Peripheral Arterial Disease (PAD)

A marker for myocardial infarction and ischaemic stroke

Overview
PAD (peripheral arterial disease) a marker for MI and IS Epidemiological data on PAD

Risk factors Prevalence Atherothrombosis coexistence of PAD, coronary and cerebrovascular disease Natural history Low ABPI as an independent predictor of ischaemic risk

Symptomatology of PAD Diagnosis and management of PAD Clopidogrel a new standard of treatment for atherothrombosis

PAD a marker for MI and IS

Atherothrombosis = thrombus formation on top

of existing atherosclerosis Occurs in multiple arterial beds

Cerebrovascular disease (ischaemic stroke, transient ischaemic attack) Coronary artery disease (stable/unstable angina, myocardial infarction) PAD (intermittent claudication, critical leg ischaemia, amputation, gangrene, necrosis)

Risk factors for PAD

Gender (male) Age Smoking

PAD

Hypertension
Diabetes Hyperlipidaemia Fibrinogen

Atherosclerosis

Atherothrombosis

Homocysteinaemia

Ischaemic stroke

Myocardial infarction

Murabito JM et al. Circulation 1997;96:4449; Laurila A et al. Arterioscler Throm Vasc Biol 1997;17:29102913; Malinow MR et al. Circulation 1989;79:11801188; Brigden ML. Postgrad Med 1997;101:249262.

Prevalence of PAD variation according to diagnostic criterion

6.3 million individuals with symptomatic, established PAD

are diagnosed in the USA and EU1

Epidemiological studies imply that real* prevalence may be

approx. 20 million (= 9.5% of the population > 50 years old)

In 613 men and women (mean age 66 years), real prevalence

was found to be underestimated by two- to seven-fold2

ABPI (ankle:brachial pressure index) correlates with

angiographically determined disease3

ABPI < 0.9 is a marker of diffuse atherothrombosis4
1

17 Western European countries. Statistical Supplement; WHO Yearbooks, Annual Statistics, 1997; Criqui MH et al. Vasc Med 1997;2:221226; 3Shinozaki T et al. J Clin Epidemiol 1998;15:12631269; 4Kornitzer M et al. Angiology 1995;46:211219. *ABPI < 0.9, symptomatic or not, diagnosed or not.
2

Epidemiology of PAD effect of age and gender

Epidemiological data on PAD vary according to:
Population studied

Method of diagnosing PAD

Incidence and prevalence of intermittent claudication*

increase with age Prevalence in men aged 4550 years is 1% Prevalence is 33.5% in men aged > 50 years Similar trend in women, increase with age
More common in men than in women
Twice as many men as women aged > 50 years have intermittent

claudication (3.5% and 2%, respectively)

Predominance in males disappears after age of 70

Weitz JI et al. Circulation 1996;94:30263049. * Rose questionnaire criteria Bull. Wld Hlth Org. 1962;27:645-658

Atherothrombosis coexistence of symptomatic PAD and coronary or cerebrovascular disease

50 40 30

Men

Women Concurrent cardiovascular disease (MI, CABG, stroke or stroke surgery)

20
10 0

Yes

No

PAD

Yes

No

Criqui MH et al. Vasc Med 1997;2:221226.

Atherothrombosis symptomatic atherosclerosis in CAPRIE (overlap between PAD, CAD and CVD)
CAPRIE1 (n = 19 185)
Cerebrovascular disease (CVD) Coronary artery disease (CAD)

24.6% 3.8%

7.3% 3.3%

29.9%
11.9%

19.2%
Peripheral Arterial Disease (PAD)
1CAPRIE

Steering Committee. Lancet 1996;348:13291339.

Patients with PAD are at risk of MI, IS and death

CAPRIE data
Coronary outcome

Cerebrovascular outcome

6 3-year cumulative event rate (%) 5 4 3 2 1 0

5.1 4.2 3.6

5.2

Clopidogrel Aspirin

Patients qualifying for CAPRIE on the basis of PAD

Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1128 (Abstr 4).

5-year natural history of PAD

100 patients with claudication who do not seek medical advice

100 patients with asymptomatic PAD

Local Events
Worsening claudication 25 patients Surgical revascularization 10 patients Major amputation 2 patients
Dormandy JA. Hosp Update 1991;April:314318.

100 patients diagnosed with claudication

Systemic Events
10 to 20 non-fatal MIs or strokes

PLUS
30 deaths: CHD 15 Other cardiovascular and cerebrovascular 5 Non-cardiovascular 10

PAD mortality 10-year survival rates of subjects in the San Diego Artery Study
1.00

Normal 0.75

Survival

0.50 0.25 0.00

Asymptomatic

Symptomatic
Severe symptomatic

6 8 Time (years)

10

12

Criqui MH et al. N Engl J Med 1992;326:381386.

Relative 5-year PAD mortality rates versus other common pathologies

100 90 80 70 Patients (%) 60 50 40 30 20 10

86

15
Breast cancer1

18
Hodgkin's disease1

28

38

PAD2

Colon and Lung cancer1 rectal cancer1

1American

Cancer Society. Cancer Facts and Figures 1997. RF, Bernhard VM. In: Vascular Surgery (Rutherford RB, ed). Philadelphia, PA: WB Saunders: 1989;chap 53.

2Kampozinski

Intermittent claudication an independent risk factor for increased mortality rates

In the Whitehall study (n = 18 388), mortality rates in

individuals with intermittent claudication were twice as high as those in healthy controls (17 years follow-up study)
Increased mortality even after adjustment for coronary

risk factors Cardiac ischaemia at baseline Systolic blood pressure Plasma cholesterol concentration Smoking behaviour Employment grade Degree of glucose intolerance
Smith GD et al. Circulation 1990;82:19251931.

Low ABPI is a strong predictor of cardiovascular mortality

Reduced ABPI is a significant independent predictor of

cardiovascular and coronary mortality

Age-adjusted relative risks for 10-year cardiovascular and

coronary mortality are higher in those with ABPI < 0.9

The risk of cardiovascular death increases with decreasing

ABPI
ABPI measurement is underutilized and can be usefully

incorporated in risk assessment and screening programmes

ABPI measurements are inexpensive, simple and non-

invasive
Kornitzer M et al. Angiology 1995;46:211219. McKenna M et al. Atherosclerosis 1991;87:119128. Dormandy JA et al. J Cardiovasc Surg 1989;30:5057.

ABPI inverse relationship with 5-year risk of cardiovascular events and death
2.5 Risk relative to ABPI 10.2% relative risk increase per 0.1 decrease in ABPI (p = 0.041)

2.0

1.5

1.0 0.0 0.2 0.4 ABPI

Dormandy JA, Creager MA. Cerebrovasc Dis 1999;9(Suppl 1):1128 (Abstr 4).

0.6

0.8

1.0

Symptomatology of PAD
Intermittent claudication

Exercise-induced ischaemic calf-muscle pain while walking and/or weakness, relieved by rest

Mortality rate from stroke and MI two to three times greater than in age-matched controls1
Prognosis varies with multiple risk factors and/or severity of disease

Critical limb ischaemia Pain at rest, eventually resulting in gangrene and amputation2
1Dormandy

JA et al. J Cardiovasc Surg 1989;30:5057. 2European Working Group on Critical Leg Ischemia. Circulation 1991;84(Suppl IV):IV1IV26.

Diagnosis of PAD
Evaluation of pulses and auscultation of bruits Ankle:arm blood pressure index (ABPI)
Ratio of ankle:brachial systolic blood pressure Simple, non-invasive, suitable for routine screening

Exercise testing
Pain-free and maximal walking distance Size and duration of drop in ankle systolic BP upon

claudication

Weitz JI et al. Circulation 1996;94:30263049.

Management of PAD patients

Lifestyle modification

Smoking cessation Regular exercise training Diet

Pharmacological treatment

Antiplatelet therapy Control risk factors (e.g. hypertension, blood glucose) Vasodilators for symptomatic relief?

Management of PAD intervention

Endovascular

Revascularization (angioplasty) Stent placement

Surgical

Endarterectomy

Peripheral bypass graft

Amputation

Management of PAD antiplatelet agents are a key component of treatment

Rationale:
Platelet aggregation, a key event in atherothrombosis, can

be inhibited by antiplatelet agents

Risk levels of stroke and MI are significantly greater than

those of gangrene and amputation

Modify natural history of PAD

Compound Ticlopidine Clopidogrel Aspirin Mode of action ADP receptor antagonism ADP receptor antagonism Inhibition of TxA2 synthesis PAD indication Yes (some countries) Yes No

CAPRIE study design

19 185 patients with recent IS, recent MI or

established PAD
Clopidogrel 75 mg od versus aspirin 325 mg od Follow-up of 13 years (mean 1.91 years) Combined primary endpoint of IS, MI or vascular

death
CAPRIE Steering Committee. Lancet 1996;348:13291339.

CAPRIE efficacy profile of clopidogrel

160 8.7% relative risk reduction, p = 0.043

Event rate/1000 patients/year

120

Event rate per year Placebo3 * 77 58 53

7.7% 5.8% 5.3%

80

19

24

Aspirin1 Clopidogrel1 * extrapolated curve 3

40

9 12 15 18 21 24 27 Time from Randomization (Months)

30

33

36

1CAPRIE

Steering Committee. Lancet 1996;348:13291339. Trialists' Collaboration. BMJ 1994;308:81106. 3Fisher LD. J Am Coll Cardiol 1998;31(Suppl A):49A.
2Antiplatelet

Based on the APTC findings,2 in a population similar to CAPRIE, for each 1000 patients treated per year, aspirin can be expected to prevent 19 events and clopidogrel, 24.1

CAPRIE safety profile of clopidogrel

300 250
Number of Patients
P < 0.05

104

Clopidogrel Aspirin

200 150 100 50 0

71
P < 0.05
P < 0.01

255
191 37

51

GI haemorrhages

Hospitalization for GI bleeding events

GI ulcer

* The proportions of patients with diarrhoea, rash or pruritus were higher in the clopidogrel group than in the aspirin group
1CAPRIE 3Lok

Steering Committee. Lancet 1996;348:13291339; 2Bogousslavsky J. Cerebrovasc Dis 1998;8(Suppl 4):43; DJA. Eur Heart J 1998;19(Abstract Suppl):52.

Summary 1
PAD is a marker of atherosclerosis in the coronary

and cerebral arteries

PAD is often underestimated and underdiagnosed,

and requires proper diagnosis:

ABPI is a non-invasive, easily performed measurement that reliably predicts ischaemic risk in PAD patients

Risk factors need to be managed: smoking cessation,

regular exercise training

Antiplatelet therapy is a key component of treatment

Summary 2

Clopidogrel provides increased benefit over aspirin

for secondary prevention in atherothrombotic patients, including those with diagnosed PAD
Reduces the risk of all major events

(IS, MI, vascular death)

Offers better gastrointestinal safety and tolerability

in comparison with aspirin