a 2 - epidemiology, natural history, risk factorsepidemiology, natural history, risk factors table...

84 Objectives and Methodology of the Consensus Process

Finally, in the course of developing this document,it became clear that in some key areas no strong opinions are held because of absence of sufficient relevanthard data. These "Critical Issues" have been identifiedas such in the document. Consensus documents suchas this must, of necessity, be ephemeral. The scientificprocess was completed in the middle of 1999 and represents the up-to-date view at that time. It must beaccepted that further evidence will make some of theconclusions in the document out of date and incorrectin subsequent years. The participating societies therefore commit themselves to continuing the updateprocess (Figure 1).

References

1. Second European Consensus Document on Chronic Critical LegIschaemia. Eur J Vasc Surg 1992;6(Suppl A): 1-28.

2. Working Party on Thrombolysis. Thrombolysis in the management of lower limb peripheral arterial occlusion-A consensusdocument. Am J Cardiol1998; 81: 207-218.

3. Pentecost MJ, Criqui MH, Dorros G, et al. Guidelines forperipheral percutaneous transluminal angioplasty of theabdominal aorta and lower extremity vessels. Circulation 1994;89(1):511-531.

4. Rutherford RB, Baker JD, Ernst C, et aI. Recommended standards for reports dealing with lower extremity ischemia:Revised version. J VaseSurg 1997;26(3):517-538.

5. Sackett DL, Oxman AD, Guyatt GH. Users' guide to the medicalliterature. I. How to get started. JAMA 1993;270: 2093-2095.

6. Guyatt GH, Sackett DL, Cook DJ,et aI. Users' guide to the medicalliterature. II.How to use an article about therapy or pre\'ention. JAMA 1993;270: 2598-2601.

A2EPIDEMIOLOGY, NATURAL HISTORY,

RISK FACTORS

A2.1Introduction to Epidemiology

The management of the patient with peripheral arterial disease (PAD) has to be planned in the context of theepidemiology of the disease and, in particular, theapparent risk factors or markers predicting spontaneous deterioration. It is also necessary to know themagnitude of the problem together with the likelyoutcome in patients with differing severity of PAD toanalyse outcome measures and to assess the socioeconomic impact of the disease. A detailed search of all

Eur J Vase Endovasc Surg Vol 19 Supplement A, June 2000

the relevant publications was performed for this chapter. The resulting full analysis of the data has beenpublished separately in Seminars ill Vascular Surgery.lA full list of references and complete tables of dataalso can be found in that publication. Those tables arethe basis for the summary figures and diagrams reproduced in this document.

A2.2Intermittent Claudication

A 2.2.1The Problem of Defining Intermittent Claudication

Intermittent claudication (IC) is usually diagnosed bya history of leg pain on exercise that is relieved by rest.Several questionnaires have been developed for epidemiological use. Other diagnostic methods includeinterview, clinical examination, and noninvasive tests.In looking at methods for identifying IC in the population, it must be remembered that it is merely a symptom of PAD and that the measurement of symptoms isnotoriously difficult. A patient with quite severe PADmay not have the symptom of IC because some othercondition limits exercise. Likewise, patients with verymild PAD may have symptoms of IC if they are veryactive.

Questiollllaires

The WHO/Rose Questionnaire has been the mostwidely used cardiovascular questionnaire for theidentification of patients with Ie. It was designed in1962 by Rose,2 was subsequently adopted by theWHO, and has been widely used to estimate the prevalence of intermittent claudication.s In one survey in alarge population in France, this questionnaire wasshown to be highly specific (99.8%) in excludinghealthy individuals but only moderately sensitive(67.5%) in detecting those with claudication comparedwith physicians' assessments of symptoms (Table 1}.3In other words, there were only 0.2% false; false positives are questionnaire-positive individuals who werenot patients with intermittent claudication) but 32.5%false negatives (false negatives are patients with intermittent claudication who were questionnaire negative). The classification was extended in 1985 toinclude "possible.claudicants" (ie, those patients withexercise leg pain that is not present at rest, but who arenot otherwise fully concordant with the Rose criteria)

Epidemiology, Natural History, Risk Factors

Tabl e 1. Diagnost ic performance of various techniques for defining IQPAD

85

WHO/Rose questionnaireRose, 19622

Richard et al, 19723

lsacsson , 19722.'Criqui et al, 19851

Edinburgh questionnaireLeng & Fowkes, 1992;lVHO/Rosc qllcsliollllaire and ABPI < 0.9Criqui ct al, 1985~

Ogren et al, 1993="

' Probable claudication "Possible claudication

Sensitivity (%)

9267.5309'20"

91

71.215

Diagnostic performanceSpecificity (%)

10099.89899'95.9"

99

91.398

to try to improve the questionnaire's sensitivity, but atthe expense of a slight decrease in specificity,'

The Edinburgh Claudication Questionnaire isdesigned to be self-administered." The main differences compared with the WHO/Rose questionnaireare i) patients answering negatively to leg pain or discomfort when walking do not continue with the questionnaire and ii) the patient is asked to mark theplace(s) of the pain on a diagram. This questionnairewas validated in a study of approximately 300 patientsolder than 55 years who consulted their general practitioner. When compared with the independent assessment of two blinded clinicians, the questionnaireshowed a sensitivity of 91% and a specificity of 99%for the diagnosis of 1e.5 Table 1 shows that the principal problem with questionnaires seems to be that theyare too rigorous (low sensitivity), therefore underestimating the true prevalence of Ie. Furthermore, theinaccuracy of any questionnaire probably variesaccording to the age, occupation, and other characteristics of the population to which it is applied. The conclusion is that one must be wary of any epidemiological data based solely on questionnaires.

Clinical assessment

Although leg pain associated with exercise and relievedby rest is suggestive of IC, it is not sufficient on its ownfor a definite diagnosis. A detailed history taken by aclinician will help to identify those patients whose legpain on exercise is attributable to another cause, forexample, nerve root compression or severe venousinsufficiency. However, the addition of a clinical examination does not necessarily eliminate the errors foundon questionnaires alone. False-positive rates of up to44% and false-negative rates of up to 19% have beenreported after verification by noninvasive tests.s-'

The single most important part of the physical

examination to confirm a diagnosis of IC is palpationof the patient's peripheral pulses . It must be remembered, however, that an absent pulse may be attributable to causes other than arterial disease. A prospective study of 1,000 children aged between 1 and 10years were examined for the presence of dorsalis pedisand posterior tibial pulses." The posterior tibial pulsewas invariably present, whereas the dorsalis pediswas congenitally absent in 12% of the children. Inaddition, the prevalence of absence of dorsalis pediswas three times as high in white children comparedwith black children. A further study by Ludbrook etal? examined pulses in patients admitted to hospitalfor noncardiovascular causes. In the 0- to 19-yearage-group, the posterior tibial and dorsalis pedisarteries were absent in 0.2% and 8.7% of patients,respectively?

At least one pulse is not detected in approximately10% of the adult population when the femoral, posterior tibial, and dorsalis pedis arteries are palpated.l?However, 3% of these were asymptomatic (Figure 2).At least part of the problem is observer error in detecting pulses. Similar variability or reproducibility in thedetection of peripheral pulses was found in two studies in hospital patients.v" However, the authors ofthese two studies reached very different conclusions..In the first, they found that the agreement between theobservers improved during the study and reached"satisfactory levels,"? and in the second, the authorsthought that there was "very great observer error,"which did not diminish during the study."

It has been suggested that, for most ep idemiologicalresearch, palpation of the peripheral pulses is probably too insensitive a measure of PAD. However, thesituation in general practice appears to be different.The authors of a large general practice study inHolland, in 2,455 patients with leg complaints, concluded that palpation of both foot pulses is the keyprocedure for the clinical diagnosis of PAD.l2 This

Eur J Vase Endo vasc Surg \'0119 Supplement A, June 2000

86 Epidemiology, Natural History, Risk Factors

enables the general practitioner to exclude the diagnosis in many patients with a high degree of certainty,establish the diagnosis in a small group of patients,and identify a limited group who require further noninvasive testing. Figure 2 shows the interrelationsbetween intermittent claudication, pulselessness, andankle:brachial pressure index (ABPI) in 666 men andwomen.

AI/kle: brachial pressllre index

For epidemiology purposes, the most useful noninvasive test is the ABPI. The Doppler ankle systolic pressure has been shown to correlate closely with directintraarterial recordings.w'! The Doppler probe is alsoeasier to use than other techniques, such as plethysmography.15,16 The Doppler is very inexpensive; themeasurements are rapid, painless, and can be wellstandardised.w Although it has been suggested thatstrain-gauge plethysmography is more accurate thanthe Doppler for ABPI, it is more difficult to use, and atleast one study suggests that it is no more reproducible.'? It is generally recognised that the Dopplersystolic pressure may be inaccurate if the artery is notcompressible, as occurs, for instance, in some diabeticpatients. In addition, the use of ABPI measurementdepends on the brachial pressure being a true centralsystolic pressure. This may not be the case in patientswith subclavian artery stenosis, which is most frequent in diabetic patients and patients with CLI.

IntermittentClaudication

n =25

46

ASPI < 0.9n = 95

The variability in measuring ankle pressure hasbeen examined in several studies. tO,18.19.20,21 In onestudy,'? ankle systolic pressure was found to vary in away similar to arm systolic pressure, whereas "goodreproducibility" was found in another study1 8 whentwo successive measurements were made. Baker andDix19found that repeated measurements produced anaverage range of 0.18 in the ABPI, and Carterv foundthat 95% of repeat ABPI were within 9% of the average.22 The variability in both ankle systolic pressureand ABPl measured on different occasions by differentobservers appears to have only a marginal effect onbetween-subject variability."

It has been suggested that a resting ABPI of 0.90 is upto 95% sensitive in detecting angiogram-positive diseaseand almost 100% specific in identifying apparentlyhealthy individuals.20.22,23.24.25,26 Although specificity inthe normal population is close to 100%, in patients with,for instance, diabetes, the specificity will be less. Most ofthese studies have used selected, symptomatic, hospitalpatients and controls who were considered healthybecause they were young or had no signs or symptoms.Individuals with vascular disease who had an angiegraphically normal limb also were used as controls.Thus, it is not known how ABPI in the general population would correlate with angiographic findings inPAD. However, results among those with severe disease likely would be similar to those found in hospitalpatients. The Edinburgh Artery Study found an association between ABPI and disease severity in the general population." Table 1 compares the sensitivity and

One or moreabsent ankle pulse

n =70

Fig. 2. Interrelation between intermittent claudication, pulselcssness, and AOPI in 666 men and womcn.w

Eur JVase Endovasc Surg \'0119 Supplement A, June 2000

Epidemiology, Natural History, Risk Factors 87

15

10

Annual incidenceper 1,000 men

5

908050 60 70Age (years)

40O-l----,---.,....---r--r-----r-----,

30

__ Widmer & Da Silva, 1991

__ Leng et ai, 1991

••••••• Bainton et aI, 1994

_.. Bowlin et ai, 1994

- - - - Murabito et at, 1997

Fig. 3. Incidence of Ie in men at different <lges in five population studies.

specificity of the various methods that have been usedto study the incidence and prevalence of IC and PAD.It should always be remembered that the ABPI, orindeed the palpation of pulses, assesses PAD, which isnot necessarily synonymous with Ie.

A 2.2.2Incidence of Intermittent Claudication

Knowledge of the incidence and prevalence of IC isessential for socioeconomic calculations and for healthcare planning on both a regional and a national basis.Estimates of the incidence of IC or PAD in a population are subject to a number of errors. Only a minorityof patients with demonstrable PAD complain of symptoms of IC, whereas many patients with IC arc elderlyand consider that their symptoms are part of growingold; therefore, they do not seek medical advice.Patients' occupations and habitats greatly influencethe appearance of symptoms. Thus, the proportionwho consult their general practitioner varies from 10%in the inner city30 to 50% in rural communities."Because most of the patients who consult their physicians are not referred to a specialist, incidences basedon hospital referrals are gro ssly underestimated.v

Although questionnaires enable a wider and lessselected population to be sampled, as already stated,they tend to overdiagnose arterial disease.30;l1;l3.J.l;l3.36

Studies that focus on working populations also canresult in bias, for two reasons: First, the presence of thesymptoms may be related to the nature of the work.Thus, IC has been found to be more common amongagricultural workers than in civil servants, Second,individuals incapacitated by PAD may be automatically excluded by the nature of their work. Figure 3

shows the incidence of IC in men at different ages invarious studies, with an obvious wide variation in theabsolute figures that can only partly be explained bydifferences in methodology. It is interesting, however,that the two studies of unselected populations thatalso used ABPI measurements report the lowest incidence of Ie. Within each study, there is a general pattern of a gradual increase in incidence up to the age ofat least 60 years. Figure 4 shows the weighted meanincidence of IC found in five large population-basedstudies.

A 2.2.3Prevalence of Intermittent Claudication

Many more studies have been done regarding theprevalence rather than the incidence of Ie. However,prevalence rates also differ depending on the studypopulation and the diagnostic methods used. Evenwhen the same diagnostic technique is used, this canresult in different prevalence rates, depending on theage, sex, and geographic location of the populationstudied. Thus, reported prevalence rates for IC usingthe Rose questionnaire vary from 0.4% to 14.4%.32Table 2 contains the larger studies using methodologythat is relatively reliable. Figure 5 summarises thesedata.

In the Limburg study, 3,654 individuals aged 40 to79 years were examined by their general practitioners,and the diagnosis of IC was based on medical history,clinical examination, and data from the patient's history,39 Independently of the general practice, the practice assistants assessed ABPI using a pocket Dopplerdevice and a mercury sphygmomanometer. An ABPIof less than 0.95, measured twice within a week, was

Eur J Vase Endovasc Surg Vo119Supplement A, June 2000

88

8

7

6

... 5~00(;)

~ 40CIII"Cjj 3.5

2

o-1-----,--30-34


Age group

Fig. 4. Weighted mean incid ence of int ermittent claudication from five large population-based stud ies.

Table 2: Prevalence of Ie in men in large population studies

Study Location Population sample Age (yrs) Prevalence (%)

Hughson et aI, 1978" Oxford shire 1,716 45-69 2.2De Backer et al, 19793:l Belgium 8,252 4D-49 0.8

5D-59 2.3Reunanen et al, 198233 Finland 5,738 3D-39 0.6

4D-49 1.95D-59 4.6

Fowkes et al, 19914~ Edinburgh, Scotland 1,592 55-74 4.5'Stoffers et al, 19913· Holl and 3,654 men & women 45-54 0.6

55-64 2.567-74 8.8

Smith et al, 199po Scotland 10,042 men & women olD-59 1.1Novo et al, 1992" Palermo 1,558 men & women 4D-49 4.7

5D-59 9.2

"Overall prevalence for men and women aged 55-74 years: 4.5%.

considered evidence of PAD. An ABPI of less than 0.95probably overestimates PAD. TI,e prevalence of PADin this study ranged from 1.4% for that diagnosedusing the strict Rose criteria to 1.8% for that diagnosedby general practitioners and 6.1% when an ABPI ofless than 0.95 was used. Similar figures were obtainedfrom the Edinburgh Artery Study and the ScottishHeart Health Study, using similar methodclogies.w"The latter was one of the largest studies, over 10,000subjects, to use clinical examination for diagnosing Ie.The Finnish study was also similar in magnitude andmethodology as were the results.P The Oxford studywas unusual in that questionnaire-positive subjectsalso had postexercise as well as resting pressure measurements."

Eur JVase Endovasc Surg Vol 19 Supplement A, June 2000

In the larger, more reliable studies, there is a reasonable consistency in the results; at around the age of 60years, the prevalence of Ie in men is 3% to 6%. Figure6 shows these results graphically, giving a rough ideaof the changing prevalence with age in men. Althoughthe prevalence in men is always greater than that forwomen at all ages, no clear pattern emerges of anychanges in the ratio with age, with ratios varying froma little oyer 1 to over 8 in one study.

Prcoalencc ofasymptomatic disease

The prevalence of asymptomatic disease can be estimated only by using noninvasive techniques. The


0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.00

Age-group

Fig. 5. Weighted mean prevalence of intermittent claudication in large population-based studies.

most widely used noninvasive test to detect asymptomatic disease has been the measurement of ankle systolic pressures.lO,H,~~ The Basle studyv used pulsewaveforms detected by oscillography, and a USAstudy also included a reactive hyperemia test."Noninvasive diagnostic tests have not been widelyused in epidemiological surveys of PAD. The prevalence of asymptomatic disease in various studiesranges from 0.9% to 22%, with the ratio of symptomatic to asymptomatic disease in individual studiesranging from 1:0.9 to 1:6.0.4,IO.33.42,43,45,47,~S,49,50

The detected prevalence of asymptomatic PADlargely depends on the measurement technique used.This is well illustrated in Hiatt et al's careful study inCalifornia.t! A resting ABPI of less than 0.9 isbelieved to be associated with a 50% or greater vesselstenosis and could serve as an arbitrary definition ofPAD. Detailed analysis of the available data suggeststhat for every patient with IC there are probablyanother three with asymptomatic disease causing a50% or greater stenosis of the arteries supplying thelegs.

A 2.2.4Risk Factors for Developing Intermittent Claudication

The risk factors for developing PAD are similar tothose for other atherosclerotic diseases. The influenceof age and sex in the incidence and prevalence of IChas already been considered. A number of studies have

looked at other classical risk factors, such as diabetes,hypertension, lipid abnormalities, and smoking, aswell as some more recently identified associations,such as plasma fibrinogen levels, impaired glucose tolerance, and hyperhomocysteinemia.

Diabetes mellitusand impaired glucose tolerance

Many studies have shown an association betweendiabetes mellitus and the development ofPAD.3~,H,52,53,5~,55,56,57,58,59 Overall, IC seems to be abouttwice as common amongst diabetic patients asamong nondiabetic patients. Over the last decade,mounting evidence has suggested that insulinresistance plays a key role in the so-called metabolic syndrome, which is characterised by thecoincidence of obesity, non-insulin-dependent diabetes mellitus, hyperinsulinaemia, hyperlipidaemia,hypertension, hyperuricaemia, and cardiovasculardisease.w

Smokillg

The relationship between smoking and PAD has beenrecognised since 1911,when Erb61reported that IC was3 times more common among smokers than amongnonsmokers. Interventions to decrease or 'eliminatecigarette smoking have therefore long been advocated

Eur JVase Endovasc Surg Vol 19 Supplement A, [une 2000

Epidemiology, Natural History, Risk FactorsS10

10

9

8

7?f.Q) 6oc:~ 5co> 4Q)...Q.

3

2

o

0-0

D-tO-----.. n-o

e-o

o • R-T=-Q groD--O D--O

o ~o---rf0::! 0

o Hughson et al (1978)

• De Backer et al (1979)

o Reunanen et al (1982)

• Fowkes et al (1991)

o Stoffers et al (1991)

o Smithetal(1991)

n Meijer et al (1998)

20 30 40 50 60 70 80 90

Age (years)

Fig.S, Prevalence of Ie in men in various studies.

for patients with K', It has been suggested that theassociation between smoking and PAD may be evenstronger than that between smoking and coronaryartery disease (CAD).44.56.59,62In the Framingham study,the risk at all ages was almost double for PAD compared with CAD.3-I All epidemiological studies of PADhave confirmed that cigarette smoking is a strong riskfactor for the development of Ie.10.31.33,3-IA3.53.55.56.63 Inaddition, a diagnosis of PAD is made up to a decadeearlier in smokers than in nonsmokers.44lH,65

The severity of PAD tends to increase with thenumber of cigarettes smoked.66,67,6s,69,io,71 Cigarettesmoking increased the risk of IC in both sexes, andheavy smokers had a fourfold risk of developing Ie.3-IIt has been reported that smoking cessation is associated with a rapid decline in the incidence of IC andthat the risk of IC for ex-smokers 1 year after quittingis approximately the same as that for nonsmokers.ev"However, this is at variance with the results from theEdinburgh study, which found that the relative riskof IC was 3.7 in smokers compared with 3.0 in exsmokers (discontinuation of smoking for more than5 years)."

Hypcrtcnsion

The Framingham study has provided the most convincing epidemiological evidence of a link betweenhypertension and PAD.3-I.53.55,56 Kannel and McGee3-1


showed that hypertension carried a 2.5-fold ageadjusted risk in men and a 3.9-fold age-adjusted riskin women. This is also suggested by the Edinburgh'!and the Baslev studies but not by the Whitehall'? andthe Finnish» studies, which found no associationbetween PAD and hypertension. The discrepancybetween these results may in part be due to the complex link between hypertension and Ie. Both are associated with PAD, but hypertension is probably both acause and an effect of atherosclerosis. Finally, hypertension may to some degree delay the onset of symptoms of IC a patient with PAD by elevating the centralperfusion pressure; it is not uncommon for a hypertensive patient to develop IC when high blood pressure is discovered and treated.

Haemaioiogic factors

Hyperlipidaclllia There is conflicting evidence regarding the relationship between hyperlipidaemia andPAD. In the Framingham study, a fasting cholesterollevel greater than 270 mg/dL (7 mmol/L) was associated with a doubling of the incidence of Ie. It appearsthat the ratio of total to high-density lipoprotein(HDL) cholesterol is the best predictor of occurrence ofarterial disease.P Although some studies have alsoshown that total cholesterol is a powerful independentrisk factor for PAD,3-I,67 others have failed to confirmthis association.3IA7,~8,63,i~,i5It has been suggested that


cigarette smoking may enhance the effect of hypercholesterolaemia. There is evidence that treatment ofhyperlipidaemia reduces both the progression of PADand the incidence of lC. i 6,77 An association betweenPAD and hypertriglyceridaemia has also been reported, but the strength of this association isunclear.IO,31,33,~A3,63 Hypertriglyceridaemia, however,has been shown to be associated with the progressionand systemic complications of PAD.iS Recently,Cheng> has shown that lipoprotein (a) (Lp[aj) is a significant independent risk factor for PAD.

Fibrinogen An increased plasma level of fibrinogenhas been associated with PAD in several studies, andother studies have established the role of high fibrinogen levels as a thrombotic risk.31,80,SI

HyperllOlllocysteillelllia The incidence of hyperhomocysteinemia is as high as 60% in the vascularpopulation, compared with 1% in the general population.S2,S3 It is reported that hyperhomocysteinemiawas detected in 28% to 30% of patients with premature PAD.S4,S5 The suggestion that hyperhomocysteinemia may be an independent risk factor foratherosclerosis has now been substantiated by severalstudies.86.87,ss It may be a stronger risk factor for PADthan CAD. A meta-analysis of studies concluded thatthe odds ratios for CAD were 1.6 and 1.8 in men andwomen, respectively, compared with 6.8 for PAD.89 Italso suggested that hyperhomocysteinemia mayaccount for 10% of the population risk for coronaryartery disease.

Hypercoaglllability Raised haernatocrit levels have,been found in patients with IC and have been found tobe predictors of future graft occlusion.9o,91,92 However,

this increase may well be attributable to an associationwith smoking. In the Framingham study, an elevatedhaematocrit was not associated with a greater risk ofIC.~ In one study, Ray et al93 showed that the prevalence of hypercoagulabiIity in patients with stableclaudication was 25%, compared with 11% in the general population. This increased to 40% in thosepatients requiring vascular intervention.

Coexisting riskfactors

The coexistence of at least some of the above risk factors increases the risk of PAD at least additively in thelower limbs. When cigarette smoking, diabetes mellitus, and systolic hypertension were considered in theBasle study, the relative risk increased from 2.3 to 3.3and 6.3 in those individuals with one, two, or threerisk factors, respectively." The Framingham study hasfound similar results.v In particular, inclusion of cigarette smoking dramatically escalates the risk of ICwhen combined with any other risk factors (Figure 7).

Protective factors

Inevitably, the absence of a risk factor is protective.However, other positive protective factors for thedevelopment of IC have also been identified, including moderate alcohol intake'" and a history of regularphysical activity.e

Risk of intermittent claudication

40000,.- 30"-Q)0-Q)

20..-co"-"-coQ) 10>.,co

0

Systolic BP 105Serum Cholesterol 185Glucose intolerance 0

36.6

14.6

150 195260 335o +

o Smoker• Non-smoker

_ Average risk fora 65 year old man

Fig. 7. Estimated probability of a 65-year-old man developing Ie with a specific blood pressure and cholesterol level and with, or without,diabetes, based on a 26-year data from the Framingham study (Kannel and McGee, 1985").



Genetic risk

Although a positive family history has been definitelylinked with coronary heart disease, increasing the riskby 1.5- to 2-fold,97 and stroke,so,98 it has not been confirmed as a significant risk factor for PAD. Both theNurses' Health Study and the Framingham OffspringStudy found that a family history of CAD was anindependent risk factor for CAD in women.99,l 00 TheDanish Twin Concordance study found that that CADwas higher in monozygotic twins compared withdizygotic twins.r" An interesting prospective study byMarenberg et al loo looked at 21,000 twins. The studyconcluded that a family history of early death of coronary heart disease is associated with an increased riskof death of the disease and that at least part of this riskwas attributable to a genetic element.iw

A 2.2.5Summary: Risk Factors for Developing Symptomatic

PAD

Figure 8 summarises the range of odds ratios for different risk factors. Excluding unavoidable factors, themost important risk factors for developing symptomatic PAD are diabetes and smoking, with odds ratiosof approximately 2 to 3. Hypertension and lipid abnormalities are significantly less important, and the evidence regarding their influence is more controversial.

A2.3Coexisting Vascular Diseases

Because PAD, CAD, and cerebrovascular disease(CVD) are all manifestations of atherosclerosis, it isnot surprising that the three conditions commonlyoccur together. The extent of coexisting cardiovasculardisease must be appreciated to ensure that the physician treating IC will treat it in a true context. Studieson the prevalence of CAD in patients with IC showsthat history, clinical examination, and electrocardiography typically indicate the presence of CAD in 40%to 60% of such patients, although this may be asymptomatic if exercise is severely limited by claudication. 31,55,103,I 0-1,105,106,107,108,109,110,111,112,113,114,115,116

As with asymptomatic PAD, the diagnosis of CADdepends on the sensitivity of the methods used. In onestudy, in which coronary angiograms were performed,the prevalence was as high as 90%.115 All patients presenting to the Cleveland Clinic from 1978 to 1981 forelective peripheral vascular surgery had cardiaccatheterisation to determine whether prophylactictreatment of severe CAD could improve their longterm survival. Only 10% of the 381 patients presentingwith IC had normal coronary arteries on angiography,whereas 28% had severe three-vessel disease that merited revascularisation or was already inoperable. Theconverse is also true: among individuals with CAD,the prevalence of PAD is higher than in non-CAD

Odds ratioProtective Harmful-2 -1 0 2 3 4

Male gender (cf female) ~Age (per 10 years) ~

Diabetes +Smoking ~

Hypertension +Hypercholesterolemia •Fibrinogen +

Alcohol +Fig. 8. Range of odds ratios for risk factors for developing intermittent claudication.

Eur J Vasc Endovasc Surg Vol19 Supplement A, June 2000


30

• MI

25 0 Angina

0 CHF

20

0-0

15 ~

0 0

10 ..• •

50-0

0-0 0

00.0 0.5 1.0 1.5 2.0

Fig. 9. Number and percentage of patients with cardiovascular disease in subgroups with decreasing ABPI index (Newman et aI1l7) .

individuals.P-" The relative risk of IC among Finnishmen and women with angina pectoris compared withcontrols was 7.2 and 3.9, respectively.v Aronow andAhn1l2 found that 33% of CAD patients also had PAD.In the Cardiovascular Health Study, ABPI was closelycorrelated to the number of patients with myocardialinfarction (MI), angina, and congestive heart disease(Figure 9).117

The link between PAD and CVD seems to beweaker than that with CAD. Although approximately half of all patients with IC have CADdetectable by simple clinical techniques, a muchlower proportion have demonstrable CVD.31,94.112.118By duplex examination, carotid disease has beenfound in 26% to 50% of patients with IC.1l9.120.12I,122Most of these patients will have a history of cerebralevents or a carotid bruit and seem to be at increasedrisk of further events.t-' Aronow and Ahn1l2 foundthat 33% of patients with CVD also had PAD. Thereis very little reliable information on the overlapbetween significant arterial disease in the three circulations: leg, heart, and brain. Most studies haveconcentrated on one area only and recorded onlysuperficially, if at all, the coexistence of significantarterial disease elsewhere. The large CAPRIE study

of almost 20,000 patients is an example of this, inwhich the presence or absence of claudication in thepatients enrolled after MI was based on a singlequestion.s- The other problem with the CAPRIEstudy, from an epidemiological point of view, is thatthe sizes of three populations of patients with PAD,recent MI, or recent cerebrovascular accidentenrolled in the CAPRIE study were kept artificiallysimilar by the protocol.

A more realistic picture of the overlap betweenPAD, CAD, and CVD is probably given by Aronowand Ahn's prospective study in 1,886 patients agedolder than 62 years.u- CAD, PAD, and CVD (diagnosed by clinical history or electrocardiograph[ECG]) were all more prevalent among men thanwomen. Only 37% of these patients had no clinicalevidence of PAD, CAD, or CVD. Figure 10 illustrates the overlap between PAD, CAD, and CVD inthese two studies. The evidence available from all ofthe relevant studies suggests that approximately60% of patients with PAD will have significant disease in the cardiac or cerebral circulation, andapproximately 40% of patients with coronary disease or significant cerebral circulatory disease willalso have PAD.


S14

Cerebral

PAOD

Aronow &Ahn


Cerebral

PAOD

CAPRIE

Fig. 10. Overlap between PAD, CAD, and CVD in 1,886 patients aged >62 years. 37% of whom had no CAD, CVD, or PAD (adapted fromAronow & Alm1l2 and CAPRIE62).

A2.4Fate of Patients With Peripheral Arterial Disease

A 2.4.1Fate of Local Disease in the Legs

Intermittent claudication can progress in four differentways:

1. Improvement or stabilisation2. Worsening claudication not requiring intervention3. A need for intervention such as surgical revascular

isation or angioplasty4. A need for amputation

Worsening claudication

Although PAD is progressive in the pathologicalsense, its clinical course is surprisingly benign in mostcascs .P' Large population studies provide the mostreliable figures. These include the Basle study findingsregarding the course of PAD, which are probably typical. This study documented angiographic progressionof the disease in 63% of patients 5 years after the initial diagnosis." However, of those who had survivedfor 5 years after the diagnosis, 66% still had no limiting Ie. Hospital-based series, even if essentially nonsurgical, tend to identify patients with IC who havemore severe disease or whose symptoms are progressing. A recent multinational study, which recruitedpatients predominately from nonsurgical hospitalclinics, showed that 6% deteriorated in terms of walk-


ing distance over the first year.111 All of the evidenceover the last 40 years since the classic study by Bloor125

has not materially altered the impression that onlyabout a quarter of patients with IC will ever significantly deteriorate. This symptomatic stabilisation maybe due to the development of collaterals, metabolicadaptation of ischaemic muscle by an increase in aerobic enzyme content and capillary density, or thepatient altering his or her gait to favour nonischaemicmuscle groups. The conditions of the remaining 25%of patients with IC deteriorate; this is most frequentduring the first year after diagnosis (7%-9%) compared with 2% to 3% per annum thereafter.125,126

There is a wide variation in different series in theproportion of patients with IC who ultimately requireintervention, from 3% 127 to 22%,100 which dependslargely on the type of claudicant enrolled in the study.The lower figures are likely to be a truer reflection ofwhat happens to all patients with IC, because thehigher figures are mostly from centers to which moresevere cases have been referred. Bloor's reportedmajor amputation rates of 7% over 5 years and 12%over 10 years have been supported by other studiesthat also looked at selected populations severaldecades ago.103,10U05 However, two more recentreviews also highlight that major amputation is arelatively rare outcome of claudication, with only 1% to3.3% of patients with IC needing major amputationover a 5-year period.m.12s

This is likely to reflect an increase in successful limbsalvage procedures rather than a change in the localprogression of the disease. The Basle and Framinghamstudies, which are the two large-scale studies that


Odds ratio

S15

•

Male gender (cf female)

Age (per 10 years)

Diabetes

Smoking

Hypertension

Hypercholesterolaemia

Fibrinogen

Alcohol

Hyperhomocysteinemfa

Protective-3 -2 1

I I

+

2!

Harmful3 4 5, I ,

6!

7I

+Fig. 11. Range of odds ratio s for risk factors for the progression of local d isease in the legs.

have looked at unselected patients, found that fewerthan 2% of PAD patients required major amputation .57,73 In summary, the existing data suggest thatonly one fourth of all patients with IC deteriorate progressively, and with an intervention rate of approximately 5%, only 1% or 2% of all patients with IC willever need a major amputation. Although amputationis the major fear of patients informed that they ha vecirculatory disease of the legs, they can rest assuredthat this is an unlikely outcome.

A 2.4.2Risks Factors for the Progression of Local Disease in

the Leg

Primary risk factors for vascular disease in generaltend to be only weak secondary risk factors in patientswith Ie. Figure 11 summarises some of the studies thathave looked at the magnitude of the risk for the progression of local disease with various risk factors.

Smoking

Smoking is the most important risk factor that can beinfluenced . Cronenwett et al129 found that patientswith IC who had smoked at least 40 pack-yearsrequired reconstructive vascular surgery over threetimes more frequently than those who had smoked

less. The most extreme example is the study byJuergens et al,13° who reported a major amputationrate of 11% in patients with IC who smoked comparedwith no major amputations in nonsmokers.

Diabetes

PAD in patients with diabetes is more aggressive, withearly large vessel involvement coupled with microangiopathy. McDaniel and Cronenwett'> showed thatpatients with IC and diabetes had a 35% risk of sudden ischaemia and a 21% risk of major amputation,compared with 19% and 3%, respectively, in nondiabetic patients. Two other studies have also foundincrea sed major amputation rates in patients with ICand diabetes.131,m Similar results were found byDormandy and Murray and Ielnes et al. lII ,l26

ABPI

In a prospective trial in nearly 2,000 patients with ICwhose entry characteristics were analysed to look forpredictors of deterioration of PAD (eg, need for arterial surgery or major amputation), the most significant predictor was an ABPI less than 0.5.111 This carried a relative hazard ratio of 2.3, a finding similar tothat of [elnes et al,126who found that a low ABPI was

Eur J Vase Endovasc Surg Vo119 Supplement A, June 2000


associated with a relative risk of 2.4 for local progression. Over the 6.5-year follow-up in this study,no major amputations were required in patients withan initial ankle pressure greater than 70 mm Hg,although the proportion of patients with diabeteswas unusually small (5.4%).126 Several studies haveindicated that in those patients with IC in the loweststrata of ankle pressure (ie, 40-60 mm Hg), the risk ofprogression to severe ischaemia or actual limb losswas 8.5% per annum,126,133,13-I.135 whereas one of thestudies showed a clear stepwise correlation betweenoutcome and decreasing ankle pressure.126There is asuggestion that claudication has a more benigncourse in women. In most of the large populationstudies of prevalence, there was a male:female ratioof approximately 2:1 for patients with IC, comparedwith ratios of 3:1 to 13:1 in series studying the diseaseat a later stage.36,I03,I07,125,131,132 Dormandy andMurray'!' found that men had a relative risk of 1.66for deterioration of leg ischaemia compared withwomen.

Hupertension

Although Jelnes et al126noted that the risk of deterioration was related to systemic arterial pressure, thestudy by Dormandy and Murray,"! which includedpatients on antihypertensive medication, and whichperformed a multivariate analysis to correct for thepresence of other risk factors, found that hypertensiondid not influence the local progression of PAD.

A2.5Progression of Systemic Atherosclerosis

The evidence for coexisting arterial disease in patientswith PAD has already been reviewed. Patients witheither asymptomatic or symptomatic PAD generallyhave widespread arterial disease and therefore have asignificantly increased risk of stroke, MI, and cardiovascular death. PAD should therefore be viewed as asign of potentially diffuse and significant arterial disease. Recent reports show a 1% to 3% annual incidenceof nonfatal MI.1I1,128 The Edinburgh Artery study hasshown that patients with IC have a significantlyincreased risk of angina (relative risk, 2.31) whereasasymptomatic PAD patients have a slightly increasedrisk of MI and stroke.P? The frequency of these eventsseems to be correlated with PAD severity, as assessedby ABPI or the presence of popliteal trifurcation disease. 1I1,138 Indeed, Ogren et al1l8found that anABPI lessthan 0.9 was the best predictor of stroke in 68-year-oldmen with asymptomatic carotid stenosis. Table 3 summarises the limited information about the incidence ofnonfatal cardiovascular events in patients with ICThere seems to be general agreement that between 2%and 4% of patients with IC have a nonfatal cardiovascular event within the first year.

A 2.5.1Mortality

In the 1950s, Allen et aIm stated that half of the existing patients with IC would be dead within 5 years,

Table 3: The incidence of nonfatal cardiovascular events in patients with intermiUent claudication

Study No of patients

Bloor, 1961123 1,476Begg& Richards, 1962 1().l 198Peabody et al, 1974 139 162

Kallero et al, 1985' 3:3 368

Widmer et al, 1986 110 236Gilliland et al, 1986' 18 400

Dormandy & Murray, 1991111 1,969

Davey Smith et a!' 1991'~1 18,403

Leng et al, 1996137 1,592

CAPRIE, 1996·~ 19,185

Em J Vase Endovasc Surg Vol 19 Supplement A, June 2000

Follow-up (yrs)

55-1318

0.1-11

115.5

5

1-3

Nonfatal cardiovascular events ('Yo)

2028.7Cardiac: 44 men; 34 womencerebral: 4 men; 3 womenCardiac: 6.5cerebral: 7.9Cardiac: 15.5 cerebral: 12.4Cardiac: 14cerebral: 5Cardiac: 1.2cerebral: 1Possible MI: 20.1angina: 16.5MI:8.2angina: 9.6CVD:6.8MI:2.9CVD: 5.3


100

80

~ 60a...7ii>.~

::l 40f/')

20

00 5 10 15

Follow up (years)

Fig. 12. Survival of patients with intermittent claudication and match ed controls.

Controls

IC

517

and Stammers'P added that those aged 55 to 60 yearswould die of CAD within 5 years. Although theseopinions now seem overly pessimistic, they show anappreciation of the higher mortality rate of patientswith symptomatic PAD. Bloor125 estimated that a claudicant's life expectancy was decreased by 10 years.Despite disparity in patient selection, over two dozenstudies show some degree of agreement about theoverall mortality in those with Ie. The 5-, 10-, and 15year mortality rates from all causes are approximately30%, 50%, and 70%, respectively-an outlook that isnot much better than that following resection of aDuke's B carcinoma of the colon. This emphasisesmost clearly that the real danger for the patient withsymptoms of leg ischaemia, intermittent claudication,is not losing the leg but rather suffering prematurecardiovascular complications or death. Both patientsand their physicians should therefore give therapeuticpriority to the latter.

The Coronary Artery Surgery Study (CASS) compared survival in 2,296 patients with PAD and 13,953controls. Patients with PAD were found to have a 25%greater likelihood of dying compared with those without (hazard ratio, 1.25).1-14 ABPI has also been correlated with mortality in two studies.6•H 5 In the first study,with 1,492women older than 65 years, the 4-year mortality rate in those with an ABPI greater than 0.9 was9.5%, compared with 53.7% in those with an AI3PI of0.9 or less.s Similar results were found in the secondstudy, in 1,537 men and women older than 60 years,which found mortality rates after 1 to 2 years' followup of 1.7% in those with an ABPI greater than 0.9 and6.9% in those with an ABPI of 0.9 or less.!"

Of particular interest are the studies in which thedifference in mortality rates between claudicant andnonclaudicant patients was adjusted for differencesin known risk factors such as smoking, hyperlipidemia, and hypertension. Such risk factors would beexpected to be commoner in and contribute to ahigher mortality rate in patients with fC, Theincreased risk of death in claudicant patients waslargely unchanged despite the adjustment for riskfactors. These surprising but consistent results suggest that there may be a special, as yet unidentifiable, risk factor in patients with IC other than simplyatherosclerosis. Figure 12 pools the results from allstudies comparing mortality rates of claudicantpatients with those of a matched nonclaudicatingpopulation. As expected, the two lines divergesteadily at a constant slope, indicating that on average the mortality rate of claudicant patients is 2.5tim es that of nonclaudicant patients.

A 2.5.2Cause of Death in Patients With Intermittent

Claudication

Although CAD is by far the most common cause ofdeath among patients with PAD, the proportion is stillsurprisingly low (40%-60%), with CVD accounting for10% to 20% of deaths. Other vascular events, mostlyruptured aortic aneurysm, account for approximately10%. Thus, 20% to 30% of patients with PAD die ofnoncardiovascular causes (Figure 13).


S18 Epidemiology, Natural History, Risk Factors

Cerebral 4%

Cardiac55%

Patients with Ie General ooculation >40 years

Fig.13. Cause of death in patients with IC and in the general population in Germany in 1996 (source: Federal Stalistical Office of Germany).

A 2.5.3Summary: Fate of the Claudicant

Figure 14 summarises the fate of the claudicant, whichis relatively benign as regards local disease in the leg,but which is increasingly malignant in terms of fataland nonfatal serious cardiovascular events. Onlyapproximately 5% of patients with IC need surgical orendovascular intervention over 5 years for eithersevere claudication or deterioration to critical limbischaemia. Approximately 2% of patients with IC everneed a major amputation.

A 2.5.4Risk Factors for Systemic Morbidity or Mortality

Not surprisingly, the presence or absence of severeCAD seems to determine a claudicant's fate.Dormandy and Murray found that patients with ICand CAD were twice as likely to die as those withoutCAD.111 Both Begg and Richardsw' and Juergens et a1l3O

noted that claudicant patients with clinical or electrocardiograph evidence of coronary ischaemia had survival curves similar to those who had survived an MI.

Because low ABPI «0.5) has been shown to be related to the severity of CAD, it is not surprising that thisindex has also been associated with an increased mortality risk.s McDermott et all46 have shown that theABPI is a powerful tool for predicting survival inpatients with PAD; patients with an ABPI of 0.3 or lesshad a significantly poorer survival rate than those withan ABPI of 0.31 to 0.91 (relative risk, 1.8).A recent studyhas shown that, in multivariate analysis, hypertriglyc-


eridaemia (2:2 mmol/L) was the only independent factor associated with deterioration of ABPI (relative risk,1.8) and with the onset of CLI (relative risk, 1.9),78SmokingW.H8.H9 diabetes,I05.106.I07,108,109,111,126.W hypertension,I04.111.126 white cell count,111.148 asymptomatic carotiddisease.w and fibrinogenH8.151 have all been reported aspredictors of mortality. Smoking increases mortalityrates among patients with IC by between 1.5 and 3.0.5

Figure 15 illustrates the odds ratios for different riskfactors; it is interesting that diabetes and smoking seemto be less of a risk for total mortality than for progression of local disease in the legs (see Figure 11). The ABPIseems to be a far better predictor of all-cause mortalityin these patients.

A2.6Critical Limb Ischaemia

Critical limb ischaemia (CLI) is the term used todelineate those patients whose arterial disease hasresulted in a breakdown of the skin (ulcer or gangrene) or pain in the foot even at rest. It thereforecoincides with stages III and IV of the Fontaineclassification. This equates to the Rutherford 4, 5,and 6 categories of the New SVS-ISCVSRecommendation of Reporting Standards.tv Theprincipal reason for adopting this broad inclusivedefinition is that most of the epidemiological datarelate to this whole group. It is not possible to talkabout the natural progression of these patientsbecause they inevitably require active intervention.Although numerically far less than patients with


55 to 60 will bealive without newV event in 5 years

Another 100 patientswith claudication willnot present to a doctor

-

30 willV die within

5 years C

16 cardiac4 cerebral

3 other vascular7 non-vascular

5to 10non-fatal C

events in5 years

~r-_...:~_SYstemicoutcome -"'- -,

100 patients presentingto doctor with claudication

e I 25will Ideteriorate

n

5 will require anintervention and 2 will

require a major amputation

-:~nleg

75 stabilisor improveclaudicatio

I At least another 300 people Lwith asymptomatic PAOD 1-

l!========!J

Fig. 14. Five-year fate of the claudicant.

IC, patients with CLI demand a disproportionatelylarge commitment both in medical effort and economically. They also represent the major workloadfor vascular surgical units. However, it is onlymuch more recently that data have been collectedon large series of CLI patients outside the context ofspecific surgical procedures.

A 2.6.1Incidence and Prevalence of eLi

There is little direct information on the incidence ofCLI. Catalano's' assessed its incidence in North Italyusing three different approaches. First, a prospective 7year study on the incidence of CLI in 200 patients withIC and 190 controls (development); second, a prospective 3-month study of hospitalisations for CLI in a sample of hospitals in Lombardy (hospitalisations); andthird, encoding the major amputations performed inthe hospitals in two regions (Lombardy for 6 months,Emilia Romagna for 2 years) (major amputations). The

results from the three approaches were substantiallyequivalent in order of magnitude (Table 4).

Based on a national survey, the Vascular SurgicalSociety of Great Britain and Ireland concluded thatthere were 20,000 patients with CLI in the population,an annual incidence of 400 per million per year. l54 Theincidence of CLI can also be extrapolated from the better-documented prevalence studies of Ie. If oneassumes that the overall prevalence of claudication is3% and that 5% of patients with IC will develop CLIover 5 years, this gives an incidence of CLI of 300 permillion per year. Finally, the incidence of CLI can becalculated from the number of major amputations performed (Table 6). Assuming that 90% of major amputations are performed for ischaemia and that only 25%of patients with CLI ever require a major amputation,it can be calculated that the incidence of CLI is approximately 500 to 1,000 per million per year. Surprisinglyperhaps, the incidences calculated using these different methodologies are very similar. Roughly, one newpatient per year will develop CLI for every 100patients with IC in the population.

Table 4: Incidence of CLI and major amputations in the population aged >45 years in Northern Italy using three different approachestv

Incidence of CLI(per million per year)

Incidence of major amputations(per million per year)

Development of CLIHospitalisations for CLIMajor amputations

LombardyEmilia Romagna

450652

577530

112160

172154

Em J Vase Endovasc Surg Vol 19 Supplement A, June 2000


Protective-2 1

, !

Odds ratio

Harmful2 3

I4

I

Male gender (cf female)

Age (per 10 years)

ASPI «0.5 to >0.8)

Diabetes

Smoking

Hypertension

CAD •I

Fig. 15. Range of odds ratios (univariate) for risk factors for all-cause mortality.

A 2.6.2Risks Factors for the Development of Critical Limb

Ischaemia

The risk factors for the development of CLI are exactly the same as those for the progression of local disease, the most important, apart from age, being smoking and diabetes.

Age

As already stated, the prevalence of PAD increasesrapidly with age, as does the hospital admissionsrate.v Major amputations are also more common inthe elderly. In a 3-year prospective study of lower limbmajor amputations in Malmohus county in Sweden,45% of the amputees were at least 80 years 01d.155In aDanish national discharge survey in 1980, the incidence of lower limb major amputations increasedfrom 0.3 per 100,000 per year for those younger than40 years, to 226 per 100,000 per year for those olderthan 80 years.I56

Smoking

Cigarette smoking increases both the risk of developing PAD and its progression. The risks associated with

Eur J Vase Endovasc Surg Vol19 Supplement A, June 2000

smoking apply to all ages and increase with the number of cigarettes smoked.J29 In multivariate analyses,smoking has been shown to be an independent riskfactor6-1,9U55and to be more important in causing PADthan CAD.9~ Major amputation is more commonamong patients with IC who are heavy smokers'F andwho continue to smoke.w

Diabetes

Diabetes mellitus affects 2% to 5% of Western populations. However, 40% to 45% of all amputees arediabetic. Therefore, diabetic PAD patients areapproximately 10 times more likely to need anamputation than nondiabetic PAD patients. TheBasle study reported that major amputations were11 times more frequent in diabetic PAD patientsthan in nondiabetic PAD patlents.?' One studyreported the progression of CLI to gangrene to be40% in diabetic patients compared with 9% in nondiabetic patients.v The correlation between diabetesand major amputation rates is independent of otherrisk factors, including age and smoking.t>'However, smoking does appear to have an additiveeffect.15s Those with diabetes generally undergomajor amputations at an earlier age than those without diabetes.159,16o,161


A 2.7Fate of Patients With Critical Limb Ischaemia

It is no longer possible to describe the natural historyof the critically ischaemic limb, because most patientsnow undergo some form of arterial reopening procedure. Table Sa shows the mortality rates in some largeseries of patients, most of whom newly presented withCLI to a vascular surgical center. It is interesting tonote the variation in the proportion of patients wheresome form of revascularisation was attempted. Insome highly specialised and aggressive units, 90% ormore of the patients had an attempted revascularisation. The primary amputation rate varied fromapproximately 10% to approximately 40%. Theremaining patients had general supportive and medical treatment only. The studies in Table Sa are mostlyfrom single centres. Perhaps a better picture of whathappens to an average patient who develops CLIwould come from multicentre audit data. Some examples of these are shown in Table 5b.

More recently, several studies have reported the fateof patients with recently diagnosed CLI after 1- and 2years' follow-up. Wolfel62 in Britain has reported 1year mortality rates of around 20% in unselectedpatients with CLI, while a study in Zurich found asimilar proportion dying over 6 months.w In aprospective observational study in Italy, 574 patientswere recruited in 69 centres mainly on the basis ofclinical findings of CLI (rest pain and/or trophiclesions). At the end of three months, 50 (8.7%) patientshad died, 3 (0.5%) had an MI, 6 (1.0%) a stroke, 70(12.2%) a major amputation, while 103 (17.9%) hadpersistent CLI. In a subsequent follow-up report 21.9%(121/552) were dead at 1 year, while an additional 44(11%) died during the second year, giving an overall 2year mortality of 31.6%.1~ As expected, the overallincidence of vascular deaths was much higher thanthat for non-vascular deaths (34.5 vs 8.5%, respectively). Cardiovascular deaths were also relatively higherat the end of the first (36.4 vs 6.6% respectively) thanat the end of the second (29.5 vs 13.6%, respectively)year of follow-up.t-'

Finally, there are some good-quality data from multicentre, closely monitored trials of pharmacotherapyfor CLI. These are summarised in Table 5c.Unfortunately, these data only relate to a subgroup ofpatients who are completely unreconstructable or inwhom attempts at reconstruction have failed. It is onlysuch patients who are entered into randomised, placebo-controlled clinical pharmacotherapy trials.Information about the spontaneous course of CLI cantherefore be deduced from those patients who receiveplacebo. The results for this subgroup reveal the

appalling prospect that approximately 40% will losetheir leg within 6 months, whereas up to 20% willdie,176.177.178.179 In most of these studies, less than half ofthe patients were alive without a major amputationafter 6 months.177,178.179 De Weese and Roblo;found thatvirtually all (95%) patients who presented withischaemic gangrene and 80% of those presenting withrest pain were dead within 10 years.

A2.8Changing Outcome of Critical Limb Ischaemia

There is an ongoing controversy, often fueled byunverified retrospective audit data from large andchanging populations, as to whether there is a significant reduction in amputations as a result of more vascular reopening procedures in patients with CLI.I80,181A recent, particularly careful, study of a fixed population in Sweden over 8 years strongly suggests that adecrease in primary amputation (from 42% to 27%),associated with a corresponding increase in revascularisations, resulted in an overall decrease in amputations from 61% to 47%.182 In the United Kingdom, thenumber of major amputations has reached a plateau,possibly reflecting increasingly successful limb salvage.l83 A decline in major amputation rate has alsobeen reported in Denmark: from 34.5/100,000 in 1983to 25/100,000 in 1990.1&1 Between 1981 and 1990 inScotland, the major amputation rate fell by 22%.185However, this study highlighted incon sistencies within different age-sex groups. Thus, in the populationyounger than 65 years, the major amputation ratedecreased by 45%, whereas in those older than 65years, it increased by 54%.

Major amputation rates also decreased in men, butthere was a paradoxical increase in women. Duringthe period of this study, the reduction in major amputation rate was accompanied by a doubling of the rateof arterial reconstructions, with an increase in allage-sex groups. In Western Finland, Luther reported a22-year (1970-1991) retrospective survey of surgicalpatient data compared with population data, whichshowed a 2.5-fold increase in major amputations from1970 to 1991.I86 Figure 16 summarises in diagram formthe initial overall treatment of all patients presentingwith CLI, and Figure 17 summarises the data fromstudies looking only at "end-stage" CLI, those patientswho are unsuitable for revascularisation or in whomrevascularisation has failed and cannot be repeated(Table 5c).

Allowing for the different periods of follow-up, it is .surprising that the fate of the patients with CLI whohave just presented and are considered for primary

Eur J Vase Endovasc Surg \'0119 Supplement A, June 2000


Table 5: Fate of patients with critical limb ischaemia

No patients/limbs

Attemptedre-vascularisation(%)

Primaryamputation Follow-up Mortality

(%) (yrs) rate (%)

Alive Alivewith without

persistent amputationCLI (%)

Amputation

(%)

a) Surgical seriesMcGrath et al,m 1983 2,064 22.6 4.2Ouriel et 011, 165 1988 362 56.3 43.6 3 71Griffith and Callum,"61988 402 67.1 36.8 2 50

28Holdsworth,1671997 319 43 18 1 12 (amp) 51

8 (revasc)Veith et al,If" 1981 755 89.9 10 5 52Taylor et 011,169 1991 627 97.2 2.8 1.95 2.3 7.0Hickey et al, ~09 1991 315 88 14.2 5 41

b) MulticflltrcseriesWolfe, 162 1986 409 61 7 1 18 26ICAI Group,l6-l 1997 522 44.4 9.4 2 31.6 55 13.8 13.8

c) Ullrecollstrllctable or primaryfailed reconstructionTonnensen et 011,170 1978 21 19Lowe et 011,176 1982 13 30.7 23 6mo 23Belch et al,m 1983 13 7.69 6mo 23 53.8 15.4Schuler et al,17I 1984 63 9.52 14.2 2mo 4.7 14.3Telles et 011,172 1984 17 29.4 1 mo. 29.4Norgren ct al,1781990 52 44.2 6mo 31 43.4Bliss et 011, 179 1991 71 6mo 11 42 46.4Balzer et al,t73 1991 58 1 moGuilmot & Diot,m 1991 41 3 19.5Lcpantalo & Matzke.F? 1996 105 (136) 12 54 19.5

reconstruction is not much better than that of patientsin whom reconstruction is impossible or has failed.

A2.9Major Amputation

A 2.9.1Incidence and Prevalence of Major Amputation

The concept of patients who have a poor outcome,steadily progressing through increasingly severe claudication to rest pain, ulcers, and ultimately amputation, is incorrect. As already pointed out, an acuteonset of CLI carries a particularly bad prognosis. In arecent study, it was found that more than hairof 713patients having a below-knee major amputation forischaemic disease had no symptoms of leg ischaemiaas recently as 6 months prevlously!" In 1986 inEngland and Wales, nearly 5,000 new patients werereferred for prosthesis fitting after major amputationsfor CLI.ISS There are no accurate data on the number ofpatients in the United Kingdom undergoing majoramputation without referral for a prosthesis but, usingthe figures available for progression of claudication,total major amputations may be in excess of 15,000 perannum (300 per million per annumj.t'" This compareswith estimates of 500/million population/annum inSweden.l?" 250/million/annum in Denmark.ts' and


280/million/annum in the United States'?' (Table 6).In Holland, Hoogcndoomt'? has reported on the majoramputation rate according to the level of majoramputation.

A 2.9.2Risk Factors for Major Amputation

Although not substantiated by an adequate prospective study, the presence of gangrene and ulceration(Fontaine IV), but not necessarily the size or numberof ulcers, seems to be associated with a poorer prognosis than rest pain alone (Fontaine III).193 In the JointVascular Research Group in Britain study,J62 patientswith CLI who had gangrene or ulceration were twiceas likely to require a major amputation as those withrest pain alone. Juergens et alt30 noted a 5-fold increasein a similar group over a 5-year period. Several studies have shown that survival without amputation inCLI patients is related to ABPLH6,194,195 This is not surprising; ABPI has already been shown to be one of themost accurate predictors of mortality in claudicantpatients (see also A 3.2.3, Criteria for Success, p S32).111The precise magnitude of the effect and whether it issimilar in patients with rest pain alone and those whoalso have trophic changes has been much debated.The Joint Vascular Research Group in Britain'< foundthat there were significantly (p < 0.01) more viable legsat 1 year among those patients with CLI who had rest

Cured25%


Fig. 16. The fate of patient s with CLI.

Fig. 17. Outcome at 6 months in patients who were either unsuitable for, or who failed, revascularisation.

523

pain (Fontaine III) and an ankle pressure greater than40 mm Hg compared with those with rest pain and anankle pressure less than 40 mrn Hg . This differentiation, however, was lost in those patients with ulceration or gangrene (Fontaine IV). It was therefore concluded that although ankle pressure was a predictor ineLI patients with rest pain alone, it was of little additional value in those patients with ulceration andgangrene.

Level of nIIlpll In Iion

A review of 16 reports over the last 30 years showsthat the ratio of below-knee (BK) to above-knee (AK)amputation is usually near 1 and has not changedover the years.1%.197.198.199,200,201,202,20J,20-l,205.206.207,208.209,2IO,211

A more accurate picture of the changing pattern ofamputation may be obtained by looking at longitudinal studies from the same centre. In one series, theintroduction of an aggressive team approach to amputation increased the BK-to-AK ratio from an unusually lowOl-; to 2.1.198 Data from published series looking at the delayed healing and revision rates for BKamputations show that primary healing ranged from30% to 92% (mean, 70% to 75%)187.197,198.20J.20-l.205.21UIJ.lli

and the re-amputation rate from 4% to 30% (mean,15%).20S.210.2tI ,215.216,217,218 Approximately another 15%

had delayed or secondary healing, which, in somecases, required debridement and further proceduressuch as wedge excision in an attempt to maintain leglength.219,22o,221,222,223 Of the 30% of BK amputees whosewounds do not heal primarily, approximately half willneed a higher major amputation.W ,lli,226,227,228 Less

Em J Vase Endovasc Surg \'0119 Supplement A, June 2000


Table 6: Estimated number of major amputations/annum in different countries

Country Estimated number/million/annum

Dormandy & Ray, 1996' 39

Norgren, 1990190

Ebskov et al, 199·118-1Kacy et al, 1982191

Hoogendoorn, 1988192

PeIl et al, 1994133

Luther, 19941S6

UKSwedenDenmarkUSAHolIandScotlandWestern Finland

300500250280246142120

blood flow is required to keep tissues healed than toachieve healing, and Kihn et al197reported that once aBK major amputation healed, only 4% of such patientsever require a higher amputation.

Data from 51 hospitals in six European countrieswere collected regarding 713 patients requiring a BKarnputatlon.t" In this study, at 3 months, 59% ofstumps had healed, 19% required an amputation at ahigher level, and 11% remained unhealed. The surgeons' assessment of the likelihood of healing waswrong in 21% of cases in which the operating surgeonbelieved that healing would occur. It was also wrongin 52% of cases in which it was thought that healingwould not occur. Similarly, it is generally believed thatincreasing the proportion of BK to AK amputationsmust inevitably lead to a higher failure rate. Neither ofthese beliefs is borne out by comparative studies of theliterature.

A 2.9.3Fate of the Amputee

Two to three times as many BK amputees achieve fullmobility compared with AK amputees, and there hasnot been any dramatic change in 20 years. I96,I99,205,215,217Initial rehabilitation may take up to 9 months, but by2 years, 30% of amputees are not using their prostheses.t96Older patients, women, and bilateral amputeesare particularly bad at mobilising.196,lli Kihn et a1l96

noted that only 25% of amputees had palpable footpulses in the contralateral limb and that, over a 2-yearperiod, approximately 15% required contralateralmajor amputation. Although the need for majoramputation was related to the absence of distal pulses,10% of the amputees with palpable contralateral footpulses also lost that foot within 2 years. Early hospitalmortality rates after BK amputation range in mostseries from 3% to 10%, whereas the hospital mortalityafter an AK amputation is nearer20%.196,193,201,202,203,205,207,212,215,217,224,228,229 It is unlikely thatthis increased mortality rate is directly due to thehigher level of amputation. Rather, it is due to theselection of the older and "high-risk" patients, who


have little prospect of rehabilitation, for what is considered a more reliable procedure in terms of primaryhealing, and the fact that they have more widespreadarterial disease. However, several reports have relatedoperative mortality to coexisting medical conditions,such as diabetes and cardiovascular, cerebrovascular,and respiratory disease and found no significant correlation.196,2os This difference is maintained for up to 2years, when mortality rates of 25% to 35% for BK and45% for AK amputees are seen.190,195,193,215

A 2.9.4Summary: Major Amputation

Figure 18 summarises the fate of the BK amputee. Fiveyears after a BK amputation, 30% will have had amajor contralateral amputation, 50% will be dead, andonly 20% will be alive with one intact leg.

The nature of the onset of CLI may also be important. Between 30% and 70% of patients who developacute CLI require major primary amputation, possiblybecause they tend not to be treated in specialist centers, and because patients with acute CLI will not havehad the opportunity to develop collaterals.tv

A2.10Conclusions

There are still surprisingly little good epidemiologicaldata on PAD compared with CAD or CVD. It is, however, clear that the prevalence of symptomatic andasymptomatic PAD is greater than previouslythought. Both groups carry a high risk of death ormorbidity because of vascular disease in other territories. CLI is much rarer but carries an even worse prognosis, in terms of both morbidity and mortality, whichis comparable to some of the most malignant cancers.The current treatment modalities, in terms of eitherpreventing progression of local disease in the legs ormodifying the high mortality, are not particularlysuccessful.

Early


After 2 years

S25

1° healing60%

; Perioperative; death 10%

Full mobility. 40%

Contralateralamputation15%

Figure 18: Early and 2-year fate of the below-knee amputee (from Dormandy & Ray).

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830 Outcome Assessment Methodology in Peripheral Arterial Disease

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A3OUTCOME ASSESSMENT METHODOLOGY IN

PERIPHERAL ARTERIAL DISEASE

A3.1Impetus for Outcomes Research

Although the value of lifesaving therapies is boldlydisplayed in both the medical and lay press, mostmedical treatment provided in the developed countries is directed toward improvement in quality of life.

. Interventions for claudication and eLI are examples oftherapies directed toward the relief of symptoms andimprovement in quality of life. The goal of all suchinterventions is to reduce the adverse impact of an illness or disorder on the patient's life and improve thepatient's sense of well-being and productivity. As thecosts of health care continue to spiral upward, governments and third-party payers are seeking to contain costs by limiting reimbursement to those therapies proven to be effective, either in saving lives orimproving quality of life. Ultimately, the decision toadvocate a treatment, and the decision by payers andregulatory bodies for reimbursement involves a tradeoff between the additional costs incurred and effectiveness gained by performing that treatment.'

Multiple studies have been published reporting theexperience of centres on the short and long-termresults of performing interventions for PAD.

a 2 - epidemiology, natural history, risk factorsepidemiology, natural history, risk factors table...

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