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.^[1]

• Global prevalence: >200 million people affected, with rising incidence due to aging populations and increasing rates of diabetes and smoking ^[2].^[3]
• Clinical spectrum: from asymptomatic disease → claudication → chronic limb-threatening ischemia (CLTI) → amputation.^[4]
• Associated risk: 10PAD patients have a 2–6× higher risk of myocardial infarction, stroke, and cardiovascular death ^[5].
• Clinical burden: ~25% of patients with CLTI undergo major amputation within 1 year, despite modern therapies.^[6]
• Overlap with other vascular diseases: patients often have concurrent 4Aneurysms, 7carotid disease, or coronary artery disease.^[5]

Atherosclerosis (dominant cause)

• Inflow lesions: aortoiliac.
• Outflow lesions: femoropopliteal, tibial, pedal.^[7]
• Risk factors: smoking, diabetes mellitus, hypertension, dyslipidemia, chronic kidney disease, obesity, sedentary lifestyle.^[4]

Other etiologies

• Embolism: cardiac (AF, mural thrombus) or proximal arterial source.^[4] See 12VTE for thromboembolism principles.
• Thrombosis: acute occlusion of pre-existing stenosis.
• Vasculitis: Takayasu arteritis, Buerger disease, giant cell arteritis.^[8]
• Trauma/Iatrogenic: vascular injury, catheterization.^[9] See 16EVTM for trauma management.
• Radiation-induced arterial disease.^[10]

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.^[11]

Patterns of Disease

• Aortoiliac: Leriche syndrome (claudication, impotence, absent femoral pulses).^[10]
• Femoropopliteal: most common site.
• Infrapopliteal/tibial: common in diabetes/renal failure, often CLTI.^[4]

Asymptomatic disease

• Detected by abnormal ABI (<0.9).^[12]
• Still associated with high systemic CV risk.^[5]

Claudication

• Exercise-induced, reproducible muscle pain relieved by rest.^[10]
• Localizes to site: buttock (aortoiliac), thigh (femoral), calf (femoropopliteal), foot (tibial).^[10]

Chronic Limb-Threatening Ischemia

Risk stratification: The Society for Vascular Surgery 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 ^[13],[14].

WIfI Classification Summary

Acute Limb Ischemia

• Classic presentation—the 6 Ps: Pain, Pallor, Pulselessness, Paresthesia, Paralysis, and Poikilothermia (coolness).^[10] Motor and sensory deficits indicate advanced ischemia requiring urgent intervention.
• Immediate management: Systemic anticoagulation with intravenous unfractionated heparin (unless contraindicated) should be initiated immediately to prevent thrombus propagation. Severity staging using the Rutherford classification (I–III) guides treatment urgency. 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 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 ^[4].

Rutherford ALI Classification

Clinical evaluation

Ankle-Brachial Index (ABI): <0.9 indicates PAD; <0.5 indicates severe ischemia; >1.3 suggests arterial calcification (medial sclerosis), commonly seen in diabetes and chronic kidney disease.^[12]

Imaging Studies

Imaging Modalities for PAD

• Duplex Ultrasound: first-line imaging modality; uses peak systolic velocity (PSV) ratios to grade stenosis severity (PSV ratio >2.0 indicates ≥50% stenosis).^[15]
• Computed Tomography Angiography (CTA): provides detailed anatomic mapping of the entire arterial tree; preferred for planning revascularization in most patients.^[4]
• Magnetic Resonance Angiography (MRA): alternative cross-sectional imaging when CTA is contraindicated (renal insufficiency, contrast allergy); gadolinium-based agents carry lower nephrotoxicity risk.^[16]
• Digital Subtraction Angiography (DSA): intra-procedural gold standard for anatomic assessment; allows simultaneous diagnosis and therapeutic intervention.^[17] 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.^[4]
• 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.^[18]

Medical Therapy

• Risk factor modification: smoking cessation (most critical intervention)^[19],[20], blood pressure control (target <130/80 mmHg), optimal diabetes management (HbA1c <7%), and lipid management.^[4]
• Supervised exercise therapy: structured walking programs (3 sessions/week, 30–60 minutes) improve claudication distance by 50–200% and are a Class I recommendation (Level of Evidence A) ^[21].
• Antiplatelet therapy: aspirin (75–325 mg daily) or clopidogrel (75 mg daily). The CAPRIE trial demonstrated clopidogrel superiority in the PAD subgroup (8.7% relative risk reduction; p=0.0028) ^[22].
• Statin therapy: high-intensity therapy (e.g., atorvastatin 40–80 mg) reduces cardiovascular events and limb events (HPS, SPARCL trials).^[23],[24] Target 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 ^[25].
• Cilostazol: phosphodiesterase-3 inhibitor that increases walking distance and improves quality of life;^[26] 100 mg twice daily (not approved in Europe due to concerns about cardiac safety).
• Post-revascularization antithrombotic therapy: after lower extremity revascularization, rivaroxaban 2.5 mg BID plus aspirin reduces acute limb ischemia and MACE compared with aspirin alone (VOYAGER-PAD), balancing efficacy against increased bleeding risk in appropriate candidates ^[27].

Endovascular therapy

• Aortoiliac interventions: angioplasty with selective stenting is the standard approach; primary stenting is preferred for iliac artery lesions due to superior patency (5-year patency >85%).^[7] 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).^[10]
• 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).^[28],[29]
• 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.^[30]
• 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.
• Infrapopliteal interventions: balloon angioplasty remains the primary approach for tibial arteries in CLTI; drug-eluting stents or DCB may be considered for focal lesions. Retrograde (pedal) access is used when antegrade crossing fails.
• 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.^[10]

Open surgery

Selection of bypass versus endovascular therapy in CLTI is guided by conduit availability, anatomic complexity, and patient factors. The BEST-CLI trial demonstrated that when single-segment great saphenous vein is available and anatomic complexity is high (GLASS Stage III or extensive tibial disease), a bypass-first strategy produces superior limb salvage and amputation-free survival 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 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 ^{[31],[32],[14]}.

For popliteal artery aneurysm causing acute limb ischemia, 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 ^[33],[34].

Follow-up

Post-Revascularization Surveillance Protocol

• Surveillance:
• Duplex ultrasound (DUS) at 1, 6, and 12 months post-intervention, then annually,^[4],[35] to detect hemodynamically significant restenosis (PSV ratio >2.5 or >50% diameter reduction).^[15]
• Ankle-brachial index (ABI) or toe-brachial index (TBI)^[36] 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)^[10] 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.^[27]
• Wound care: Multidisciplinary wound management—including pressure offloading, debridement, infection control, and glycemic optimization—is essential in CLTI patients to maximize limb salvage after revascularization.
• Registry participation: National registries (e.g., Swedvasc, Vascunet) track long-term outcomes and provide quality benchmarks for institutional performance evaluation and continuous quality improvement.^{[37],[38],[39]}

Tables

Table 7.1. Fontaine and Rutherford Classification of PAD^[10]

Table 7.2. Evidence-Based Medical Therapy in PAD^{[22],[23],[24],[25],[21],[26]}

Table 7.3. Endovascular vs Open Surgery for PAD^{[7],[14],[10]}

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

SVS WIfI wound classification system for CLTI risk stratification

The SVS WIfI classification system stratifies 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. Objective ischemia thresholds include toe pressure (I0: ≥40 mmHg; I1: 30–39 mmHg; I2: <30 mmHg; I3: <30 mmHg with rest pain) and 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 ^[13],[14].

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 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 ^[14].

GLASS Anatomic Staging

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

The BEST-CLI trial provides level-1 evidence for revascularization strategy in 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 ^{[31],[32],[14]}.

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 ^[4].

Post-revascularization antithrombotic therapy (VOYAGER-PAD)

The VOYAGER-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 ^[27].

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:

• 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 ^[36],[6].

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 ^[40], prompting regulatory warnings and clinical concern.

However, subsequent large real-world analyses, including the Medicare-based SAFE-PAD study, did not confirm an increased mortality signal through mid-term follow-up ^[41]. 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.