Inter-Society Consensus for the Management of Peripheral ...karkirurgi.org/lenker/TASC II Norgren 07.pdf · Inter-Society Consensus for the Management of Peripheral Arterial Disease

Inter-Society Consensus for the Managementof Peripheral Arterial Disease (TASC II)

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5Grading of recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6

SECTION A e EPIDEMIOLOGY OF PERIPHERAL ARTERIAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6

A1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6A1.1 Incidence and prevalence of asymptomatic peripheral arterial disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S6A1.2 Incidence and prevalence of symptomatic peripheral arterial disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7A1.3 Epidemiology of peripheral arterial disease in different ethnic groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7

A2 Risk Factors for Peripheral Arterial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S7A2.1 Race . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.2 Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.3 Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.4 Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.5 Diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.6 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.7 Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S8A2.8 Inflammatory markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A2.9 Hyperviscosity and hypercoagulable states . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A2.10 Hyperhomocysteinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A2.11 Chronic renal insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A2.12 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

A3 Fate of the Leg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A3.1 Asymptomatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9A3.2 Intermittent claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S10A3.3 Critical limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S11A3.4 Acute leg ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S11A3.5 Amputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S11

A4 Co-existing Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S12A4.1 Coronary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S12A4.2 Cerebral artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13A4.3 Renal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13

A5 Fate of the Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13A5.1 Asymptomatic and claudicating peripheral arterial disease patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S13A5.2 Severity of peripheral arterial disease and survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S14

SECTION B e MANAGEMENT OF CARDIOVASCULAR RISK FACTORS AND CO-EXISTING DISEASE . . . . . . . . . . S14

B1 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S14B1.1 Identifying the peripheral arterial disease patient in the population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S14B1.2 Modification of atherosclerotic risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S16

B1.2.1 Smoking cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S16

1078–5884/000001 + 75 $32.00/0 � 2006 Published by Elsevier Ltd.

S2 L. Norgren and W. R. Hiatt et al.

B1.2.2 Weight reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S17B1.2.3 Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S17B1.2.4 Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18B1.2.5 Diabetes [see also section D2.4] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S18B1.2.6 Homocysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S19B1.2.7 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S19B1.2.8 Antiplatelet drug therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S19

B2 Health Economics of Risk-factor Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20B2.1 Cost-effectiveness of smoking cessation interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S20B2.2 Cost-effectiveness of exercise interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S21B2.3 Cost-effectiveness of pharmacologic interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S21

B3 Future Aspects of Controlling Ischemic Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S21

B4 Co-existing Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S22

B5 Co-existing Carotid Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23

B6 Co-existing Renal Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23

SECTION C e INTERMITTENT CLAUDICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23

C1 Characterization of Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23C1.1 Definition of intermittent claudication and limb symptoms in peripheral arterial disease . . . . . . . . . . . . . . . . . . S23C1.2 Differential diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23C1.3 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S23

C2 Diagnostic Evaluation of Patients with Peripheral Arterial Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S25C2.1 Ankle pressure measurements (ankle-brachial index) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S25C2.2 Exercise testing to establish the diagnosis of peripheral arterial disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S26C2.3 Alternative stress tests for patients who cannot perform treadmill exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S27

C3 Outcome Assessment of Intermittent Claudication in Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S27

C4 Treatment of Intermittent Claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S28C4.1 Overall strategy and basic treatment for intermittent claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S28

C4.1.1 Overall strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S28C4.1.2 Exercise rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S28

C4.2 Pharmacotherapy for intermittent claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S30C4.2.1 Drugs with evidence of clinical utility in claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S30C4.2.2 Drugs with supporting evidence of clinical utility in claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S31C4.2.3 Drugs with insufficient evidence of clinical utility in claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S31

C5 Future Treatments for Claudication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32

SECTION D e CHRONIC CRITICAL LIMB ISCHEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32

D1 Nomenclature and Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S32D1.1 Patients presumed at risk for critical limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33D1.2 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33

D2 Clinical Presentation and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33D2.1 Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S33D2.2 Ulcer and gangrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S34D2.3 Differential diagnosis of ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S34D2.4 Diabetic foot ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S34

D2.4.1 Pathways to ulceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35D2.4.2 Types of ulcers and presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S35

D3 Macrocirculatory Pathophysiology in Critical Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36D3.1 Skin microcirculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S36

Eur J Vasc Endovasc Surg Vol 33, Supplement 1, 2007

S3TASC II Inter-Society Consensus on Peripheral Arterial Disease

D4 Differential Diagnosis of Ischemic Rest Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37D4.1 Diabetic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37D4.2 Complex regional pain syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S37D4.3 Nerve root compression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D4.4 Peripheral sensory neuropathy other than diabetic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D4.5 Night cramps . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D4.6 Buerger’s disease (thrombangitis obliterans) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D4.7 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38

D5 Investigations of Critical Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D5.1 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38D5.2 Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S38

D6 Prevention of Critical Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39D6.1 Risk factors associated with the foot . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39D6.2 The role of peripheral neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39

D7 Treatment of Critical Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39D7.1 Overall strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39D7.2 Basic treatment: pain control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S39D7.3 Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S40D7.4 Management of ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S40D7.5 Amputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S42D7.6 Pharmacotherapy for critical limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S43

D7.6.1 Prostanoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S43D7.6.2 Vasodilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S43D7.6.3 Antiplatelet drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S43D7.6.4 Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44D7.6.5 Vasoactive drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

D7.7 Other treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44D7.7.1 Hyperbaric oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44D7.7.2 Spinal cord stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

D8 Health Economics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

D9 Future Aspects of Treatment of Critical Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S44

SECTION E e ACUTE LIMB ISCHEMIA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45

E1 Definition and Nomenclature for Acute Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45E1.1 Definition/etiology of acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45

E2 Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45E2.1 Clinical evaluation of acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45

E2.1.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45E2.1.2 Physical examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S45E2.1.3 Clinical classification of acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S46E2.1.4 Differential diagnosis of acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S47

E2.2 Investigations for acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48E2.2.1 Other routine laboratory studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48E2.2.2 Imaging e arteriography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S48E2.2.3 Other imaging techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

E3 Treatment of Acute Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49E3.1 Endovascular procedures for acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49

E3.1.1 Pharmacologic thrombolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S49E3.1.2 Contraindications to thrombolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50E3.1.3 Other endovascular techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50

E3.2 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50E3.2.1 Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S50



E3.2.2 Surgical technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S51E3.3 Results of surgical and endovascular procedures for acute limb ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S51E3.4 Management of graft thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52E3.5 Management of a thrombosed popliteal aneurysm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52E3.6 Amputation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52E3.7 Immediate post-procedural issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52

E3.7.1 Reperfusion injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S52

E4 Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53E4.1 Systemic/limb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53E4.2 Follow-up care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

E5 Economic Aspects of Acute Limb Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

E6 Future Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S53

SECTION F e REVASCULARIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54

F1 Localization of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54F1.1 Classification of lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S54F1.2 Classification of inflow (aorto-iliac) disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S55F1.3 Classification of femoral popliteal disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S55

F2 Aortoiliac (Supra Inguinal) Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S55F2.1 Endovascular treatment of aorto-iliac occlusive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S55F2.2 Surgical treatment of aorto-iliac occlusive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S56

F3 Infrainguinal Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57F3.1 Endovascular treatment of infrainguinal arterial occlusive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S57F3.2 Endovascular treatment of infrapopliteal occlusive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S60F3.3 Surgical treatment of infrainguinal occlusive disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S60

F3.3.1 Bypass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S60F3.3.2 Conduit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S61F3.3.3 Adjunct procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S61F3.3.4 Profundoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S61F3.3.5 Secondary revascularization procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S62

F4 Antiplatelet and Anticoagulant Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S63

F5 Surveillance Programs Following Revascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S63

F6 New and Advancing Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S63

SECTION G e NON-INVASIVE VASCULAR LABORATORY AND IMAGING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64

G1 Non-Invasive Vascular Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64G1.1 Segmental limb systolic pressure measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64G1.2 Segmental plethysmography or pulse volume recordings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S64G1.3 Toe pressures and the toe-brachial index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65G1.4 Doppler Velocity Wave Form analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

G2 Imaging Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65G2.1 Indications for and types of imaging in patients with intermittent claudication or critical limb ischemia . . . . S65G2.2 Choice of imaging methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65

G2.2.1 Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S65G2.2.2 Color-assisted duplex ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66G2.2.3 Magnetic resonance angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66G2.2.4 Multidetector computed tomography angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S66

TASC Writing Group e Conflict of Interest Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S68

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S68


Eur J Vasc Endovasc Surg 33, S1eS75 (2007)

doi:10.1016/j.ejvs.2006.09.024, available online at http://www.sciencedirect.com on

Inter-Society Consensus for the Managementof Peripheral Arterial Disease (TASC II)

L. Norgren,1* W.R. Hiatt,2* J.A. Dormandy, M.R. Nehler, K.A. Harris and F.G.R. Fowkeson behalf of the TASC II Working Group

1Department of Surgery, University Hospital, Orebro, Sweden2University of Colorado School of Medicine and Colorado Prevention Center, Denver, USA

Introduction

The Trans-Atlantic Inter-Society Consensus Documenton Management of Peripheral Arterial Disease (TASC)was published in January 20001e3 as a result of cooper-ation between fourteen medical and surgical vascular,cardiovascular, vascular radiology and cardiology so-cieties in Europe and North America. This comprehen-sive document had a major impact on vascular careamongst specialists. In subsequent years, the fieldhas progressed with the publication of the CoCaLisdocument4 and the American College of Cardiology/American Heart Association Guidelines for the Man-agement of Peripheral Arterial Disease.5 Aiming tocontinue to reach a readership of vascular specialists,but also physicians in primary health care who see pa-tients with peripheral arterial disease (PAD), anotherconsensus process was initiated during 2004. Thisnew consensus document has been developed witha broader international representation, includingEurope, North America, Asia, Africa and Australia,and with a much larger distribution and disseminationof the information. The goals of this new consensus areto provide an abbreviated document (compared withthe publication in 2000), to focus on key aspects of di-agnosis and management, and to update the informa-tion based on new publications and the newerguidelines, but not to add an extensive list of refer-ences. Unreferenced statements are, therefore, to befound, provided they are recognized as common prac-tice by the authors, with existing evidence. The

*Corresponding authors.E-mail addresses: [email protected], [email protected]

recommendations are graded according to levels of ev-idence. It should also be emphasized that good practiceis based on a combination of the scientific evidencedescribed below, patients’ preferences, and local avail-ability of facilities and trained professionals. Goodpractice also includes appropriate specialist referral.

Process

Representatives of sixteen societies from Europe, NorthAmerica, Australia, South Africa and Japan were elec-ted from their respective society and were calledtogether in 2004 to form the new Working Group. Spe-cialists in health economics, health outcomes andevidence-based medicine were also included to elabo-rate on the text for the following sections: history,epidemiology and risk factors; management ofrisk factors; intermittent claudication; critical limbischemia; acute limb ischemia; and technologies(intervention/revascularization and imaging).

The Working Group reviewed the literature and, af-ter extensive correspondence and meetings, proposeda series of draft documents with clear recommenda-tions for the diagnosis and treatment of PAD. Eachparticipating society reviewed and commented onthese draft consensus documents. The liaison memberfrom each society then took these views back to theWorking Group, where all of the amendments, addi-tions and alterations suggested by each participatingsociety were discussed, and the final ConsensusDocument was agreed upon.

The participating societies were then again invitedto review the final document and endorse it if theyagreed with its contents. If an individual participating


mailto:[email protected]

mailto:[email protected]


society did not accept any specific recommendation,this is clearly indicated in the final document.Therefore, except where such specific exclusions areindicated, this Consensus Document represents theviews of all of the participating societies.

Compared with the original TASC, more emphasishas been put on diabetes and PAD. The text is pre-sented in such a way that vascular specialists will stillfind most of the information they require, while gen-eral practitioners and primary health physicians willeasily find guidance for diagnosis and diagnostic pro-cedures, referral of patients and expected outcome ofvarious treatment options.

Grading of recommendations

Recommendations and selected statements are ratedaccording to guidance issued by the former US Agencyfor Health Care Policy and Research,6 now renamedthe Agency for Healthcare Research and Quality:

Grade Recommendation

A Based on the criterion of at leastone randomized, controlled clinical trial aspart of the body of literature of overallgood quality and consistency addressingthe specific recommendation

B Based on well-conducted clinical studiesbut no good quality randomized clinicaltrials on the topic of recommendation

C Based on evidence obtained from expertcommittee reports or opinions and/orclinical experiences of respectedauthorities (i.e. no applicable studies ofgood quality)

Note that the grade of recommendation is based on thelevel of available evidence and does not necessarilyrelate to the clinical importance.

Acknowledgements

The development of this document was supported byan unrestricted educational grant from sanofi-aventis.Additional support for publication of the documentwas also provided by Bristol-Myers Squibb.* Thesponsors did not participate in any of the discussionsor provide recommendations as to the preparation ofthese guidelines. The TASC Steering Committee ac-knowledges the administrative and logistic assistance

*The TASC Working Group also acknowledges Otsuka Pharma-ceuticals for defraying some travel costs and, together withMitsubishi Pharma, supplying additional support for the futuredissemination of these guidelines.


from Medicus International, with great appreciationof the work performed by Dr Barbara Byth.

SECTION A e EPIDEMIOLOGY OF PERIPHERALARTERIAL DISEASE

A1 Epidemiology

The management of the patient with peripheral arte-rial disease (PAD) has to be planned in the contextof the epidemiology of the disease, its natural historyand, in particular, the modifiable risk factors for thesystemic disease as well as those that predict deteri-oration of the circulation to the limb.

A1.1 Incidence and prevalence of asymptomaticperipheral arterial disease

Total disease prevalence based on objective testing hasbeen evaluated in several epidemiologic studies and isin the range of 3% to 10%, increasing to 15% to 20% inpersons over 70 years.7e9 The prevalence of asymptom-atic PAD in the leg can only be estimated by using non-invasive measurements in a general population. Themost widely used test is the measurement ofthe ankle-brachial systolic pressure index (ABI). (Fordetailed discussion of the ABI, see Section C2.1.) Aresting ABI of �0.90 is caused by hemodynamically-significant arterial stenosis and is most often used asa hemodynamic definition of PAD. In symptomaticindividuals, an ABI �0.90 is approximately 95% sensi-tive in detecting arteriogram-positive PAD and almost100% specific in identifying healthy individuals. Usingthis criterion, several studies have looked at symptom-atic and asymptomatic PAD patients in the same popu-lation. The ratio of the two is independent of age and isusually in the range of 1:3 to 1:4. The Edinburgh ArteryStudy found that, using duplex scanning, a third of thepatients with asymptomatic PAD had a complete occlu-sion of a major artery to the leg.10 The PARTNERS (PADAwareness, Risk, and Treatment: New Resources forSurvival) study screened 6979 subjects for PAD usingthe ABI (with PAD defined as an ABI of�0.90 or a priorhistory of lower extremity revascularization). Subjectswere evaluated if they were aged �70 years or aged50e69 years with a risk factor for vascular disease(smoking, diabetes) in 320 primary care practices inthe United States.11 PAD was detected in 1865 patientswhich was 29% of the total population. Classic claudi-cation was present in 5.5% of the newly diagnosed pa-tients with PAD and 12.6% of the patients with a priordiagnosis of PAD had claudication. The NationalHealth and Nutritional Examination Survey recently


reported on an unselected population of 2174 subjectsaged �40 years.9 The prevalence of PAD, as definedby an ABI of �0.90, ranged from 2.5% in the age group50e59 years to 14.5% in subjects >70 years (there wasno information about the proportion of subjects withan ABI of�0.90 who had symptoms in the legs). In au-topsies of unselected adults, 15% of men and 5% ofwomen who were asymptomatic, had a 50% or greaterstenosis of an artery to the leg. It is interesting to com-pare this with the finding that 20% to 30% of subjectswith complete occlusion of at least one coronary arteryon autopsy are asymptomatic. Some of the apparentinconsistency regarding data on the prevalence ofsymptomatic PAD is due to methodology, but in sum-mary it can be concluded that for every patient withsymptomatic PAD there are another three to four sub-jects with PAD who do not meet the clinical criteriafor intermittent claudication.

A1.2 Incidence and prevalence of symptomaticperipheral arterial disease

Intermittent claudication (IC) (see section C1.1 for def-inition) is usually diagnosed by a history of muscularleg pain on exercise that is relieved by a short rest.Several questionnaires have been developed for epi-demiological use. In looking at methods for identify-ing IC in the population, it must be rememberedthat while it is the main symptom of PAD, the mea-surement of this symptom does not always predictthe presence or absence of PAD. A patient with quitesevere PAD may not have the symptom of IC becausesome other condition limits exercise or they are seden-tary. In contrast, some patients with what seems to beIC may not have PAD (for example, spinal stenosiscan produce symptoms like IC in the absence of

vascular disease). Likewise, patients with very mildPAD may develop symptoms of IC only when theybecome very physically active.

The annual incidence of IC is more difficult to mea-sure and probably less important than its prevalence(unlike the case of the relatively very much smallernumber of patients with critical limb ischemia [CLI]).The prevalence of IC would appear to increase fromabout 3% in patients aged 40 to 6% in patients aged60 years. Several large population studies have lookedat the prevalence of IC and Fig. A1 shows a calculatedmean prevalence weighted by study sample size. In therelatively younger age groups, claudication is morecommon in men but at older ages there is little differ-ence between men and women. A surprising findingin population screening studies is that between 10%and 50% of patients with IC have never consulteda doctor about their symptoms.

A1.3 Epidemiology of peripheral arterial diseasein different ethnic groups

Non-white ethnicity is a risk factor for PAD. Blackethnicity increases the risk of PAD by over two-fold,and this risk is not explained by higher levels of otherrisk factors such as diabetes, hypertension or obesity.12

A high prevalence of arteritis affecting the distal arteriesof young black South Africans has also been described.

A2 Risk Factors for Peripheral Arterial Disease

Although the various factors described in this sectionare usually referred to as risk factors, in most cases theevidence is only for an association. The criteria usedto support a risk factor require a prospective, con-trolled study showing that altering the factor alters

Fig. A1. Weighted mean prevalence of intermittent claudication (symptomatic PAD) in large population-based studies.



the development or course of the PAD, such as hasbeen shown for smoking cessation or treatment of dys-lipidemia. Risk may be conferred by other metabolicor circulatory abnormalities associated with diabetes.

A2.1 Race

The National Health and Nutrition Examination Sur-vey in the United States found that an ABI �0.90 wasmore common in non-Hispanic Blacks (7.8%) than inWhites (4.4%). Such a difference in the prevalence ofPAD was confirmed by the recent GENOA (Genetic Ep-idemiology Network of Arteriopathy) study,13 whichalso showed that the difference was not explained bya difference in classical risk factors for atherosclerosis.

A2.2 Gender

The prevalence of PAD, symptomatic or asymptom-atic, is slightly greater in men than women, particu-larly in the younger age groups. In patients with IC,the ratio of men to women is between 1:1 and 2:1.This ratio increases in some studies to at least 3:1 inmore severe stages of the disease, such as chronicCLI. Other studies have, however, shown a more equaldistribution of PAD between genders and even apredominance of women with CLI.

A2.3 Age

The striking increase in both the incidence and preva-lence of PAD with increasing age is apparent from theearlier discussion of epidemiology (Fig. A1).

A2.4 Smoking

The relationship between smoking and PAD has beenrecognized since 1911, when Erb reported that ICwas three-times more common among smokers thanamong non-smokers. Interventions to decrease oreliminate cigarette smoking have, therefore, longbeen advocated for patients with IC. It has been sug-gested that the association between smoking and PADmay be even stronger than that between smokingand coronary artery disease (CAD). Furthermore, adiagnosis of PAD is made approximately a decadeearlier in smokers than in non-smokers. The severityof PAD tends to increase with the number of cigarettessmoked. Heavy smokers have a four-fold higher riskof developing IC compared with non-smokers.Smoking cessation is associated with a decline in theincidence of IC. Results from the Edinburgh ArteryStudy10 found that the relative risk of IC was 3.7 in


smokers compared with 3.0 in ex-smokers (who haddiscontinued smoking for less than 5 years).

A2.5 Diabetes mellitus

Many studies have shown an association betweendiabetes mellitus and the development of PAD. Over-all, IC is about twice as common among diabeticpatients than among non-diabetic patients. In patientswith diabetes, for every 1% increase in hemoglobinA1c there is a corresponding 26% increased risk ofPAD.14 Over the last decade, mounting evidence hassuggested that insulin resistance plays a key role ina clustering of cardiometabolic risk factors whichinclude hyperglycemia, dyslipidemia, hypertensionand obesity. Insulin resistance is a risk factor forPAD even in subjects without diabetes, raising therisk approximately 40% to 50%.15 PAD in patientswith diabetes is more aggressive compared to non-diabetics, with early large vessel involvement coupledwith distal symmetrical neuropathy. The need fora major amputation is five- to ten-times higher indiabetics than non-diabetics. This is contributed toby sensory neuropathy and decreased resistance toinfection. Based on these observations, a consensusstatement from the American Diabetes Associationrecommends PAD screening with an ABI every 5 yearsin patients with diabetes.16

A2.6 Hypertension

Hypertension is associated with all forms of cardio-vascular disease, including PAD. However, the rela-tive risk for developing PAD is less for hypertensionthan diabetes or smoking.

A2.7 Dyslipidemia

In the Framingham study, a fasting cholesterol levelgreater than 7 mmol/L (270 mg/dL) was associatedwith a doubling of the incidence of IC but the ratioof total to high-density lipoprotein (HDL) cholesterolwas the best predictor of occurrence of PAD. In an-other study, patients with PAD had significantlyhigher levels of serum triglycerides, very low-densitylipoprotein (VLDL) cholesterol, VLDL triglycerides,VLDL proteins, intermediate density lipoprotein(IDL) cholesterol, and IDL triglycerides and lowerlevels of HDL than controls.17 Although some studieshave also shown that total cholesterol is a powerfulindependent risk factor for PAD, others have failedto confirm this association. It has been suggested thatcigarette smoking may enhance the effect of


hypercholesterolemia. There is evidence that treat-ment of hyperlipidemia reduces both the progressionof PAD and the incidence of IC. An association be-tween PAD and hypertriglyceridemia has also been re-ported and has been shown to be associated with theprogression and systemic complications of PAD. Lipo-protein(a) is a significant independent risk factor forPAD.

A2.8 Inflammatory markers

Some recent studies have shown that C-reactive pro-tein (CRP) was raised in asymptomatic subjects whoin the subsequent five years developed PAD com-pared to an age-matched control group who remainedasymptomatic. The risk of developing PAD in thehighest quartile of baseline CRP was more than twicethat in the lowest quartile.18

A2.9 Hyperviscosity and hypercoagulable states

Raised hematocrit levels and hyperviscosity have beenreported in patients with PAD, possibly as a conse-quence of smoking. Increased plasma levels of fibrino-gen, which is also a risk factor for thrombosis, havebeen associated with PAD in several studies. Bothhyperviscosity and hypercoagulability have also beenshown to be markers or risk factors for a poorprognosis.

A2.10 Hyperhomocysteinemia

The prevalence of hyperhomocysteinemia is high in thevascular disease population, compared with 1% in thegeneral population. It is reported that hyperhomo-cysteinemia is detected in about 30% of young patientswith PAD. The suggestion that hyperhomocysteinemiamay be an independent risk factor for atherosclerosishas now been substantiated by several studies. It maybe a stronger risk factor for PAD than for CAD.

A2.11 Chronic renal insufficiency

There is an association of renal insufficiency with PAD,with some recent evidence suggesting it may be causal.In the HERS study (Heart and Estrogen/ProgestinReplacement Study), renal insufficiency was inde-pendently associated with future PAD events inpostmenopausal women.19

A2.12 Summary

Fig. A2 summarizes graphically the approximate influ-ence or association between some of the above factorsand PAD, taking a global view of the existing evidence.

A3 Fate of the Leg

A3.1 Asymptomatic

Evidence suggests that the progression of the under-lying PAD is identical whether or not the subject hassymptoms in the leg. There is nothing to suggestthat the risk of local deterioration, with progressionto CLI, is dependent on the presence or absence ofsymptoms of intermittent claudication. Whethersymptoms develop or not depends largely on the levelof activity of the subject. This is one of the reasonswhy some patients’ initial presentation is with CLI,in the absence of any earlier IC. For example, a patientwho has a reduction in their ABI just above the ische-mic rest pain level but who is too sedentary to claudi-cate, may develop CLI because of wounds resultingfrom relatively minor (often self inflicted) trauma

Fig. A2. Approximate range of odds ratios for risk factorsfor symptomatic peripheral arterial disease. Treatment ofrisk factors and the effect on the outcomes of PAD aredescribed in Chapter B.



that can not heal at this level of perfusion. It is impor-tant to detect this subgroup of patients at a time whenprotective foot care and risk factor control have theirgreatest potential to ameliorate outcomes. Functionaldecline over two years is related to baseline ABI andthe nature of the presenting limb symptoms.20 Alower ABI was associated with a more rapid declinein, for example, 6-minute walk distance.

A3.2 Intermittent claudication

Although PAD is progressive in the pathologicalsense, its clinical course as far as the leg is concernedis surprisingly stable in most cases. However, thesymptomatic PAD patient continues to have signifi-cant functional disability. Large population studiesprovide the most reliable figures. All of the evidenceover the last 40 years since the classic study by Bloorhas not materially altered the impression that onlyabout a quarter of patients with IC will ever signifi-cantly deteriorate. This symptomatic stabilizationmay be due to the development of collaterals, meta-bolic adaptation of ischemic muscle, or the patientaltering his or her gait to favor non-ischemic musclegroups. The remaining 25% of patients with IC


deteriorate in terms of clinical stage; this is most fre-quent during the first year after diagnosis (7%e9%)compared with 2% to 3% per year thereafter. This clin-ical stability is relevant to the patient’s perception oftheir severity of claudication. When these patientshave a comprehensive assessment of their actual func-tional status, measured walking distance doesprogressively deteriorate over time.20

More recent reviews also highlight that major am-putation is a relatively rare outcome of claudication,with only 1% to 3.3% of patients with IC needing ma-jor amputation over a 5-year period. The Basle andFramingham studies,21,22 which are the two large-scale studies that have looked at unselected patients,found that less than 2% of PAD patients required ma-jor amputation. Although amputation is the majorfear of patients told that they have circulatory diseaseof the legs, they can be assured that this is an unlikelyoutcome, except in diabetes patients (Fig. A3).

It is difficult to predict the risk of deterioration ina recent claudicant. The various risk factors mentionedin section A2 (above) probably all contribute to theprogression of PAD. A changing ABI is possibly thebest individual predictor, because if a patient’s ABIrapidly deteriorates it is most likely to continue to do

Fig. A3. Fate of the claudicant over 5 years (adapted from ACC/AHA guidelines5). PAD e peripheral arterial disease;CLI e critical limb ischemia; CV e cardiovascular; MI e myocardial infarction. Adapted with permission from Hirsch ATet al. J Am Coll Cardiol 2006;47:1239e1312.


so in the absence of successful treatment. It has beenshown that in patients with IC, the best predictor ofdeterioration of PAD (e.g. need for arterial surgery ormajor amputation), is an ABI of <0.50 with a hazardratio of more than 2 compared to patients with anABI >0.50. Studies have also indicated that in thosepatients with IC in the lowest strata of ankle pressure(i.e. 40e60 mmHg), the risk of progression to severeischemia or actual limb loss is 8.5% per year.

A3.3 Critical limb ischemia

The only reliable large prospective population studieson the incidence of CLI showed a figure of 220 newcases every year per million population.23 However,there is indirect evidence from studies looking at theprogression of IC, population surveys on prevalenceand assumptions based on the major amputation rates.Surprisingly, the incidence calculated using thesedifferent methodologies is very similar. There will beapproximately between 500 and 1000 new cases ofCLI every year in a European or North Americanpopulation of 1 million.

A number of studies have allowed an analysisof the risk factors that seem to be associated withthe development of CLI. These are summarized inFig. A4. These factors appear to be independent andare, therefore, probably additive.

It is no longer possible to describe the naturalhistory of patients with CLI because the majority ofthese patients now receive some form of active

Fig. A4. Approximate magnitude of the effect of risk factorson the development of critical limb ischemia in patientswith peripheral arterial disease. CLI e critical limbischemia.

treatment. Treatment very much depends on the cen-ter to which the patient is referred. Large surveys sug-gest that approximately half the patients with CLI willundergo some type of revascularization, although insome, particularly active, interventional centers an at-tempt at reconstruction is reported in as many as 90%of CLI patients. Fig. A5 provides an estimate of theprimary treatment of these patients globally and theirstatus a year later.

There are some good-quality data from multicenter,closely monitored trials of pharmacotherapy for CLI.These only relate to a subgroup of patients who are un-reconstructable or in whom attempts at reconstructionhave failed. (It is only such patients who are enteredinto randomized, placebo-controlled, clinical pharma-cotherapy trials.) The results for this subgroup revealthe appalling prospect that approximately 40% willlose their leg within 6 months, and up to 20% will die(note that these data refer to 6 months’ follow-up andcannot be directly compared with the 1-year data inFig. A5).

A3.4 Acute leg ischemia

Acute limb ischemia denotes a quickly developing orsudden decrease in limb perfusion, usually producingnew or worsening symptoms and signs, and oftenthreatening limb viability. Progression of PAD fromclaudication to rest pain to ischemic ulcers or gan-grene may be gradual or progress rapidly reflectingsudden worsening of limb perfusion. Acute limb is-chemia may also occur as the result of an embolicevent or a local thrombosis in a previously asymptom-atic patient.

There is little information on the incidence ofacute leg ischemia, but a few national registries andregional surveys suggest that the incidence is around140/million/year. Acute leg ischemia due to embolihas decreased over the years, possibly as a consequenceof less cardiac valvular disease from rheumatic feverand also better monitoring and anticoagulant manage-ment of atrial fibrillation. Meanwhile the incidence ofthrombotic acute leg ischemia has increased. Evenwith the extensive use of newer endovascular tech-niques including thrombolysis, most published seriesreport a 10% to 30% 30-day amputation rate.

A3.5 Amputation

There is an ongoing controversy, often fuelled byunverified retrospective audit data from large andchanging populations, as to whether there is a signifi-cant reduction in amputations as a result of more



Fig. A5. Fate of the patients presenting with chronic critical leg ischemia. CLI e critical limb ischemia.

revascularization procedures in patients with CLI.Careful, independent studies from Sweden, Denmarkand Finland all suggest that increased availability anduse of endovascular and surgical interventions haveresulted in a significant decrease in amputation forCLI. In the United Kingdom, the number of majoramputations has reached a plateau, possibly reflectingincreasingly successful limb salvage, but older studiesin the United States have not shown benefit of revas-cularization on amputation rates.24

The concept that all patients who require an ampu-tation have steadily progressed through increasinglysevere claudication to rest pain, ulcers and, ultimately,amputation, is incorrect. It has been shown that morethan half of patients having a below-knee major am-putation for ischemic disease had no symptoms ofleg ischemia whatsoever as recently as 6 months pre-viously.25 The incidence of major amputations fromlarge population or nation-wide data varies from120 to 500/million/year. The ratio of below-knee to

above-knee amputations in large surveys is around1:1. Only about 60% of below-knee amputations healby primary intention, 15% heal after secondary proce-dures and 15% need to be converted to an above-kneelevel. 10% die in the peri-operative period. The dismal1- to 2-year prognosis is summarized in Fig. A6.

A4 Co-existing Vascular Disease

Because PAD, CAD and cerebral artery disease are allmanifestations of atherosclerosis, it is not surprisingthat the three conditions commonly occur together.

A4.1 Coronary

Studies on the prevalence of cardiovascular disease inpatients with PAD show that the history, clinical exam-ination and electrocardiogram identify a prevalence ofCAD and cerebral artery disease in 40% to 60% of such

Fig. A6. Fate of the patient with below-knee amputation.



patients. In the PARTNERS study, 13% of subjectsscreened had an ABI of �0.90 and no symptomaticCAD or cerebral artery disease, 16% had both PADand symptomatic CAD or cerebral artery disease,and 24% had symptomatic CAD and cerebral arterydisease and a normal ABI.11 As with asymptomaticPAD, the diagnosis of CAD depends on the sensitivityof the methods used. In the primary care setting, ap-proximately half of those patients diagnosed withPAD also have CAD and cerebral artery disease; inPAD patients referred to hospital, the prevalence ofCAD is likely to be higher. The extent of the CAD,both by angiography and by computed tomography(CT) measured coronary calcium, correlates with theABI. Not surprisingly, patients with documentedCAD are more likely to have PAD. The prevalence ofPAD in patients with ischemic heart disease varies indifferent series from around 10% to 30%. Autopsystudies have shown that patients who die from a myo-cardial infarction are twice as likely to have a signifi-cant stenosis in the iliac and carotid arteries ascompared to patients dying from other causes.

A4.2 Cerebral artery disease

The link between PAD and cerebral artery diseaseseems to be weaker than that with CAD. By duplex ex-amination, carotid artery disease occurs in 26% to 50%of patients with IC, but only about 5% of patients withPAD will have a history of any cerebrovascular event.There is also a good correlation between carotid inti-mal thickness and the ABI. There is a range of overlapin disease in the cerebral, coronary and peripheral

circulations reported in the literature, representedsemi-quantitatively in Fig. A7. In the REACH (Reduc-tion of Atherothrombosis for Continued Health) sur-vey26 of those patients identified with symptomaticPAD, 4.7% had concomitant CAD, 1.2% had concomi-tant cerebral artery disease and 1.6% had both. Thusin this survey, about 65% of patients with PAD hadclinical evidence of other vascular disease. However,in one prospective study of 1886 patients aged 62 orover only 37% of subjects had no evidence of diseasein any of the three territories.27

A4.3 Renal

Studies have also looked at the prevalence of renal ar-tery stenosis in patients with PAD. The prevalence ofrenal artery stenosis of 50% or over ranges from 23%to 42% (compare this to the prevalence of renal arterystenosis in the hypertensive general population,which is around 3%). Although it has not been studiedspecifically it is very likely that renal artery stenosisis also a partly independent risk factor for mortalityin patients with PAD since renal artery stenosis of50% or over is associated with a 3.3-fold highermortality rate than in the general population.

A5 Fate of the Patient

A5.1 Asymptomatic and claudicating peripheralarterial disease patients

The increased risk of cardiovascular events in patientswith PAD is related to the severity of the disease in

Fig. A7. Typical overlap in vascular disease affecting different territories.26 Based on REACH data. PAD e peripheralarterial disease.



the legs as defined by an ABI measurement. The an-nual overall major cardiovascular event rate (myocar-dial infarction, ischemic stroke and vascular death) isapproximately 5%e7%.

Excluding those with CLI, patients with PAD havea 2% to 3% annual incidence of non-fatal myocardialinfarction and their risk of angina is about two- tothree- times higher than that of an age-matched popu-lation. The 5-, 10- and 15-year morbidity and mortalityrates from all causes are approximately 30%, 50% and70%, respectively (Fig. A3). CAD is by far the mostcommon cause of death among patients with PAD(40%e60%), with cerebral artery disease accountingfor 10% to 20% of deaths. Other vascular events, mostlyruptured aortic aneurysm, cause approximately 10% ofdeaths. Thus, only 20% to 30% of patients with PAD dieof non-cardiovascular causes.

Of particular interest are the studies in which thedifference in mortality rates between patients with ICand an age-matched control population was largelyunchanged despite the adjustment for risk factorssuch as smoking, hyperlipidemia and hypertension.These surprising, but consistent, results suggest thatthe presence of PAD indicates an extensive and severedegree of systemic atherosclerosis that is responsiblefor mortality, independent of the presence of risk fac-tors. Fig. A8 summarizes the results from all studiescomparing mortality rates of claudicating patientswith those of an age-matched control population. Asexpected, the two lines diverge, indicating that, onaverage, the mortality rate of claudicant patients is2.5-times higher than that of non-claudicant patients.

A5.2 Severity of peripheral arterial disease and survival

Patients with chronic CLI have a 20% mortality in thefirst year after presentation, and the little long-term

Fig. A8. Survival of patients with peripheral arterial disease.IC e intermittent claudication; CLI e critical limb ischemia.


data that exists suggests that mortality continues atthe same rate (Fig. A8). The short-term mortality ofpatients presenting with acute ischemia is 15% to20%. Once they have survived the acute episode, theirpattern of mortality will follow that of the claudicantor patient with chronic CLI, depending on the out-come of the acute episode.

There is a strong correlation between ABI, as a mea-sure of the severity of the PAD, and mortality. Anumber of studies, using different ABI ‘cut-off’ pointshave demonstrated this relationship. For instance, ina study of nearly 2000 claudicants, patients with anABI <0.50 had twice the mortality of claudicantswith an entry ABI of >0.50.28 The Edinburgh ArteryStudy10 has also shown that the ABI is a good predic-tor of non-fatal and fatal cardiovascular events as wellas total mortality, in an unselected general population.It has also been suggested that there is an almost lin-ear relationship between ABI and fatal and non-fatalcardiovascular events; each decrease in ABI of 0.10 be-ing associated with a 10% increase in relative risk fora major vascular event. In a study of patients withtype 2 diabetes (Fig. A9), the lower the ABI the higherthe 5-year risk of a cardiovascular event.29

SECTION B e MANAGEMENT OF CARDIO-VASCULAR RISK FACTORS AND

CO-EXISTING DISEASE

B1 Risk Factors

B1.1 Identifying the peripheral arterial disease patientin the population

Patients with peripheral arterial disease (PAD) havemultiple atherosclerosis risk factors and extensive

Fig. A9. Adjusted odds of a cardiovascular event by ankle-brachial index.29 Data from the placebo arm of the Appro-priate Blood Pressure Control in Diabetes study29 show aninverse correlation between ABI and odds of a major cardiovas-cular event. ABI e ankle-brachial index; CV e cardiovascular;MI e myocardial infarction. Reproduced with permissionfrom Mehler PS et al. Circulation 2003;107:753e756.


atherosclerotic disease, which puts them at markedlyincreased risk for cardiovascular events, similar topatients with established coronary artery disease(CAD).30 A reduced blood pressure in the ankle rela-tive to the arm pressure indicates the presence ofperipheral atherosclerosis, and is an independentrisk factor for cardiovascular events. This has beenmost recently studied in a meta-analysis of 15 popula-tion studies and showed that an ankle-brachial index(ABI) �0.90 was strongly correlated with all-causemortality independent of the Framingham RiskScore.31 Thus, current recommendations from numer-ous consensus documents, including the recentAmerican College of Cardiology/American HeartAssociation (ACC/AHA) guidelines on PAD, identifypatients with PAD as a high-risk population whorequire intensive risk factor modification and needantithrombotic therapy.5 This section will discuss anapproach to identification of PAD as a means to definea high-risk population and the management of each ofthe major risk factors to reduce the incidence ofcardiovascular events.

Over two-thirds of the patients with PAD are asymp-tomatic or have atypical leg symptoms and thus maynot be recognized as having a systemic cardiovasculardisease. Also, approximately half of the patients withPAD have not yet suffered a major cardiovascular event.Therefore, many patients with PAD are not identified,resulting in inadequate identification and treatment oftheir atherosclerosis risk factors.11

The initial clinical assessment for PAD is a historyand physical examination. A history of intermittentclaudication is useful in raising the suspicion of

PAD, but significantly underestimates the true pre-valence of PAD. In contrast, palpable pedal pulseson examination have a negative predictive value ofover 90% that may rule out the diagnosis in manycases. In contrast, a pulse abnormality (absent or di-minished) significantly overestimates the true preva-lence of PAD. Thus, objective testing is warranted inall patients suspected of having PAD. The primarynon-invasive screening test for PAD is the ABI (seesection C2 for further discussion of the ABI and ABIscreening criteria). In the context of identifying ahigh-risk population, persons who should be consid-ered for ABI screening in the primary care or commu-nity setting include: (1) subjects with exertional legsymptoms, (2) subjects aged 50e69 years who alsohave cardiovascular risk factors and all patients overthe age of 70 years,11 and (3) subjects with a 10-yearrisk of a cardiovascular event between 10% and 20%in whom further risk stratification is warranted. Car-diovascular risk calculators are readily available inthe public domain, such as the SCORE for use inEurope (www.escardio.org) and the Framingham forthe US (www.nhlbi.nih.gov/guidelines/cholesterol).

Patients with PAD, defined as an ABI �0.90, areknown to be at high risk for cardiovascular events(Fig. B1). As discussed in section A, mortality ratesin patients with PAD average 2% per year and therates of non-fatal myocardial infarction, stroke andvascular death are 5% to 7% per year.32,33 In addition,the lower the ABI, the higher the risk of cardiovascu-lar events, as shown in Fig. B2.34 A similar increasedmortality risk has also been observed in patientswith an increased ABI as shown in Fig. B2. Therefore,

Fig. B1. Algorithm for use of the ABI in the assessment of systemic risk in the population. Primary prevention: No antipla-telet therapy; LDL (low density lipoprotein) <3.37 mmol/L (<130 mg/dL) except in patients with diabetes where the LDLgoal is <2.59 mmol/L (<100 mg/dL) even in the absence of CVD (cardiovascular disease); appropriate blood pressure(<140/90 mmHg and <130/80 mmHg in diabetes/renal insufficiency). Secondary prevention: Prescribe antiplatelettherapy; LDL <2.59 mmol/L (<100 mg/dL) (<1.81 mmol/L [<70 mg/dL] in high risk); appropriate blood pressure(<140/90 mmHg and <130/80 mmHg in diabetes/renal insufficiency). See section B1.2 and surrounding text for references.In patients with diabetes, HbA1c <7.0%. See text for references. ABI e ankle-brachial index; PAD e peripheral arterialdisease; CLI e critical limb ischemia.


http://www.escardio.org

http://www.nhlbi.nih.gov/guidelines/cholesterol


Fig. B2. All cause mortality as a function of baseline ABI. Excess mortality was observed at ABI values <1.00 and >1.40.34

ABI e ankle-brachial index. Reproduced with permission from Resnick HE et al. Circulation 2004;109(6):733e739.

an abnormal ABI identifies a high-risk population thatneeds aggressive risk factor modification and anti-platelet therapy.

B1.2 Modification of atherosclerotic risk factors

As highlighted above, patients with PAD typicallyhave multiple cardiovascular risk factors, which putsthem at markedly increased risk for cardiovascularevents. This section will discuss an approach to eachof the major risk factors of this disorder.

B1.2.1 Smoking cessationSmoking is associated with a marked increased riskfor peripheral atherosclerosis. The number of packyears is associated with disease severity, an increasedrisk of amputation, peripheral graft occlusion andmortality. Given these associations, smoking cessationhas been a cornerstone of the management of PADas is the case for CAD.35 Other drugs for smokingcessation are becoming available.

In middle-aged smokers with reduced pulmonaryfunction, physician advice to stop smoking, coupledwith a formal cessation program and nicotine


replacement is associated with a 22% cessation rateat 5 years compared with only a 5% cessation rate inthe usual care group.36 By 14 years, the interventiongroup had a significant survival advantage. A numberof randomized studies have supported the use of bu-propion in patients with cardiovascular disease, with3-, 6- and 12-month abstinence rates of 34%, 27% and22%, respectively, compared with 15%, 11% and 9%,respectively, with placebo treatment.37 Combining bu-propion and nicotine replacement therapy has beenshown to be more effective than either therapy alone(Fig. B3).38 Thus, a practical approach would be toencourage physician advice at every patient visit,combined with behavior modification, nicotine re-placement therapy and the antidepressant bupropionto achieve the best cessation rates.

The role of smoking cessation in treating the symptomsof claudication is not as clear; studies have shownthat smoking cessation is associated with improvedwalking distance in some, but not all patients. There-fore, patients should be encouraged to stop smokingprimarily to reduce their risk of cardiovascular events,as well as their risk of progression to amputation andprogression of disease, but should not be promised im-proved symptoms immediately upon cessation. Recent

Fig. B3. Percent abstinence for bupropion SR, nicotine replacement, or both, versus placebo.38 Reproduced with permissionfrom Jorenby DE et al. N Engl J Med 1999;340(9):685e691.


studies have shown a three-fold increased risk of graftfailure after bypass surgery with continued smokingwith a reduction in that risk to that of non-smokerswith smoking cessation.39

B1.2.2 Weight reductionPatients who are overweight (body mass index [BMI]25e30) or who are obese (BMI>30) should receivecounseling for weight reduction by inducing negativecaloric balance with reduction of calorie intake,carbohydrate restriction and increased exercise.

B1.2.3 HyperlipidemiaIndependent risk factors for PAD include elevatedlevels of total cholesterol, low-density lipoprotein(LDL) cholesterol, triglycerides, and lipoprotein(a).Factors that are protective for the development ofPAD are elevated high-density lipoprotein (HDL)cholesterol and apolipoprotein (a-1) levels.

Direct evidence supporting the use of statins tolower LDL cholesterol levels in PAD comes from theHeart Protection Study (HPS).33 The HPS enrolledover 20,500 subjects at high risk for cardiovascularevents including 6748 patients with PAD, many ofwhom had no prior history of heart disease or stroke.Patients were randomized to simvastatin 40 mg, anti-oxidant vitamins, a combination of treatments, orplacebo using a 2� 2 factorial design, with a 5-yearfollow up. Simvastatin 40 mg was associated witha 12% reduction in total mortality, 17% reduction invascular mortality, 24% reduction in coronary heartdisease events, 27% reduction in all strokes anda 16% reduction in non-coronary revascularizations.Similar results were obtained in the PAD subgroup,whether they had evidence of coronary disease atbaseline or not. Furthermore, there was no thresholdcholesterol value below which statin therapy wasnot associated with benefit. Thus, the HPS demon-strated that in patients with PAD (even in the absenceof a prior myocardial infarction or stroke), aggressiveLDL lowering was associated with a marked

Recommendation 1. Smoking cessation in peri-pheral arterial disease

� All patients who smoke should be strongly andrepeatedly advised to stop smoking [B].

� All patients who smoke should receive a pro-gram of physician advice, group counselingsessions, and nicotine replacement [A].

� Cessation rates can be enhanced by the additionof antidepressant drug therapy (bupropion)and nicotine replacement [A].

reduction in cardiovascular events (myocardial infarc-tion, stroke and vascular death). A limitation of theHPS was that the evidence in PAD was derivedfrom a subgroup analysis in patients with symptom-atic PAD. Despite these limitations, all patients withPAD should have their LDL cholesterol levels loweredto <2.59 mmol/L (<100 mg/dL). To achieve theselipid levels, diet modification should be the initialapproach, however, in most cases, diet alone will beunable to decrease the lipids levels to the values men-tioned above; therefore, pharmacological treatmentwill be necessary.

A more recent meta-analysis of statin therapyconcluded that in a broad spectrum of patients,a 1 mmol/L (38.6 mg/dL) reduction in LDL choles-terol level was associated with a 20% decrease in therisk of major cardiovascular events.40 This benefitwas not dependent on the initial lipid levels (even pa-tients with lipids in the ‘‘normal’’ range responded),but did depend on the baseline assessment of cardio-vascular risk. Since patients with PAD are at high risk,and were included as a subgroup in this meta analy-sis, the majority of these patients would be consideredcandidates for statin therapy.

Current recommendations for the management oflipid disorders in PAD are to achieve an LDL choles-terol level of<2.59 mmol/L (<100 mg/dL) and to treatthe increased triglyceride and low HDL pattern.41,42

The recent ACC/AHA guidelines recommend as ageneral treatment goal achieving an LDL cholesterollevel <2.59 mmol/L (<100 mg/dL) in all patients withPAD and in those at high risk (defined as patients withvascular disease in multiple beds) the goal should bean LDL cholesterol level <1.81 mmol/L (<70 mg/dL).5

In patients with PAD who have elevated triglyceridelevels where the LDL cholesterol cannot be accuratelycalculated, the recommendation is to achieve a non-HDL-cholesterol level <3.36 mmol/L (<130 mg/dL),43

and in the highest risk patients (with vascular diseasein multiple beds) the non-HDL-cholesterol goal shouldbe <2.56 mmol/L (<100 mg/dL).

Patients with PAD commonly have disorders ofHDL cholesterol and triglyceride metabolism. Theuse of fibrates in patients with coronary artery diseasewho had an HDL cholesterol level <1.04 mmol/L(<40 mg/dL) and an LDL cholesterol level<3.63 mmol/L (>140 mg/dL) was associated with areduction in the risk of non-fatal myocardial infarctionand cardiovascular death.44 Niacin is a potent drugused to increase HDL cholesterol levels, with theextended-release formulation providing the lowestrisk of flushing and liver toxicity. In patients withPAD, niacin has been associated with regression offemoral atherosclerosis and reduced progression of



coronary atherosclerosis.45,46 Whether fibrates and/orniacin will reduce the progression of peripheral ather-osclerosis or reduce the risk of systemic cardiovascularevents in patients with PAD is not yet known.

B1.2.4 HypertensionHypertension is associated with a two- to three-foldincreased risk for PAD. Hypertension guidelinessupport the aggressive treatment of blood pressurein patients with atherosclerosis, indicating PAD. Inthis high-risk group the current recommendation isa goal of <140/90 mmHg, and <130/80 mmHg ifthe patient also has diabetes or renal insufficiency.47,48

Regarding drug choice, all drugs that lower bloodpressure are effective at reducing the risk of cardiovas-cular events. Thiazide diuretics are first-line agents,angiotensin converting enzyme (ACE) inhibitors or an-giotensin receptor blockers should be used in patientswith diabetic renal disease or in congestive heartfailure, and calcium channel blockers for difficult to

Recommendation 2. Lipid control in patientswith peripheral arterial disease (PAD)

� All symptomatic PAD patients should havetheir low-density lipoprotein (LDL)-cholesterollowered to <2.59 mmol/L (<100 mg/dL) [A].

� In patients with PAD and a history of vasculardisease in other beds (e.g. coronary artery dis-ease) it is reasonable to lower LDL cholesterollevels to <1.81 mmol/L (<70 mg/dL) [B].

� All asymptomatic patients with PAD and noother clinical evidence of cardiovascular diseaseshould also have their LDL-cholesterol levellowered to <2.59 mmol/L (<100 mg/dL) [C].

� In patients with elevated triglyceride levelswhere the LDL cannot be accurately calculated,the LDL level should be directly measured andtreated to values listed above. Alternatively, thenon-HDL (high-density lipoprotein) cholesterollevel can be calculated with a goal of <3.36mmol/L (<130 mg/dL), and in high-risk patientsthe level should be<2.59 mmol/L (<100 mg/dL).

� Dietary modification should be the initial inter-vention to control abnormal lipid levels [B].

� In symptomatic PAD patients, statins should bethe primary agents to lower LDL cholesterol levelsto reduce the risk of cardiovascular events [A].

� Fibrates and/or niacin to raise HDL-cholesterollevels and lower triglyceride levels should beconsidered in patients with PAD who haveabnormalities of those lipid fractions [B].


control hypertension. Most patients will require multi-ple agents to achieve desired blood pressure goals. TheACE inhibitor drugs have also shown benefit in PAD,possibly beyond blood-pressure lowering in high-riskgroups. This was documented by specific results fromthe HOPE (Heart Outcomes Prevention Evaluation)study in 4046 patients with PAD.49 In this subgroup,there was a 22% risk reduction in patients randomizedto ramipril compared with placebo, which was inde-pendent of lowering of blood pressure. Based on thisfinding, the United States Federal Drug Administrationhas now approved ramipril for its cardioprotective ben-efits in patients at high risk, including those with PAD.Thus, in terms of a drug class, the ACE inhibitors wouldbe recommended in patients with PAD.

Beta-adrenergic blocking drugs have previouslybeen discouraged in PAD because of the possibilityof worsening claudication symptoms. However, thisconcern has not been borne out by randomizedtrials; therefore, beta-adrenergic-blocking drugs canbe safely utilized in patients with claudication.50 Inparticular, patients with PAD who also have concomi-tant coronary disease may have additional cardio-protection with beta-adrenergic-blocking agents.Therefore, beta-adrenergic-blocking agents may beconsidered when treating hypertension in patientswith PAD.

B1.2.5 Diabetes [see also section D2.4]Diabetes increases the risk of PAD approximatelythree- to four-fold, and the risk of claudication two-fold. Most patients with diabetes have other cardio-vascular risk factors (smoking, hypertension and

Recommendation 3. Control of hypertension inperipheral arterial disease (PAD) patients

� All patients with hypertension should haveblood pressure controlled to <140/90 mmHgor <130/80 mmHg if they also have diabetesor renal insufficiency [A].

� JNC VII and European guidelines for themanagement of hypertension in PAD shouldbe followed [A].

� Thiazides and ACE inhibitors should be consid-ered as initial blood-pressure lowering drugsin PAD to reduce the risk of cardiovascularevents [B].

� Beta-adrenergic-blocking drugs are not contra-indicated in PAD [A].


dyslipidemia) that contribute to the developmentof PAD. Diabetes is also associated with peripheralneuropathy and decreased resistance to infection,which leads to an increased risk of foot ulcers andfoot infections.

Several studies of both type 1 and type 2 diabeteshave shown that aggressive blood-glucose loweringcan prevent microvascular complications (particu-larly retinopathy and nephropathy); this has notbeen demonstrated for PAD, primarily because thestudies conducted to date examining glycemic con-trol in diabetes were neither designed nor poweredto examine PAD endpoints.51,52 The current AmericanDiabetes Association guidance recommends hemo-globin A1C of <7.0% as the goal for treatment of di-abetes ‘‘in general’’, but points out that for ‘‘theindividual patient,’’ the A1C should be ‘‘as close tonormal (<6%) as possible without significant hypo-glycemia.’’ However, it is unclear whether achievingthis goal will effectively protect the peripheral circu-lation or prevent amputation.53 A single study inpatients with type 2 diabetes and a history of cardio-vascular disease did not show a benefit of loweringblood glucose levels with the insulin-sensitizingagent pioglitazone on the primary endpoint of thestudy (cardiovascular morbidity and mortality) butdid show a reduction in the risk of a secondary end-point of myocardial infarction, stroke and vasculardeath.51,54 Additional studies will be necessary todefine the role of insulin sensitizing agents in themanagement of cardiovascular complication of diabetesin patients with PAD.

B1.2.6 HomocysteineAn elevated plasma homocysteine level is an indepen-dent risk factor for PAD. While supplement withB-vitamins and/or folate can lower homocysteinelevels, high-level evidence for the benefits in termsof preventing cardiovascular events is lacking. Twostudies of supplemental B vitamins and folic acid inpatients with CAD demonstrated no benefit and

Recommendation 4. Control of diabetes inperipheral arterial disease (PAD)

� Patients with diabetes and PAD should haveaggressive control of blood glucose levelswith a hemoglobin A1c goal of <7.0% or asclose to 6% as possible [C].

even a suggestion of harm, so this therapy cannotbe recommended.55,56

B1.2.7 InflammationMarkers of inflammation have been associated withthe development of atherosclerosis and cardiovascu-lar events. In particular, C-reactive protein is indepen-dently associated with PAD.

B1.2.8 Antiplatelet drug therapyAspirin/acetylsalicylic acid (ASA) is a well-recog-nized antiplatelet drug for secondary preventionthat has clear benefits in patients with cardiovascu-lar diseases. Numerous publications from the An-tithrombotic Trialists’ Collaboration have concludedthat patients with cardiovascular disease will realizea 25% odds reduction in subsequent cardiovascularevents with the use of aspirin/ASA.57 These find-ings particularly apply to patients with coronary ar-tery and cerebral artery diseases. This most recentmeta-analysis has also clearly demonstrated thatlow-dose aspirin/ASA (75e160 mg) is protective,and probably safer in terms of gastrointestinalbleeding than higher doses of aspirin/ASA. Thus,current recommendations would strongly favor theuse of low-dose aspirin/ASA in patients with car-diovascular diseases. However, the initial Antith-rombotic Trialists’ Collaboration meta-analysis didnot find a statistically significant reduction in car-diovascular events in PAD patients treated with as-pirin/ASA who did not have other evidence ofvascular disease in other territories.58 However, inthe more recent meta-analysis, when the PAD datawere combined from trials using not only aspirin/ASA but also clopidogrel, ticlopidine, dipyridamoleand picotamide, there was a significant 23% oddsreduction in ischemic events in all subgroups of pa-tients with PAD. Antiplatelet drugs are clearly indi-cated in the overall management of PAD, althoughthe efficacy of aspirin/ASA is uniformly shown onlywhen PAD and cardiovascular disease coexist.59

Recommendation 5. Use of folate supplementa-tion in peripheral arterial disease (PAD)

� Patients with PAD and other evidence of car-diovascular disease should not be given folatesupplements to reduce their risk of cardiovas-cular events [B].



Picotamide is an antiplatelet drug that inhibitsplatelet thromboxane A2 synthase and antagonizesthromboxane receptors that has a mortality benefitin the subgroup of patients with PAD who alsohave diabetes.60 In that study, the drug signifi-cantly reduced 2-year, all-cause mortality, but notthe incidence of non-fatal cardiovascular events.Based on these data, further study is warrantedbefore a recommendation can be made in regardsto picotamide.

In addition to aspirin/ASA, the thienopyridinesare a class of antiplatelet agents that have been stud-ied in patients with cardiovascular disease. Ticlopi-dine has been evaluated in several trials in patientswith PAD, and has been reported to reduce the riskof myocardial infarction, stroke and vascular death.61

However, the clinical usefulness of ticlopidine is lim-ited by side effects such as neutropenia and thrombo-cytopenia. Clopidogrel was studied in the CAPRIE(Clopidogrel versus Aspirin in Patients at Risk ofIschemic Events) trial and shown to be effectivein the symptomatic PAD population to reduce therisk of myocardial infarction, stroke and vasculardeath. The overall benefit in this particular groupwas a 24% relative risk reduction over the use ofaspirin/ASA.32 This represents a number needed totreat with clopidogrel compared with aspirin/ASAof 87 patients to prevent an event. Clopidogrelhas a safety profile similar to aspirin/ASA, withonly rare reports of thrombocytopenia. Patientsundergoing surgical procedures are at increasedrisk of bleeding when taking anti-thrombotics includ-ing heparins, aspirin/ASA or clopidogrel. Thus,temporary cessation of these drugs should be indi-vidualized based on the type of surgery and/orendovascular intervention/revascularization to reducebleeding risks.

Recent publications in patients with acute coro-nary syndromes suggest that combination therapywith aspirin/ASA and clopidogrel is more effectivethan with aspirin/ASA alone, but at a higher riskof major bleeding.62 A recent study of clopidogrelcombined with aspirin/ASA (versus aspirin/ASAalone) was performed in a high-risk population con-sisting of patients with established cardiovasculardisease (including PAD) and patients without a his-tory of cardiovascular disease but who had multiplerisk factors. This study showed no overall benefit ofthe combination of antiplatelet drugs as comparedwith aspirin/ASA alone on the outcome of myo-cardial infarction, stroke and vascular death.63

Thus, combination therapy cannot be recommendedin patients with stable PAD, and if clopidogrel isconsidered it should be used as monotherapy.


B2 Health Economics of Risk-factor Management

For all cardiovascular risk factors, including smokingcessation, the most effective and cost-effective inter-ventions are those that combine a government-ledaction with individual prevention interventions. Inother words, laws that reduce the amount of addedsalt in processed foods and that increase taxes on to-bacco are more cost effective than individual preventionalone, but a combination of both is best.64

The issue in dealing with risk factors is the overallbudgetary impact of enforcing compliance to pub-lished guidelines. This is due to the large size of thepopulation at risk and the difficulty of organizingthe follow up of chronic patients treated by numeroushealth professionals. An additional difficulty forpayers is that the health and economic benefits aredelayed while resources for treatment have to beexpended at once. Studies on dyslipidemia, diabetesand hypertension have shown that compliance withguidelines is usually cost effective, within the rangeof $20e30,000 per added year of life. This holds truewhen several risk factors are associated.65,66

The effectiveness and cost-effectiveness of a num-ber of lifestyle interventions, including smoking ces-sation, exercise and diet, have been assessed by theCochrane Collaboration.

B2.1 Cost-effectiveness of smoking cessation interventions

For smoking cessation, the performance of professionalsin detection and interventions (including follow-up

Recommendation 6. Antiplatelet therapy inperipheral arterial disease (PAD)

� All symptomatic patients with or withouta history of other cardiovascular disease shouldbe prescribed an antiplatelet drug long term toreduce the risk of cardiovascular morbidity andmortality [A].

� Aspirin/ASA is effective in patients with PADwho also have clinical evidence of other formsof cardiovascular disease (coronary or carotid)[A].

� The use of aspirin/ASA in patients with PADwho do not have clinical evidence of other formsof cardiovascular disease can be considered [C].

� Clopidogrel is effective in reducing cardiovas-cular events in a subgroup of patients withsymptomatic PAD, with or without other clini-cal evidence of cardiovascular disease [B].


appointments, self-help materials and nicotine gum)is improved by training, although the overall effecton quit rates is modest. However, ‘‘training can beexpensive, and simply providing programs for healthcare professionals, without addressing the constraintsimposed by the conditions in which they practice, isunlikely to be a wise use of health care resources’’.67

Advising patients to use the telephone services is aneffective strategy.67

The unit cost of advice alone is estimated $5 perpatient, while counseling costs $51 per patient. Addingpharmacologic agents to counseling increases the quitrate and is cost effective: assuming that a long-termquitter increases his life expectancy by an average2 years, the cost-effectiveness ratio of added pharmaco-logical intervention ranges from $1 to $3,000 perlife-year gained.68

B2.2 Cost-effectiveness of exercise interventions

Exercise interventions are heterogenic, includingone-to-one counseling/advice or group counseling/advice; self-directed or prescribed physical activity;supervised or unsupervised physical activity; home-based or facility-based physical activity; ongoingface-to-face support; telephone support; writteneducation/motivation material; and self monitoring.The intervention can be delivered by one or a numberof practitioners including physicians, nurses, healtheducators, counselors, exercise leaders, and peers.Interventions ‘‘have a positive moderate sized effecton increasing self-reported physical activity andmeasured cardio-respiratory fitness, at least in the shortto mid-term’’.69 Assuming an adherence of 50% inthe first year and 30% in subsequent years, the cost-effectiveness ratio of unsupervised exercise is lessthan $12,000 per life year gained. Supervised exercisehas a cost-effectiveness ratio ranging from $20,000e$40,000 per life year gained (the strategies are moreefficient in elderly males with multiple risk factors).70

B2.3 Cost-effectiveness of pharmacologic interventions

It is difficult to recommend one drug over anotherfor risk factor modification on cost-effectiveness con-siderations because drug prices are subject to varia-tions between countries and over time. Although thisis true for all interventions, the case of a newer drugused in prevention of cardiac risk factors is particularin that the medical benefits of one treatment overanother are usually small and, therefore, the cost-effectiveness ratio is highly dependent on drug prices.The global cost-effectiveness analysis on the reduction

of cardiovascular disease risk63 found that treatmentby a combination of statin, beta blocker, diuretic andaspirin was most efficient in avoiding death and dis-ability. When oral anti-platelet agents are considered,assuming a threshold of up to £20,000e40,000 per ad-ditional quality-adjusted life year (QALY), clopidogrelwould be considered cost effective for treatment dura-tion of 2 years in patients with peripheral arterialdisease. For a lifetime treatment duration, clopidogrelwould be considered more cost effective than aspirinas long as treatment effects on non-vascular deathsare not considered.71

Because recent studies have often failed to demon-strate a benefit on mortality, the efficiency of drug treat-ments has been measured in ‘cost per major eventaverted’ and is, therefore, not comparable to ‘cost perlife year gained’, although there is a relationshipbetween the two. For example, the cost effectivenessof 40 mg/day simvastatin in high-risk patients is£4,500 (95% CI: 2,300e7,400) per major vascular eventaverted, but the result is highly sensitive to the statincost. In this context, it is likely that the use of an off-patent statin would prove more efficient.72 For patientswith high cardiovascular risk, the use of ACE inhibitorsappears very cost effective in most countries, as shownby the results of the HOPE study: less than $10,000 perevent averted in the various developed countrieswhere the economic analyses were undertaken.73

In conclusion, the risk-management strategy chosenmay differ depending on whether the individual orpopulation perspectives are considered. In a populationperspective with an objective of sustainability andaccess, public interventions to reduce smoking, saltand fat intake, combined with the prescription of cheapand off-patent drugs, are preferred. If the individualperspective is considered, however, newer and moreexpensive drugs offer additional health benefits atreasonable cost-effectiveness ratios.

B3 Future Aspects of Controlling IschemicRisk Factors

It is clear that decreasing the level of any risk factor,such as blood pressure and LDL cholesterol, canhelp improve prognosis. However, it is not clearwhat the optimal values are in the general popula-tion and in individual disease states. Future studiesare also needed to define guidelines for differentclinical presentations: should blood pressure belowered to 140/90 mmHg in patients with PAD, orshould it be lower? Should these values alsobe usable in critical leg ischemia? Is there aJ-shaped curve (an increased risk at very low bloodpressure values)?



Modifying several risk factors is at least asbeneficial as changing only one. Combination therapywith several drugs will become inevitable. However,what is the compliance of the patients who are facedwith such combination therapy? Future studiesshould clarify whether the ‘polypill’ (several drugsin one pill) could help in achieving the goals of im-proved risk factor modification. Calculations shouldbe made on the costs of such combination therapyversus the change in long-term prognosis.

Diabetes sharply increases total cardiovascularrisk; are the current goals for blood pressure andlipids strict enough to control this risk? Studies areneeded to show whether the choice of antihyperten-sive drugs should be guided by their influence oninsulin resistance or other metabolic parameters.

It is becoming evident that inflammatory processesplay an important role in the atherosclerotic process.It is not yet clear if drugs that target chronic inflam-mation (e.g. antibiotics) would add to usual risk factormanagement in controlling the progress of the ather-osclerotic process.

B4 Co-existing Coronary Artery Disease

The prevalence of CAD in patients with PAD is high,which strongly increases the risk for cardiac mortalityand morbidity in these patients (see section A4.1).4,26

Therefore, all PAD patients should be considered athigh risk for clinically significant CAD, for which sev-eral guidelines exist.74,75 Patients should be evaluatedfor evidence of CAD.

Treatment decisions for coexisting CAD shouldbe based on current practice standards, and patientswho have unstable symptoms (acute coronarysyndrome, decompensated heart failure) should bereferred to a cardiovascular physician for appropri-ate diagnosis and treatment. For patients with stableCAD, management should be guided by the sever-ity of the symptoms and co-morbid conditions.Most patients with severe cardiac symptoms willrequire coronary angiography to determine theappropriate means for revascularization. All patientsshould be given appropriate medical therapy totreat symptoms and atherosclerotic risk factors (seesection B1).

Cardiac assessment scores may be useful in thecontext of patients being considered for peripheralrevascularization.76 In patients with a high cardiacrisk assessment score, current guidelines recommendfurther evaluation of the patient for possible coronaryrevascularization.76 However in the recent Coronary


Artery Revascularization Prophylaxis (CARP) trial ofpatients with peripheral vascular disease who wereconsidered high risk for perioperative complicationsand had significant CAD, coronary revascularizationdid not reduce overall mortality or perioperativemyocardial infarction.77 In addition, patients who un-derwent coronary revascularization had a significantlylonger time to vascular surgery compared withpatients who did not. Therefore, this strategy ofa pre-emptive coronary revascularization prior toperipheral vascular surgery should not normallybe pursued.

In most patients, perioperative use of beta-adrenergic-blocking agents is associated withreduced cardiovascular risks of surgery. Recent stud-ies have shown that beta-adrenergic blockade withbisoprolol significantly decreased the risk for cardio-vascular events during vascular surgery andafterwards.78,79 Besides controlling symptoms ofmyocardial ischemia, treatment with beta-blockingagents also has the benefit of favorably influencingprognosis in these patients.80

Recommendation 7. Management of coronaryartery disease (CAD) in peripheral arterial diseasepatients

� Patients with clinical evidence of CAD (angina,ischemic congestive heart failure) should beevaluated and managed according to currentguidelines [C].

� Patients with PAD considered for vascular sur-gery may undergo further risk stratificationand those found to be at very high risk man-aged according to current guidelines for coro-nary revascularization [C].

� Routine coronary revascularization in prepara-tion for vascular surgery is not recommended[A].

Recommendation 8. Use of beta-blocking agentsbefore vascular surgery

� When there are no contraindications, beta-adrenergic blockers should be given periopera-tively to patients with peripheral arterialdisease undergoing vascular surgery in orderto decrease cardiac morbidity and mortality [A].


B5 Co-existing Carotid Artery Disease

The prevalence of carotid artery disease in PADpatients is also high (see section A4.2); and patientswith PAD are at an increased risk for cerebrovascularevents. Evaluation of the carotid circulation shouldbe based on a history of transient ischemic attack orstroke. Further evaluation and consideration for revas-cularization should be based on current guidelines.81,82

B6 Co-existing Renal Artery Disease

Patients with PAD are at an increased risk for reno-vascular hypertension. The management of patientswith PAD and atherosclerotic renal artery disease isfocused on control of hypertension and preservationof renal function. In such cases, evaluation and treat-ment should be based on current guidelines.5,83,84

These patients should be referred to an appropriatecardiovascular physician.

SECTION C e INTERMITTENT CLAUDICATION

C1 Characterization of Patients

C1.1 Definition of intermittent claudication and limbsymptoms in peripheral arterial disease

The majority of patients with peripheral arterial dis-ease (PAD) have limited exercise performance andwalking ability. As a consequence, PAD is associated

Recommendation 9. Management of carotid ar-tery disease in peripheral arterial disease (PAD)patients

� The management of symptomatic carotid ar-tery disease in patients with PAD should bebased on current guidelines [C].

Recommendation 10. Management of renal ar-tery disease in peripheral arterial disease (PAD)patients

� When renal artery disease is suspected in PADpatients, as evidenced by poorly controlledhypertension or renal insufficiency, patientsshould be treated according to current guide-lines and consider referral to a cardiovascularphysician [C].

with reduced physical functioning and quality of life.In patients with PAD, the classical symptom is inter-mittent claudication (which means to limp), which ismuscle discomfort in the lower limb reproduciblyproduced by exercise and relieved by rest within10 minutes. Patients may describe muscle fatigue, ach-ing or cramping on exertion that is relieved by rest. Thesymptoms are most commonly localized to the calf, butmay also affect the thigh or buttocks. Typical claudica-tion occurs in up to one-third of all patients with PAD.Importantly, patients without classical claudicationalso have walking limitations that may be associatedwith atypical or no limb symptoms.85 Typical claudica-tion symptoms may not occur in patients who have co-morbidities that prevent sufficient activity to producelimb symptoms (i.e. congestive heart failure, severepulmonary disease, musculoskeletal disease) or inpatients who are so deconditioned that exercise is notperformed. Therefore, patients suspected of havingPAD should be questioned about any limitations theyexperience during exercise of the lower extremitiesthat limits their walking ability.

PAD is caused by atherosclerosis that leads toarterial stenosis and occlusions in the major vesselssupplying the lower extremities. Patients with inter-mittent claudication have normal blood flow at rest(and, therefore, have no limb symptoms at rest).With exercise, occlusive lesions in the arterial supplyof the leg muscles limits the increase in blood flow,resulting in a mismatch between oxygen supply andmuscle metabolic demand that is associated withthe symptom of claudication. Acquired metabolicabnormalities in the muscle of the lower extremityalso contribute to the reduced exercise performancein PAD.

C1.2 Differential diagnosis

Table C1 shows the differential diagnosis of intermit-tent claudication (IC); Table C2 shows potential causesof occlusive arterial lesions in the lower extremityarteries potentially causing claudication.

C1.3 Physical examination

The physical examination should assess the circula-tory system as a whole. Key components of the generalexamination include measurement of blood pressurein both arms, assessment of cardiac murmurs, gallopsor arrhythmias, and palpation for an abdominal aorticaneurysm (does not exclude the presence of an an-eurysm). Less specific aspects of the physical examina-tion for PAD include changes in color and temperature



Table C1. Differential diagnosis of intermittent claudication (IC)

Condition Location Prevalence Characteristic Effect ofexercise

Effect ofrest

Effect ofposition

Othercharacteristics

Calf IC Calf muscles 3e5% ofadultpopulation

Cramping,achingdiscomfort

Reproducibleonset

Quicklyrelieved

None May have atypicallimb symptoms onexercise

Thigh andbuttock IC

Buttocks, hip,thigh

Rare Cramping,aching discomfort

Reproducibleonset

Quicklyrelieved

None ImpotenceMay have normalpedal pulses withisolated iliac arterydisease

Foot IC Foot arch Rare Severe pain onexercise

Reproducibleonset

Quicklyrelieved

None Also may presentas numbness

Chroniccompartmentsyndrome

Calf muscles Rare Tight, burstingpain

After muchexercise(jogging)

Subsidesvery slowly

Relief withelevation

Typically heavymuscled athletes

Venousclaudication

Entire leg,worse in calf

Rare Tight, burstingpain

After walking Subsidesslowly

Relief speededby elevation

History ofiliofemoral deepvein thrombosis,signs of venouscongestion, edema

Nerve rootcompression

Radiatesdown leg

Common Sharp lancinatingpain

Induced bysitting, standingor walking

Often presentat rest

Improved bychange inposition

History of backproblemsWorse with sittingRelief when supineor sitting

SymptomaticBakers cyst

Behind knee,down calf

Rare Swelling,tenderness

With exercise Presentat rest

None Not intermittent

Hip arthritis Lateral hip,thigh,

Common Aching discomfort After variabledegree ofexercise

Not quicklyrelieved

Improvedwhen notweight bearing

Symptoms variableHistory ofdegenerativearthritis

Spinalstenosis

Often bilateralbuttocks,posterior leg

Common Pain and weakness May mimic IC Variable reliefbut can take along time torecover

Relief bylumbar spineflexion

Worse withstanding andextending spine

Foot/anklearthritis

Ankle, foot,arch

Common Aching pain After variabledegree ofexercise

Not quicklyrelieved

May be relievedby not bearingweight

Variable, may relateto activity level andpresent at rest

IC e intermittent claudication.

of the skin of the feet, muscle atrophy from inabilityto exercise, decreased hair growth and hypertrophied,slow-growing nails. The presence of a bruit in theregion of the carotid, aorta or femoral arteries mayarise from turbulence and suggest significant arterial

Table C2. Causes of occlusive arterial lesions in lower extremityarteries potentially causing claudication

Atherosclerosis (PAD)ArteritisCongenital and acquired coarctation of aortaEndofibrosis of the external iliac artery (iliac artery syndrome incyclists)Fibromuscular dysplasiaPeripheral emboliPopliteal aneurysm (with secondary thromboembolism)Adventitial cyst of the popliteal arteryPopliteal entrapmentPrimary vascular tumorsPseudoxanthoma elasticumRemote trauma or irradiation injuryTakayasu’s diseaseThromboangiitis obliterans (Buerger’s disease)Thrombosis of a persistent sciatic artery


disease. However, the absence of a bruit does notexclude arterial disease.

The specific peripheral vascular examination re-quires palpation of the radial, ulnar, brachial, carotid,femoral, popliteal, dorsalis pedis and posterior tibialartery pulses. The posterior tibial artery is palpatedat the medial malleolus. In a small number ofhealthy adults, the dorsalis pedis pulse on the dor-sum of the foot may be absent due to branching ofthe anterior tibial artery at the level of the ankle. Inthis situation, the distal aspect of the anterior tibialartery may be detected and assessed at the ankle.Also, a terminal branch of the peroneal artery maybe palpated at the lateral malleolus. For simplicity,pulses may be graded from 0 (absent), 1 (dimin-ished) and 2 (normal). An especially prominent pulseat the femoral and/or popliteal location should raisethe suspicion of an aneurysm. A diminished orabsent femoral pulse suggests aorto-iliac arteryocclusive disease, which reduces inflow to the limb.In contrast, a normal femoral, but absent pedal,



pulse suggests significant arterial disease in the legwith preserved inflow. Pulses should be assessed inboth legs and pulse abnormalities correlated withleg symptoms to determine the lateralization ofthe disease.

Patients with an isolated occlusion of an internaliliac (hypogastric) artery may have normal femoraland pedal pulses at rest and after exercise, but buttocksclaudication (and impotence in males). Similar symp-toms may occur in patients with stenosis of the com-mon or external iliac artery. These patients may alsohave normal pulses at rest, but loss of the pedal pulsesafter exercise. The loss of the pedal pulse is coincidentwith a drop in ankle pressure due to the inability of thelarge vessels (in the presence of occlusive disease) toprovide sufficient flow to maintain distal pressurewith muscle vasodilation during exercise.

Despite the utility of the pulse examination, thefinding of absent pedal pulses tends to over-diagnosePAD, whereas if the symptom of classic claudicationis used to identify PAD, it will lead to a significantunder-diagnosis of PAD.86 Thus, PAD must be con-firmed in suspected patients with non-invasive testingusing the ankle-brachial index, or other hemodynamicor imaging studies described below.

C2 Diagnostic Evaluation of Patients withPeripheral Arterial Disease

C2.1 Ankle pressure measurements(ankle-brachial index)

Measuring the pressure in the ankle arteries has be-come a standard part of the initial evaluation ofpatients with suspected PAD. A common method of

Recommendation 11. History and physicalexamination in suspected peripheral arterialdisease (PAD)

� Individuals with risk factors for PAD, limbsymptoms on exertion or reduced limb func-tion should undergo a vascular history to eval-uate for symptoms of claudication or otherlimb symptoms that limit walking ability [B].

� Patients at risk for PAD or patients with re-duced limb function should also have a vascularexamination evaluating peripheral pulses [B].

� Patients with a history or examination sugges-tive of PAD should proceed to objective testingincluding an ankle-brachial index [B].

measurement uses a 10e12 cm sphygmomanometercuff placed just above the ankle and a Doppler instru-ment used to measure the systolic pressure of theposterior tibial and dorsalis pedis arteries of eachleg (Fig. C1). These pressures are then normalized tothe higher brachial pressure of either arm to formthe ankle-brachial index (ABI). The index leg is oftendefined as the leg with the lower ABI.

The ABI provides considerable information. Areduced ABI in symptomatic patients confirms theexistence of hemodynamically significant occlusivedisease between the heart and the ankle, with a lowerABI indicating a greater hemodynamic severity of oc-clusive disease. The ABI can serve as an aid in differen-tial diagnosis, in that patients with exercise-related legpain of non-vascular causes will have a normal anklepressure at rest and after exercise. In patients withPAD who do not have classic claudication (are eitherasymptomatic or have atypical symptoms) a reducedABI is highly associated with reduced limb function.This is defined as reduced walking speed and/ora shortened walking distance during a timed 6-minutewalk. From a systemic perspective, a reduced ABI isa potent predictor of the risk of future cardiovascularevents, as discussed in section B1.1. This risk is re-lated to the degree of reduction of the ABI (lowerABI predicts higher risk) and is independent ofother standard risk factors. The ABI thus has thepotential to provide additional risk stratification inpatients with Framingham risk between 10% and20% in 10 years, in that an abnormal ABI in this in-termediate-risk group would move the patient tohigh risk in need of secondary prevention whereasa normal ABI would lower the estimate of risk indi-cating the need for primary prevention strategies(see Fig. B1).

The ABI should become a routine measurement inthe primary care practice of medicine. When used inthis context, screening of patients aged 50e69 yearswho also had diabetes or a smoking history, or screen-ing all persons over the age of 70 resulted in a preva-lence of PAD of 29%.11 The reproducibility of the ABIvaries in the literature, but it is significant enough thatreporting standards require a change of 0.15 in anisolated measurement for it to be considered clinicallyrelevant, or >0.10 if associated with a change in clin-ical status. The typical cut-off point for diagnosingPAD is �0.90 at rest.

The value of a reduced ABI is summarized asfollows:

� Confirms the diagnosis of PAD� Detects significant PAD in (sedentary) asymptom-

atic patients


Fig. C1. Measurement of the ABI. ABI e ankle-brachial index.

� Used in the differential diagnosis of leg symptomsto identify a vascular etiology

� Identifies patients with reduced limb function (in-ability to walk defined distances or at usual walkingspeed)

� Provides key information on long-term prognosis,with an ABI �0.90 associated with a 3e6-fold in-creased risk of cardiovascular mortality

� Provides further risk stratification, with a lower ABIindicating worse prognosis

� Highly associated with coronary and cerebral arterydisease

� Can be used for further risk stratification in patientswith a Framingham risk score between 10%e20%.

In some patients with diabetes, renal insufficiency, orother diseases that cause vascular calcification, the tib-ial vessels at the ankle become non-compressible. Thisleads to a false elevation of the ankle pressure. Thesepatients typically have an ABI >1.40 and, in some ofthese patients, the Doppler signal at the ankle cannotbe obliterated even at cuff pressures of 300 mmHg. Inthese patients additional non-invasive diagnostic test-ing should be performed to evaluate the patient forPAD (discussed in section G1.3). Alternative tests in-clude toe systolic pressures, pulse volume recordings,transcutaneous oxygen measurements or vascularimaging (most commonly with duplex ultrasound).


When any of these tests is abnormal, a diagnosis ofPAD can be reliably made.

C2.2 Exercise testing to establish the diagnosisof peripheral arterial disease

As discussed above, patients with claudication whohave an isolated iliac stenosis may have no pressuredecrease across the stenosis at rest and, therefore,

Recommendation 12. Recommendations forankle-brachial index (ABI) screening to detectperipheral arterial disease in the individualpatient.

An ABI should be measured in:

� All patients who have exertional leg symptoms[B].

� All patients between the age of 50e69 and whohave a cardiovascular risk factor (particularlydiabetes or smoking) [B].

� All patients age �70 years regardless of risk-factor status [B].

� All patients with a Framingham risk score10%e20% [C].


a normal ABI at rest. However, with exercise theincrease inflow velocity will make such lesions hemo-dynamically significant. Under these conditions, exer-cise will induce a decrease in the ABI that can bedetected in the immediate recovery period and thusestablish the diagnosis of PAD. The procedure requiresan initial measurement of the ABI at rest. The patient isthen asked to walk (typically on a treadmill at 3.2 km/h(2 mph), 10%e12% grade) until claudication painoccurs (or a maximum of 5 minutes), following whichthe ankle pressure is again measured. A decrease inABI of 15%e20% would be diagnostic of PAD. If a tread-mill is not available then walking exercise may be per-formed by climbing stairs or in the hallway.

C2.3 Alternative stress tests for patients who cannotperform treadmill exercise

Certain patient populations should not be asked toundergo treadmill testing as previously described,including those who have severe aortic stenosis, uncon-trolled hypertension or patients with other exercise-limiting co-morbidities, including advanced congestiveheart failure or chronic obstructive pulmonary disease.87

Patients who cannot perform treadmill exercise canbe tested with active pedal plantar flexion. Activepedal plantar flexion has demonstrated excellentcorrelation with treadmill testing, and should beconsidered an appropriate alternative to treadmill

testing. A second alternative is to inflate a thigh cuffwell above systolic pressure for 3 to 5 minutes, pro-ducing a similar degree of ‘‘reactive’’ hyperemia.The decrease in ankle pressure 30 seconds after cuffdeflation is roughly equivalent to that observed1 minute after walking to the point of claudicationon a treadmill. Unfortunately, many patients do nottolerate the discomfort associated with this degreeand duration of cuff inflation and, in modern vascularlaboratories, this is rarely performed.

Discussion of additional diagnostic tests to estab-lish the diagnosis of PAD can be found in section G.

Fig. C2 shows an algorithm for the diagnosis of PAD.

C3 Outcome Assessment of IntermittentClaudication in Clinical Practice

Intermittent claudication is a symptom of peripheralarterial disease that profoundly limits the patient’sability to walk and as a result is associated with a re-duced exercise performance. This reduction in exerciseperformance can be easily quantified with a gradedtreadmill test where the time of onset of claudicationpain (claudication onset time) and peak walking timecan be determined at baseline. The treadmill test willalso allow the clinician to determine if the patientexperiences typical claudication pain with exercise,or other symptoms that limit exercise. This assessmentwill help guide therapy because if claudication is not

Fig. C2. Algorithm for diagnosis of peripheral arterial disease. TBI e toe brachial index; VWF e velocity wave form; PVR epulse volume recording. Reproduced with permission from Hiatt WR. N Engl J Med 2001;344:1608e1621.



the major symptom limiting exercise then specificclaudication therapies may not be indicated.

Once claudication is established as the major symp-tom limiting exercise, then the primary goal of claudi-cation therapy is to relieve the symptoms duringwalking and improve exercise performance and com-munity activities. Appropriate treatment of the claudi-cant must address both the specific lower-extremitydisability and the systemic impact of the disease. Ide-ally, treatment will result in an improvement in boththe vascular status of the lower extremity and reducethe patient’s subsequent risk of fatal and non-fatal car-diovascular events. In clinical trials of claudicationtherapy, the primary endpoint is usually a treadmilltest of the peak walking time or distance as well asthe time or distance for the onset of claudication.88

The same parameters can be assessed to determinethe clinical benefit of any claudication therapy in an in-dividual patient. In addition, changes in the physicaldomains of the Medical Outcomes Short Form 36 (SF-36) or the Walking Impairment Questionnaire (WIQ)serve as patient-based measures of treatment effect.The complete assessment of the outcomes of treatmentof the claudicant, therefore, requires the use of bothclinical and patient-based parameters.

C4 Treatment of Intermittent Claudication

C4.1 Overall strategy and basic treatmentfor intermittent claudication

C4.1.1 Overall strategyPatients with claudication experience reversible muscleischemia during walking that is characterized bycramping and aching in the affected muscle. These

Recommendation 13. Determining success oftreatment for intermittent claudication.

Patient-based outcome assessment (includinga focused history of change in symptoms) is themost important measure; however, if quantitativemeasurements are required the following may beused:

1. Objective measures include an increase in peakexercise performance on a treadmill [B].

2. Patient-based measures would include animprovement on a validated, disease-specifichealth status questionnaire; or the physicalfunctioning domain on a validated generichealth status questionnaire [B].


symptoms result in a severe limitation in exercise per-formance and walking ability. The exercise limitation isassociated with marked impairments in walking dis-tance, walking speed and overall function. Patientswith claudication are physically impaired and, there-fore, the treatment goals are to relieve symptoms,improve exercise performance and daily functionalabilities. The initial approach to the treatment of limbsymptoms should focus on structured exercise and,in selected patients, pharmacotherapy to treat the exer-cise limitation of claudication (risk factor modificationand antiplatelet therapies are indicated to decrease therisk of cardiovascular events and improve survival).Failure to respond to exercise and/or drug therapywould lead to the next level of decision making, whichis to consider limb revascularization. However, in pa-tients in whom a proximal lesion is suspected (findingsof buttocks claudication, reduced or absent femoralpulse) the patient could be considered for revasculari-zation without initially undergoing extensive medicaltherapy. The overall strategy is summarized in Fig. C3.

C4.1.2 Exercise rehabilitationIn patients with claudication, there is a considerablebody of evidence to support the clinical benefits ofa supervised exercise program in improving exerciseperformance and community-based walking ability.This intervention has been thoroughly reviewed,both in terms of mechanism of the training effect,as well as practical guidelines for the exerciseprogram.89,90 Several studies have suggested thatsome level of supervision is necessary to achieve opti-mal results (general, unstructured recommendationsto exercise by the physician do not result in any clinicalbenefit). In prospective studies of supervised exerciseconducted for 3 months or longer, there are clear in-creases in treadmill exercise performance and a lessen-ing of claudication pain severity during exercise.91

The predictors of response to the training programinclude achieving a high level of claudication pain dur-ing the training sessions and 6 months or longer offormal training and walking exercise (versus othertraining modalities). Training on a treadmill has beenshown to be more effective than strength training orcombinations of training modalities. However, differentmodes of exercise training have been applied includingupper extremity cycle ergometer exercise that isassociated with a training response. The mechanismsof response to exercise training have been reviewedpreviously and include improvements in walking effi-ciency, endothelial function and metabolic adaptationsin skeletal muscle.90

The exercise prescription should be based onexercise sessions that are held three times a week,


Fig. C3. Overall treatment strategy for peripheral arterial disease. BP e blood pressure; HbA1c e hemoglobin A1c; LDL elow density lipoprotein; MRA e magnetic resonance angiography; CTA e computed tomographic angiography.Reproduced with permission from Hiatt WR. N Engl J Med 2001;344:1608e1621.

beginning with 30 minutes of training but then increas-ing to approximately 1 hour per session. During the ex-ercise session, treadmill exercise is performed ata speed and grade that will induce claudication within3e5 minutes. The patient should stop walking whenclaudication pain is considered moderate (a lessoptimal training response will occur when the patientstops at the onset of claudication). The patient will thenrest until claudication has abated, after which thepatient should resume walking until moderate

claudication discomfort recurs. This cycle of exerciseand rest should be at least 35 minutes at the start ofthe program and increase to 50 minutes as the patientbecomes comfortable with the exercise sessions(but always avoiding excessive fatigue or leg discom-fort). In subsequent visits, the speed or grade of thetreadmill is increased if the patient is able to walk for10 minutes or longer at the lower workload withoutreaching moderate claudication pain. Either speedor grade can be increased, but an increased grade is



recommended if the patient can already walk at 2 mph(3.2 km/h). An additional goal of the program is toincrease patient walking speed up to the normal3.0 mph (4.8 km/h) from the average PAD patientwalking speed of 1.5e2.0 mph (approximately 2.4e3.2 km/h).

Many patients may have contraindications for exer-cise (e.g. severe CAD, musculoskeletal limitations orneurological impairments). Other patients may be un-willing to participate in supervised sessions if theyhave long distances to travel to the exercise facility, ifan appropriate rehabilitation program is not availablein their area, or if the expenses incurred are too great.The prevalence of contraindications to an exercise pro-gram ranges from 9%e34% depending on the popula-tion studied. The major limitation of exerciserehabilitation is the lack of availability of a supervisedsetting to refer patients. Though exercise therapy is ofproven effectiveness, some patients are simply notwilling to persist with an exercise program in order tomaintain the benefit. In addition, a claudicationexercise program in a patient with diabetes who hassevere distal neuropathy may precipitate foot lesionsin the absence of proper footwear.

C4.2 Pharmacotherapy for intermittent claudication

Patients with IC should all receive drug and lifestyletreatment for their cardiovascular risk factors and coex-isting diseases to prevent cardiovascular events(myocardial infarction, stroke and death) associatedwith atherosclerosis. However, this approach will typ-ically not provide a significant reduction or eliminationof symptoms of claudication. Thus, claudication drugtherapy for relief of symptoms typically involves differ-ent drugs than those that would be used for risk reduc-tion (an exception may be lipid-lowering therapy).However, a number of types of drugs have been

Recommendation 14. Exercise therapy in inter-mittent claudication

� Supervised exercise should be made availableas part of the initial treatment for all patientswith peripheral arterial disease [A].

� The most effective programs employ treadmillor track walking that is of sufficient intensityto bring on claudication, followed by rest,over the course of a 30e60 minute session. Ex-ercise sessions are typically conducted threetimes a week for 3 months [A].


promoted for symptom relief, with varying levels ofevidence to support their use. Not all the drugspresented in this section are universally available, soaccess to certain agents may be limited in certain coun-tries. Finally, current drug therapy options do notprovide the same degree of benefit as does a supervisedexercise program or successful revascularization.

C4.2.1 Drugs with evidence of clinical utility inclaudicationNote that not all these drugs are available in every country

CilostazolCilostazol is a phosphodiesterase III inhibitor with

vasodilator, metabolic and antiplatelet activity. Thebenefits of this drug have been described in a meta-analysis of six randomized, controlled trials involving1751 patients, including 740 on placebo, 281 on cilos-tazol 50 mg twice-daily (BID), 730 on cilostazol100 mg BID. The 73 on cilostazol 150 mg BID and232 on pentoxifylline 400 mg thrice-daily (TID) wereexcluded from the analysis.92 This analysis demon-strated that the net benefit of cilostazol over placeboin the primary endpoint of peak treadmill perfor-mance ranged from 50e70 meters depending on thetype of treadmill test performed. Cilostazol treatmentalso resulted in a significant overall improvement inthe quality of life measures from the WIQ and SF-36. In a study comparing cilostazol to pentoxifylline,cilostazol was more effective.93 Side effects includedheadache, diarrhea, and palpitations. An overallsafety analysis of 2702 patients revealed that the ratesof serious cardiovascular events, and all-cause andcardiovascular mortality was similar between drugand placebo groups.94 However, since the drug is inthe phosphodiesterase III inhibitor class of drugs, itshould not be given to patients with any evidence ofcongestive heart failure because of a theoretical con-cern for increased risk of mortality. This drug hasthe best overall evidence for treatment benefit inpatients with claudication.

NaftidrofurylNaftidrofuryl has been available for treating in-

termittent claudication for over 20 years in severalEuropean countries. It is a 5-hydroxytryptaminetype 2 antagonist and may improve muscle metabo-lism, and reduce erythrocyte and platelet aggregation.In a meta-analysis of five studies involving a total of888 patients with intermittent claudication, naftidro-furyl increased pain-free walking distance by 26%compared with placebo ( p¼ 0.003).95 Similar resultsshowing benefits on treadmill performance and qualityof life were confirmed in three recent studies of over1100 patients followed for 6e12 months.96e98 In allthree studies the same dose of 600 mg/day was


administered. Side effects were minor and notdifferent to placebo; most frequently occurring com-plaints in the different studies were mild gastro-intestinal disorders.

C4.2.2 Drugs with supporting evidence of clinicalutility in claudication

Carnitine and Propionyl-L-CarnitinePatients with peripheral arterial disease develop

metabolic abnormalities in the skeletal muscles ofthe lower extremity. Thus, claudication is not simplythe result of reduced blood flow, and alterationsin skeletal muscle metabolism are part of the patho-physiology of the disease. L-carnitine and propionyl-L-carnitine interact with skeletal muscle oxidativemetabolism, and these drugs are associated with im-proved treadmill performance. Propionyl-L-carnitine(an acyl form of carnitine) was more effective thanL-carnitine in improving treadmill walking distance.In two multicenter trials of a total of 730 patients,initial and maximal treadmill walking distanceimproved more with propionyl-L-carnitine thanplacebo.99,100 The drug also improved quality of lifeand had minimal side effects as compared withplacebo. Additional trials in the broad populationof patients with claudication will be necessary to es-tablish the overall efficacy and clinical benefit ofthese drugs.

Lipid lowering drugsPatients with PAD have endothelial and metabolic

abnormalities secondary to their atherosclerosis,which may be improved with statin therapy. Thereare several promising studies evaluating the effectsof statin drugs on exercise performance. While the re-sults are preliminary, several positive trials suggestthat further study is warranted.101,102 Further studiesare ongoing to determine the clinical benefits ofthese observations, including prevention of diseaseprogression in addition to symptom relief.

C4.2.3 Drugs with insufficient evidence of clinicalutility in claudication

PentoxifyllinePentoxifylline lowers fibrinogen levels, improves red

cell and white cell deformability and thus lowers bloodviscosity. While early trials were positive on the end-point of improvement in treadmill exercise perfor-mance, later studies demonstrated that pentoxifyllinewas no more effective than placebo on improving tread-mill walking distance or functional status assessedby questionnaires. Several meta-analyses have con-cluded that the drug is associated with modest increasesin treadmill walking distance over placebo, but the

overall clinical benefits were questionable.103e105

The clinical benefits of pentoxifylline in improvingpatient-assessed quality of life have not been exten-sively evaluated. While tolerability of the drug isacceptable, pentoxifylline does not have an extensivesafety database.

Isovolemic hemodilutionIsovolemic hemodilution has been advocated for

the treatment of claudication, presumably by lower-ing viscosity of whole blood, but it is still uncertainwhether the increase in blood flow compensates forthe decrease in oxygen-carrying capacity of the blood.There are insufficient trials to support this therapyand it is only of historical interest.

Antithrombotic agentsAspirin/ASA and other antiplatelet agents (clopi-

dogrel) are important in the long-term treatment ofpatients with PAD to reduce their risk of cardiovascu-lar events with well established efficacy. However, nostudies have shown a benefit of antiplatelet or anti-coagulant drugs in the treatment of claudication.106

VasodilatorsArteriolar vasodilators were the first class of

agents used to treat claudication. Examples includedrugs that inhibit the sympathetic nervous system(alpha blockers), direct-acting vasodilators (papaver-ine), beta2-adrenergic agonists (nylidrin), calciumchannel blockers (nifedipine) and angiotensin-converting enzyme inhibitors. These drugs have notbeen shown to have clinical efficacy in randomized,controlled trials.107 There are several theoreticalreasons why vasodilators may not be effective, in-cluding the possibility that vasodilator drugs maycreate a steal phenomenon by dilating vessels innormally perfused tissues thus shifting the distribu-tion of blood flow away from muscles supplied byobstructed arteries.

L-ArginineL-arginine has the ability to enhance endothelium-

derived nitric oxide and, thus, improve endothelialfunction. One study of nutritional supplementationwith L-arginine improved pain-free but not peakwalking time.108 However, a recent study of L-argininetreatment in acute myocardial infarction showed noclinical benefit and excess mortality.108 Further studieswould be needed to determine if this treatment wouldhave benefit and no unacceptable risk.

Acyl coenzyme A-cholesterol acyltransferase inhibitorsDrugs in this class may reduce cholesterol accumu-

lation in arterial plaque, thus affecting the naturalhistory of atherosclerosis. A study with avasimibein claudication demonstrated no clear evidence ofefficacy and possible adverse effects on low-densitylipoprotein cholesterol levels.109



5-Hydroxytryptamine antagonistsKetanserin is a selective serotonin (S2) antagonist

that lowers blood viscosity and also has vasodilatorand antiplatelet properties. Controlled trials of thisdrug have shown it not to be effective in treatingclaudication.110 Importantly, the drug has been associ-ated with increased risk of mortality in a subgroup ofpatients treated with potassium-wasting diuretics,precluding its role for any indication.111

AT-1015 is a selective 5-hydroxytryptamine antago-nist that was studied in multiple doses in claudication.The drug was ineffective, and there were toxicity con-cerns at the highest dose.112 Therefore, this drug cannotbe recommended at this time.

Sarpogrelate showed promising results in 364 pa-tients followed for 32 weeks, without safety concerns.113

Additional trials will be necessary to determine theoverall benefits and safety of drugs in this class.

ProstaglandinsProstaglandins have been used in several studies in

patients with critical leg ischemia with some successin wound healing and limb preservation. In patientswith claudication, prostaglandin E1 (PGE1) has beenbest studied. Intravenous administration of a prodrugof PGE1 showed positive effects on treadmill per-formance.114 Several studies have been performedwith oral beraprost. While there was a positive trialin Europe, there have been negative trials in theUSA.115,116 While intravenous administration ofPGE1 may have modest benefits, the overall evidencedoes not support the use of this drug class forclaudication.

BuflomedilBuflomedil has an alpha-1 and -2 adrenolytic effects

that result in vasodilatation. This drug has antiplateleteffects, results in improvements in red cell deformabil-ity and weakly antagonizes calcium channels. Two rel-atively small studies have shown marginally positiveeffects on treadmill performance.117,118 However, con-cerns have been raised about publication bias of onlypositive trials. Therefore, evidence is insufficient tosupport the use of this agent at this time.

DefibrotideDefibrotide is a polydeoxyribonucleotide drug

with antithrombotic and hemorheological properties.Several small studies suggest a clinical benefit, butlarger trials would be necessary to better understandthe clinical benefits and any risks of therapy.119e121

Other agentsSeveral studies have evaluated the role of Vitamin E,

chelation therapy, omega-3 fatty acids, ginko-bilobaand lowering of homocysteine levels in the treat-ment of claudication. None of these therapies haveproven effective.


C5 Future Treatments for Claudication

Angiogenic growth factorsVascular endothelial growth factor (VEGF) and

basic fibroblast growth factor (bFGF) are mitogenicagents that stimulate the development of new vessels.When bFGF protein was given intra-arterially,patients with claudication had an improvement in ex-ercise performance.122 Newer applications deliver theagent as gene therapy in a viral vector given intra-muscularly. Unfortunately, initial studies have notbeen positive with VEGF.123 Therefore, more studieswill be needed to address the overall efficacy andmodes and frequency of administration of angiogenicfactors in the treatment of claudication.

SECTION D e CHRONIC CRITICALLIMB ISCHEMIA

D1 Nomenclature and Definitions

Critical limb ischemia (CLI) is a manifestation of pe-ripheral arterial disease (PAD) that describes patientswith typical chronic ischemic rest pain (see Table D1,Fontaine and Rutherford classifications, respectively)or patients with ischemic skin lesions, either ulcersor gangrene. The term CLI should only be used inrelation to patients with chronic ischemic disease,defined as the presence of symptoms for more than2 weeks. It is important to note in this section thatthere are limited data available compared with theother sections. CLI populations are difficult to study,with large numbers of patients lost to follow-up ordying in longitudinal studies, leading to incompletedata sets.

The diagnosis of CLI should be confirmed by theankle-brachial index (ABI), toe systolic pressure ortranscutaneous oxygen tension. Ischemic rest painmost commonly occurs below an ankle pressure of50 mmHg or a toe pressure less than 30 mmHg. Other

Recommendation 15. Pharmacotherapy forsymptoms of intermittent claudication

� A 3- to 6-month course of cilostazol shouldbe first-line pharmacotherapy for the relief ofclaudication symptoms, as evidence showsboth an improvement in treadmill exerciseperformance and in quality of life [A].

� Naftidrofuryl can also be considered for treat-ment of claudication symptoms [A].


causes of pain at rest should, therefore, be consideredin a patient with an ankle pressure above 50 mmHg,although CLI could be the cause.

Some ulcers are entirely ischemic in etiology; othersinitially have other causes (e.g. traumatic, venous, orneuropathic) but will not heal because of the severityof the underlying PAD. Healing requires an inflam-matory response and additional perfusion abovethat required for supporting intact skin and underly-ing tissues. The ankle and toe pressure levels neededfor healing are, therefore, higher than the pressuresfound in ischemic rest pain. For patients with ulcersor gangrene, the presence of CLI is suggested by anankle pressure less than 70 mmHg or a toe systolicpressure less than 50 mmHg. (It is important to under-stand that there is not complete consensus regardingthe vascular hemodynamic parameters required tomake the diagnosis of CLI.)

D1.1 Patients presumed at risk for critical limb ischemia

A subgroup of PAD patients fall outside the definitionof either claudication or CLI. These patients havesevere PAD with low perfusion pressures and lowankle systolic pressures, but are asymptomatic. Theyare usually sedentary and, therefore, do not claudicate,or they may have diabetes with neuropathy and

Table D1. Classification of peripheral arterial disease: Fontaine’sstages and Rutherford’s categories

Fontaine Rutherford

Stage Clinical Grade Category Clinical

I Asymptomatic 0 0 AsymptomaticIIa Mild claudication I 1 Mild claudicationIIb Moderate to

severeclaudication

I 2 Moderateclaudication

I 3 Severeclaudication

III Ischemic rest pain II 4 Ischemic rest painIV Ulceration or

gangreneIII 5 Minor tissue lossIII 6 Major tissue loss

Recommendation 16. Clinical definition of criti-cal limb ischemia (CLI)

� The term critical limb ischemia should be usedfor all patients with chronic ischemic rest pain,ulcers or gangrene attributable to objectivelyproven arterial occlusive disease. The termCLI implies chronicity and is to be distin-guished from acute limb ischemia [C].

reduced pain perception. These patients are presumedvulnerable to develop clinical CLI. The naturalhistory of this subgroup of severe PAD is not well-characterized, but outcomes of excess mortality andamputation would be expected. The term ‘chronic sub-clinical ischemia’ has been ascribed to this subgroup.

Natural history studies of claudication documentthat few patients progress to CLI. Many patients whopresent with CLI are asymptomatic prior to its devel-opment.54 However, research in this area is lacking,understandably, for patients who are asymptomaticand can only be detected by more routine ABI testing.

D1.2 Prognosis

It is important to diagnose CLI because it confersa prognosis of high risk for limb loss and for fataland non-fatal vascular events, myocardial infarctionand stroke. In general, the prognosis is much worsethan that of patients with intermittent claudication.Observational studies of patients with CLI who arenot candidates for revascularization suggest thata year after the onset of CLI, only about half thepatients will be alive without a major amputation,although some of these may still have rest pain,gangrene or ulcers (see section A). Approximately25% will have died and 25% will have requireda major amputation. Their prognosis is in manyways similar to that of some malignancies. Thediagnosis of CLI thus predicts a poor prognosis forlife and limb. Patients should have aggressive modi-fication of their cardiovascular risk factors and shouldbe prescribed antiplatelet drugs. Ultimately, much ofthe care of CLI patients is palliative in nature, anissue that is very important when consideringrevascularization or amputation.

D2 Clinical Presentation and Evaluation

D2.1 Pain

CLI is dominated by pedal pain (except in diabetic pa-tients, where superficial pain sensation may be alteredand they may experience only deep ischemic pain,

Recommendation 17. Cardiovascular risk modifi-cation in critical limb ischemia (CLI)

� CLI patients should have aggressive modifica-tion of their cardiovascular risk factors [A].



such as calf claudication and ischemic rest pain). Inmost cases, the pedal pain is intolerably severe; itmay respond to foot dependency, but otherwise re-sponds only to opiates. The pain is caused by ische-mia, areas of tissue loss, ischemic neuropathy ora combination of these; it occurs or worsens with re-duction of perfusion pressure. In most cases, walkingcapacity is very severely impaired, with walking oftenbecoming almost impossible.

Ischemic rest pain most typically occurs at night(when the limb is no longer in a dependent position)but in severe cases can be continuous. The pain is local-ized in the distal part of the foot or in the vicinity of anischemic ulcer or gangrenous toe. The pain often wakesthe patients at night and forces them to rub the foot, getup, or take a short walk around the room. Partial reliefmay be obtained by the dependent position, whereaselevation and cold increase the severity of the pain. Of-ten, patients sleep with their ischemic leg danglingover the side of the bed, or sitting in an armchair; asa consequence ankle and foot edema develop. In severecases, sleep becomes impossible because pain sets inafter only a short period of supine rest, causing inmany patients a progressive further decline of theirgeneral physical and psychological condition.

Ischemic rest pain is often accompanied by paincaused by peripheral ischemic neuropathy, the mecha-nism of which is not well established. This results insevere, sharp, shooting pain that does not necessarilyfollow the anatomic distribution of the nerves but usu-ally is most pronounced at the distal part of the extrem-ity. The pain often occurs at night, with episodes lastingminutes to hours but with constant diffuse pain re-maining in between. Ischemic rest pain should not beconfused with neuropathic pain (see section D4.1).

D2.2 Ulcer and gangrene

Patients with CLI may also present with ischemic ul-cers or gangrene. It is important to note that some pa-tients may progress through rest pain into tissue loss.However, in many patients, notably those with dia-betic neuropathy, the initial presentation is with a neu-roischemic ulcer or gangrene. There are significantdifferences between patients with and without diabe-tes at this stage of CLI; these are delineated in sectionD2.4 which specifically addressed diabetic foot ulcers.

Gangrene usually affects the digits or, in a bedriddenpatient, the heel (as this is a pressure point). In severecases, gangrene may involve the distal parts of the fore-foot. It is usually initiated by a minor local trauma.Local pressure (ill fitting shoes) or the use of localheat (increasing metabolic demands) can also lead to


ulcer and gangrene formation on other locations onthe foot or leg. Gangrenous tissue, if not infected, canform an eschar, shrink and eventually mummify and,if the underlying circulation is adequate enough (orhas been made adequate enough by treatment) to sup-port the process, spontaneous amputation may follow.In contrast to the focal and proximal atheroscleroticlesions of PAD found typically in other high-riskpatients, in patients with CLI and diabetes the occlu-sive lesions are more likely to be more diffuse and dis-tally located, particularly in infrageniculate arteries.Importantly, PAD in patients with diabetes is usuallyaccompanied by peripheral neuropathy with impairedsensory feedback, enabling the silent progression ofthe ischemic process. Thus, a patient with diabetesand severe, asymptomatic PAD could also have a ‘piv-otal event’ that leads acutely to an ischemic ulcer anda limb-threatening situation. A common example isthe use of new, tight or ill fitting shoes in a patientwith neuropathy. Thus, an asymptomatic, usuallyundiagnosed patient can lapse, apparently abruptly,into CLI. By identifying a patient with sub-clinical dis-ease and instituting preventive measures, it may bepossible to avoid CLI or at least prompt early referralif the patient develops CLI.

D2.3 Differential diagnosis of ulcers

The majority of lower-leg ulcers above the ankle havea venous origin whereas ulcers in the foot are mostlikely due to arterial insufficiency (see Fig. D1).

Table D2 depicts the common characteristics of footand leg ulcers.

D2.4 Diabetic foot ulcers

While CLI is a significant risk factor for non-healingof diabetic foot ulcers, it is not the sole major factorassociated with the development of diabetic footlesions. Diabetic foot ulcers are, therefore, discussedseparately in this section. Fig. D2 demonstratesthe distribution of diabetic foot ulcers. Diabetic footcomplications are the most common cause of non-traumatic lower extremity amputations in the world.It is estimated that 15% of people with diabeteswill develop a foot ulcer during their lifetime andapproximately 14%e24% of people with a foot ulcerwill require an amputation. Up to 85% of amputationsmay be prevented by early detection and appropriatetreatment.124 Risk factors for ulcer formation includeperipheral neuropathy, which leads to an insensatefoot and structural foot deformity. It is estimatedthat approximately 30% of people with diabetes


have mild-to-severe forms of diabetic nerve damage.Many diabetic foot ulcers and lower extremity ampu-tations can be prevented through early identificationof the patient at risk and preventive foot care, by

Fig. D1. Approximate frequencies of various ulceretiologies.

both the health care provider and the patient, asdescribed in the section D6 on the prevention of CLI.

D2.4.1 Pathways to ulcerationThe most common pathway associated with thedevelopment of diabetic ulcers include: neuropathy(loss of protective sensation), coupled with pressurepoints (foot deformity) and repetitive activity.126

Motor nerve defects and limited joint mobilitycan cause foot deformities, with pressure pointsfurther predisposing the patient to foot lesions.Consequences of autonomic neuropathy include lossof sweating, dry fissured skin and increased arteriove-nous shunting. Healing requires a greater increase inperfusion than needed to maintain intact skin.

D2.4.2 Types of ulcers and presentationDiabetic foot ulcerations can be divided into threebroad categories: ischemic, neuro-ischemic and neu-ropathic ulcers. The presentation of the classical neu-ropathic and ischemic ulcers is depicted in Table D3.Although the majority of diabetic ulcers are neuro-pathic (Fig. D3), ischemia has to be excluded in allulcers given its major impact on outcome. All patientswith a foot ulcer should have an objective assessmentof their vascular status at first presentation and ona regular basis; the assessment should include history(claudication), pulses and ABI. Pulse examinationalone is an inadequate vascular examination in thesepatients. Any diabetic patient with a foot ulcer shouldbe further evaluated in the vascular laboratory (seesection G).

Increased arteriovenous shunt blood flow, due toautonomic neuropathy, can result in a relativelywarm foot, falsely reassuring the clinician. The clini-cian should be aware of the relative incompressibilityof calcified distal arteries in a diabetic, such that the

Table D2. Characteristics of common foot and leg ulcers

Origin Cause Location Pain Appearance Role ofrevascularization

Arterial Severe PAD, Buerger’sdisease,

Toes, foot, ankle Severe Various shape,pale base, dry

Important

Venous Venous insufficiency Malleolar, esp. medial Mild Irregular, pinkbase, moist

None

Mixed venous/arterial Venousinsufficiencyþ PAD

Usually malleolar Mild Irregular, pink base If non-healing

Skin infarct Systemic disease,embolism

Lower third of leg, malleolar Severe Small, often multiple None

Neuropathic Neuropathy fromdiabetes, vitamindeficiency, etc

Foot/plantar surface(weight-bearing),associated deformity

None Surrounding callus,often deep, infected

None

Neuroischemic Diabeticneuropathyþ ischemia

Locations common to bothischemic and neuroischemicAs arterial

Reduceddue toneuropathy

As arterial As arterial



Fig. D2. Distribution of diabetic foot ulcers.125 Copyright � 1999 American Diabetes Association from Diabetes Care, Vol. 22,1999; 157e162. Modified with permission from The American Diabetes Association.

ABI may be within normal limits. Due to the possibil-ity of a falsely elevated ABI, the importance of toepressures and tcPO2 measurements cannot be under-estimated (see section D5). Some patients have clearsigns of critical limb ischemia e for example a toe ortcPO2 pressure <30 mmHg e while in others theblood flow is impaired to a lesser degree e for exam-ple toe pressures between 30e70 mmHg e but theyare still unable to heal foot lesions.

Symptoms and signs of neuropathic versus ischemiculcers appear in Table D3.

Table D3. Symptoms and signs of neuropathic versus ischemiculcers

Neuropathic ulcer Ischemic ulcer

Painless PainfulNormal pulses Absent pulsesRegular margins, typicallypunched-out appearance

Irregular margins

Often located on plantarsurface of foot

Commonly located on toes,glabrous margins

Presence of calluses Calluses absentor infrequent

Loss of sensation, reflexesand vibration

Variable sensory findings

Increase in blood flow(AV shunting)

Decrease in blood flow

Dilated veins Collapsed veinsDry, warm foot Cold footBony deformities No bony deformitiesRed appearance Pale, cyanotic

Recommendation 18. Evaluation of peripheralarterial disease (PAD) in patients with diabetes

� All diabetic patients with an ulceration shouldbe evaluated for PAD using objective testing [C].


D3 Macrocirculatory Pathophysiology inCritical Limb Ischemia

CLI occurs when arterial lesions impair blood flow tosuch an extent that the nutritive requirements of thetissues cannot be met. This is usually caused by mul-tilevel arterial occlusive disease.128 In some cases, thehemodynamic consequences of arterial lesions may becompounded by a decreased cardiac output.

CLI is considered to be the result of multisegmentarterial occlusive disease in most cases. Realizingthis is most important in managing patients with pre-sumed rest pain, as the influence of circulation on thepain syndrome can be difficult to determine, partic-ularly in a patient with neuropathy.

� Patients with diffuse multisegment disease, bothsupra and infrainguinal are significant managementproblems, as proximal revascularizations may notremain patent due to lack of arterial outflow with-out additional infrainguinal procedures. Shoulda major amputation be required, the risk of non-healing is considerable due to proximal occlusivedisease

� In patients with diabetes, arteries proximal to theknee joint are often spared or moderately diseased,and the majority of occlusions occur at the tibial pe-roneal trunk and distally. Often, the peroneal arteryand the dorsalis pedis artery are open beyond theseocclusions and serve as potential distal targets fora bypass.

D3.1 Skin microcirculation

The skin microcirculation is unusual in many ways,most notably that nutritional capillary blood flowonly represents approximately 15% of the normal totalblood flow in the foot, the remainder having a non-nutritive thermoregulatory function only. Patientswith CLI develop microcirculatory defects including


Fig. D3. Relative prevalence of different diabetic ulcer etiologies.127

endothelial dysfunction, altered hemorheology andwhite blood cell activation and inflammation. The nor-mal function of the skin microcirculation can be consid-ered in regard to two aspects: a complex microvascularflow regulatory system and a series of defense mecha-nisms. The microvascular flow-regulating systemincludes extrinsic neurogenic mechanisms, intrinsiclocal mediators and modulation by circulating humoraland blood-borne factors. The endothelium also partici-pates in the regulation of flow by the release of vasodi-latory mediators such as prostacyclin and nitric oxideand several endothelium-derived contractile factors(e.g. endothelin). In addition to the microvascularflow-regulating system, there are several microvascu-lar defense mechanisms. In CLI, there is a maldistribu-tion of the skin microcirculation in addition toa reduction in total blood flow. The importance of thelocal microcirculatory response in individual patientswith CLI is suggested by the wide overlap in ankle ortoe blood pressure, which assess the macrocirculation,in patients with and without CLI.

Capillary microscopy studies have confirmed anheterogeneous distribution of skin microcirculatoryflow. This is also accompanied by a reduction intcPO2.129

In summary, although PAD is the underlying andprincipal defect in patients with CLI, the low tissueperfusion pressure sets up a number of complex localmicrocirculatory responses, which may contribute torest pain and trophic changes. Many of these pro-cesses can be viewed as an inappropriate responseof the microcirculatory flow regulatory mechanismand its normal defense mechanisms. Therefore, al-though the primary aim of treatment must be the cor-rection of the PAD, attempts to manipulate andnormalize the microcirculatory changes pharmacolog-ically may enhance the results of revascularizationand may be one option in patients in whom revasc-ularization is impossible or has failed.

D4 Differential Diagnosis of Ischemic Rest Pain

The various causes of foot pain that may be mistakenfor ischemic rest pain are considered in their appro-ximate order of frequency.

D4.1 Diabetic neuropathy

Diabetic neuropathy usually results in a decrease insensation. In some patients neuropathy can result insevere, seriously disabling pain in the foot. This isoften described as a burning or shooting sensationthat is frequently worse at night, when there is less dis-traction, making it more difficult to distinguish fromatypical ischemic rest pain. (It should be noted thatthis type of pain is seen in the relatively early ‘neuritic’phase of diabetic neuropathy, often before diabeticneuropathy has been clinically recognized.) Diagnosticfeatures that may be helpful in distinguishing diabeticneuropathy from ischemic rest pain are a symmetricaldistribution in both legs, association with cutaneoushypersensitivity and failure to relieve it by depen-dency of the foot. The patient may have other signsof a diabetic neuropathy, such as decreased vibratorysensation and decreased reflexes.

D4.2 Complex regional pain syndrome

Patients with complex regional pain syndrome (for-merly named causalgia or reflex sympathetic dystro-phy) are often referred to vascular specialists forevaluation of their limb circulation. In general, the cir-culation is adequate (ABI, toe-brachial index [TBI]normal). One form of complex regional painsyndrome is caused by inadvertent ischemic damageto peripheral nerves that may be associated withdelayed revascularization and, therefore, may be clas-sified as a postoperative complication. This is one of



the rare conditions in which lumbar sympathectomymay be indicated.

D4.3 Nerve root compression

A number of spinal conditions may result in nerve rootcompression, giving rise to continuous pain. It is typi-cally associated with backache and the pain distribu-tion following one of the lumbosacral dermatomes.

D4.4 Peripheral sensory neuropathy other thandiabetic neuropathy

Any condition giving rise to isolated sensory neuro-pathy can produce pain in the foot, which can beconfused with ischemic rest pain. Peripheral neuro-pathy other than that caused by diabetic neuropathymay be caused by vitamin B12 deficiency, or syringo-myelia. Leprosy also may rarely result in a neuro-pathic ulcer. Alcohol excess, toxins, and somecommonly used drugs, such as some cancer chemo-therapy agents, may on rare occasion produce aperipheral neuropathy.

D4.5 Night cramps

Night cramps, as opposed to restless legs, are verycommon and occasionally difficult to diagnose. Theyare usually associated with muscle spasm and usuallyinvolve the calf, very rarely the foot alone. They maybe associated with chronic venous insufficiency, buttheir precise cause is unknown.

D4.6 Buerger’s disease (thrombangitis obliterans)

Buerger’s disease also may present with rest pain inthe toes or feet, usually in younger smokers, and isno longer exclusively seen in male patients. The path-ophysiology is distal limb ischemia, due to an occlu-sive, inflammatory vascular process involving botharteries and veins.

D4.7 Miscellaneous

A number of other miscellaneous conditions cangive rise to pain in the foot, including local inflamma-tory diseases such as gout, rheumatoid arthritis,digital neuroma, tarsal tunnel nerve compression orplantar fasciitis.


D5 Investigations of Critical Limb Ischemia

D5.1 Physical examination

As a majority of patients with CLI have not sufferedearlier symptoms of PAD (intermittent claudication)it is important to have the diagnosis of CLI inmind when examining any patient with leg pain orulcer development.

A first step is to document the location and qualityof the pulses. Other less specific findings may includehair loss, muscle atrophy, atrophy of subcutaneoustissues and skin and appendages, dry fissured skin,discoloration and dependant hyperemia.

In patients with ulcers there may be other etiologiesbesides arterial disease (see Fig. D1 and Table D2).Swelling is usually only a feature when there is activeinfection or rest pain that prevents patients fromelevating their foot in bed at night.

D5.2 Investigations

� General investigations of atherosclerotic disease(see section B)

� Physiologic e Confirmation of the diagnosis andquantification of the arterial flow

B Ankle pressure e In patients with ischemic ulcersthe ankle pressure is typically 50e70 mmHg, andin patients with ischemic rest pain it is typically30e50 mmHg

B Toe pressures e should include toe pressures indiabetic patients (critical level <50 mmHg)

B tcPO2 (critical level <30 mmHg)B Investigation of microcirculation (usually used as

a research tool) e CLI is associated with redu-ced total flow as well as maldistribution of flowand activation of an inflammatory process. A com-bination of tests to assess healing and quantifyflow may be indicated due to the rather poor sen-sitivity and specificity of the single test. Testsinclude:� Capillaroscopy� Fluorescence videomicroscopy� Laser Doppler fluxometry

� Anatomic (Imaging) e Refer to section G.

Recommendation 19. Diagnosis of critical limbischemia (CLI)

� CLI is a clinical diagnosis but should besupported by objective tests [C].


D6 Prevention of Critical Limb Ischemia

As with all forms of systemic atherosclerosis, earlydetection of PAD and aggressive management of car-diovascular risk factors should reduce the incidenceand severity of CLI. For example, smoking cessationis associated with a decreased risk of progressionfrom earlier stages of PAD to CLI130 (see section B).

D6.1 Risk factors associated with the foot

Early identification of the patient who is at risk forCLI is essential in order to recognize potential prob-lems and develop preventive intervention strategiesto avoid complications. Patients with atheroscleroticPAD, Buerger’s disease, diabetes and any other condi-tion that can cause a loss of protective sensation tothe foot or interferes with wound healing are at riskof developing ulcerations and a future amputation.Persons with diabetes are at a higher risk for develop-ing lower extremity complications. A thorough footexamination will assist in identifying those patientswho are at risk. Once an individual is classifiedas high risk, a visual foot inspection should beperformed at every visit and referral to a foot carespecialist for further assessment is recommended.

D6.2 The role of peripheral neuropathy

Loss of protective sensation or peripheral neuropathyplaces the patient at a higher risk for developing footrelated complications. Foot deformities may be theresult of motor neuropathy. Therefore, recognition ofstructural deformities such as hammer toes andbunions, or altered biomechanics such as callus for-mation due to prominent bony deformity, as well aslimited joint mobility identify the patient as highrisk. Footwear should be inspected to determine if itprovides adequate support and protection for thefoot. Properly fitting shoes must accommodate anyfoot deformities. Improper or poorly fitting shoes area major contributor to foot ulcerations, especially forpeople with diabetes.

Preventive foot care strategies for patients at riskof developing foot complications is essential for

Recommendation 20. Indications for evaluationfor critical limb ischemia

� All patients with ischemic rest pain symptomsor pedal ulcers should be evaluated for CLI [B].

limb preservation. These strategies include patienteducation and appropriate management of high-riskpatients. Patients should be educated on the impor-tance of self-care of the feet, including proper footcare and footwear assessment. Early detection of footproblems and early intervention may decrease the fre-quency and severity of lower extremity complications.Soft, conforming rather than correctional orthotics arevaluable. Therefore, patients (or their family if theirvision is impaired) should be performing daily footinspections at home.

D7 Treatment of Critical Limb Ischemia

D7.1 Overall strategy (Fig. D4)

The primary goals of the treatment of CLI are to relieveischemic pain, heal (neuro)ischemic ulcers, preventlimb loss, improve patient function and quality oflife and prolong survival. A primary outcome wouldbe amputation-free survival. In order to achieve theseoutcomes, most patients will ultimately need a revas-cularization procedure requiring referral to a vascularspecialist. Other components of treatment of patientswith CLI are medical interventions to control painand infection in the ischemic leg, prevention ofprogression of the systemic atherosclerosis, andoptimization of cardiac and respiratory function. Forsome CLI patients with severe co-morbidities ora very limited chance of successful revascularization,a primary amputation may be the most appropriatetreatment. Cardiovascular risk factor control is man-datory in CLI patients as well as in all PAD patients(see section B).

D7.2 Basic treatment: pain control

Pain management is essential in improving functionand quality of life. The hallmark of CLI is ischemicrest pain and painful ulceration. Pain is usuallylocated to skin and possibly bone structures. Pain

Recommendation 21. Importance of early identi-fication of peripheral arterial disease (PAD)

� Early identification of patients with PAD at riskof developing foot problems is essential forlimb preservation [C]. This can be achievedby daily visual examination by the patient ortheir family and, at every visit, referral to thefoot specialist.



Fig. D4. Algorithm for treatment of the patient with critical limb ischemia. Contraindications are: patients not fit forrevascularization; revascularization not technically possible; benefit cannot be expected (i.e. widespread ulceration-gangrene e see also section D7.5). CLI e critical limb ischemia; MRA e magnetic resonance angiography; CTA e computedtomographic angiography.

control is a critical aspect of the management of thesepatients. Ideally, relief of pain is achieved by reperfu-sion of the extremity. However, while planning the re-vascularization, adequate pain control must be a goalof management in all patients. Furthermore, in pa-tients for whom revascularization is not an option,narcotic pain relief is commonly needed.

Physicians should assess pain severity and ade-quacy of pain relief in all patients at regular visits.Initial attempts at pain relief should include the useof acetaminophen/paracetamol or nonsteroidal anti-inflammatory medications, although the latter arerarely effective and narcotic medications are fre-quently required. Caution should be used in thelatter in patients with hypertension, or renal insuffi-ciency. Control of pain is usually more effective ifanalgesia is given regularly rather than on demand.Placing the affected limb in the dependent positionprovides partial relief of ischemic pain in somepatients. Therefore, tilting the bed downward maybe a helpful measure in addition to analgesia.Patients with CLI are often depressed and pain con-trol can be improved by use of antidepressantmedications.

Recommendation 22. Early referral in criticallimb ischemia (CLI)

� Patients with CLI should be referred to a vascu-lar specialist early in the course of their diseaseto plan for revascularization options [C].


D7.3 Revascularization

The natural history of CLI is such that intervention is in-dicated to salvage a useful and pain-free extremity. Thetreatment chosen depends upon the pre-morbidcondition of the patient and the extremity as well asestimating the risk of intervention based on co-morbidconditions and the expected patency and durabilityof the reconstruction. In CLI, multi-level disease isfrequently encountered. Adequate inflow must beestablished prior to improvement in the outflow.

After revascularization, ulcer healing may requireadjunctive treatments that may be best achieved incollaboration between the vascular specialist andspecialists in foot care.

(See also section F.)

D7.4 Management of ulcers

The management of the patient with CLI and footulcers illustrates the need for a multidisciplinaryapproach to the treatment of CLI patients. Thesepatients should be treated according to the follow-ing principles.

Recommendation 23. Multidisciplinary approachto treatment of critical limb ischemia

� A multidisciplinary approach is optimal to con-trol pain, cardiovascular risk factors and otherco-morbid disease [C].


Restoration of perfusionThe successful treatment of a foot ulcer rests with

the possibility of increasing the perfusion to the foot.The determination of whether or not a revasculariza-tion procedure is possible will set the tone for the en-suing treatment. A revascularization procedureshould be considered if clear signs of CLI are presentor if healing does not occur in a neuro-ischemic ulcerdespite optimal off-loading, treatment of infection, ifpresent, and intensive wound care. After revasculari-zation, local wound care and possibly foot salvageprocedures must be considered.

Local ulcer care and pressure reliefPrior to a revascularization procedure the ulcer can

be treated with a non-adherent gauze and should beoff-loaded if there is an increase in pressure or shearstress. Off-loading can be achieved by several methodsincluding shoe modifications, orthotics and castingtechniques,16,131,132 depending on the localization ofthe ulcer and the severity of the ischemia. Once perfu-sion is improved, adequate off-loading becomes moreimportant as the increase in blood flow may not com-pensate for the repetitive tissue trauma due to poorlyfitted shoes. The local treatment of a revascularizedfoot ulcer can be carried out in many fashions anda multitude of products exist. An in-depth discussionof each ulcer care product is beyond the scope of thiswork but the basic principles of wound care shouldbe adhered to. These principles include: removingnecrotic/fibrotic tissue from the ulcer, keeping a moistwound environment and eliminating infection, asdiscussed below.

Treatment of infectionLocal infection is a severe complication of a neuro-

ischemic ulcer, as it tends to run a more severe courseand should be treated urgently. Signs of systemic tox-icity, such as fever or elevated C-reactive protein, areuncommon. The infection should be identified asearly as possible and its level of involvement assessedand aggressively treated. Severe foot infections in di-abetic patients are usually polymicrobial with grampositive cocci, gram negative rods and anaerobic or-ganisms.133 Once the clinical diagnosis of an infectionis made and cultures of the wound obtained, empiricantibiotic treatment should be initiated immediately.Broad spectrum antibiotic therapy can be adjustedonce the causative micro-organisms are determinedand results of the culture sensitivity have beenobtained. A growing concern is the rise in the inci-dence of multidrug-resistant Staphylococcus aureus,which is up to 30% in some studies.134 Managementof a deep infection usually also includes drainageand debridement of necrotic tissue. Antibiotic therapyis believed to be important in the prevention of

further spreading of infection in patients with CLI.Once the acute infection is under control, a revascular-ization procedure can be performed in a second stage.

Salvage proceduresLimb salvage after revascularization is defined as

preservation of some or all of the foot. An attempt ata foot salvage procedure should take place after arevascularization procedure has been performed ifpossible. A waiting period of at least 3 days has beensuggested, this allows for sufficient time for the resto-ration of perfusion and for demarcation to occur.

The level of adequate circulation, extent of infec-tion, if any and remaining function of the foot are fac-tors considered when choosing the level of a footsalvage procedure. Foot salvage procedures can be di-vided into two categories. The first category involvesamputation of some part of the foot. Table D4 showsthe different levels of local foot amputations.

The natural history of a minor foot amputationshould be considered when choosing the appropriatelevel of amputation in order to account for the sub-sequent changes in mechanical force and pressureon the foot. For example, a hallux or partial firstray amputation increases the resultant vector offorce on the second ray (through metatarsal shaft).This increase in force traversing through the secondray can cause a contracture of the second toe, lead-ing to an increased pressure at both the sub

Table D4. Different levels of local foot amputations

Digit (partial or total)Ray (digit and metatarsal)Midfoot (transmetatarsal; tarso-metatarsal; transverse tarsal)Symes (ankle)

Recommendation 24. Optimal treatment forpatients with critical limb ischemia (CLI)

� Revascularization is the optimal treatment forpatients with CLI [B].

Recommendation 25. Treatment for infections incritical limb ischemia (CLI)

� Systemic antibiotic therapy is required in CLIpatients who develop cellulitis or spreadinginfection [B].



metatarsal head area and the distal pulp of the toe.These changes in pressure require appropriate shoeand insole modifications to avoid foot complications.A high percentage of patients with a great toeand/or first ray amputation go on to have a secondamputation either on the same foot or the contra-lateral foot.

Amputation of the lateral toes and rays (fourth andfifth digits) does not cause the same increase in me-chanical force and pressure on the adjacent digits asdescribed above. Hence, the considerations of shoewear and inner sole modifications are different withthis scenario.

When multiple medial rays are involved or the is-chemia is proximal to the metatarsal heads, but distalto the tarso-metatarsal joint, a mid foot amputationshould be considered. A transmetatarsal amputationprovides a stump adequate for walking with minimalshoe and innersole modifications.

The second category of foot salvage involves thedebridement of the wounds, including excision ofbone. These procedures permit the foot to keep itsgeneral outward appearance intact, while disturbingthe internal architecture that is causing the increasedpressure. Foot salvage procedures, short of amputa-tion, that can be used in the revascularized footinclude exostectomy, arthroplasty, metatarsal headexcision and calcanectomy.

Diabetes control and treatment of co-morbidityAs in all patients with diabetes, those with concom-

itant CLI should have optimization of glycemic con-trol. Diabetic patients with a neuro-ischemic footulcer frequently have a poor health status. Factorsthat can negatively affect wound healing such ascardiac failure or poor nutritional status should beevaluated and treated appropriately.

D7.5 Amputation

Major amputation (above the ankle) in CLI is neces-sary and indicated when there is overwhelming infec-tion that threatens the patient’s life, when rest paincannot be controlled, or when extensive necrosis hasdestroyed the foot. Using these criteria, the numberof major limb amputations should be limited.

Recommendation 26. Multidisciplinary care incritical limb ischemia (CLI)

� Patients with CLI who develop foot ulcerationrequire multidisciplinary care to avoid limbloss [C].


Primary amputation is defined as amputation ofthe ischemic lower extremity without an antecedentattempt at revascularization. Amputation is consid-ered as primary therapy for lower limb ischemiaonly in selected cases. Unreconstructable arterial dis-ease is generally due to the progressive nature of theunderlying atherosclerotic occlusive disease.

Revascularization of the lower extremity remains thetreatment of choice for most patients with significantarterial occlusive disease.

Unreconstructable vascular disease has become themost common indication for secondary amputation,accounting for nearly 60% of patients. Secondary am-putation is indicated when vascular intervention is nolonger possible or when the limb continues to deteri-orate despite the presence of a patent reconstruction.Persistent infection despite aggressive vascularreconstruction is the second most common diagnosis.

Many amputations can be prevented and limbs pre-served through a multi-armed, limb-salvage treatmentof ischemic necrosis with antibiotics, revascularizationand staged wound closure that may necessitate the useof microvascular muscle flaps to cover major tissuedefects. On the other hand, and very importantly,amputation may offer an expedient return to a usefulquality of life, especially if a prolonged course of treat-ment is anticipated with little likelihood of healing.Non-ambulatory elderly patients with CLI representa particularly challenging group. These patients fre-quently have flexion contractures that form from theprolonged withdrawal response to the pain. Aggres-sive vascular reconstruction does not provide thesepatients with a stable and useful limb, and primaryamputation is a reasonable option.135 Therefore, theimportant issue is to identify a subgroup of CLI patientsbetter served by an amputation than attempts ofrevascularization. Technical aspects, foot woundhealing issues and co-morbidities of the patientsshould be considered.

It is the implicit goal of amputation to obtain pri-mary healing of the lower extremity at the mostdistal level possible. The energy expenditure of am-bulation increases as the level of amputation risesfrom calf to thigh. Preservation of the knee jointand a significant length of the tibia permits the useof lightweight prostheses, minimizes the energy ofambulation, and enables older or more frail patientsto walk independently.136 Therefore, the lowestlevel of amputation that will heal is the ideal sitefor limb transection.

Clinical determination of the amputation levelresults in uninterrupted primary healing of thebelow-knee stump in around 80% and the above-kneestump in around 90% of cases.137 Measurement of tcPO2


combined with clinical determination may be of valueto predict healing at various levels of amputation.138

Figures from specialized centers are better than theglobal figures shown in Fig. A6. Amputations have var-iable outcome and more risk with higher proximal am-putations. Ambulatory status of patients afteramputation is shown in Table D5.

A major amputation that is above the foot will re-quire a prosthesis. Meticulous technique is essentialto ensure a well-formed and well-perfused stumpwith soft tissue covering the transected end of thebone. Major amputations are usually performed atthe below-knee (preferred) or above-knee level de-pending on the level of arterial occlusion and tissueischemia. A return to independent ambulation is theultimate challenge for patients undergoing majoramputation of the lower extremity. Patients witha well-healed below-knee amputation stumphave a greater likelihood of independent ambulationwith a prosthesis than those with an above-kneeamputation, who have a less than 50% chance ofindependent ambulation.

D7.6 Pharmacotherapy for critical limb ischemia

When open or endovascular intervention is not tech-nically possible or has failed, the question arises asto whether pharmacological treatment is an option.The consequences of the severely reduced perfusionpressure on the distal microcirculation have to beovercome. Pharmacotherapy, or any other treatment

Recommendation 27. Amputation decisions incritical limb ischemia (CLI)

� The decision to amputate and the choice of thelevel should take into consideration the poten-tial for healing, rehabilitation and return ofquality of life [C].

that produces modest improvements in circulation,is more likely to be successful in patients who wereasymptomatic before developing their foot lesionand in those with shallow foot lesions where the levelof ischemia is close to the margin (i.e. those withborderline perfusion pressures).

D7.6.1 ProstanoidsProstanoids prevent platelet and leukocyte activationand protect the vascular endothelium, which couldplay a role in the management of CLI. These drugsare administered parenterally over several weeks.Side effects include flushing, headache, and hypoten-sion of a transient nature. Nine double-blind random-ized trials on prostanoid treatment have beenpublished.146e154 Three PGE1 studies showed a benefiton reducing ulcer size, but these studies did not showfavorable outcomes on other critical clinical end-points. Six studies of the stable PGI2 analog, iloprost,were performed, not all of which were positive. Ameta-analysis of the data demonstrated that patientson active treatment had a greater chance (55% vs.35%) to survive and keep both legs during thefollow-up period. In clinical practice, iloprost seemsto be of benefit to about 40% of patients in whomrevascularization is not possible. In a recent trial oflipo-ecraprost versus placebo, this prostanoid failedto reduce death and amputation during 6 months fol-low-up.155 Prediction of response is, however, difficultand prostanoids are rarely used due to these facts.

D7.6.2 VasodilatorsDirect-acting vasodilators are of no value, as they willprimarily increase blood flow to non-ischemic areas.

D7.6.3 Antiplatelet drugsAlthough long-term treatment with aspirin/ASA andticlopidine may reduce progression of femoral athero-sclerosis and exert a beneficial effect on the patency of-peripheral by-passes (Cochrane review156) there is noevidence that these drugs would improve outcomes

Table D5. Ambulatory status 6e12 months following amputation

Author (year) N Percentage fittedwith a prosthesis

Percentage*

AmbulatoryComments

Ruckley (1991)139 191 80% 74% Randomized trialSiriwardena (1991)140 267 e 63% US VAMC DataHagberg (1992)141 24 100% 96%Houghton (1992)142 193 e 16% 20% LFUStirnemann (1992)143 126 70% 70% Primary versus Failed bypassMcWhinnie (1994)144 61 66% 52%Nehler (2003)145 94 e 39% 11% LFU

*Time intervals are 6e12 months postoperatively from below-knee amputation (BKA). Modest ambulatory results are due to 1) mortalityprior to rehabilitation; 2) failure to heal BKA; 3) failure to complete rehabilitation program.LFU e lost to follow up; VAMC e Veterans Affairs Medical Center.



in CLI. However, as in all patients with PAD, antiplate-let drugs do reduce the risk of systemic vascular events.

D7.6.4 AnticoagulantsUnfractionated heparin is frequently used as prophy-laxis and as adjuvant treatment to vascular surgicalprocedures, but has not been tried for symptoms ofCLI. Two studies have looked at low molecular weightheparin (LMWH) in CLI patients with ulcers. Thesewere negative trials. Vitamin K antagonists have notbeen tried for the treatment of symptoms of CLI.

Defibrinating agents have not been shown to im-prove healing of ischemic ulcers or to reduce the numberof amputations.

D7.6.5 Vasoactive drugsA Cochrane review157 evaluated eight trials on intra-venous naftidrofuryl for CLI. The drug was not effec-tive in reducing the symptoms of CLI. Pentoxifyllinewas evaluated in two placebo controlled studies inpatients with CLI, with inconclusive results.158,159

D7.7 Other treatments

D7.7.1 Hyperbaric oxygenA Cochrane review160 concluded that hyperbaric ther-apy significantly reduced the risk of major amputationin patients with diabetic ulcers. However, the resultsshould be interpreted with caution because of method-ological shortcomings. Other pathologies related toPAD and diabetes were not evaluated using this kindof treatment. Therefore, given the absence of provenbenefit and high cost, this therapy is not generally rec-ommended. Nonetheless, hyperbaric oxygen may beconsidered in selected patients with ischemic ulcerswho have not responded to, or are not candidatesfor, revascularization.

D7.7.2 Spinal cord stimulationA Cochrane review161 of six studies including patientswith CLI concluded that spinal cord stimulation was

Recommendation 28. Use of prostanoids in criti-cal limb ischemia (CLI)

� Previous studies with prostanoids in CLI sug-gested improved healing of ischemic ulcersand reduction in amputations [A].

� However, recent trials do not support the ben-efit of prostanoids in promoting amputation-free survival [A].

� There are no other pharmacotherapies that canbe recommended for the treatment of CLI [B].


significantly better than conservative treatment in im-proving limb salvage in patients without any optionto vascular reconstruction.

D8 Health Economics

Studies published on the cost of treating CLI presentdata on surgical revascularization, percutaneoustransluminal angioplasty and stenting and primaryamputation.162e166

Whatever the treatment considered, the costs aremultiplied by a factor 2 to 4 when the procedure ini-tially planned has failed, for example angioplastyrequiring immediate or delayed crossover grafting,bypass requiring revision after thrombosis or second-ary amputation, and when renal and pulmonary co-morbidities or complications are present. Results areconsistent across countries, although individual costsof procedures vary. The order of magnitude for thecost of PTA is $10,000 ($20,000 if the procedure failsinitially or later), the cost for bypass grafting is$20,000 ($40,000 if revision is required), the cost foramputation is $40,000. Adding rehabilitation willusually double the costs.

D9 Future Aspects of Treatment of CriticalLimb Ischemia

The most striking feature of CLI is the dismal progno-sis for both life and limb outcomes no matter whattreatment is employed. This is because most patientshave generalized atherosclerosis. One may, therefore,consider what magnitude of treatment options is real-istic for the single patient. A successful revasculariza-tion may reduce pain and improve quality of life fora limited period of time, but frequently this goal isnot achieved. Amputation may be a good alternativeto reduce pain, though amputees may have an evenmore reduced life expectancy. Medical treatmentthat favorably modifies cardiovascular risk is recom-mended for all patients, while symptomatic treatmentof the limb has to be individualized.

Preliminary trials of intramuscular gene transferutilizing naked plasmid DNA encoding phVEGF165have given promising results on symptoms of CLI167

while others have been negative. Several trials are us-ing viral vectors to increase gene transfer efficiency.Besides vascular endothelial growth factor (VEGF),fibroblast growth factor, angiopoietin and other growthfactors are under investigation.168 Preliminary trials ofintramuscular injection of autologous bone-marrowmononuclear cells to stimulate vascular growth169

have been promising. Most trials are in Phase I or II


and the appropriate use of gene therapy in vascularpractice remains to be proven.

In conclusion, there is low-level evidence for spinalcord stimulation to improve outcome of patients withCLI, should revascularization not be possible. Prosta-noid treatment may also be of value; however, onlya limited proportion of patients will respond to thistreatment, as mentioned. Results of other pharmaco-therapies are far from good.170,171 Gene therapy hasshown promising early efficacy but further trialsare warranted.

SECTION E e ACUTE LIMB ISCHEMIA

E1 Definition and Nomenclature forAcute Limb Ischemia

E1.1 Definition/etiology of acute limb ischemia

Acute limb ischemia (ALI) is any sudden decrease inlimb perfusion causing a potential threat to limb via-bility. Presentation is normally up to 2 weeks follow-ing the acute event. Fig. E1 shows the frequency ofdifferent etiologies for ALI.

Timing of presentation is related to severity ofischemia and access to healthcare. Patients with em-bolism, trauma, peripheral aneurysms with emboliand reconstruction occlusions tend to present early(hours) due to lack of collaterals, extension of throm-bus to arterial outflow, or a combination of both. Onthe other hand, later presentations e within days etend to be restricted to those with a native thrombosisor reconstruction occlusions (Fig. E2).

E2 Evaluation

E2.1 Clinical evaluation of acute limb ischemia

E2.1.1 HistoryThe history should have two primary aims: queryingleg symptoms relative to the presence and severity oflimb ischemia (present illness) and obtaining back-ground information (e.g. history of claudication, recent

intervention on the proximal arteries or diagnosticcardiac catheterization), pertaining to etiology, differ-ential diagnosis and the presence of significant con-current disease.

Present illnessLeg symptoms in ALI relate primarily to pain or

function. The abruptness and time of onset of thepain, its location and intensity, as well as change inseverity over time, should all be explored. Theduration and intensity of the pain and presence ofmotor or sensory changes are very important in clini-cal decision-making and urgency of revascularization.For example, thrombolysis may be less effective forthrombosis of >2 weeks duration compared withmore acute thrombosis (post hoc analysis of theSTILE data174).

Past historyIt is important to ask whether the patient has had

leg pain before (e.g. a history of claudication),whether there have been interventions for ‘poor circu-lation’ in the past, and whether the patient has beendiagnosed as having heart disease (e.g. atrial fibrilla-tion) or aneurysms (i.e. possible embolic sources). Thepatient should also be asked about serious concurrentdisease or atherosclerotic risk factors (hypertension,diabetes, tobacco abuse, hyperlipidemia, familyhistory of cardiovascular disease, strokes, blood clotsor amputations). A more complete discussion of riskfactors can be found in section A.

E2.1.2 Physical examinationThe findings of ALI may include ‘‘5 P’s’’:

� Pain: time of onset, location and intensity, changeover time

� Pulselessness: the accuracy of pedal pulse palpationis highly variable and, therefore, absent pulse find-ings are suggestive but not diagnostic of ALI andpalpable pulses alone do not rule it out. Bedsidemeasurement of ankle blood pressure should beperformed immediately (technique see section C).Usually, very low pressure is obtained or the Dopplersignal may be absent. If performed correctly, the

Fig. E1. Etiology of acute limb ischemia. (Summarizes Berridge et al. 2002 and Campbell et al. 1998172,173).



Fig. E2. Time to presentation in relation to etiology.

finding of absent flow signals in the foot arteries ishighly consistent with a diagnosis of ALI

� Pallor: change in color and temperature is a com-mon finding in ALI (although temperature may besubject to environmental conditions); the finding ismost important when different from the contralat-eral limb. Venous filling may be slow or absent

� Paresthesia: numbness occurs in more than half ofpatients

� Paralysis: is a poor prognostic sign.

Recommendation 29. Assessment of acute limbischemia (ALI)

� Due to inaccuracy of pulse palpation and thephysical examination, all patients with sus-pected ALI should have Doppler assessmentof peripheral pulses immediately at presenta-tion to determine if a flow signal is present [C].


E2.1.3 Clinical classification of acute limb ischemiaThe main question to be answered by the history andphysical examination is the severity of the ALI, whichis the major consideration in early management deci-sions. Is the limb viable (if there is no further progres-sion in the severity of ischemia), is its viabilityimmediately threatened (if perfusion is not restoredquickly), or are there already irreversible changesthat preclude foot salvage?

The three findings that help separate ‘threatened’from ‘viable’ extremities (Table E1) are:

� Presence of rest pain,� Sensory loss, or� Muscle weakness

Muscle rigor, tenderness, or findings of pain withpassive movement are late signs of advanced ischemiaand probable tissue loss.

Table E1. Separation of threatened from viable extremities175

Category Description/prognosis Findings Doppler signalsy

Sensory loss Muscle weakness Arterial Venous

I. Viable Not immediately threatened None None Audible Audible

II. Threateneda. Marginal Salvageable if promptly

treatedMinimal (toes) or none None (Often) inaudible Audible

b. Immediate Salvageable with immediaterevascularization

More than toes, associatedwith rest pain

Mild, moderate (Usually) inaudible Audible

III. Irreversible Major tissue loss orpermanent nerve damageinevitable

Profound, anesthetic Profound,paralysis (rigor)

Inaudible Inaudible

yObtaining an ankle pressure is very important. However, in severe ALI, blood flow velocity in the affected arteries may be so low thatDoppler signals are absent (see section C for technical description of method). Differentiating between arterial and venous flow signalsis vital: arterial flow signals will have a rhythmic sound (synchronous with cardiac rhythm) whereas venous signals are more constantand may be affected by respiratory movements or be augmented by distal compression (caution needs to be taken not to compress the ves-sels with the transducer). Reproduced with permission from Rutherford RB et al. J Vasc Surg 1997;26(3):517e538.


Data presented summarize both registry and clini-cal trial data and show the frequency of different cat-egories of acute limb ischemia on presentation(Fig. E3).

� Category III: all patients from registries who un-dergo primary amputation

� Category II: all patients from randomized trials whopresent with sensory loss

� Category I: all patients from randomized trials whopresent without sensory loss

E2.1.4 Differential diagnosis of acute limb ischemiaThere are three levels of differential diagnosis in ALI:

1. Is there a condition mimicking arterial occlusion?2. Are there other non-atherosclerotic causes of arte-

rial occlusion present and, if not,3. Is the ischemia caused by an arterial thrombosis or

embolus?

The conditions that can cause or mimic acutearterial occlusion are listed in Table E2.

Arterial trauma or dissectionOvert arterial trauma is not difficult to diagnose,

but iatrogenic trauma, especially as a result of recentarterial catheterization, is often overlooked. It shouldbe considered in all hospitalized patients undergoinginvasive diagnosis and treatment who present withfemoral artery occlusion.

Recommendation 30. Cases of suspected acutelimb ischemia (ALI)

� All patients with suspected ALI should be eval-uated immediately by a vascular specialist whoshould direct immediate decision making andperform revascularization because irreversiblenerve and muscle damage may occur withinhours [C].

Thoracic aortic dissections may progress distally toinvolve the abdominal aorta and also an iliac artery.Tearing interscapular or back pain associated with hy-pertension would obviously point to such a thoracicaortic dissection, but these may be obscured by otherevents and the patient’s inability to give a good his-tory. It should be considered when faced with acuteunilateral or bilateral iliac occlusion.

ErgotismErgotism is rare. It may affect almost any artery

and may progress to thrombosis but rarely presentsas an immediately threatened limb.

HIV arteriopathyHIV patients with severe immune compromise and

CD4 counts less than 250/cm3 can develop acuteischemia of upper or lower extremities. This entityinvolves the distal arteries with an acute and chroniccellular infiltrate in the vasa vasorum and viral proteinin the lymphocytes. Occasionally, a hypercoaguablefocus is found, but primarily the occlusion appearsdue to the underlying vasculopathy. Standard therapiesincluding thrombectomy, bypass and thrombolysishave been used, with relatively high reocclusion andamputation rates.

Popliteal adventitial cysts and popliteal entrapmentPopliteal adventitial cysts and popliteal entrap-

ment may be discovered before they induce throm-bosis if they cause claudication, but they sometimesfirst present with thrombosis. Like a thrombosedpopliteal aneurysm, the degree of ischemia is oftensevere. Popliteal entrapment affects younger pa-tients, but popliteal adventitial cysts can present atan older age and may be indistinguishable fromperipheral arterial disease (PAD). The absence of ath-erosclerotic risk factors and the location of theobstruction, best ascertained by duplex scan, shouldsuggest the etiology.

Thrombosed popliteal artery aneurysmThrombosed popliteal artery aneurysms are com-

monly mistaken for acute arterial embolism. The popli-teal artery is the sole axial artery traversing the knee.Severe ischemia results either because thrombosis

Fig. E3. Categories of acute limb ischemia on presentation. *Some of these patients are moribund. In some series this groupis up to 15%.



occurs in the absence of previous arterial narrowingand the lack of collateral vessels or because priorasymptomatic or symptomatic embolization has oc-cluded the majority of the tibial outflow. As poplitealaneurysms are bilateral in approximately 50% of cases,detecting a prominent popliteal pulse in the oppositeleg may help to identify the cause. These patients alsotend to have dilated femoral arteries and may haveabdominal aortic aneurysms. Once suspected, duplexultrasound is the quickest way to confirm the diagnosis.

ThromboembolismArterial embolism is suspected in patients with

atrial arrhythmia (flutter/fibrillation), congestive heartfailure, or valvular heart disease. A rare cause canbe paradoxical embolization in a patient with venousthromboembolism and a cardiac septal defect. Thecontralateral limb is often normal. Patients usually donot have any antecedent claudication symptoms.Arteriographic findings include multiple areas witharterial filling defects (particularly at bifurcations),morphology (meniscus sign) consistent with embolus,lack of collaterals and absence of atheroscleroticdisease in unaffected segments. Echocardiography(often transesophageal) is useful to locate the sourceof thromboemboli.

Table E2. Differential diagnosis of acute limb ischemia

* Conditions mimicking acute limb ischemia- Systemic shock (especially if associated with chronic

occlusive disease)- Phlegmasia cerulea dolens- Acute compressive neuropathy

Differential diagnosis for acute limb ischemia (other thanacute PAD)

- Arterial trauma- Aortic/arterial dissection- Arteritis with thrombosis (e.g. giant cell arteritis,

thromboangiitis obliterans)- HIV arteriopathy- Spontaneous thrombosis associated with a hypercoagulable

state- Popliteal adventitial cyst with thrombosis- Popliteal entrapment with thrombosis- Vasospasm with thrombosis (e.g. ergotism)- Compartment syndrome

Acute PAD- Thrombosis of an atherosclerotic stenosed artery- Thrombosis of an arterial bypass graft- Embolism from heart, aneurysm, plaque or critical stenosis

upstream (including cholesterol or atherothrombotic embolisecondary to endovascular procedures)

- Thrombosed aneurysm with or without embolization

*Two of the three conditions (deep vein thrombosis, neuropathy)that may mimic arterial occlusion should be expected to have arte-rial pulses, except if occult chronic peripheral arterial diseaseexisted prior to the acute event. Low cardiac output makes thechronic arterial ischemia more manifest in terms of symptomsand physical findings.


AtheroembolismEmbolism of cholesterol crystals and other debris

from friable atherosclerotic plaques in proximal ar-teries may lodge in the distal circulation and infarcttissue. Although also called ‘‘blue toe syndrome’’ forthe appearance of painful cyanotic lesions on thetoes of affected patients, more proximal organs suchas the kidneys, bowel and pancreas may also beaffected by atheroemboli.

Thrombosed arterial segmentPatients with thrombosed arterial segments often

have atherosclerotic disease at the site of thrombosis.They may have an antecedent history of claudicationand the contralateral limb often has abnormal circula-tion. Some hypercoagulable states, such as antiphos-pholipid antibody syndrome or heparin-inducedthrombocytopenia can also cause thrombosis in situ,and these should be considered in patients withoutother overt risk factors for arterial disease.

Thrombosed arterial bypass graftPatients with thrombosed arterial bypass grafts

have a prior history of vascular disease, limb incisionsfrom previous surgery and a thrombosed graft thatcan be visualized on duplex imaging.

Compartment syndromeSee section E3.7.1.

E2.2 Investigations for acute limb ischemia

Patients with ALI should be evaluated in the samefashion as those with chronic symptoms (see sectionG) but the severity and duration of ischemia at thetime of presentation rarely allow this to be done atthe outset. Ideally, all patients with acute ischemiashould be investigated with imaging, however, theclinical condition and access to appropriate medicalresources may preclude such investigations.

E2.2.1 Other routine laboratory studiesThe following laboratory studies should be obtainedin patients with ALI: electrocardiogram, standardchemistry, complete blood count, prothrombin time,partial thromboplastin time and creatinine phosphoki-nase level. Patients with a suspected hypercoagulablestate will need additional studies seeking anticardioli-pin antibodies, elevated homocysteine concentrationand antibody to platelet factor IV.

E2.2.2 Imaging e arteriographyArteriography is of major value in localizing an ob-struction and visualizing the distal arterial tree. Italso assists in distinguishing patients who will


benefit more from percutaneous treatment than fromembolectomy or open revascularization procedures.

In limb-threatening ischemia, an important consider-ation is whether the delay in performing formal angio-graphy in an angiographic suite can be tolerated.Angiography makes the most sense when catheter-basedtreatment is an option.

E2.2.3 Other imaging techniquesComputed tomographic angiography/Magnetic

resonance angiographyComputed tomographic angiography (CTA) and

magnetic resonance (MR) angiography may also beused in the setting of ALI to diagnose and delineatethe extent of disease. MR imaging of the vasculaturecan be cumbersome and time-consuming which maydelay treatment. The advantages of CTA include itsspeed, convenience and ability for cross-sectional im-aging of the vessel. The main disadvantage of CTA isits dependence on iodinated contrast media. Inpatients with ALI who may also require catheter angi-ography and intervention, this added load of contrastmight increase the risk of renal injury to the patient.

Recommendation 31. Anticoagulant therapy inacute limb ischemia (ALI)

� Immediate parenteral anticoagulant therapy isindicated in all patients with ALI. In patientsexpected to undergo imminent imaging/therapy on arrival, heparin should be given [C].

E3 Treatment of Acute Limb Ischemia

The initial goal of treatment for ALI is to prevent throm-bus propagation and worsening ischemia. Therefore,immediate anticoagulation with heparin is indicated.The standard therapy (except in cases of heparin anti-bodies) is unfractionated heparin intravenously(Fig. E4). Based on the results of randomized trials,172

there is no clear superiority for thrombolysis versussurgery on 30 day limb salvage or mortality. Access toeach is a major issue, as time is often critical. Nationalregistry data from Europe176 and the United States177

indicate that surgery is used three- to five-fold morefrequently than thrombolysis.

E3.1 Endovascular procedures for acute limb ischemia

E3.1.1 Pharmacologic thrombolysisThree randomized studies have confirmed the impor-tant role of catheter-directed thrombolytic therapyin the treatment of ALI.174,178,179 The less invasivenature of a catheter-based approach to this patientpopulation can result in reduced mortality and mor-bidity compared with open surgery. Thrombolytictherapy is, therefore, the initial treatment of choicein patients in whom the degree of severity allowstime (i.e. severity levels I and IIa). More recent ad-vances in endovascular devices and techniques, how-ever, allow for more rapid clot removal and maypermit treatment of patients with more advanceddegree of ischemia. Advantages of thrombolytic ther-apy over balloon embolectomy include the reducedrisk of endothelial trauma and clot lysis in branchvessels too small for embolectomy balloons. Gradual

Fig. E4. Algorithm for management of acute limb ischemia. Category I e Viable Category IIA e Marginally ThreatenedCategory IIB e Immediately Threatened; a Confirming either absent or severely diminished ankle pressure/signals;*In some centers imaging would be performed.



low-pressure reperfusion, may be advantageous tothe sudden, high-pressure reperfusion associatedwith balloon embolectomy. Systemic thrombolysishas no role in the treatment of patients with ALI.

The choice of lytic therapy depends on many factorssuch as location and anatomy of lesions, duration ofthe occlusion, patient risk factors (co-morbidities)and risks of procedure. Because emboli newly arrivedin the leg may have previously resided for some timeat their site of origin, these ‘old’ emboli may be moreresistant to pharmacological thrombolysis than ‘re-cent’ in-situ thrombus. Contraindications to pharma-cologic thrombolysis must be taken into consideration.

E3.1.2 Contraindications to thrombolysisSee Table E3

E3.1.3 Other endovascular techniquesWhen thrombolysis reveals underlying localizedarterial disease, catheter-based revascularization be-comes an attractive option. Stenoses and occlusionsare rarely the sole cause of ALI or even severe chronicsymptoms but these commonly lead to superimposedthrombosis and, therefore, should be treated to avoidrecurrent thrombosis.

Percutaneous aspiration thrombectomy (PAT) andpercutaneous mechanical thrombectomy (PMT) pro-vide alternative non-surgical modalities for the treat-ment of ALI without the use of pharmacologicthrombolytic agents. Combination of these techniques

Table E3. Contraindications to thrombolysis

Absolute contraindications1. Established cerebrovascular event (excluding TIA within previous2 months)2. Active bleeding diathesis3. Recent gastrointestinal bleeding (within previous 10 days)4. Neurosurgery (intracranial, spinal) within previous 3 months5. Intracranial trauma within previous 3 months

Relative contraindications1. Cardiopulmonary resuscitation within previous 10 days2. Major nonvascular surgery or trauma within previous 10 days3. Uncontrolled hypertension (systolic >180 mmHg or diastolic>110 mmHg)4. Puncture of noncompressible vessel5. Intracranial tumor6. Recent eye surgery

Minor contraindications1. Hepatic failure, particularly those with coagulopathy2. Bacterial endocarditis3. Pregnancy4. Active diabetic proliferative retinopathy

These contraindications were established for systemic thrombolysis.The markedly improved safety profile of regional thrombolysis iswell recognized, and the risk benefit of regional thrombolysis invarious above conditions is highly dependent on individual physi-cian practice/experience. The only contraindication in the TOPAStrial was pregnancy.


with pharmacologic thrombolysis may substantiallyspeed up clot lysis, which is important in more ad-vanced ALI where time to revascularization is critical.In practice, the combination is almost always used.

Percutaneous aspiration thrombectomy (PAT)PAT is a technique that uses thin-wall, large-lumen

catheters and suction with a 50-mL syringe to removeembolus or thrombus from native arteries, bypassgrafts and run-off vessels. It has been used togetherwith fibrinolysis to reduce time and dose of thefibrinolytic agent or as a stand-alone procedure.

Percutaneous mechanical thrombectomy (PMT)Most PMT devices operate on the basis of hydro-

dynamic recirculation. According to this concept, dis-solution of the thrombus occurs within an area ofcontinuous mixing referred to as the ‘‘hydrodynamicvortex.’’ This selectively traps, dissolves, and evacu-ates the thrombus. Non-recirculation devices, whichfunction primarily by direct mechanical thrombusfragmentation, have been used less frequently for pe-ripheral arterial disease because of the higher risk ofperipheral embolization and higher potential for vas-cular injury. The efficiency of PMT depends mainly onthe age of the thrombus; fresh thrombus respondsbetter than older organized clot. Small clinical serieshave demonstrated short-term (30 day) limb salvageof 80%e90%.

E3.2 Surgery

E3.2.1 IndicationsImmediate revascularization is indicated for the pro-foundly ischemic limb (class IIb) (Table E1). It mayalso be considered in those with profound sensoryand motor deficits of very short duration, as revascu-larization completed within a few hours of onset ofsevere symptoms may produce remarkable recovery.Beyond this short window, major neuromusculardamage is inevitable. The method of revascularization(open surgical or endovascular) may differ dependingon anatomic location of occlusion, etiology ofALI, contraindications to open or endovascular treat-ment and local practice patterns. Previously, urgencyof treatment made surgery the treatment of choicein many cases. However, recent methodologicaladvances within endovascular management, and rec-ognition that improved circulation significantly pre-cedes patency with this approach, have made thetime factor less important if endovascular service isreadily available.

In considering operative versus percutaneous re-vascularization, it must be recognized that the timefrom the decision to operate until reperfusion may


be substantially longer than anticipated because offactors outside of the surgeons’ control (e.g. operatingtheater availability, anesthesia preparation, technicaldetails of the operation).

Anatomic location of the acute occlusionIn cases of suprainguinal occlusion (no femoral

pulse) open surgery may be the preferred choice oftreatment. For instance, a large embolus in the com-mon proximal iliac artery or distal aorta may mosteffectively be treated with catheter embolectomy.Also, suprainguinal graft occlusion may best betreated with surgery in most cases. Endovascularmanagement with femoral access of a proximal lesion(often involving thrombosis) may not be possible/appropriate or available (see below).

Infrainguinal causes of ALI, such as embolism orthrombosis, are often treated with endovascularmethods. Initial therapy with catheter-based thrombol-ysis should be considered in cases of acute thrombosisdue to vulnerable atherosclerotic lesions or late bypassgraft failures. In this manner, the underlying occlusivedisease is revealed and appropriate adjunctivemanagement may be chosen.

In cases of trauma, for many reasons, surgery willbe the treatment of choice in the majority of cases.Infrainguinal grafts often occlude due to obstructivelesions proximal to, within and distal to the graft,thus, simple thrombectomy will not solve the under-lying lesion. Catheter-based thrombolysis, on theother hand, will dissolve clot and identify theresponsible underlying lesion. Endovascular treatmentof these lesions may then be employed. If the lesion isdiscrete this may suffice, and even if the underlyingdisease is diffuse and extensive, it may serve as atemporizing measure, a bridge to a later bypass.

E3.2.2 Surgical techniqueEmboli are preferentially removed surgically if theyare lodged proximally in the limb or above the ingui-nal ligament. Surgery may also be considered if theinvolved limb has no underlying atherosclerosis.When no further clot can be retrieved, some form ofintraoperative assessment of the adequacy of clot re-moval is required. The most common of these is‘completion’ angiography; alternatively, ultrasound-based methods may be used.

Distal clot may be treated by intraoperative throm-bolysis with instillation of high doses of thrombolyticagents for a brief period followed by irrigation or addi-tional passages of the balloon catheter. Repeat angio-graphy followed by clinical and Doppler examinationof the patient should be performed on the operatingtable. However, as described in section E3.2.1,

catheter-directed thrombolysis may have advantagesif conditions allow its use.

In patients with arterial thrombosis, an underlyinglocal lesion and residual thrombus must be sought af-ter clot extraction. Often this may be suspected fromthe tactile sensations and need for deflation at pointsduring the withdrawal of the inflated balloon catheter.Here completion angiography will help decide be-tween proceeding with a bypass or PTA. Fortunately,arterial thrombosis superimposed on an already nar-rowed artery will ordinarily cause a less severe degreeof ischemia because of predeveloped collaterals. Un-der these circumstances, patients may not be operatedon initially but rather undergo catheter-directedlytic therapy.

In patients with suprainguinal occlusion extra-anatomic bypass surgery may be required.

E3.3 Results of surgical and endovascular proceduresfor acute limb ischemia

Catheter-directed thrombolysis (CDT) has becomea commonly employed technique in the treatment ofALI. Between 1994 and 1996, three large, prospective,randomized trials174,178,179 were reported that focusedon the comparison of CDT and surgical revasculariza-tion for treatment of ALI. Limb salvage and mortalityrates are recognized as the most important outcome,and the 1-year data are summarized in Table E4.172

Comparison of these studies is limited by certaindifferences in protocol and case mix (e.g. acute vs.subacute or chronic limb ischemia; thrombotic vs.embolic occlusion; native vs. bypass graft occlusion;proximal vs. distal occlusions). End points in eachof the studies also vary: the Rochester study used‘‘event free survival’’; the STILE trial used ‘‘compos-ite clinical outcome’’; and the TOPAS study used‘‘arterial recanalization and extent of lysis.’’ Onlythe Rochester trial showed any advantage for CDTby primary end points. However, the late end pointof limb salvage, required in these trials, may havefavored surgery, as CDT was naturally linked withendovascular treatment of the underlying lesions(the patient being in a radiology suite at the time).

Recommendation 32. Completion arteriography

� Unless there is good evidence that adequatecirculation has been restored, intraoperativeangiography should be performed to identifyany residual occlusion or critical arterial lesionsrequiring further treatment [C].



Table E4. Comparison of catheter-directed thrombolysis and surgical revascularization in treatment of limb ischemia

Results at Catheter-Directed Thrombolysis (CDT) Surgical Revascularization

Patients Limb salvage Mortality Patients Limb salvage Mortality

Rochester178 12 months 57 82% 16% 57 82% 42%STILE174 6 months 246 88.2% 6.5% 141 89.4% 8.5%TOPAS179 12 months 144 82.7% 13.3% 54 81.1% 15.7%

Except for discrete lesions, PTA is not as durable asbypass, the inevitable result of being randomized tosurgery. Such linkage may be inevitable inrandomized trials, but in practice the underlying le-sion(s) should be treated by the method giving themost durable results.

The data from the randomized, prospective studiesin ALI, suggest that CDT may offer advantages whencompared with surgical revascularization. These ad-vantages include reduced mortality rates and a lesscomplex surgical procedure in exchange for a higherrate of failure to avoid persistent or recurrent ische-mia, major complications and ultimate risk of ampu-tation. In addition, it appears that reperfusion withCDT is achieved at a lower pressure and may reducethe risk of reperfusion injury compared to opensurgery. Thus, if the limb is not immediately or irrevers-ibly threatened, CDT offers a lower-risk opportunityfor arterial revascularization. Using this approach, theunderlying lesions can be further defined by angiogra-phy, and the appropriate percutaneous or surgicalrevascularization procedure can be performed. There-fore, it seems reasonable to recommend CDT as initialtherapy in these particular settings, to be potentiallyfollowed by surgical revascularization as needed.

E3.4 Management of graft thrombosis

In general, at least one attempt to salvage a graftshould be done, although individual considerationsmay apply. When treating late graft thrombosis, themain goals are to remove the clot and correct the un-derlying lesion that caused the thrombosis. Alterationin the inflow and outflow arteries is usually causedby the progression of atherosclerosis and should betreated with either PTA/stent or bypass grafting, asdetailed elsewhere. Lesions intrinsic to the graft aredependent on the type of conduit. Venous bypassgrafts may develop stenoses, typically at the site ofa valve. After thrombolysis and identification of thelesion, it may be treated with either PTA/stent orsurgical revision, the latter usually being favored forits superior long-term results. Prosthetic grafts de-velop intimal hyperplasia, typically at the distal


anastomosis. These rubbery lesions respond differ-ently to PTA than do the typical eccentric atheroscle-rotic plaque and do not yield as durable results.Many surgeons have suggested that treatment shouldbe exposure of the involved anastomosis, with graftthrombectomy and patch angioplasty of the narrowedgraft/artery anastomosis or replacement of the graft.However, in case of the latter, the expected patencyusing another type of graft should be considered (i.e.replacing a failing vein graft).

E3.5 Management of a thrombosed popliteal aneurysm

Patients with thrombosed popliteal artery aneurysmsinitially undergo arteriography. If a distal tibial targetis present, then they are treated as a critical limbischemia case with tibial bypass. If no tibial targetsare identified on arteriography, regional thrombolysisis the treatment of choice providing the limb is viable.Small series demonstrate successful identification oftibial targets in over 90% and successful surgicalrevascularization.

E3.6 Amputation

Amputation in ALI may be complicated by bleedingdue to an increased prevalence of concomitant antico-agulation. In addition, the site of amputation is moreoften proximal, as the calf muscle is usually compro-mised. The ratio of above-knee to below-knee ampu-tation is 4:1 compared to the usual 1:1 for criticallimb ischemia. The incidence of major amputation isup to 25%. When further evaluated, 10%e15% of pa-tients thought to be salvageable undergo therapyand ultimately require major amputation, and 10%of patients with ALI present unsalvageable.

E3.7 Immediate post-procedural issues

E3.7.1 Reperfusion injuryCompartment syndromeFasciotomy following successful revascularization

for ALI was required in 5.3% of cases in the UnitedStates from 1992e2000. Fasciotomy for presumably


more severe cases in tertiary referral hospitals is25%.177 With extremity reperfusion, there is increasedcapillary permeability, resulting in local edema andcompartment hypertension. This leads to regional ve-nule obstruction, nerve dysfunction and, eventually,capillary and arteriolar obstruction and muscle andnerve infarction. Clinical presentation includes painout of proportion to physical signs, paresthesia andedema. Compartment pressures can be measured,and pressures of �20 mmHg are a clear indicationfor fasciotomy. The anterior compartment is mostcommonly involved, but the deep posterior compart-ment (in which the tibial nerve is located) is the mostfunctionally devastating if affected.

RhabdomyolysisLaboratory evidence for myoglobinuria is observed

in up to 20%. Half of patients with creatine kinaselevels >5000 units/L will develop acute renal failure.Urine myoglobin >1142 nmol/L (>20 mg/dL) is alsopredictive of acute renal failure. The pathophysiologyinvolves tubular necrosis by myoglobin precipitates(favored in a acidic urine), tubular necrosis due tolipid peroxidation and renal vasoconstriction (exacer-bated by fluid shifts into the damage muscle compart-ment). Clinical features include tea colored urine,elevated serum creatine kinase and positive urinemyoglobin assay. Therapy is primarily hydration, al-kalinizing the urine and eliminating the source ofmyoglobin. Mannitol and plasmapheresis have notbeen found to be beneficial.

E4 Clinical Outcomes

E4.1 Systemic/limb

Mortality rates for ALI range from 15%e20%. Thecause of death is not provided in most series and ran-domized trials. Major morbidities include majorbleeding requiring transfusion/and or operative in-tervention in 10%e15%, major amputation in up to25%, fasciotomy in 5%e25% and renal insufficiency

Recommendation 33. Treatment of choice forcompartment syndrome

� In case of clinical suspicion of compartmentsyndrome, the treatment of choice is a four-compartment fasciotomy [C].

in up to 20%. Functional outcomes have at presentnot been studied.

Improvement in arterial circulation is relatively sim-ple to assess in that the vast majority of patients withALI have no pedal Doppler signals at presentationor they have an ankle-brachial index (ABI) �0.20.Therefore, any improvement in these parameterspostoperatively is considered successful.

E4.2 Follow-up care

All patients should be treated with heparin in the im-mediate postoperative period. This should be fol-lowed by warfarin often for 3e6 months or longer.Patients with thromboembolism will need long-termanticoagulation, from years or life long. However,there are no clear guidelines regarding duration oftherapy. The risk of recurrent limb ischemia in therandomized trials was high during the follow-upinterval.174,178,179 Therefore, prolonged warfarintherapy is an appropriate strategy, despite the cumu-lative bleeding risk. It is important to seek the sourceof embolism after revascularization, whether cardiacor arterial; however, in many cases no sourceis identified.

Certainly, if long-term anticoagulation is contrain-dicated, due to bleeding risk factors, platelet inhibi-tion therapy should be considered. Appropriatesystemic therapies as outlined above (see section B)should be provided.

E5 Economic Aspects of Acute Limb Ischemia

The recent literature has added very little to the find-ings presented in the first TASC document. Whenthrombolysis is used in association with angioplasty,the costs are identical to those of surgical revasculari-zation at roughly $20,000. The relative benefits ofsurgery have been discussed above. The choice ofstrategy is based on availability and outcome ratherthan on cost considerations.180

E6 Future Management

The increased use of percutaneous therapies with orwithout surgical revascularization is the trend for fu-ture therapy in ALI. The use of protection devices toprevent embolization, as in the carotid circulation,will also become part of therapy. Alternative oraltherapies for anticoagulation may hold promise.



SECTION F e REVASCULARIZATION

F1 Localization of Disease

The determination of the best method of revasculari-zation for treatment of symptomatic peripheral arte-rial disease (PAD) is based upon the balancebetween risk of a specific intervention and the degreeand durability of the improvement that can be ex-pected from this intervention. Adequate inflow andappropriate outflow are required to keep the revascu-larized segment functioning. The location and mor-phology of the disease must be characterized priorto carrying out any revascularization to determinethe most appropriate intervention. A variety ofmethods yielding both anatomic and physiologicinformation are available to assess the arterial cir-culation. (Refer to section G for preferred imagingtechniques.)

In a situation where a proximal stenosis is of ques-tionable hemodynamic significance, pressure measure-ments across it to determine its significance (criteria:threshold peak systolic difference 5e10 mmHg pre-vasodilatation and 10e15 mmHg post-vasodilatation)may be made. A recent development, that is yet to bevalidated, is direct flow measurements using a thermo-dilution catheter rather than pressure gradients.Hyperemic duplex scanning has also been suggested.

In general, the outcomes of revascularization de-pend upon the extent of the disease in the subjacentarterial tree (inflow, outflow and the size and lengthof the diseased segment), the degree of systemicdisease (co-morbid conditions that may affect life ex-pectancy and influence graft patency) and the typeof procedure performed. Results of large-scale clinicaltrials must be considered within the context of theindividual patient’s situation, considering all co-morbidities when deciding upon a recommendedtreatment course for that individual.

The endovascular techniques for the treatment ofpatients with lower extremity ischemia include bal-loon angioplasty, stents, stent-grafts and plaque

Recommendation 34. Intra-arterial pressure mea-surements for assessment of stenosis

� If there is doubt about the hemodynamic signif-icance of partially occlusive aortoiliac disease,it should be assessed by intra-arterial pressuremeasurements across the stenosis at rest andwith induced hyperemia [C].


debulking procedures. Thrombolysis and percutane-ous thrombectomy have been described in the sectionon acute limb ischemia. Surgical options include au-togenous or synthetic bypass, endarterectomy or an in-tra-operative hybrid procedure.

Outcomes of revascularization procedures dependon anatomic as well as clinical factors. Patency follow-ing percutaneous transluminal angioplasty (PTA) ishighest for lesions in the common iliac artery andprogressively decreases for lesions in more distal ves-sels. Anatomic factors that affect the patency includeseverity of disease in run off arteries, length of thestenosis/occlusion and the number of lesions treated.Clinical variables impacting the outcome also includediabetes, renal failure, smoking and the severity ofischemia.

F1.1 Classification of lesions

While the specific lesions stratified in the followingTASC classification schemes have been modifiedfrom the original TASC guidelines to reflect inevitabletechnological advances, the principles behind the clas-sification remain unchanged. Thus ‘A’ lesions repre-sent those which yield excellent results from, andshould be treated by, endovascular means; ‘B’ lesionsoffer sufficiently good results with endovascularmethods that this approach is still preferred first,unless an open revascularization is required forother associated lesions in the same anatomic area;‘C’ lesions produce superior enough long-term resultswith open revascularization that endovascularmethods should be used only in patients at high riskfor open repair; and ‘D’ lesions do not yield goodenough results with endovascular methods to justifythem as primary treatment. Finally it must be under-stood that most PAD requiring intervention is charac-terized by more than one lesion, at more than onelevel, so these schemes are limited by the necessityto focus on individual lesions.

Recommendation 35. Choosing between tech-niques with equivalent short- and long-term clin-ical outcomes

� In a situation where endovascular revasculari-zation and open repair/bypass of a specificlesion causing symptoms of peripheral arterialdisease give equivalent short-term and long-term symptomatic improvement, endovasculartechniques should be used first [B].


F1.2 Classification of inflow (aorto-iliac) disease(Fig. F1, Table F1)

F1.3 Classification of femoral popliteal disease(Fig. F2, Table F2)

F2 Aortoiliac (Supra Inguinal) Revascularization

F2.1 Endovascular treatment of aorto-iliacocclusive disease

Although aortobifemoral bypass appears to havebetter long-term patency than the currently availableendovascular strategies for diffuse aortoiliac occlusive

Recommendation 36. Treatment of aortoiliaclesions

� TASC A and D lesions: Endovascular therapy isthe treatment of choice for type A lesions andsurgery is the treatment of choice for type Dlesions [C].

� TASC B and C lesions: Endovascular treatmentis the preferred treatment for type B lesionsand surgery is the preferred treatment forgood-risk patients with type C lesions. Thepatient’s co-morbidities, fully informed patientpreference and the local operator’s long-termsuccess rates must be considered whenmaking treatment recommendations for type Band type C lesions [C].

Recommendation 37. Treatment of femoral popli-teal lesions

� TASC A and D lesions: Endovascular therapy isthe treatment of choice for type A lesions andsurgery is the treatment of choice for type Dlesions [C].

� TASC B and C lesions: Endovascular treatmentis the preferred treatment for type B lesionsand surgery is the preferred treatment forgood-risk patients with type C lesions. Thepatient’s co-morbidities, fully informed patientpreference and the local operator’s long-termsuccess rates must be considered whenmaking treatment recommendations for type Band type C lesions [C].

disease, the risks of surgery are significantly greaterthan the risks of an endovascular approach, in termsof not only mortality but also major morbidity anddelay in return to normal activities. Therefore, theassessment of the patient’s general condition andanatomy of the diseased segment(s) become centralin deciding which approach is warranted.

The technical and initial clinical success of PTA ofiliac stenoses exceeds 90% in all reports in the litera-ture. This figure approaches 100% for focal iliaclesions. The technical success rate of recanalizationof long segment iliac occlusions is 80%e85% with orwithout additional fibrinolysis. Recent device devel-opments geared towards treatment of total occlusions,however, have substantially improved the technicalsuccess rate of recanalization.181

Becker et al. found 5-year patency rate of 72% in ananalysis of 2697 cases from the literature, noting a bet-ter patency of 79% in claudicants.182 Rutherford andDurham found a similar 5-year patency of 70%.183

A recent study reported a primary patency of 74%(primary assisted patency of 81%) 8 years after stentplacement suggesting durability of patency of iliacartery stenting.184 Factors negatively affecting thepatency of such interventions include quality of runoff vessels, severity of ischemia and length of diseasedsegments. Female gender has also been suggestedto decrease patency of external iliac artery stents.185

Table F3 presents the estimated success rate of iliacartery angioplasty from weighted averages (range)from reports of 2222 limbs.

Choice of stent versus PTA with provisional stent-ing was addressed in a prospective randomized,multicenter study.186 Results showed that PTA withprovisional stenting had a similar outcome to primarystenting with 2-year reintervention rates of 7% and4%, respectively, for PTA and primary stenting (notsignificant). The 5-year outcomes of the groups werealso similar with 82% and 80% of the treated iliacartery segments remaining free of revascularizationprocedures after a mean follow-up of 5.6 years�1.3.187 A meta-analysis by Bosch and Hunink com-pared the results of aortoiliac PTA versus aortoiliacstenting using a Medline search of the post-1989 liter-ature and yielded only six articles (including 2116patients) with sufficient detail to allow stratificationover subgroups with various risk levels for long-term patency.188 Technical success was higher forstenting, whereas complication rates and 30-day mor-tality rates did not differ significantly. In patients withintermittent claudication the severity-adjusted 4-yearprimary patency rates (�95% confidence intervals)after excluding technical failures, for PTA and stent-ing, were: 68% (65%e71%) and 77% (72%e81%),



Fig. F1. TASC classification of aorto-iliac lesions. CIA e common iliac artery; EIA e external iliac artery; CFA e commonfemoral artery; AAA e abdominal aortic aneurysm.

respectively. Including technical failures, the 4-yearprimary patency rates are 65% (PTA) versus 77%(stent) for stenosis and 54% (PTA) versus 61% (stent)for occlusion. The relative risk of long-term failurewas reduced by 39% after stent placement comparedwith PTA. This robust report uses data from olderstudies and it is reasonable to expect that the newertechniques and equipment available today wouldlead to even better results.

The outcome of two different self-expanding stentsfor the treatment of iliac artery lesions was compared


in a multicenter prospective randomized trial.189 The1-year primary patencies were 94.7% and 91.1% (notsignificant), respectively, with similar complicationand symptomatic improvement rates regardless ofthe type of stent.

F2.2 Surgical treatment of aorto-iliac occlusive disease

Bilateral surgical bypass from the infra-renal abdomi-nal aorta to both femoral arteries is usually



recommended for diffuse disease throughout the aor-toiliac segment (Fig. F3). The aorta may be ap-proached via a transperitoneal or retroperitonealapproach. Interest is increasing in laparoscopic ap-proach. The configuration of the proximal anastomo-sis (end-to-end versus end-to-side) has not beenreliably shown to influence patency. The use ofPTFE versus Dacron as a conduit in this position isbased on the preference of the surgeon. Younger pa-tients (<50 years of age) with lower primary and sec-ondary patency have a greater need for secondarybypass.190

Recent interest in endarterectomy has been revivedalthough it is not as widely practiced as bypassgrafting and may be more technically challenging. Re-ported 5-year primary patency rates range from 60%to 94%, reflecting a degree of variability dependingupon the operator.

In some situations, when an abdominal approach isto be avoided due to anatomic considerations (‘hostileabdomen’) or cardiac and/or pulmonary risks, a

Table F1. TASC classification of aorto-iliac lesions

Type A lesions- Unilateral or bilateral stenoses of CIA- Unilateral or bilateral single short (�3 cm)

stenosis of EIAType B lesions

- Short (�3 cm) stenosis of infrarenal aorta- Unilateral CIA occlusion- Single or multiple stenosis totaling 3e10 cm

involving the EIA not extending into theCFA

- Unilateral EIA occlusion not involving theorigins of internal iliac or CFA

Type C lesions- Bilateral CIA occlusions- Bilateral EIA stenoses 3e10 cm long not

extending into the CFA- Unilateral EIA stenosis extending into the

CFA- Unilateral EIA occlusion that involves the

origins of internal iliac and/or CFA- Heavily calcified unilateral EIA occlusion

with or without involvement of origins ofinternal iliac and/or CFA

Type D lesions- Infra-renal aortoiliac occlusion- Diffuse disease involving the aorta and

both iliac arteries requiring treatment- Diffuse multiple stenoses involving the

unilateral CIA, EIA and CFA- Unilateral occlusions of both CIA and EIA- Bilateral occlusions of EIA- Iliac stenoses in patients with AAA re-

quiring treatment and not amenable toendograft placement or other lesions re-quiring open aortic or iliac surgery

CIA e common iliac artery; EIA e external iliac artery; CFA ecommon femoral artery; AAA e abdominal aortic aneurysm.

modified retroperitoneal approach or a unilateral by-pass with a femoro-femoral crossover may be used.Consideration should be given to using an axillo (bi)femoral (Fig. F4) or cross-over femoral (Fig. F5)bypass in patients with increased co-morbidities,making a transabdominal approach less desirable.Patency rates depend upon the indication for thereconstruction and the justification for the unilateralbypass (normal inflow artery versus high surgicalrisk). In some cases, patency of unilateral bypass canbe supplemented by endovascular means. Thethoracic aorta has also been used as an inflow artery.

Extra-anatomic bypass rarely performs as well asaortobifemoral bypass in diffuse disease and, there-fore, is seldom recommended for claudication. Evi-dence is lacking in recommending the preferredmaterial for anatomic or extra-anatomic prostheticbypass procedures. Table F4 summarizes the patencyat 5 and 10 years after aortobifemoral bypass andTable F5 the patency rates at 5 years after extra-anatomic bypass.

F3 Infrainguinal Revascularization

F3.1 Endovascular treatment of infrainguinal arterialocclusive disease

Endovascular treatment of infrainguinal disease inpatients with intermittent claudication is an estab-lished treatment modality. The low morbidity andmortality of endovascular techniques such as PTAmakes it to the preferred choice of treatment in lim-ited disease such as stenoses/occlusions up to 10 cmin length.

The technical and clinical success rate of PTA offemoropopliteal artery stenoses in all series exceeds95% (range 98%e100%, standard error 1.0%).192 De-vice developments such as hydrophilic guide wiresand technical developments, such as subintimal re-canalization, provide high recanalization rates in to-tal occlusions of more than 85% (range 81%e94%,standard error 2.9%).193 The technique of subintimalangioplasty is not as dependent on length, butrather on the presence of normal vessel above andbelow the occlusion to allow access.194 Table F6summarizes pooled results of femoral poplitealdilatations.

The mid- and long-term patency rates weresummarized in a meta-analysis by Muradin192 andin three randomized studies assessing the efficacyof stents.195e197

Risk factors for recurrence were analyzed by multi-variate stepwise backward regression analyses in


Fig. F2. TASC classification of femoral popliteal lesions. CFA e common femoral artery; SFA e superficial femoral artery.

various studies. Clinical stage of disease (intermittentclaudication versus critical limb ischemia), length oflesion and outflow disease were most commonlyfound as independent risk factors for restenoses.Recently, a study by Schillinger of 172 patients suc-cessfully undergoing PTA of the superficial femoraland popliteal arteries observed that 6-month patencyrates were related to hs-CRP levels at baseline and


at 48 hours after intervention.198 SSA and fibrinogenlevel were not significantly predictive.

There is general agreement that for acute failure ofPTA of an SFA lesion, stent placement is indicated. Arecent randomized trial has demonstrated signifi-cantly higher primary patency rates of stenting vs.PTA of femoropopliteal artery lesions TASC A and Bat 1-year follow up.199


Randomized trials comparing PTA versus bypasssurgery (BP) in infrainguinal arterial obstructive dis-ease are almost nonexistent. This can be explainedpartially by the following facts: BP is more commonlyperformed in extensive disease with long lesions andCLI. PTA is more commonly performed in limited dis-ease with IC and short obstructions (following theoriginal TASC recommendations 34 and 35). However,Wolf et al. published a multicenter, prospective ran-domized trial comparing PTA with BP in 263 menwho had iliac, femoral or popliteal artery obstruc-tion.200 This study of patients randomly assigned toBP or PTA showed no significant difference in out-comes during a median follow-up of 4 years (survival,patency and limb salvage). In 56 patients, cumulative1-year primary patency after PTA was 43% and afterbypass surgery was 82%, demonstrating that forlong superficial femoral artery (SFA) stenoses or oc-clusions, surgery is better than PTA. This contrastsa recent randomized study of 452 patients which

Table F2. TASC classification of femoral popliteal lesions

Type A lesions- Single stenosis �10 cm in length- Single occlusion �5 cm in length

Type B lesions- Multiple lesions (stenoses or occlusions),

each �5 cm- Single stenosis or occlusion �15 cm not

involving the infra geniculate poplitealartery

- Single or multiple lesions in the absenceof continuous tibial vessels to improveinflow for a distal bypass

- Heavily calcified occlusion �5 cm inlength

- Single popliteal stenosisType C lesions

- Multiple stenoses or occlusions totaling>15 cm with or without heavycalcification

- Recurrent stenoses or occlusions that needtreatment after two endovascularinterventions

Type D lesions- Chronic total occlusions of CFA or SFA

(>20 cm, involving the popliteal artery)- Chronic total occlusion of popliteal artery

and proximal trifurcation vessels

CFA e common femoral artery; SFA e superficial femoral artery.

Table F3. Estimated success rate of iliac artery angioplasty fromweighted averages (range) from reports of 2222 limbs

% Claudication Technicalsuccess

Primary patency

1 yr 3 yr 5 yr

76% (81e94) 96% (90e99) 86%(81e94)

82%(72e90)

71%(64e75)

demonstrated no difference in amputation-free sur-vival at 6 months; however, surgery was somewhatmore expensive.201

Medical treatment after PTA and stent placementis recommended to prevent early failure because ofthrombosis at the site of intervention. Standardtherapy is heparinization during the intervention toincrease activated clotting time to 200e250 seconds.After PTA and stenting of femoropopliteal arteries,a life-long antiplatelet medication is recommended topromote patency (acetylsalicylic acid or clopidogrel).Life-long antiplatelet therapy is also recommendedto prevent cardiovascular events as recommended insection B. Much of the supporting evidence forperi-procedural antiplatelet and adjuvant therapy isextrapolated from that related to the coronarycirculation.

Fig. F3. Bilateral bypass from infra renal abdominal aorta toboth femoral arteries.

Fig. F4. Axillo (bi) femoral bypass.



F3.2 Endovascular treatment of infrapoplitealocclusive disease

Endovascular procedures below the popliteal arteryare usually indicated for limb salvage and there areno data comparing endovascular procedures tobypass surgery for intermittent claudication inthis region.

Angioplasty of a short anterior or posterior tibialartery stenosis may be performed in conjunctionwith popliteal or femoral angioplasty. Use of thistechnique is usually not indicated in patients withintermittent claudication.

There is increasing evidence to support a recom-mendation for angioplasty in patients with CLI andinfrapopliteal artery occlusion where in-line flow tothe foot can be re-established and where there ismedical co-morbidity. In the case of infrapoplitealangioplasty, technical success may approach 90%with resultant clinical success of approximately 70%in some series of patients with CLI. Salvage rates arereported as being slightly higher.

Predictors of successful outcome include a shorterlength of occlusion and a lesser number of vesselstreated. The complication rate (2.4%e17% dependingupon the definition) can usually be treated by

Table F4. Patency at 5 and 10 years after aortobifemoral bypass191

Indication 5-year % patency(range)

10-year % patency(range)

Claudication CLI Claudication CLI

Limb based 91 (90e94) 87 (80e88) 86 (85e92) 81 (78e83)Patient based 85 (85e89) 80 (72e82) 79 (70e85) 72 (61e76)

CLI e critical limb ischemia.

Fig. F5. Cross-over femoral bypass.


endovascular or surgical techniques and a failed an-gioplasty does not preclude subsequent bypass.

It remains controversial whether infrapopliteal PTAand stenting should be performed in patients with ICfor improvement of outflow and for an increasedpatency of proximal PTA, stenting and bypass surgery.There is insufficient evidence to recommend infra-popliteal PTA and stenting in patients with inter-mittent claudication.

F3.3 Surgical treatment of infrainguinal occlusive disease

In the case of multilevel disease, the adequacy of inflowmust be assessed anatomically or with pressuremeasurements and occlusive disease treated prior toproceeding with an outflow procedure. In some situa-tions, a combined approach with dilatation of proximallesions and bypassing of distal lesions shouldbe performed.

A recent study has shown a trend towards increas-ingly complex bypass grafts (composite and splicedvein) to more distal arteries in patients with greaterco-morbidities, such as diabetes, renal failure and cor-onary artery disease; however, mortality rates have re-mained constant.202 A recent large study showed thatgender did not adversely affect the morbidity ormortality of lower extremity revascularization.

F3.3.1 BypassInfrainguinal bypass procedures need toarise from a pat-ent and uncompromised inflow artery although theactual level (common femoral artery versus superficialfemoral or popliteal artery) does not correlate withpatency. If the infrainguinal bypass is constructed fol-lowing an inflow procedure, patency is improved by

Table F5. Patency rates at 5 years after extra-anatomic bypass

Procedure 5-year % patency (range)

Axillo uni femoral bypass 51 (44e79)Axillo bi femoral bypass 71 (50e76)Femoral femoral bypass 75 (55e92)

Table F6. Pooled results of femoral popliteal dilatations

1-year %patency(range)



PTA: stenosis 77 (78e80) 61 (55e68) 55 (52e62)PTA: occlusion 65 (55e71) 48 (40e55) 42 (33e51)PTAþ stent:stenosis

75 (73e79) 66 (64e70)

PTAþ stent:occlusion

73 (69e75) 64 (59e67)

PTA e Percutaneous Transluminal Angioplasty.


making the proximal anastomosis to a native arteryrather than the inflow graft (usually limb of aortobife-moral bypass).203 The quality of the outflow artery isa more important determinant of patency than the actuallevel where the distal anastomosis is performed. A distalvessel of the best quality should be used for the distalanastomosis. There is no objective evidence to preferen-tially select either tibial or peroneal artery, since theyare typically of equal caliber. The results of femoral cruralbypass have not been subjected to meta-analysis.Five-year assisted patency rates in grafts constructedwith vein approach 60% and those constructed withprosthetic material are usually less than 35%. Reportshave documented the suitability of constructing bypassgrafts to plantar arteries with reasonable success rates(5-year salvage 63%, 5-year primary patency 41%).

F3.3.2 ConduitVein has better long-term patency than prosthetic inthe infra inguinal region (Table F7). Over the shortterm, PTFE has delivered near equivalent results inthe above-knee position (Fig. F6). A meta-analysissuggests much less satisfactory results of polytetra-fluoroethylene-coated grafts (PTFE) to the infra-popliteal arteries (5-year patency: primary 30.5%,

Recommendation 38. Inflow artery for femoro-distal bypass

� Any artery, regardless of level (i.e. not only thecommon femoral artery), may serve as an in-flow artery for a distal bypass provided flowto that artery and the origin of the graft is notcompromised [C].

Recommendation 39. Femoral distal bypass out-flow vessel

� In a femoral tibial bypass, the least diseaseddistal artery with the best continuous run-offto the ankle/foot should be used for outflow re-gardless of location, provided there is adequatelength of suitable vein [C].

Table F7a. 5-year patency following femoral popliteal bypass191

Claudication CLI

Vein 80 66Above-knee PTFE 75 47Below-knee PTFE 65 65

CLI e critical limb ischemia; PTFE e polytetrafluoroethylene graft.

secondary 39.7%).204 The consequences of a prostheticgraft occlusion may be more severe than a vein graftocclusion.205 A recent study questioned the wisdomof using a prosthetic graft when acceptable vein wasavailable in order to ‘save the vein’. Using this strat-egy, up to 33% of subsequent secondary bypass graftsdid not have adequate vein available at that time. Thelong saphenous vein (also known as the greater sa-phenous vein), either in a reversed or in situ configu-ration offers the best match of size and quality. In itsabsence, other venous tissue including contralaterallong saphenous vein, short (lesser) saphenous vein,femoral vein and arm vein have been used (Fig. F7).There is no difference in patency rates between insitu and reversed vein grafts. Differences in outcomewill depend upon indications for surgery, the qualityof the vessels, and co-morbidities. Venous grafts allhave better results than prosthetic materials.

F3.3.3 Adjunct proceduresWhen a prosthetic bypass graft is placed into thebelow-knee popliteal or distal artery adjunct proce-dures, such as arteriovenous fistula at or distal tothe bypass and the use of a vein interposition/cuff,have been suggested. However, randomized trials210

have shown that the addition of a distal arteriovenousfistula adds no benefit with respect to patency and,therefore, cannot be recommended. The use of a ve-nous cuff or patch has been promising in the below-knee popliteal or distal anastomosis in some series,although no comparison trials indicate the best typeof patch technique.211

F3.3.4 ProfundoplastyStenosis at the origin of the profunda femorisartery may lead to decreased flow through collateralvessels in the presence of a SFA occlusion and may

Table F7b. Randomized trials of types of conduits206e209

Above-knee femoral popliteal bypass 5-year patency

Vein 74e76%PTFE 39e52%

PTFE e polytetrafluoroethylene graft.

Recommendation 40. Femoral below-knee popli-teal and distal bypass

� An adequate long (greater) saphenous vein isthe optimal conduit in femoral below-kneepopliteal and distal bypass [C]. In its absence,another good-quality vein should be used [C].



compromise the patency of an aortic/extra anatomicinflow operation. In the presence of SFA occlusion itis recommended that a stenosis of the profunda fem-oris artery be corrected during inflow procedures. Iso-lated profundoplasty as an inflow procedure (sparinga femoral distal bypass) may be considered in thepresence of: 1) excellent inflow; 2) >50% stenosis ofthe proximal 1/3 profunda; and 3) excellent collateralflow to the tibial vessels.

F3.3.5 Secondary revascularization proceduresSecondary patency results from the salvage of an oc-cluded bypass and assisted patency results frompre-occlusion intervention. The non-tolerance of veingrafts to thrombosis and the success of assisted pa-tency support the previous recommendations that all

Fig. F6. Above-knee femoral popliteal bypass.


venous bypass grafts be followed by a regular regimeof duplex scanning with set parameters for interven-tion including angioplasty (open or transluminal) orshort segment interposition. This recommendationhas recently been questioned by a randomized, con-trolled trial showing no cost benefit of such anapproach.212 In the presence of an occluded butestablished graft, thrombolysis may be indicated inthe very early stages to remove clot and reveal thecause of the thrombosis. When limb salvage is as-sessed following failure of an infrainguinal bypassthe original indication for surgery is an important fac-tor. The 2-year limb salvage rates for occluded graftsdone for claudication is 100%, for rest pain is 55%and when done for tissue loss is 34%. The early occlu-sion of a graft (<30 days occlusion) led to a very poor2-year limb salvage rate of 25%.213

Fig. F7. Femoral tibial bypass.


F4 Antiplatelet and Anticoagulant Therapies

Adjuvant therapy has been recommended to improvethe patency rate following lower extremity bypassgrafts. Antiplatelet agents have a beneficial effectthat is greater in prosthetic than in autogenousconduits.156 A meta-analysis published in 1999 dem-onstrated that the relative risk of infra inguinal graftocclusion in patients on aspirin/ASA was 0.78.214

The recommendation for aspirin/ASA therapy is sim-ilar for patients undergoing lower extremity balloonangioplasty.59 The addition of dipyridamole or ticlopi-dine has been supported by some studies but largerrandomized trials will be necessary to make a firm rec-ommendation.215 Autogenous grafts may be treatedwith warfarin216 but this is accompanied by a risk ofhemorrhage and this decision must be made on an in-dividual patient basis.59 All patients should receiveantiplatelet therapy following a revascularization.For those receiving anticoagulation, and in those fewtreated with both antiplatelet agents and anticoagu-lants, extra vigilance is required due to the increasedrisk of bleeding. Recent articles have been publishedexpressing concern that patients undergoing inter-vention for PAD are not receiving the optimal care fortheir atherosclerotic process. As previously stated, allpatients should undergo assessment and treatmentfor their underlying atherosclerosis regardless of theneed for intervention for limb salvage.

F5 Surveillance Programs FollowingRevascularization

Following construction of an infrainguinal autoge-nous bypass graft, it has been recommended in thepast that a program of regular graft review with du-plex scanning be undertaken.217 The purpose of thisis to identify lesions that predispose to graft thrombo-sis and allow their repair prior to graft occlusion. Arecent multicentered, randomized, controlled trialhas shown that duplex surveillance after venousfemoral distal bypass grafts leads to no significantclinical benefit or quality of life improvement at 18

Recommendation 41. Antiplatelet drugs as adju-vant pharmacotherapy after revascularization

� Antiplatelet therapy should be started preoper-atively and continued as adjuvant pharmaco-therapy after an endovascular or surgicalprocedure [A]. Unless subsequently contraindi-cated, this should be continued indefinitely [A].

months. The previous recommendation of routineduplex scanning following autogenous lower extremitybypass has proven to be not cost-effective according tothis study.212 In practice, many surgeons continue aprogram of vein graft surveillance awaiting furtherconfirmation of the findings of this trial.

F6 New and Advancing Therapies

Newer surgical techniques have tended to involve min-imally invasive arterial reconstructions including lapa-roscopic aortic reconstructions. The use of combinedtherapies (transluminal and operative) may lead to ‘min-imally’ invasive surgery. In infrainguinal reconstruction

Recommendation 42. Clinical surveillance pro-gram for bypass grafts

� Patients undergoing bypass graft placement inthe lower extremity for the treatment of claudi-cation or limb-threatening ischemia should beentered into a clinical surveillance program.This program should consist of:B Interval history (new symptoms)B Vascular examination of the leg with palpa-

tion of proximal, graft and outflow vesselpulses

B Periodic measurement of resting and, if possi-ble, post-exercise ankle-brachial indices

� Clinical surveillance programs should be per-formed in the immediate postoperative periodand at regular intervals (usually every 6months) for at least 2 years [C].

Table F8. Cumulative observed morbidity outcomes for bypass incritical limb ischemia

Parameter Short term(first year)

Long term(3e5 years)

Mean time to pedal wound healing 15e20 weeks eIncisional wound complications* 15%e25% ePersistent severe ipsilaterallymphedemax

10%e20% Unknown

Graft stenosis** 20% 20%e30%Graft occlusion 10%e20% 20%e40%Graft surveillance studies 100% 100%Major amputation 5%e10% 10%e20%Ischemic neuropathy Unknown UnknownGraft infectiony 1%e3% ePerioperative death (primarilycardiovascular)

1%e2% e

All death (primarily cardiovascular) 10% 30%e50%

* Not all requiring reoperation.xNot well-studied.

** Greater in series of composite and alternate vein conduit.yGreatest in prosthetic grafts.



the use of semi-closed endarterectomy is gaining someinterest. Additionally, in the attempt to reduce the mor-bidity of wound complications and the negative effectsof this on patency, the use of endoscopic vein prepara-tion and/or harvest is being investigated.

Recently drug-eluting stents were tested in a random-ized study against bare stents in femoropopliteal arteryobstructive disease in claudicants.218 This study evalu-ated the effectiveness of nitinol self-expanding stentscoated with a polymer impregnated with sirolimus(rapamycin) versus uncoated nitinol stents in patientswith IC and SFA obstructions. The in-stent mean lumendiameter was significantly larger in the sirolimus-eluting stent group (4.95 mm versus 4.31 mm in theuncoated stent group; p¼ 0.047). The results of this trialrequire further confirmation and longer-term follow up.Results of a recent small randomized trial suggest earlyresults of primary nitinol stenting of SFA dilatations hada superior result to dilatation alone.199

The impact of ePTFE coated stents (stentgrafts) wastested in a randomized trial by Saxon et al.219 At2 years follow-up, primary patency remained 87%(13 of 15 patients) in the stentgraft group versus only25% (three of 12 patients) in the PTA group ( p¼ 0.002).

Endovascular brachytherapy (BT) with g-emittingsources such as 192Ir was investigated with respectto the rate of intimal hyperplasia and restenoses.220

Minar et al. tested endovascular BT in femoropoplitealobstructions and IC in a randomized trial. The overallrecurrence rate after 6 months was significantlylower (28.3% versus 53.7%) for the PTAþ BT groupcompared with the PTA. Cumulative patency wasalso significantly higher at 12 months (63.6% versus35.5%). Advice for general use will require moreextensive and longer-term study.

Fig. F8. Results summary: Average results for surgicaltreatment. Ao-bi-fem e Aortobifemoral bypass; Fem-pop efemoropopliteal; BK e below knee; Ax-bi-fem e Axillobife-moral; PTA e Percutaneous Transluminal Angioplasty;Ax-uni-fem e Axillounifemoral bypass; pros e prosthetic.


The focus of newer adjuvant therapies is to increasethe robustness of percutaneous interventions makingthem more applicable and durable to a broader rangeof lesions. These local therapies must be combined withsystemic management of the atherosclerotic process.

Table F8 summarizes the cumulative observedmorbidity outcomes for bypass in critical limb ische-mia, and Fig. F8 summarizes the average results forsurgical treatment.

SECTION G e NON-INVASIVE VASCULARLABORATORY AND IMAGING

G1 Non-invasive Vascular Laboratory

The routine evaluation of patients with peripheralarterial disease (PAD) can include a referral to thevascular laboratory. Non-invasive hemodynamic mea-surements can provide an initial assessment of the loca-tion and severity of the arterial disease. These tests canbe repeated over time to follow disease progression.

G1.1 Segmental limb systolic pressure measurement

Segmental limb pressure (SLP) measurements arewidely used to detect and segmentally localize hemo-dynamically significant large-vessel occlusive lesionsin the major arteries of the lower extremities. Segmen-tal pressure measurements are obtained in the thighand calf in the same fashion as the ankle pressure. Asphygmomanometer cuff is placed at a given levelwith a Doppler probe over one of the pedal arteries,and the systolic pressure in the major arteries underthe cuff is measured. The location of occlusive lesionsis apparent from the pressure gradients between thedifferent cuffs. Limitations of the method include:(1) missing isolated moderate stenoses (usually iliac)that produce little or no pressure gradient at rest;(2) falsely elevated pressures in patients with diabetescalcified, incompressible arteries; and (3) the inabilityto differentiate between arterial stenosis or occlusion.

G1.2 Segmental plethysmography or pulsevolume recordings

A plethysmograph is an instrument that detects andgraphically records changes in limb volume. Limb cuffsare placed around the leg at selected locations and con-nected to a plethysmograph, which produces a pulsevolume recording (PVR). Normally, a single large thighcuff is used along with regular-sized calf and ankle cuffs,plus a brachial cuff that reflects the undampened cardiac


contribution to arterial pulsatility. The latter is useful instandardizing the lower-limb PVR and in detecting poorcardiac function as a cause of low-amplitude tracings. Toobtain accurate PVR waveforms the cuff is inflatedto w60e65 mmHg, which is sufficient to detect volumechanges without resulting in arterial occlusion.

SLP and PVR measurements alone are 85% accu-rate compared with angiography in detecting and lo-calizing significant occlusive lesions. Furthermore,when used together, the accuracy approached95%.221 For this reason, these two diagnostic methodsare commonly used together when evaluating PAD.Using SLP and PVR in combination ensures that pa-tients with diabetes who have calcified arteries suffi-cient to produce falsely elevated SLP will be readilyrecognized and correctly assessed by PVR.

G1.3 Toe pressures and the toe-brachial index

Patients with long-standing diabetes, renal failure andother disorders resulting in vascular calcification can de-velop incompressible tibial arteries, which cause falselyhigh systolic pressures. Non-compressible measure-ments are defined as a very elevated ankle pressure(e.g. �250 mmHg) or ankle-brachial index (ABI) >1.40.In this situation, measurement of toe pressures providesan accurate measurement of distal limb systolic pres-sures in vessels that do not typically become non-com-pressible. A special small occlusion cuff is usedproximally on the first or second toe with a flow sensor,such as that used for digital plethysmography. The toepressure is normally approximately 30 mmHg lessthan the ankle pressure and an abnormal toe-brachial in-dex (TBI) is<0.70. The measurement of toe pressures re-quires a non-invasive vascular laboratory with standardenvironmental conditions, expertise and equipmentnecessary to make the measurement. False positive re-sults with the TBI are unusual. The main limitation in pa-tients with diabetes is that it may be impossible tomeasure toe pressure in the first and second toes dueto inflammatory lesions, ulceration, or loss of tissue.

G1.4 Doppler Velocity Wave Form analysis

Arterial flow velocity canbe assessed using a continuous-wave Doppler at multiple sites in the peripheralcirculation. Doppler waveforms evolve from a normaltriphasic pattern to a biphasic and, ultimately, monopha-sic appearance in those patients with significantperipheral arterial disease (PAD). When assessed overthe posterior tibial artery, a reduced or absent forwardflow velocity was highly accurate for detecting PAD(and also isolated tibial artery occlusive disease that

may occur in patients with diabetes).12 While the test isoperator-dependent, it provides another means to detectPAD in patients with calcified tibial arteries.

G2 Imaging Techniques

G2.1 Indications for and types of imaging in patients withintermittent claudication or critical limb ischemia

Imaging is indicated if some form of revascularization(endovascular or open surgical) would be advised ifa suitable lesion is demonstrated. The patient’s dis-ability and functional limitations due to impairedwalking ability should be the major determinant indeciding on revascularization. This is considered interms of claudication distance and the effect of thislimitation on the patient’s lifestyle, as well as theirindependence and capacity for self care. In cases ofcritical limb ischemia (CLI), imaging and revasculari-zation are mandatory, provided contraindications donot prohibit surgical or endovascular intervention.

The expense and morbidity rate for duplex scanningand other non-invasive methods are far less than for in-vasive angiography. With the introduction of magneticresonance angiography (MRA) and computed tomo-graphic angiography (CTA), it is now possible to usenon-invasive imaging in many situations to assess thesuitability of the underlying lesions for the proposed in-tervention before committing to invasive angiography.

G2.2 Choice of imaging methods

The main reason for imaging is to identify an arteriallesion that is suitable for revascularization with eitheran endovascular or open surgical technique. Thecurrent options for imaging are angiography, duplexultrasound, MRA and CTA. Potential side effectsand contraindications should be considered in choos-ing the imaging modality. Intra-arterial angiographyrequires contrast medium that is potentially nephro-toxic. Multidetector computed tomographic angiogra-phy (MDCTA) requires a contrast medium load of>100 mL. Several methods exist to reduce renal injury,including hydration and protective drugs such asN-acetylcysteine. The usage of alternate contrastagents (see G2.2.1) may also be considered. Wherethe use of iodinated contrast medium is to be re-stricted or avoided, MRA and also duplex ultrasonog-raphy may allow planning for surgery.

G2.2.1 AngiographyAngiography, considered the ‘‘gold standard’’ imagingtest, carries certain risks: approximately 0.1% risk of



severe reaction to contrast medium, 0.7% complicationsrisk severe enough to alter patient management,and 0.16% mortality risk and significant expense.Other complications include arterial dissection, athe-roemboli, contrast-induced renal failure and accesssite complications (i.e. pseudoaneurysm, arteriove-nous fistula and hematoma). These problems havebeen greatly mitigated by technological improvementsin the procedure, including the use of nonionic contrastagents, digital subtraction angiography, intra-arterialpressure measurements across a stenosis withand without vasodilator (significance peak systolicdifference 5e10 mmHg pre-vasodilatation and10e15 mmHg post-vasodilatation), and more sophisti-cated image projection and retention. Alternatively,carbon dioxide and magnetic resonance contrast agents(i.e. gadolinium) can be used instead of conventionalcontrast media. In high-risk (e.g. renal impairment) pa-tients, restriction to a partial study with selected viewsrather than visualizing the entire infrarenal arterial treehas decreased the contrast load, length of study and as-sociated risks. Despite this, full angiography, with visu-alization from the level of the renal arteries to the pedalarteries using digital subtraction angiography (DSA)techniques, remains the choice in most cases.

G2.2.2 Color-assisted duplex ultrasonographyColor-assisted duplex imaging has been proposed as anattractive alternative to angiography. In addition to be-ing completely safe and much less expensive, duplexscanning, in expert hands, can provide most of the es-sential anatomic information plus some functional in-formation (for instance, velocity gradients acrossstenoses). The lower extremity arterial tree can be visu-alized, with the extent and degree of lesions accuratelyassessed and arterial velocities measured. Disadvan-tages include the length of the examinations and vari-ability of skill of the technologist. In addition, cruralarteries are challenging to image in their entirety.

G2.2.3 Magnetic resonance angiographyIn many centers, MRA has become the preferredimaging technique for the diagnosis and treatmentplanning of patients with PAD. The advantages ofMRA include its safety and ability to provide rapidhigh-resolution three-dimensional (3D) imaging ofthe entire abdomen, pelvis and lower extremities inone setting. The 3D nature of magnetic resonance im-aging implies that image volumes can be rotated andassessed in an infinite number of planes. MRA is use-ful for treatment planning prior to intervention and inassessing suitability of lesions for endovascular ap-proaches. Pre-procedure MRA may minimize use ofiodinated contrast material and exposure to radiation.


The high magnetic field strength in MRA excludespatients with defibrillators, spinal cord stimulators,intracerebral shunts, cochlear implants etc., and thetechnique also excludes the <5% patients affected byclaustrophobia that is not amenable to sedation. Stentswithin segments of peripheral vessels may producea susceptibility artifact that can render evaluation ofthese segments difficult. However, the signal losswith stents is extremely dependent on the metallic al-loy, with nitinol stents producing minimal artifact. Incontrast to CTA (see section G2.2.4), the presence ofcalcium in vessels does not cause artifacts on MRAand this may represent a potential advantage in exam-ining diffusely calcified vessels in patients with diabe-tes and patients with chronic renal failure.

MRA techniques can be gadolinium contrast-based(contrast-enhanced MRA or CE-MRA) or non-con-trast-based (time-of-flight techniques). In general, CE-MRA techniques utilize a moving table (floating table)approach and sequentially following a bolus of con-trast through multiple (usually 3e4) stations extendingfrom the abdomen to the feet. CE-MRA has replacednon-contrast MRA for the assessment of peripheralvessels, as this technique provides rapid imagingwith substantively better artifact-free images.222

Time-resolved CE-MRA is usually performed in con-junction with moving table CE-MRA, providing anadditional examination of infra-inguinal vessels anddynamic images free of venous contamination.

CE-MRA has a sensitivity and specificity of >93%for the diagnosis of PAD compared with invasive angi-ography.222 A number of studies have demonstratedthat CE-MRA has better discriminatory power thancolor-guided duplex ultrasound for the diagnosis ofPAD. Recent advancements in CE-MRA methodolo-gies that include refinements such as usage of a venousocclusion cuff around the thigh to modulate contrastdelivery to the foot, and parallel imaging methodshave greatly improved the ability to image distalvessels in a high resolution manner (<1� 1 mm inplane).223,224 MRA may consistently pick up morepatent vessels than DSA below the knee and couldpotentially obviate the need for invasive angiography.225

G2.2.4 Multidetector computed tomography angiographyMultidetector computed tomography angiography(MDCTA) is being widely adopted for the initial diag-nostic evaluation and treatment planning of PAD. Therapid evolution of technology and the deploymentof fast MDCTA multislice systems in the communityand the familiarity with CT technology and ease ofuse are some factors driving its popularity. Multi-slice MDCTA enables fast imaging of the entirelower extremity and abdomen in one breath-hold at


sub-millimeter isotropic voxel resolution. Althoughprospectively designed studies with MDCTA arecurrently lacking, there are emerging data that thesensitivity, specificity and accuracy of this techniquemay rival invasive angiography.226,227

The major limitations of MDCTA include the usageof iodinated contrast (z120 mL/exam), radiation ex-posure and the presence of calcium.226 The latter cancause a ‘blooming artifact’ and can preclude assessmentof segments with substantive calcium. Stented seg-ments can also cause significant artifact and may pre-clude adequate evaluation. However, the ability toevaluate vessel wall lumen in stented and calcified seg-ments is dependent on the technique (window/level,reconstruction kernel, and type of image [maximum in-tensity projection versus multiplanar reformation etc]).

To summarize, if a patient qualifies for invasivetherapy, angiography will, ultimately, be required inalmost all elective cases, preoperatively for surgicalreconstruction and before or during catheter-basedinterventions. Duplex scanning is used selectivelymainly to characterize specific lesions in regard totheir suitability for endovascular treatment. However,it should be kept in mind that arterial reconstructivesurgery can be performed on the basis of duplex scan-ning alone in some cases. The different imagingmethods are compared in Table G1.

Recommendation 43. Indications and methods tolocalize arterial lesions

� Patients with intermittent claudication whocontinue to experience limitations to their qual-ity of life after appropriate medical therapy (ex-ercise rehabilitation and/or pharmacotherapy)or patients with critical limb ischemia, may beconsidered candidates for revascularization ifthey meet the following additional criteria: (a)a suitable lesion for revascularization is identi-fied; (b) the patient does not have any systemiccontraindications for the procedure; and (c) thepatient desires additional therapy [B].

� Initial disease localization can be obtained withhemodynamic measures including segmentallimb pressures or pulse volume recording [B].

� When anatomic localization of arterial occlu-sive lesions is necessary for decision making,the following imaging techniques are recom-mended: duplex ultrasonography, magneticresonance angiography and computed tomo-graphic angiography (depending on localavailability, experience, and cost) [B].

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TASC Writing Group e Conflict of InterestDisclosures

The following authors have declared no competinginterests: Kevin Bell; Joseph Caporusso; John Dor-mandy; Isabelle Durand-Zaleski; Kenneth A Harris;Kimihiro Komori; Johannes Lammer; Christos Liapis;Salvatore Novo; Mahmood Razavi; John Robbs;Nicholaas Schaper; Hiroshi Shigematsu; MarcSapoval; Christopher White, John White.

The following authors have declared competinginterests:

- Denis Clement has been invited to lecture at con-gresses and symposia by all major pharmaceuticalcompanies

- Mark Creager serves as a consultant for BristolMyers Squibb, sanofi-aventis, Genzyme, SigmaTau, and KOS. He receives research supportfrom sanofi-aventis and is on the speakers bureaufor the Bristol-Myers Squibb/sanofi-aventisPartnership

- Gerry Fowkes has received research support andad hoc consulting fees from sanofi-aventis

- Kenneth Harris has been a speaker for sanofi-aventis on the TASC project

- William Hiatt has received research support andis on the speakers bureau of the Bristol-MyersSquibb/sanofi-aventis Pharmaceuticals Partner-ship. He has received honoraria from OtsukaPharmaceuticals and research support from SigmaTau Pharmaceuticals and Kos Pharmaceuticals

- Michael Jaff has been paid consulting fees forCordis Endovascular and is on the speakersbureau of the Bristol-Myers Squibb/sanofi-aventisPharmaceuticals Partnership

- Emile Mohler III is on the speakers bureau of theBristol-Myers Squibb/sanofi-aventis Pharmaceuti-cals Partnership, Merck, Pfizer and Astra-Zeneca

- Mark Nehler has received grants from sanofi-aventis and Mitsubishi Pharma, and royaltiesfrom Elsevier

- Lars Norgren has been paid consulting fees asa member/chairman of clinical trials and asa speaker for Mitsubishi Pharma, sanofi-aventis,Schering AG and Merck-Sante

- Robert B Rutherford acts as a consultant for Endo-vasc, Inc.

- Peter Sheehan has received research grants fromGenzyme and Nissan, and is on the speakersbureau of the Bristol-Myers Squibb/sanofi-aventisPharmaceuticals Partnership

- Henrik Sillesen has received consulting fees fromPfizer, sanofi-aventis and Merck. Speakers fees


from Pfizer, sanofi-aventis, Merck, Astra-Zeneca,Solvay and Bristol-Myers Squibb. Financial sup-port was provided for a research assistant fromVivolution, Pfizer, Bristol-Myers Squibb and Gore

- Kenneth Rosenfield is on the scientific Advisoryboard for Abbott, Boston Scientfic, CardioMind,Cordis, ev3 and Medtronic; serves as a conslutantfor Abbot, Bard, Endotex, Genzyme, PathwayMedical and Xtent; and is a shareholder of Cardio-Mind, Medical Simulation and Xtent. In addition,he has received education/research grants fromAbbott, Accumetrix, Bard, Boston Scientific,Cordis, The Medicines Co. and Medtronic

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Accepted 15 September 2006

Available online 29 November 2006


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Inter-Society Consensus for the Management of Peripheral ...karkirurgi.org/lenker/TASC II Norgren 07.pdf · Inter-Society Consensus for the Management of Peripheral Arterial Disease