patients with coronary artery disease (CAD). The risk of mortality at 5 years from cardiovascular causes was about three times higher among men with IC than men without this symptom. Substantially similar findings are reported from smaller populations in studies measuring only symptomatic PAD [4]. By the 1970s, it was clear that the ratio between systolic arterial pressure at the ankle and in the brachial artery (Ankle Brachial Index, ABI), measured using Doppler ultrasound, was a valid and noninvasive approach for identifying patients with atherosclerosis of the legs [5]. Schroll and Munk [6], in 1974, measured the ABI in 666 patients (360 men and 306 women) born in 1914, who were therefore 60 years old at the time; the index was considered pathological if it was lower than 0.9 on one or both sides. It was, in fact, abnormal in 16% of the men and 13% of the women. Symptoms related to IC, investigated using a WHO questionnaire, were found in 5.8% of the men and 1.3% of the women.
In analysing these epidemiological figures, it is essential to bear in mind the type of population studied, the geographic/climatic features of the area involved and the prevalence of risk factors. However, the method employed to detect the disease remains fundamental: interviews and questionnaires on the symptoms for IC, and a low ABI for PAD, setting the threshold for pathology at V 0.9 [17]. The best-known and most widely used questionnaires for assessing prevalence are the Edinburgh group’s WHO/Rose version, with modifications, and the San Diego questionnaire. For the first, sensitivity is reportedly 91% and specificity 99% for the diagnosis of IC [18] based on assessments of the findings taken blindly by two doctors. This questionnaire, however, may not be sensitive enough for patients who are unable to walk and therefore report no
Table 2 Rutherford categories Category
Clinical description
0 1 2 3 4 5 6
Asymptomatic Mild claudication Moderate claudication Severe claudication Ischemic rest pain Minor tissue loss Major tissue loss
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Table 3 Study
No. of patients
[3]
5738 5224 360 306 82 105 809 783 2214 2870 6760 8346 3052 4663
[6] [8] [9] [10] [11] [12]
men women men women men women men women men women men women men women
Age
Prevalence of ABI abnormalities (%)
Prevalence of IC (%)
– – 16 13 26.7
2.1 1.8 5.8 1.3 6.4
55 – 74
24.6
4.5
65 – 85
14 11 3 3.3 16.9 20.5
2
30 – 59 60 >60 (mean 72)
45 – 64 70
symptoms [19], or for those with atypical symptoms in the legs. The ABI offers excellent sensitivity, reaching 95% in comparison with angiographic confirmation of disease [20]. The limits of detection using the ABI have been described [21], as well as the sensitivity and specificity of other noninvasive diagnostic methods such as measurement of peripheral pulses, the exercise test and the test for reactive hyperemia [19]. Patients with PAD may present more severe clinical forms of IC, with pain in the legs at rest, trophic lesions or both; this is called critical limb ischemia (CLI). These patients may need surgical revascularization, or even amputation of the limb. The prevalence of these forms, known as chronic CLI in contrast with acute critical ischemia, ranges from 0.05% to 0.1% of the general population [15,22]. A rather simple estimate finds 15– 20% of patients with IC are likely to progress to CLI. Thus, among people over the age of 50, when the prevalence of IC rises steeply—between 5% and 10%—CLI can be seen in 1% of the general population. In reality, however, not all cases of CLI are preceded by a phase of IC. These extrapolations therefore suffer from a margin of error, just like those where the prevalence of CLI is based on the rate of amputation of the legs in certain populations.
3. Risk factors The risk factors for PAD are the same as for atherosclerotic disorders in other vascular districts, although some tend to prevail differently in specific districts. The two risk factors with the greatest weight, however, are cigarette smoking and diabetes mellitus. Apart from age and sex, which we have already mentioned, diabetics have at least twice the risk of IC compared to nondiabetics [23]. Amputation of a limb and gangrene are 10 times more frequent among diabetic patients with PAD than among nondiabetic PAD cases [24]. In addition to the diabetes, insulin resist-
1 2.2 1.2
ance and hyperinsulinemia seem to be additional risk factors for PAD [25,26]. Early studies already found that cigarette smoking was the risk factor most closely related to PAD [4]. In the Framingham study, 78% of the cases of IC were smokers [27]. The risk of developing this disease is two to seven times greater among smokers and also appears to be related to the number of cigarettes smoked [28,29]. Like diabetes, smoking raises the risk of amputation and reduces the chance of successful surgical revascularization [30]. Stopping smoking seems to lead to a more favourable progression of IC [31]. The physiopathological mechanisms that might explain why smoking facilitates atherosclerosis include endothelial dysfunction due to the reduction or loss of nitric-oxide-dependent vasodilation [32]. Among ‘‘major’’ risk factors, hypertension and high blood cholesterol seem to have a less clear-cut role in PAD. In the Framingham study [33], high blood pressure involved at least double the risk of developing PAD, and some reports suggest that men are more likely to develop PAD than women. In the Finnish study by Reunanen et al. [3], however, hypertension was not significantly related to IC. Hooi et al. [34] recently reported that hypertension, combined with advanced age, cigarette smoking and diabetes were all risk factors for IC and PAD. The effects of blood lipid disorders as a risk factor for PAD are debated. In the Framingham study [35], cholesterol levels over 270 mg/100 ml were associated with a doubling of the frequency of IC. However, in later reports, at lower cholesterol levels (240 mg/100 ml), this association became less evident [28]. Subsequent findings, such as those of Hughson et al. [4], Criqui et al. [25] and Zimmerman et al. [36], have not confirmed the association between high blood cholesterol and PAD. Nevertheless, the Edinburgh Artery Study [29] found an association with total cholesterol and an inverse one with HDL cholesterol. It now appears that hemostatic factors may be involved in PAD. High blood levels of fibrinogen and homocysteine seem certain to play a part and appear to have a strong
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Table 4 Study
Prevalence of associated cardiovascular disease in patients with ABI abnormalities (%)
Prevalence of associated cardiovascular disease in patients with IC (%)
Reunanen et al. (1982) Fowkes et al. (1991) Meijer et al. (1998) Smith et al. (1980)
–
44.3 (men) 31.2 (women) 54 – 41
71 48 (men); 33 (women) –
association with PAD. The odds ratio (OR) for developing PAD is >6 for hyperhomocysteinemia [37], and some studies found that high blood fibrinogen and high viscosity were associated with PAD [38]. There is no firm evidence that other hemostatic factors tested to date—PAI-1, von Willebrand factor, factor VII activity—are related in any way to PAD [39].
4. Comorbidity and natural history Since the risk factors for atherosclerotic disease of the legs are qualitatively no different from those in other districts, such as the coronary arteries and brain, it is no surprise that PAD is very frequently associated with other cardiovascular diseases such as CAD and cerebrovascular disease (CVD). When the first Framingham report on the incidence of IC was published in 1970, its authors suggested that the increased risk of IC in CAD patients suggested ‘‘a common underlying basis for claudication and CAD’’ [35]. A later report from the Framingham group [28] found electrocardiographic (ECG) abnormalities or clinical symptoms of CAD in 40 – 60% of subjects developing IC. Coronarographic findings on patients undergoing revascularization of the lower limbs indicate coronary involvement in as many as 90% [40]. From this viewpoint, therefore, PAD can be considered a marker of systemic atherosclerosis. Some of the epidemiological studies mentioned earlier reported the prevalence of cardiovascular diseases, as set out in Table 4. Not only patients with IC but also those with an abnormal ABI—which include those with asymptomatic arterial disease—are more likely to have PAD plus atherosclerosis of other site(s). The fact that atherosclerotic disease frequently occurs in more than one site helps explain the natural history of PAD, which tends to cause limited local progression (worsening of claudication symptoms, need for amputation) but high levels of cardiovascular morbidity and mortality. There are fairly concordant data from studies with at least a 1– 4-year follow-up showing that the symptoms do get worse in 15– 30% of PAD patients, and 7% ends up needing surgical revascularization, or amputation, although the annual amputation rate becomes lower with longer intervals from diagnosis [41 –43].
Recent information on local progression of the disease comes from the Edinburgh Artery Study with its 5-year follow-up: Of the 116 cases of IC detected at baseline, 28.8% still had symptoms of IC, 8.2% had had surgery for revascularization or amputation and 1.4% had developed leg ulcers [44]. This evident association between PAD and cardiovascular diseases raises the question of the prognostic implications for PAD patients, in terms of cardiovascular morbidity and mortality. As we mentioned, early observations already showed the apparently higher rate of cardiovascular mortality among patients with IC. Reunanen [3], however, questioned whether IC alone was a risk factor for increased cardiovascular mortality and, in fact, after correcting the figures for the presence of CAD, these authors found that IC no longer had any effect on mortality. Later studies confirmed that IC found in response to a questionnaire was associated with a significant increase in the risk of cardiovascular mortality. One of these was reported by Smith et al. [45], who followed up 18,388 subjects for 17 years and found that the risk of vascular mortality was three times higher for males with ‘‘probable’’ IC, independently of cardiovascular comorbidity. The more recent San Diego study [46], with a 10-year follow-up, showed that patients with PAD diagnosed on the basis of the ABI had five times the normal risk of vascular death; excluding those who already had cardiovascular diseases at baseline, the ratio still remained 4 for men and 5.7 for women. In Criqui’s California study [46], the prognosis for symptomatic PAD was worse. The natural course of CLI is even less benign, both locally and systemically. Dormandy et al. [47] reported that 90% of patients with CLI needed surgical revascularization, and 10 – 40% needed primary amputation. Mortality among these patients was 20% in the first year and 40– 70% at 5 years. All patients with gangrene and 80% of those with pain at rest died within 10 years. In an Italian study [48] of 1569 patients with CLI, approximately 19% died within the first year. At 6 months, 12% needed amputation and 47.5% had persistent CLI. Smoking and diabetes were the ‘‘weightiest’’ prognostic factors for amputation, but an ABI < 0.5 also seemed to have prognostic significance as a predictor of amputation [43]. In the ICAI study [48], ABI was a predictor of mortality and amputation only when it was ‘‘not measurable.’’
5. ABI as a marker of cardiovascular morbidity and mortality In actuality, the role of ABI as a predictor of morbidity and mortality is now clear. Studies in the early 1990s show that it as an independent indicator of total and cardiovascular mortality [49]. We mentioned the San Diego study, which found a high risk of cardiovascular mortality among subjects with an abnormal ABI (>0.8) [46]. Ogren et al.
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[50], using multivariate analysis in a population investigated for carotid stenosis, ECG anomalies and presence of PAD, diagnosed on the basis of the ABI, found that after 8 years of follow-up, an ABI < 0.9 was associated with total mortality 2.4 times higher than normal and double the risk of cardiovascular mortality. The Cardiovascular Health Study [10] and the Edinburgh Artery Study [51], using multivariate analysis on prospective observations of a large series (5888 subjects in the CHS and 1592 in the Edinburgh study), with adequate follow-up (6 and 5 years), showed that the risk of total and cardiovascular mortality was higher in patients with ABI < 0.9, with a relative risk estimate between 1.5 and 1.8. The risk of death and nonfatal vascular events was higher in patients who had a low ABI together with risk factors such as diabetes or high blood cholesterol. The Cardiovascular Health Study established that every diminution of 0.1 in the ABI corresponded to a significant reduction in survival [52]. The predictive value of the ABI is further borne out by the correlation documented in the SHEP study [53] between an ABI < 0.9 in elderly hypertensives, with a risk ratio for total mortality of 3.8. Among women aged over 65, the risk of mortality was 3.1 [54]. In the Italian ADEP study [55], a low ABI was one of the predictors of vascular events—fatal or nonfatal—in a population with IC. While the strength of the ABI as a negative prognostic indicator seems clear, it also appears that subclinical abnormalities in the index imply a prognosis as negative as in symptomatic patients. Kornitzer et al. [56], in 1995, with a 10-year follow-up, showed that an ABI < 0.9 gave an OR of 3.63 for cardiovascular mortality; among asymptomatic subjects aged 40– 50 years, LDL cholesterol had less weight as a prognostic indicator than the ABI (OR 1.69). In the Cardiovascular Health Study, subclinical vascular abnormalities, detected instrumentally and with the ABI, involved a greater risk of developing disease than in patients with no subclinical disorder. Regardless of the presence of symptomatic PAD, which calls for local therapies, systematic screening for ABI among symptom-free subjects at cardiovascular risk is worth considering. A recent paper on the prevalence of PAD in primary care clinics is extremely interesting on this point [57]. Patients were selected using a model largely inspired by the Framingham one [28] and 6979 patients were screened, either elderly—70 years or older—or aged between 50 and 69 years but smokers or diabetics. This selection was based on high-risk situations for PAD, as indicated by epidemiological findings. Patients were considered to have peripheral vascular disease if their ABI was lower than 0.90. The prevalence of PAD was 29% (1865 patients); 44% of these only had PAD, with no atherosclerotic disease elsewhere. In 823 subjects, PAD was diagnosed for the first time; 83% of the patients already diagnosed as having PAD knew about their disease, while only 49% of their doctors did. The authors conclude that underdiagnosis and doctors’ lack of aware-
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ness of this frequent disease may be an obstacle to preventing cardiovascular ischemic events.
6. Polyvascular patients This last point regards patients with PAD plus atherosclerotic disease in another district, such as the coronaries or cerebral circulation. Besides the data we have already considered, there is further evidence that such associations are frequent in the elderly, affecting up to 9% of men aged over 65 and 3% of women [58]. What is the prognosis for these patients with coronary or cerebral vascular pathologies and PAD in the legs? One might assume that it is worse when only one district is affected, and preliminary evidence does, in fact, confirm this [59]. The relative risk of death at 5 years is significantly higher, around 1.7 in the BARI study [60] and around 1.25 in the CASS study [61]. This increase in risk in patients with coronary disease plus PAD seems to be comparable for symptomatic and asymptomatic forms [62]. If confirmed, this evidence might lead to more frequent screening for PAD—including asymptomatic forms—in patients with coronary and cerebral atherosclerotic disease and to more aggressive prophylaxis for polyvascular patients. References [1] Fontaine R, Kim M, Kieny R. Die chirurgische behandlung der peripheren durchlutungsstorungen. Helv Chir Acta 1954;5/6:499 – 533. [2] Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommened standards for report dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517 – 38. [3] Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand 1982; 44:249 – 56. [4] Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978;1:1379 – 81. [5] Carter SA. Response of ankle systolic pressure to leg exercise in mild or questionable arterial diseases. N Engl J Med 1972;287:578 – 82. [6] Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis 1981;34:261 – 9. [7] Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymtomatic and unrecognized peripheral arterial occlusive disease. Int J Epidemiol 1996;25:282 – 90. [8] Newman AB, Sutton-Tyrrell K, Rutan GH, Locher J, Kuller LH. Lower extremity arterial disease in elderly subjects with systolic hypertension. J Clin Epidemiol 1991;44:15 – 20. [9] Fowkes FGR, Housley E, Cawood ENH, Macintyre CCA, Ruckley CV, Prescott RJ. Edinburgh artery study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991;20:384 – 92. [10] Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO, Wolfson SK, for the Cardiovascular Health Study (CHS) Collaborative Research Group. Ankle – arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation 1993;88: 837 – 45. [11] Zheng ZJ, Sharrett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS, Dobs A, Evans GW, Heiss G. Associations of ankle – brachial index with clinical coronary heart disease, stroke and preclin-
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[59] Papamichael CM, Lekakis JP, Stamatelopulos KS, Papaioannou TG, Alevizaki MK, Cimponeriu AT, Kanakakis JE, Papapanagiotou A, Kalafoutis AT, Stamatelopoulos JF. Ankle brachial index as a predictor of the extent of coronary atherosclerosis and cardiovascular events in patients with coronary artery disease. Am J Cardiol 2000;86:615 – 8. [60] Sutton-Tyrrell K, Rihal C, Sellers MA, Burek K, Trudel J, Roubin G, Brooks MM, Grogen M, Sopko G, Keller N, Jandora` R, for the BARI Investigators. Long-term prognostic value of clinically evident non coronary vascular disease in patients undergoing coronary revascularization in the By-pass Angioplasty Revascularization Investigation (BARI). Am J Cardiol 1998;81:375 – 81. [61] Eagle KA, Rihal CS, Foster ED, Mickel MC, Gersh BJ, for the CASS Investigators. Long-term survival in patients with coronary artery disease: importance of peripheral vascular disease. J Am Coll Cardiol 1994;23:1091 – 5. [62] Burek KA, Sutton-Tirrell K, Brooks MM, Naydeck B, Keller N, Sellers MA, Roubin G, Jandora` R, Rihal CS. Prognostic importance of lower extremity arterial disease in patients undergoing coronary revascularization in the By-pass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol 1999;34:716 – 21.
PAD Epidemiology and pathophysiology C. Cimminiello Divisione Medicina II, Ospedale Vimercate, Milano, Italy
Abstract The real prevalence of Peripheral Arterial Disease (PAD) is considerably underestimated if only symptomatic patients (i.e those with Intermittent Claudication) are taken into account instead of subjects with instrumental abnormalities such as a low Ankle – Branchial Index (ABI). The risk of both—fatal and non-fatal—cardiovascular events is particularly high in these patients either presenting with symptoms or asymptomatic. On the contrary the tendency to local worsening (need of revascularization or amputation of leg) is reduced. PAD is markedly prevailing in elderly, with a peak of incidence after the fifth decade of life. Owing to this, Owing to this, the prevalence is not significantly different in men compared to women. The risk factors related to PAD are the same as those observed in the other locations of atherosclerosis but cigarette smoking and diabetes seem to be more often associated to PAD than the remaining factors. D 2002 Elsevier Science Ltd. All rights reserved. Keywords: Peripheral Arterial Disease; Intermittent Claudication; Ankle – Branchial Index; Atherosclerosis; Risk factors; Cardiovascular events
1. Introduction The term peripheral arterial disease (PAD) is widely used to refer to chronic arterial disease of the legs of atherosclerotic origin. Atherosclerosis is by far the most common cause—more than 90%—of arterial problems in the legs. In terms of frequency, other causes such as cardiogenic or arterio-arterial emboli, or inflammatory/autoimmune vasculitis causing necrosis of the vessel wall, are virtually negligible. The atherosclerotic plaque in the leg arteries develops the same way as in other districts. It usually grows slowly and insidiously, often causing no bother whatsoever for years, or at most a very mild symptomatology. This helps explain why the clinical symptoms of the disease tend to be more evident in the elderly. However, the size of the vessel involved—in the macro- or microcirculation, or both—influences the severity of the disease and its rate of progression. In clinical terms, PAD is divided into Fontaine et al.’s [1] four stages, set out in Table 1. A new classification has now been proposed by Rutherford et al. [2]. It comprises six clinical categories (Table 2), and its use is recommended by the Trans-Atlantic InterE-mail address: [email protected] (C. Cimminiello).
Society Consensus (TASC) Working Group for the diagnosis and assessment of the progression of PAD. Figures on the prevalence of the disease closely reflect the methods used to detect it. Early epidemiological studies were based on clinical records, and the most widespread, earliest clinical manifestation of PAD is intermittent claudication (IC). This is due to pain during walking, caused by ischemia in a group of functionally related muscles. IC can take the form of cramp-like pain, or weakness in the muscle area involved. The threshold for ischemia, hence, for symptoms, is constant, and when the patient stops walking and remains standing, the pain disappears within 1– 5 min. The location of pain gives a broad indication of the extent of vascular involvement. Atherosclerosis in the aortoiliac district causes symptoms from the buttocks down through the thigh to the calf. If the superficial femoral artery is affected, symptoms will be restricted to the calf—this being the most frequent finding. Ischemic pain in the foot during exercise points to infrapopliteal arterial involvement. Therefore, the arterial district involved is clearly a major factor in the ischemia, but others are the degree of stenosis caused by the atherosclerotic lesions and the viscosity of blood circulating there. Blood flow regulation is governed by Poiseuille’s law: F ¼ Pr4 =VL
0049-3848/01/$ - see front matter D 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 9 - 3 8 4 8 ( 0 1 ) 0 0 4 0 0 - 5
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Table 1 Fontaine’s classification Stage I Stage II IIa
IIb Stage III IIIa IIIb Stage IV IVa IVb
Asymptomatic arteriopathy Exercise-induced ischemia Intermittent claudication, pain during walking Relief of symptoms when standing Compensated disease: walking distance > 100 m Decompensated disease: walking distance < 100 m Ischemia-driven symptoms at rest Ankle Pressure Index z 50 mm Hg Ankle Pressure Index < 50 mm Hg Trophic ulcers and gangrene Limited gangrene Extensive gangrene
These initial observations clearly indicate the discrepancy between the presence of symptoms like IC and instrumental detection of PAD, as the latter method finds the disease in up to three times as many subjects. Subsequent studies (Table 3) confirmed this ratio, showing that a large majority of PAD patients have no symptoms. Stoffers et al. [7], investigating the prevalence of asymptomatic PAD in a population of 18,884 people between 45 and 74 years old, found that although the disease had been diagnosed in 6.9%, only 22% of these had symptoms. Other epidemiological features of PAD brought to light by the various studies include: (a) The prevalence appears lower among women, but the gap seems to narrow after 70 years [13]. Data on this point are, however, discordant. The Framingham study, for instance, sustains the difference remains at all ages [14]. (b) Elderly people are the most affected, especially after the age of 60. In people around 50, the frequency of IC is 1 –2%, but after age 50, respectively 0.4% and 0.7% of new cases of IC are recorded for women and men, every 2 years [14]. (c) The overall age-adjusted prevalence of PAD diagnosed on the basis of the ABI is around 12%, and the figure for IC is much lower—1 –2%—up to age 50 but rises considerably—between 5% and 7%—from the seventh decade onwards [15,16].
where F = flow, P = pressure, r = radius of the vessel, V = viscosity and L = length of the vessel. Since PAD is basically due to acute or chronic ischemia of the legs, it is clear how the above factors affect the clinical picture, which may involve no symptoms at all, pain when walking, or even ‘‘critical limb ischemia,’’ which causes pain at rest and trophic skin lesions.
2. Incidence and prevalence Early epidemiological studies of prevalence were, as noted above, based on recording claudication. In a study of four areas of Finland, conducted between 1966 and 1972, Reunanen et al. [3] interviewed 5738 men and 5224 women aged from 30 to 59 years; the prevalence of symptoms was 2.1% for the men and 1.8% for women. Other evidence brought to light in this study has since been widely confirmed and now forms a fundamental part of our knowledge of PAD:
IC was more frequent among diabetics or patients with coronary artery disease (CAD). The risk of mortality at 5 years from cardiovascular causes was about three times higher among men with IC than men without this symptom. Substantially similar findings are reported from smaller populations in studies measuring only symptomatic PAD [4]. By the 1970s, it was clear that the ratio between systolic arterial pressure at the ankle and in the brachial artery (Ankle Brachial Index, ABI), measured using Doppler ultrasound, was a valid and noninvasive approach for identifying patients with atherosclerosis of the legs [5]. Schroll and Munk [6], in 1974, measured the ABI in 666 patients (360 men and 306 women) born in 1914, who were therefore 60 years old at the time; the index was considered pathological if it was lower than 0.9 on one or both sides. It was, in fact, abnormal in 16% of the men and 13% of the women. Symptoms related to IC, investigated using a WHO questionnaire, were found in 5.8% of the men and 1.3% of the women.
In analysing these epidemiological figures, it is essential to bear in mind the type of population studied, the geographic/climatic features of the area involved and the prevalence of risk factors. However, the method employed to detect the disease remains fundamental: interviews and questionnaires on the symptoms for IC, and a low ABI for PAD, setting the threshold for pathology at V 0.9 [17]. The best-known and most widely used questionnaires for assessing prevalence are the Edinburgh group’s WHO/Rose version, with modifications, and the San Diego questionnaire. For the first, sensitivity is reportedly 91% and specificity 99% for the diagnosis of IC [18] based on assessments of the findings taken blindly by two doctors. This questionnaire, however, may not be sensitive enough for patients who are unable to walk and therefore report no
Table 2 Rutherford categories Category
Clinical description
0 1 2 3 4 5 6
Asymptomatic Mild claudication Moderate claudication Severe claudication Ischemic rest pain Minor tissue loss Major tissue loss
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Table 3 Study
No. of patients
[3]
5738 5224 360 306 82 105 809 783 2214 2870 6760 8346 3052 4663
[6] [8] [9] [10] [11] [12]
men women men women men women men women men women men women men women
Age
Prevalence of ABI abnormalities (%)
Prevalence of IC (%)
– – 16 13 26.7
2.1 1.8 5.8 1.3 6.4
55 – 74
24.6
4.5
65 – 85
14 11 3 3.3 16.9 20.5
2
30 – 59 60 >60 (mean 72)
45 – 64 70
symptoms [19], or for those with atypical symptoms in the legs. The ABI offers excellent sensitivity, reaching 95% in comparison with angiographic confirmation of disease [20]. The limits of detection using the ABI have been described [21], as well as the sensitivity and specificity of other noninvasive diagnostic methods such as measurement of peripheral pulses, the exercise test and the test for reactive hyperemia [19]. Patients with PAD may present more severe clinical forms of IC, with pain in the legs at rest, trophic lesions or both; this is called critical limb ischemia (CLI). These patients may need surgical revascularization, or even amputation of the limb. The prevalence of these forms, known as chronic CLI in contrast with acute critical ischemia, ranges from 0.05% to 0.1% of the general population [15,22]. A rather simple estimate finds 15– 20% of patients with IC are likely to progress to CLI. Thus, among people over the age of 50, when the prevalence of IC rises steeply—between 5% and 10%—CLI can be seen in 1% of the general population. In reality, however, not all cases of CLI are preceded by a phase of IC. These extrapolations therefore suffer from a margin of error, just like those where the prevalence of CLI is based on the rate of amputation of the legs in certain populations.
3. Risk factors The risk factors for PAD are the same as for atherosclerotic disorders in other vascular districts, although some tend to prevail differently in specific districts. The two risk factors with the greatest weight, however, are cigarette smoking and diabetes mellitus. Apart from age and sex, which we have already mentioned, diabetics have at least twice the risk of IC compared to nondiabetics [23]. Amputation of a limb and gangrene are 10 times more frequent among diabetic patients with PAD than among nondiabetic PAD cases [24]. In addition to the diabetes, insulin resist-
1 2.2 1.2
ance and hyperinsulinemia seem to be additional risk factors for PAD [25,26]. Early studies already found that cigarette smoking was the risk factor most closely related to PAD [4]. In the Framingham study, 78% of the cases of IC were smokers [27]. The risk of developing this disease is two to seven times greater among smokers and also appears to be related to the number of cigarettes smoked [28,29]. Like diabetes, smoking raises the risk of amputation and reduces the chance of successful surgical revascularization [30]. Stopping smoking seems to lead to a more favourable progression of IC [31]. The physiopathological mechanisms that might explain why smoking facilitates atherosclerosis include endothelial dysfunction due to the reduction or loss of nitric-oxide-dependent vasodilation [32]. Among ‘‘major’’ risk factors, hypertension and high blood cholesterol seem to have a less clear-cut role in PAD. In the Framingham study [33], high blood pressure involved at least double the risk of developing PAD, and some reports suggest that men are more likely to develop PAD than women. In the Finnish study by Reunanen et al. [3], however, hypertension was not significantly related to IC. Hooi et al. [34] recently reported that hypertension, combined with advanced age, cigarette smoking and diabetes were all risk factors for IC and PAD. The effects of blood lipid disorders as a risk factor for PAD are debated. In the Framingham study [35], cholesterol levels over 270 mg/100 ml were associated with a doubling of the frequency of IC. However, in later reports, at lower cholesterol levels (240 mg/100 ml), this association became less evident [28]. Subsequent findings, such as those of Hughson et al. [4], Criqui et al. [25] and Zimmerman et al. [36], have not confirmed the association between high blood cholesterol and PAD. Nevertheless, the Edinburgh Artery Study [29] found an association with total cholesterol and an inverse one with HDL cholesterol. It now appears that hemostatic factors may be involved in PAD. High blood levels of fibrinogen and homocysteine seem certain to play a part and appear to have a strong
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Table 4 Study
Prevalence of associated cardiovascular disease in patients with ABI abnormalities (%)
Prevalence of associated cardiovascular disease in patients with IC (%)
Reunanen et al. (1982) Fowkes et al. (1991) Meijer et al. (1998) Smith et al. (1980)
–
44.3 (men) 31.2 (women) 54 – 41
71 48 (men); 33 (women) –
association with PAD. The odds ratio (OR) for developing PAD is >6 for hyperhomocysteinemia [37], and some studies found that high blood fibrinogen and high viscosity were associated with PAD [38]. There is no firm evidence that other hemostatic factors tested to date—PAI-1, von Willebrand factor, factor VII activity—are related in any way to PAD [39].
4. Comorbidity and natural history Since the risk factors for atherosclerotic disease of the legs are qualitatively no different from those in other districts, such as the coronary arteries and brain, it is no surprise that PAD is very frequently associated with other cardiovascular diseases such as CAD and cerebrovascular disease (CVD). When the first Framingham report on the incidence of IC was published in 1970, its authors suggested that the increased risk of IC in CAD patients suggested ‘‘a common underlying basis for claudication and CAD’’ [35]. A later report from the Framingham group [28] found electrocardiographic (ECG) abnormalities or clinical symptoms of CAD in 40 – 60% of subjects developing IC. Coronarographic findings on patients undergoing revascularization of the lower limbs indicate coronary involvement in as many as 90% [40]. From this viewpoint, therefore, PAD can be considered a marker of systemic atherosclerosis. Some of the epidemiological studies mentioned earlier reported the prevalence of cardiovascular diseases, as set out in Table 4. Not only patients with IC but also those with an abnormal ABI—which include those with asymptomatic arterial disease—are more likely to have PAD plus atherosclerosis of other site(s). The fact that atherosclerotic disease frequently occurs in more than one site helps explain the natural history of PAD, which tends to cause limited local progression (worsening of claudication symptoms, need for amputation) but high levels of cardiovascular morbidity and mortality. There are fairly concordant data from studies with at least a 1– 4-year follow-up showing that the symptoms do get worse in 15– 30% of PAD patients, and 7% ends up needing surgical revascularization, or amputation, although the annual amputation rate becomes lower with longer intervals from diagnosis [41 –43].
Recent information on local progression of the disease comes from the Edinburgh Artery Study with its 5-year follow-up: Of the 116 cases of IC detected at baseline, 28.8% still had symptoms of IC, 8.2% had had surgery for revascularization or amputation and 1.4% had developed leg ulcers [44]. This evident association between PAD and cardiovascular diseases raises the question of the prognostic implications for PAD patients, in terms of cardiovascular morbidity and mortality. As we mentioned, early observations already showed the apparently higher rate of cardiovascular mortality among patients with IC. Reunanen [3], however, questioned whether IC alone was a risk factor for increased cardiovascular mortality and, in fact, after correcting the figures for the presence of CAD, these authors found that IC no longer had any effect on mortality. Later studies confirmed that IC found in response to a questionnaire was associated with a significant increase in the risk of cardiovascular mortality. One of these was reported by Smith et al. [45], who followed up 18,388 subjects for 17 years and found that the risk of vascular mortality was three times higher for males with ‘‘probable’’ IC, independently of cardiovascular comorbidity. The more recent San Diego study [46], with a 10-year follow-up, showed that patients with PAD diagnosed on the basis of the ABI had five times the normal risk of vascular death; excluding those who already had cardiovascular diseases at baseline, the ratio still remained 4 for men and 5.7 for women. In Criqui’s California study [46], the prognosis for symptomatic PAD was worse. The natural course of CLI is even less benign, both locally and systemically. Dormandy et al. [47] reported that 90% of patients with CLI needed surgical revascularization, and 10 – 40% needed primary amputation. Mortality among these patients was 20% in the first year and 40– 70% at 5 years. All patients with gangrene and 80% of those with pain at rest died within 10 years. In an Italian study [48] of 1569 patients with CLI, approximately 19% died within the first year. At 6 months, 12% needed amputation and 47.5% had persistent CLI. Smoking and diabetes were the ‘‘weightiest’’ prognostic factors for amputation, but an ABI < 0.5 also seemed to have prognostic significance as a predictor of amputation [43]. In the ICAI study [48], ABI was a predictor of mortality and amputation only when it was ‘‘not measurable.’’
5. ABI as a marker of cardiovascular morbidity and mortality In actuality, the role of ABI as a predictor of morbidity and mortality is now clear. Studies in the early 1990s show that it as an independent indicator of total and cardiovascular mortality [49]. We mentioned the San Diego study, which found a high risk of cardiovascular mortality among subjects with an abnormal ABI (>0.8) [46]. Ogren et al.
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[50], using multivariate analysis in a population investigated for carotid stenosis, ECG anomalies and presence of PAD, diagnosed on the basis of the ABI, found that after 8 years of follow-up, an ABI < 0.9 was associated with total mortality 2.4 times higher than normal and double the risk of cardiovascular mortality. The Cardiovascular Health Study [10] and the Edinburgh Artery Study [51], using multivariate analysis on prospective observations of a large series (5888 subjects in the CHS and 1592 in the Edinburgh study), with adequate follow-up (6 and 5 years), showed that the risk of total and cardiovascular mortality was higher in patients with ABI < 0.9, with a relative risk estimate between 1.5 and 1.8. The risk of death and nonfatal vascular events was higher in patients who had a low ABI together with risk factors such as diabetes or high blood cholesterol. The Cardiovascular Health Study established that every diminution of 0.1 in the ABI corresponded to a significant reduction in survival [52]. The predictive value of the ABI is further borne out by the correlation documented in the SHEP study [53] between an ABI < 0.9 in elderly hypertensives, with a risk ratio for total mortality of 3.8. Among women aged over 65, the risk of mortality was 3.1 [54]. In the Italian ADEP study [55], a low ABI was one of the predictors of vascular events—fatal or nonfatal—in a population with IC. While the strength of the ABI as a negative prognostic indicator seems clear, it also appears that subclinical abnormalities in the index imply a prognosis as negative as in symptomatic patients. Kornitzer et al. [56], in 1995, with a 10-year follow-up, showed that an ABI < 0.9 gave an OR of 3.63 for cardiovascular mortality; among asymptomatic subjects aged 40– 50 years, LDL cholesterol had less weight as a prognostic indicator than the ABI (OR 1.69). In the Cardiovascular Health Study, subclinical vascular abnormalities, detected instrumentally and with the ABI, involved a greater risk of developing disease than in patients with no subclinical disorder. Regardless of the presence of symptomatic PAD, which calls for local therapies, systematic screening for ABI among symptom-free subjects at cardiovascular risk is worth considering. A recent paper on the prevalence of PAD in primary care clinics is extremely interesting on this point [57]. Patients were selected using a model largely inspired by the Framingham one [28] and 6979 patients were screened, either elderly—70 years or older—or aged between 50 and 69 years but smokers or diabetics. This selection was based on high-risk situations for PAD, as indicated by epidemiological findings. Patients were considered to have peripheral vascular disease if their ABI was lower than 0.90. The prevalence of PAD was 29% (1865 patients); 44% of these only had PAD, with no atherosclerotic disease elsewhere. In 823 subjects, PAD was diagnosed for the first time; 83% of the patients already diagnosed as having PAD knew about their disease, while only 49% of their doctors did. The authors conclude that underdiagnosis and doctors’ lack of aware-
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ness of this frequent disease may be an obstacle to preventing cardiovascular ischemic events.
6. Polyvascular patients This last point regards patients with PAD plus atherosclerotic disease in another district, such as the coronaries or cerebral circulation. Besides the data we have already considered, there is further evidence that such associations are frequent in the elderly, affecting up to 9% of men aged over 65 and 3% of women [58]. What is the prognosis for these patients with coronary or cerebral vascular pathologies and PAD in the legs? One might assume that it is worse when only one district is affected, and preliminary evidence does, in fact, confirm this [59]. The relative risk of death at 5 years is significantly higher, around 1.7 in the BARI study [60] and around 1.25 in the CASS study [61]. This increase in risk in patients with coronary disease plus PAD seems to be comparable for symptomatic and asymptomatic forms [62]. If confirmed, this evidence might lead to more frequent screening for PAD—including asymptomatic forms—in patients with coronary and cerebral atherosclerotic disease and to more aggressive prophylaxis for polyvascular patients. References [1] Fontaine R, Kim M, Kieny R. Die chirurgische behandlung der peripheren durchlutungsstorungen. Helv Chir Acta 1954;5/6:499 – 533. [2] Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, Jones DN. Recommened standards for report dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517 – 38. [3] Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent claudication and its effect on mortality. Acta Med Scand 1982; 44:249 – 56. [4] Hughson WG, Mann JI, Garrod A. Intermittent claudication: prevalence and risk factors. Br Med J 1978;1:1379 – 81. [5] Carter SA. Response of ankle systolic pressure to leg exercise in mild or questionable arterial diseases. N Engl J Med 1972;287:578 – 82. [6] Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis 1981;34:261 – 9. [7] Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymtomatic and unrecognized peripheral arterial occlusive disease. Int J Epidemiol 1996;25:282 – 90. [8] Newman AB, Sutton-Tyrrell K, Rutan GH, Locher J, Kuller LH. Lower extremity arterial disease in elderly subjects with systolic hypertension. J Clin Epidemiol 1991;44:15 – 20. [9] Fowkes FGR, Housley E, Cawood ENH, Macintyre CCA, Ruckley CV, Prescott RJ. Edinburgh artery study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int J Epidemiol 1991;20:384 – 92. [10] Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO, Wolfson SK, for the Cardiovascular Health Study (CHS) Collaborative Research Group. Ankle – arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation 1993;88: 837 – 45. [11] Zheng ZJ, Sharrett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS, Dobs A, Evans GW, Heiss G. Associations of ankle – brachial index with clinical coronary heart disease, stroke and preclin-
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