Lower Extremity Arterial Disease

Background

Lower extremity arterial occlusive disease is the most common form of peripheral arterial disease (10PAD) and represents a major cause of morbidity, disability, and health-care costs worldwide.(GBD 2019)📄

• Global prevalence: >200 million people affected, with rising incidence due to aging populations and increasing rates of diabetes and smoking (Fowkes 2013)
• Clinical spectrum: from asymptomatic disease → claudication → chronic limb-threatening ischemia (CLTI) → amputation.(Gerhard 2016)📄
• Associated risk: 10PAD patients have a 2–6× higher risk of myocardial infarction, stroke, and cardiovascular death (Hiatt 2015)📄.
• Clinical burden: ~25% of patients with CLTI undergo major amputation within 1 year, despite modern therapies.(Conte 2019)📄
• Overlap with other vascular diseases: patients often have concurrent 4Aneurysms, 7carotid disease, or coronary artery disease.(Hiatt 2015)📄

Atherosclerosis (dominant cause)

• Inflow lesions: aortoiliac.
• Outflow lesions: femoropopliteal, tibial, pedal.(Norgren 2007)
• Risk factors: smoking, diabetes mellitus (DM), hypertension (HTN), dyslipidemia, chronic kidney disease (CKD), obesity, and sedentary lifestyle.(Gerhard 2016)📄(Tsao 2023)(Martin 2024)

Other etiologies

• Embolism: cardiac (AF, mural thrombus) or proximal arterial source.(Gerhard 2016)📄 See 12VTE for thromboembolism principles.
• Thrombosis: acute occlusion of pre-existing stenosis.
• Vasculitis: Takayasu arteritis, Buerger disease, giant cell arteritis.(Olin 2000)
• Trauma/Iatrogenic: vascular injury, catheterization.(Feliciano 2011)📄 See 16EVTM for trauma management.
• Radiation-induced arterial disease.(Rutherford 2018)

Pathophysiology

1. Endothelial dysfunction: reduced nitric oxide, increased permeability.
2. Plaque formation: LDL infiltration, oxidation, macrophage recruitment → foam cells.
3. Progression: fibrous cap, calcification, narrowing lumen.
4. Complications: thrombosis, embolization, plaque rupture.
5. Microcirculation: impaired autoregulation, collateral failure, tissue hypoxia.(Libby 2021)

Patterns of Disease

• Aortoiliac: Leriche syndrome (claudication, impotence, absent femoral pulses).(Rutherford 2018)
• Femoropopliteal: most common site.
• Infrapopliteal/tibial: common in diabetes mellitus (DM) and renal failure, often presenting as chronic limb-threatening ischemia (CLTI).(Gerhard 2016)📄 Patients with DM typically exhibit more distal, multi-level disease patterns and increased medial arterial calcification (MAC).(Das 2025)

Asymptomatic disease

• Detected by an abnormal ankle-brachial index (ABI) (<0.9).(Aboyans 2012)📄 Assessment of subclinical atherosclerosis in asymptomatic populations is increasingly recognized as a critical tool for cardiovascular risk stratification (Garg 2023).
• Associated with high systemic cardiovascular (CV) risk and a substantial global health burden (Hiatt 2015)📄(Martin 2025).

Claudication

• Exercise-induced, reproducible muscle pain relieved by rest.(Rutherford 2018)
• Localizes to site: buttock (aortoiliac), thigh (femoral), calf (femoropopliteal), foot (tibial).(Rutherford 2018)

Chronic Limb-Threatening Ischemia

Risk stratification: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) (Wound, Ischemia, foot Infection) classification provides standardized staging of threatened limbs (Stages 1–4) to predict 1-year amputation risk and estimate the benefit of revascularization. Ischemia grading incorporates objective measures—toe pressure and transcutaneous oxygen tension (TcPO₂)—per WIfI criteria. WIfI is complemented by the Global Limb Anatomic Staging System (GLASS), which characterizes anatomic complexity (Stages I–III) along the Target Arterial Path (TAP). The Global Vascular Guidelines advocate integrating these dimensions into the PLAN framework—Patient risk, Limb severity (WIfI), and ANatomic pattern (GLASS)—to guide individualized revascularization strategy (Mills 2014)^,(Conte 2019)📄.

WIfI Classification Summary

Acute Limb Ischemia

• Classic presentation—the 6 Ps: Pain, Pallor, Pulselessness, Paresthesia, Paralysis, and Poikilothermia (coolness) (Rutherford 2018). Motor and sensory deficits indicate advanced ischemia requiring urgent intervention.
• Immediate management: Systemic anticoagulation with intravenous unfractionated heparin (UFH) (unless contraindicated) should be initiated immediately to prevent thrombus propagation. Severity staging using the Rutherford classification (I–III) guides treatment urgency. Catheter-directed thrombolysis (CDT) or endovascular thrombectomy (ET) are appropriate for Rutherford I–IIa (viable or marginally threatened limb without motor deficit). Recent meta-analyses indicate that ET provides comparable limb salvage rates to CDT while potentially reducing procedural time and bleeding risks (Kusumowardani 2026). Rutherford IIb (immediately threatened limb with motor deficit) requires emergent surgical or endovascular revascularization within hours to prevent irreversible tissue loss. Rutherford III (irreversible ischemia with rigor and fixed mottling) contraindicates revascularization due to futility and high risk of reperfusion injury, compartment syndrome, and systemic complications (Gerhard 2016)📄. In pediatric populations, management of acute limb ischemia (ALI) requires specialized consideration of vessel size and etiology, with a focus on anticoagulation and tailored surgical or endovascular approaches (Meyer 2026).

Rutherford ALI Classification

Clinical evaluation

Ankle-Brachial Index (ABI): <0.9 indicates peripheral arterial disease (PAD); <0.5 indicates severe ischemia; >1.3 suggests arterial calcification (medial sclerosis), commonly seen in diabetes and chronic kidney disease.(Aboyans 2012)📄

Imaging Studies

Imaging Modalities for peripheral arterial disease (PAD)

• Duplex Ultrasound (DUS): first-line imaging modality; uses PSV ratios to grade stenosis severity (PSV ratio >2.0 indicates ≥50% stenosis).(Moneta 2010)📄 In patients with diabetes, medial arterial calcification can significantly limit the accuracy of DUS due to acoustic shadowing (Das 2025).
• Computed Tomography Angiography (CTA): provides detailed anatomic mapping of the entire arterial tree; preferred for planning revascularization in most patients.(Gerhard 2016)📄 To ensure value-based care, CTA should be reserved for patients where revascularization is clinically indicated to avoid imaging misallocation (Raskin 2025).
• Magnetic Resonance Angiography (MRA): alternative cross-sectional imaging when CTA is contraindicated (renal insufficiency, contrast allergy); gadolinium-based agents carry lower nephrotoxicity risk.(Prince 2016)
• Digital Subtraction Angiography (DSA): intra-procedural gold standard for anatomic assessment; allows simultaneous diagnosis and therapeutic intervention.(White 2006)📄 DSA is generally not recommended for primary diagnosis alone when non-invasive options are available (Raskin 2025). See 3Chapter 3 for comprehensive imaging principles.

Functional tests

• Exercise Treadmill Test: quantifies functional impairment by measuring pain-free walking distance and maximum walking distance. Standardized protocols (e.g., 2 mph at 10% grade) enable reproducible assessment of treatment response.(Gerhard 2016)📄
• Transcutaneous Oxygen Tension (TcPO₂): measures skin surface oxygen tension to assess microcirculatory perfusion. Values <30 mmHg predict poor wound healing without revascularization; values >40 mmHg indicate adequate perfusion for wound healing.(Schepers 2010)📄

Medical Therapy

• Risk factor modification: smoking cessation (most critical intervention)(Willigendael 2004)📄^,(Armstrong 2014), blood pressure control (target <130/80 mmHg), optimal diabetes management (hemoglobin A1c [HbA1c] <7%) (Das 2025), and lipid management.(Gerhard 2016)📄
• Supervised exercise therapy (SET): structured walking programs (3 sessions/week, 30–60 minutes) improve claudication distance by 50–200% and remain a Class I recommendation (Lane 2017)📄^,(Conte 2025). Recent systematic reviews confirm SET as a primary non-invasive treatment for improving both maximal and pain-free walking distances (Saadi 2025).
• Antiplatelet therapy: aspirin (75–325 mg daily) or clopidogrel (75 mg daily). The CAPRIE trial demonstrated clopidogrel superiority in the peripheral arterial disease (PAD) subgroup (8.7% relative risk reduction; p=0.0028) (CAPRIE 1996).
• Statin therapy: high-intensity therapy (e.g., atorvastatin 40–80 mg) reduces cardiovascular events and limb events (HPS, SPARCL trials).(Heart Protection 2002)^,(Amarenco 2006)📄 Target low-density lipoprotein (LDL) <70 mg/dL, or <55 mg/dL in very high-risk patients.
• Dual-pathway inhibition: rivaroxaban 2.5 mg BID plus aspirin reduces major adverse cardiovascular events (MACE) and major adverse limb events (MALE) by 24% (COMPASS trial), with increased but manageable bleeding risk (Eikelboom 2017)📄.
• Cilostazol: phosphodiesterase-3 inhibitor that increases walking distance and improves quality of life;(Thompson 2002)^,(Saadi 2025) 100 mg twice daily (not approved in Europe due to concerns about cardiac safety). The 2025 Society for Vascular Surgery (SVS) focused update reaffirms its efficacy for patients with intermittent claudication (IC) (Conte 2025).
• Post-revascularization antithrombotic therapy: after lower extremity revascularization (LER), rivaroxaban 2.5 mg BID plus aspirin reduces acute limb ischemia (ALI) and MACE compared with aspirin alone (VOYAGER-PAD), balancing efficacy against increased bleeding risk in appropriate candidates (Bonaca 2020)📄. Recent evidence highlights significant practice variations in antithrombotic selection and the potential role of extended clopidogrel therapy (Wells 2025).

Endovascular therapy

• Aortoiliac interventions: angioplasty with selective stenting has been a historical standard, but primary stenting is now preferred for common and external iliac artery lesions due to superior patency (5-year patency >85%).(Norgren 2007)^,(Conte 2025) Kissing-balloon technique is used for aortic bifurcation lesions.
• Femoropopliteal interventions:
  • Plain old balloon angioplasty (POBA): initial treatment for short, focal lesions; limited by high restenosis rates (30–60% at 1 year).(Rutherford 2018)
  • Drug-coated balloons (DCB): paclitaxel-eluting balloons reduce restenosis compared with POBA (IN.PACT SFA and LEVANT 2 trials: ~65–70% vs ~50% primary patency at 1 year).(Tepe 2015)📄^,(Rosenfield 2015)📄 Recent guidelines for intermittent claudication (IC) favor DCB or drug-eluting stents (DES) over POBA for improved long-term patency.(Saadi 2025)^,(Conte 2025)
  • Nitinol bare-metal stents (BMS): self-expanding stents for long lesions or POBA failure; subject to in-stent restenosis and stent fracture.
  • Drug-eluting stents (DES): polymer-based paclitaxel stents (e.g., Zilver PTX) improve patency over BMS in intermediate-length SFA lesions.(Dake 2011)📄
  • Covered stents: ePTFE-lined stents (e.g., Viabahn) for long occlusions or aneurysmal segments; higher profile limits use in small vessels.
  • Atherectomy and intravascular lithoplasty: adjunctive therapies for heavily calcified lesions to facilitate balloon angioplasty and reduce dissection. However, routine use of atherectomy for IC is not recommended due to a lack of high-quality evidence demonstrating superior clinical outcomes over angioplasty alone.(Saadi 2025)^,(Conte 2025)
• Infrapopliteal interventions: balloon angioplasty remains the primary approach for tibial arteries in chronic limb-threatening ischemia (CLTI); drug-eluting stents or DCB may be considered for focal lesions. Retrograde (pedal) access is used when antegrade crossing fails. For patients with IC, infrapopliteal endovascular intervention is generally not recommended.(Conte 2025)
• Outcomes: endovascular therapy achieves high initial technical success (>90%), but restenosis remains a significant limitation, particularly in long femoropopliteal and tibial lesions, necessitating surveillance and reintervention.(Rutherford 2018)

Open surgery

Selection of bypass versus endovascular therapy in chronic limb-threatening ischemia (CLTI) is guided by conduit availability, anatomic complexity, and patient factors, including comorbidities and socioeconomic status (SES). In patients with diabetes mellitus (DM), the 2025 American College of Cardiology (ACC) scientific statement emphasizes that revascularization decisions should occur within a multidisciplinary framework to optimize limb salvage and manage the high systemic cardiovascular risk associated with the disease (Das 2025). Furthermore, SES has been identified as a critical determinant of access to care and long-term outcomes following revascularization for peripheral artery disease (PAD) (Zil 2024).

The Best Endovascular versus Best Surgical Therapy for Patients with Chronic Limb-Threatening Ischemia (BEST-CLI) trial demonstrated that when single-segment great saphenous vein (GSV) is available and anatomic complexity is high (Global Anatomic Staging System [GLASS] Stage III or extensive tibial disease), a bypass-first strategy produces superior limb salvage and amputation-free survival (AFS) compared with best endovascular therapy (cohort 1). Conversely, when adequate autogenous conduit is unavailable or anatomic complexity is lower (GLASS I–II), endovascular-first and bypass-first approaches achieve comparable outcomes (cohort 2). The Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial supports bypass-first strategy in patients with life expectancy exceeding 2 years, whereas angioplasty-first is appropriate for patients with limited longevity or prohibitive surgical risk (Farber 2022)^,(BASIL 2005)^,(Conte 2019)📄.

For popliteal artery aneurysm causing acute limb ischemia (ALI), see 5Chapter 5.

Hybrid procedures

Hybrid procedures combine open surgical and endovascular techniques in a single session or staged approach to treat multilevel disease efficiently. Representative hybrid strategy: common femoral artery (CFA) endarterectomy with patch angioplasty to restore inflow, followed by ipsilateral retrograde iliac artery stenting and/or antegrade superficial femoral artery (SFA) intervention. This approach leverages the durability of CFA endarterectomy while minimizing the morbidity of extensive open reconstruction. Hybrid procedures are increasingly utilized for complex multilevel occlusive disease, particularly in patients with aortoiliac inflow lesions combined with infrainguinal outflow disease, achieving outcomes comparable to staged or purely open approaches with shorter hospital stays (Bisdas 2013)📄^,(Jung 2018)📄.

Follow-up

Post-Revascularization Surveillance Protocol

• Surveillance:
  • Duplex ultrasound (DUS) at 1, 6, and 12 months post-intervention, then annually,(Gerhard 2016)📄^,(Almasri 2018)📄 to detect hemodynamically significant restenosis (peak systolic velocity [PSV] ratio >2.5 or >50% diameter reduction).(Moneta 2010)📄
  • Ankle-brachial index (ABI) or toe-brachial index (TBI)(Potier 2011)📄 and clinical examination at each visit to assess functional status and symptom recurrence.
• Restenosis:
  • More frequent after endovascular intervention (30–60% at 1–2 years)(Rutherford 2018) than open bypass. Hemodynamically significant restenosis (>70% stenosis or symptoms) warrants reintervention with repeat angioplasty, stenting, or conversion to bypass.
• Medical therapy: Lifelong antiplatelet therapy (aspirin or clopidogrel) and high-intensity statin therapy are mandatory to reduce systemic cardiovascular events and improve graft patency. Consider dual-pathway inhibition (rivaroxaban 2.5 mg BID + aspirin) in appropriate candidates post-revascularization.(Bonaca 2020)📄 In patients with diabetes mellitus, optimized glycemic control and comprehensive management of metabolic risk factors are essential to mitigate the high risk of major adverse limb events (MALE) and cardiovascular complications (Das 2025).
• Wound care: Multidisciplinary wound management—including pressure offloading, debridement, infection control, and glycemic optimization—is essential in chronic limb-threatening ischemia (CLTI) patients to maximize limb salvage after revascularization. This integrated approach is particularly critical for patients with diabetes to ensure timely healing and prevent recurrence (Das 2025).
• Registry participation and Outcomes: National registries (e.g., Swedvasc, Vascunet) track long-term outcomes and provide quality benchmarks for institutional performance evaluation and continuous quality improvement.(Mani 2020)📄^,(Swedvasc Annual 2022)^,(Vascunet Collaboration 2019) Surveillance and registry data should also account for socioeconomic status (SES), as lower SES is associated with poorer long-term outcomes and higher rates of major amputation following vascular interventions (Zil 2024).

Tables

Table 7.1. Fontaine and Rutherford Classification of peripheral artery disease (PAD)(Rutherford 2018)^,(Gornik 2024)^,(Uyagu 2022)

Table 7.2. Evidence-Based Medical Therapy in PAD(CAPRIE 1996)^,(Heart Protection 2002)^,(Amarenco 2006)📄^,(Eikelboom 2017)📄^,(Lane 2017)📄^,(Thompson 2002)^,(Gornik 2024)

Table 7.3. Endovascular vs Open Surgery for PAD(Norgren 2007)^,(Conte 2019)📄^,(Rutherford 2018)^,(Gornik 2024)

References

1. Fowkes FGR, et al. Global prevalence of PAD. Lancet. 2013. PubMed
2. Hiatt WR, et al. PAD as systemic disease. NEJM. 2015. PubMed
3. CAPRIE Steering Committee. Clopidogrel vs aspirin in ischemic disease. Lancet. 1996. PubMed
4. Eikelboom JW, et al. COMPASS trial. NEJM. 2017. PubMed
5. Conte MS, et al. Global Vascular Guidelines on CLTI. J Vasc Surg. 2019. PubMed
6. Aboyans V, et al. ESVS/SVS Guidelines on PAD. Eur J Vasc Endovasc Surg. 2018. PubMed
7. Gornik HL, et al. 2024 ACC/AHA/SVS Guideline for the Management of Lower Extremity Peripheral Artery Disease. J Am Coll Cardiol. 2024. PMID: 38752899.
8. Uyagu OD, et al. Quality assessment and comparative analysis on the recommendations of current guidelines on screening and diagnosis of peripheral arterial disease. BMJ Open. 2022. PMID: 36104133.

SVS WIfI wound classification system for CLTI risk stratification

The Society for Vascular Surgery (SVS) Wound, Ischemia, and foot Infection (WIfI) classification system stratifies chronic limb-threatening ischemia (CLTI) risk by combining three domains: Wound (W0–3), Ischemia (I0–3), and foot Infection (fI0–3) to generate an overall limb threat stage (Stages 1–4). Higher WIfI stages correlate with increased 1-year amputation risk and greater potential benefit from revascularization. Recent scientific statements from the American College of Cardiology (ACC) reinforce WIfI as the preferred classification system for risk stratification and clinical decision-making in adults with diabetes and CLTI (Das 2025). Objective ischemia thresholds include toe pressure (I0: ≥40 mmHg; I1: 30–39 mmHg; I2: <30 mmHg; I3: <30 mmHg with rest pain) and transcutaneous oxygen tension (TcPO₂; I0: ≥40 mmHg; I1: 30–39 mmHg; I2: <30 mmHg; I3: <30 mmHg with rest pain). WIfI should be documented at baseline and reassessed after revascularization to evaluate treatment response (Mills 2014)^,(Conte 2019)📄.

WIfI Limb Threat Stage Matrix

GLASS (Global Limb Anatomic Staging System) and Target Arterial Path (TAP)

The Global Limb Anatomic Staging System (GLASS) categorizes anatomic complexity using stages I–III based on lesion severity in the femoropopliteal and infrapopliteal segments along a selected Target Arterial Path (TAP)—the single most appropriate arterial route to the foot. GLASS stage, integrated with Wound, Ischemia, and foot Infection (WIfI) and patient risk factors, forms the PLAN framework (Patient risk, Limb severity [WIfI], ANatomic complexity [GLASS]) recommended in the Global Vascular Guidelines. This integrated assessment guides treatment strategy: lower GLASS stages (I–II) favor an endovascular-first approach, while higher complexity (GLASS III) with available autogenous conduit supports bypass-first revascularization (Conte 2019)📄.

GLASS Anatomic Staging

Bypass vs endovascular selection for CLTI (BASIL and BEST-CLI)

The BEST-critical limb ischemia (CLI) trial provides level-1 evidence for revascularization strategy in chronic limb-threatening ischemia (CLTI). In cohort 1 (patients with adequate single-segment great saphenous vein and complex anatomy—GLASS III or extensive tibial disease), bypass-first surgery achieved superior outcomes including reduced major amputation and improved amputation-free survival compared with best endovascular therapy. In cohort 2 (patients without adequate autogenous conduit or with less complex anatomy—GLASS I–II), bypass using prosthetic conduit and endovascular-first approaches demonstrated similar outcomes, supporting an endovascular-first strategy in this subset. The BASIL trial provides complementary long-term data: bypass-first strategy confers survival and amputation-free survival benefits in patients with anticipated longevity exceeding 2 years, whereas angioplasty-first is appropriate for patients with limited life expectancy or prohibitive surgical risk, given equivalent 6-month outcomes and reduced perioperative morbidity (Farber 2022)^,(BASIL 2005)^,(Conte 2019)📄.

Acute limb ischemia: initial management and timing of revascularization

Initial management of acute limb ischemia requires immediate systemic anticoagulation with intravenous unfractionated heparin (unless contraindicated) to prevent thrombus propagation, followed by rapid severity classification using the Rutherford system (I–III). Treatment selection is time-sensitive and severity-dependent: catheter-directed thrombolysis is appropriate for Rutherford I–IIa (viable or marginally threatened limb without motor deficit); Rutherford IIb (immediately threatened limb with motor deficit) requires emergent revascularization within hours, often via surgical thrombectomy; Rutherford III (irreversible ischemia with rigor) contraindicates revascularization due to high risk of reperfusion injury, systemic complications, and futility (Gerhard 2016)📄.

Post-revascularization antithrombotic therapy (VOYAGER-PAD)

The VOYAGER-peripheral arterial disease (PAD) trial demonstrated that dual-pathway inhibition with rivaroxaban 2.5 mg twice daily plus aspirin after lower extremity revascularization significantly reduces acute limb ischemia and major adverse cardiovascular events (MACE) compared with aspirin alone, though at the cost of increased major bleeding (TIMI major bleeding 2.65% vs 1.87%; p=0.07). This regimen is recommended for appropriate patients without contraindications or high bleeding risk, balancing the absolute risk reduction in limb and cardiovascular events (~1.5% per year) against bleeding complications (Bonaca 2020)📄.

Post-Revascularization Antithrombotic Options

Chronic limb-threatening ischemia (CLTI) modern paradigm

Chronic limb-threatening ischemia (CLTI) represents the most severe manifestation of 10peripheral artery disease, characterized by rest pain, tissue loss, or gangrene lasting more than 2 weeks. Contemporary classification systems provide a structured framework for decision-making:

• Wound, Ischemia, and foot Infection (WIfI) staging (Wound, Ischemia, foot Infection) stratifies limb-threat severity and guides revascularization decisions.
• GLASS classification (Global Limb Anatomic Staging System) categorizes anatomic complexity of arterial disease.
• PLAN concept (Patient risk, Limb threat, ANatomic pattern) integrates patient-specific factors to individualize revascularization strategy.

Hemodynamic assessment is critical in CLTI. A toe pressure less than 30 mmHg or transcutaneous oxygen tension (TcPO₂) less than 25–30 mmHg indicates severe ischemia with poor wound-healing potential. In diabetic patients with medial arterial calcification, toe pressures provide more reliable assessment than ankle pressures, as calcified arteries may be noncompressible and yield falsely elevated ankle-brachial indices (Potier 2011)📄^,(Conte 2019)📄.

For venous causes of leg ulcers, see 13CVI.

Drug-coated device (paclitaxel) safety

The safety of paclitaxel-coated devices in femoropopliteal peripheral artery disease has been the subject of considerable controversy. A 2018 meta-analysis suggested increased late mortality with paclitaxel-coated balloons and stents compared to uncoated devices (Katsanos 2018)📄, prompting regulatory warnings and clinical concern.

However, subsequent large real-world analyses, including the Medicare-based SAFE-peripheral arterial disease (PAD) study, did not confirm an increased mortality signal through mid-term follow-up (Secemsky 2021)📄. Multiple additional analyses have yielded conflicting results, and the biological mechanism for any potential mortality signal remains unclear.

Regulatory agencies have issued advisories recommending informed discussion with patients about the uncertain risks and benefits. Current practice emphasizes shared decision-making, consideration of alternative technologies (plain balloon angioplasty, bare-metal stents, atherectomy), and individualized risk-benefit assessment. Clinicians should remain aware of evolving evidence and regulatory guidance in this area.