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Lower extremity peripheral artery disease

Atherosclerotic lower extremity peripheral artery disease in adults, from screening and physiologic testing through medical therapy, exercise, revascularization, chronic limb-threatening ischemia, and acute limb ischemia.

Definition and the four clinical subsets of peripheral artery disease

Lower extremity peripheral artery disease (PAD) is atherosclerotic obstruction of the arteries supplying the legs, from the infrarenal aorta to the pedal arteries. It is a manifestation of systemic atherosclerosis and a clinical form of atherosclerotic cardiovascular disease (ASCVD). The 2024 American College of Cardiology/American Heart Association (ACC/AHA) multisociety guideline organizes patients with objectively confirmed PAD into four clinical subsets. The subset sets the urgency, the tests, and the goals of treatment, and patients move between subsets over time.

Adapted from the 2024 ACC/AHA guideline, Table 4. CLTI replaces the older term critical limb ischemia, which implied a single perfusion threshold.

Epidemiology, risk factors, and health disparities in peripheral artery disease

PAD affects an estimated 10 to 12 million adults older than 40 years in the United States. Worldwide estimates range from at least 113 million to as many as 236 million people. In a systematic review of population studies that defined PAD by an ABI of 0.90 or less, prevalence rose steadily with age to about 21% at 80 to 84 years in high-income countries, where women had a slightly higher prevalence than men up to 75 years of age.

Smoking and diabetes are the strongest risk factors: 80% to 90% of patients revascularized for severe limb symptoms are current smokers, and diabetes carries an adjusted hazard ratio of about 5.5 for amputation. Hypertension, dyslipidemia, chronic kidney disease, elevated lipoprotein(a), and family history complete the profile. The guideline defines the population at increased risk, in whom history, examination, and ABI screening are directed.

From the 2024 ACC/AHA guideline, Table 5. The guideline also lists PAD-related risk amplifiers that raise the risk of major adverse cardiovascular events (MACE), major adverse limb events (MALE), or both: age 75 years or older, diabetes, ongoing smoking or other tobacco use, chronic kidney disease, end-stage kidney disease, polyvascular disease, microvascular disease, and depression. Incorporating them into treatment decisions is a Class 1 recommendation.

Health disparities. The 2024 guideline added a section on health disparities and recommends that clinicians and health systems identify and limit them (Class 1). Estimated lifetime risk of PAD is about 30% in Black men and 28% in Black women, compared with about 19% in White and 22% in Hispanic adults. Black patients present more often with CLTI. They receive statins, antiplatelet therapy, and supervised exercise less often and have a 2- to 4-fold higher risk of amputation, more often without an attempt at revascularization. American Indian and Hispanic populations and rural residents also have higher amputation rates. Women present 10 to 20 years later than men, with more atypical symptoms and more advanced disease. They are more likely to undergo above-knee amputation and have higher periprocedural mortality.

Atherosclerotic and nonatherosclerotic causes of limb ischemia

Atherosclerosis causes the large majority of chronic lower extremity arterial disease in adults. Its distribution follows risk factors. Smokers more often have aortoiliac and femoropopliteal disease, whereas diabetes and chronic kidney disease favor infrapopliteal (tibial) disease with heavy medial calcification, the pattern most often associated with CLTI and noncompressible ankle arteries. The superficial femoral artery in the adductor canal is the most frequently involved segment.

Nonatherosclerotic disease is considered when symptoms begin before about 50 years of age, risk factors are absent, or the distribution is atypical, because each entity has a different treatment.

Renal artery stenosis and fibromuscular dysplasia of the renal arteries are discussed with secondary causes of hypertension.

Pathophysiology of exertional and rest ischemia

Flow through a stenosis falls steeply once the lumen is narrowed by about 50% in diameter, because resistance varies inversely with the fourth power of the radius and energy is lost to turbulence at the exit of the lesion. At rest, collateral channels and distal arteriolar dilation maintain perfusion pressure, so many patients with occlusions have no symptoms. During walking, calf muscle oxygen demand rises, distal resistance falls, and the fixed proximal lesion prevents a matching rise in flow. Ankle pressure falls, the muscle becomes ischemic, and claudication follows.

The limitation is not purely hemodynamic. Chronic ischemia damages skeletal muscle mitochondria, causes myofiber atrophy and denervation, and impairs endothelium-dependent vasodilation, which explains why walking performance correlates only loosely with the ABI and why exercise training improves walking without changing the ABI.

In CLTI, resting perfusion no longer meets the metabolic needs of the skin and distal tissues, typically because disease involves several levels in series (for example, femoropopliteal and tibial occlusions together). Rest pain begins in the forefoot, worsens with elevation, and improves with dependency, because gravity adds hydrostatic pressure to the distal perfusion pressure. Healing a wound requires more perfusion than maintaining intact skin, and diabetes adds neuropathy, impaired collateral formation, and susceptibility to infection.

Natural history, cardiovascular risk, and polyvascular disease

The dominant risk in PAD is cardiovascular. In the ABI Collaboration meta-analysis of 16 population cohorts, the relation between ABI and mortality was reverse J-shaped, with the lowest risk at an ABI of 1.11 to 1.40. Ten-year cardiovascular mortality was 18.7% in men with an ABI of 0.90 or less and 4.4% in men with a normal ABI (hazard ratio 4.2), and 12.6% compared with 4.1% in women (hazard ratio 3.5). The excess risk persisted after adjustment for the Framingham risk score. A noncompressible ABI above 1.40 also marks increased mortality and is not a normal result.

Asymptomatic PAD carries a systemic risk well above that of people with a normal ABI. Event rates rise stepwise with each additional affected vascular bed. In EUCLID, myocardial infarction occurred in 4.9% of patients with symptomatic PAD over a median of 30 months despite antiplatelet therapy. Polyvascular disease, diabetes, heart failure, and a high-risk limb presentation (CLTI, prior amputation, or prior revascularization) identify the patients with the highest event rates and the largest absolute benefit from low-dose rivaroxaban with aspirin.

Most patients with claudication remain stable or improve with exercise and risk factor control; progression to CLTI is more likely with diabetes, continued smoking, chronic kidney disease, and a low ABI. ALI is uncommon (1.7% over 30 months in a contemporary trial) and concentrates in patients with prior revascularization, atrial fibrillation, or an ABI of 0.60 or less. A foot ulcer in a patient with PAD is associated with a 40% mortality at 5 years.

Claudication, atypical leg symptoms, and their differential diagnosis

Typical claudication is aching, cramping, fatigue, or tightness in a muscle group that occurs consistently during walking, does not start at rest, worsens uphill or at a faster pace, and resolves within about 10 minutes of standing still. The symptomatic muscle group lies one level below the obstruction. Calf claudication indicates femoropopliteal disease, thigh and buttock claudication indicates aortoiliac disease, and foot claudication suggests tibial or pedal disease. Bilateral buttock and thigh claudication with erectile dysfunction and absent femoral pulses is the Leriche syndrome of aortoiliac occlusion.

Classic claudication is the minority presentation. Many patients describe leg fatigue, weakness, or numbness while walking, or discomfort that needs more than 10 minutes to resolve, and the 2024 guideline includes these "other nonjoint-related exertional leg symptoms" in chronic symptomatic PAD. Neuropathy, reduced activity, and arthritis further blunt the history.

Adapted from the 2024 ACC/AHA guideline, Table 7. A normal resting and exercise ABI excludes hemodynamically significant PAD as the cause of exertional leg symptoms.

Vascular examination of the legs and feet

The examination is performed with shoes and socks removed and is repeated regularly in patients at increased risk (Class 1). Blood pressure is measured in both arms. A systolic difference of 15 to 20 mm Hg or more suggests subclavian or innominate stenosis, and the higher arm pressure is used for the ABI. Femoral, popliteal, dorsalis pedis, and posterior tibial pulses are palpated and graded 0 (absent), 1 (diminished), 2 (normal), or 3 (bounding). Examiners agree well on absent pulses and poorly on diminished ones, and an isolated absent dorsalis pedis pulse can be a normal variant. A widened or prominent popliteal pulse suggests a popliteal aneurysm.

Bruits over the abdomen, flank, or groin indicate turbulent flow. The skin shows hair loss, shiny atrophic skin, thickened nails, coolness, and delayed capillary refill. In the elevation-dependency (Buerger) test, pallor of the sole when the leg of a supine patient is elevated indicates severe ischemia. Dependent rubor with slow venous filling when the leg is lowered reflects maximal arteriolar dilation in a chronically ischemic foot. The feet are inspected between the toes, at the heels, and at pressure points for fissures, calluses, ulcers, and gangrene.

Neuroischemic ulcers are the most common pattern in diabetes. A wound that persists despite adequate perfusion raises the alternative diagnoses in guideline Table 8: vasculitic, inflammatory, infectious, malignant, and drug-induced ulcers.

Ankle-brachial index: technique and reporting categories

The resting ABI is the first diagnostic test in a patient whose history or examination suggests PAD (Class 1). It is the ratio of the higher of the dorsalis pedis and posterior tibial systolic pressures in each leg to the higher of the two brachial systolic pressures. Compared with angiographic stenosis, the resting ABI has a sensitivity of 69% to 79% and a specificity of 83% to 99% in symptomatic patients. Sensitivity is lower in diabetes and chronic kidney disease, where medial calcification raises ankle pressures.

The AHA scientific statement on ABI measurement standardizes the method. The patient rests supine for 5 to 10 minutes with the head and heels supported. Cuffs are sized so that the bladder encircles at least 40% of the limb circumference, and the ankle cuff is wrapped straight with its lower edge 2 cm above the medial malleolus. Systolic pressures are recorded with a handheld continuous-wave Doppler probe in each arm and in the dorsalis pedis and posterior tibial arteries of each ankle. The sequence is the same for every patient (for example, right arm, right posterior tibial, right dorsalis pedis, left posterior tibial, left dorsalis pedis, left arm). If the first arm pressure exceeds the second by 10 mm Hg or more, it is repeated at the end.

Reporting categories from the 2024 ACC/AHA guideline (Class 1). A decrease in ABI of more than 0.15 on serial testing indicates significant progression. A systolic difference of 15 mm Hg or more between arms is itself associated with PAD and with higher cardiovascular mortality.

Ankle-brachial index, toe-brachial index, and WIfI ischemia grade from limb pressures

The WIfI ischemia grade comes from toe pressure when one is entered, because the Global Vascular Guidelines prefer it in CLTI, and from the ABI otherwise. Indices are rounded to two decimals before categorization.

ABI = higher ankle pressure (dorsalis pedis or posterior tibial) ÷ higher brachial pressure. TBI = great-toe pressure ÷ higher brachial pressure; 0.70 or less is abnormal. The example leg on the right (ABI 0.53) is diagnostic of PAD; the left ankle arteries are noncompressible (ABI 1.50), and a toe pressure of 42 mm Hg gives a TBI of 0.30 and WIfI ischemia grade 1. The WIfI system was published with a noncompressibility threshold of 1.30; the 2024 ACC/AHA threshold of 1.40 is used here.

Toe pressures, exercise ABI, segmental pressures, waveforms, and tissue perfusion

Toe pressure and toe-brachial index. Digital arteries rarely calcify, so a toe pressure measured with a small cuff and a photoplethysmographic sensor remains valid when the ankle arteries are noncompressible. Toe pressure and TBI with waveforms are performed in suspected PAD when the resting ABI is above 1.40 (Class 1), and a TBI of 0.70 or less establishes the diagnosis. An absolute toe pressure below 30 mm Hg indicates severe ischemia and is associated with major amputation and poor wound healing. In CLTI, ABI alone is inadequate. Nearly one-quarter of patients with CLTI have an ABI of 0.90 to 1.40, and only 58% of patients with abnormal toe pressures have an abnormal ABI. Toe pressure or TBI with waveforms, transcutaneous oxygen pressure (TcPO₂), and skin perfusion pressure are reasonable to establish CLTI (Class 2a) and to estimate wound-healing potential (Class 2a). The Global Vascular Guidelines require ischemic rest pain to be accompanied by an ABI below 0.40, ankle pressure below 50 mm Hg, toe pressure below 30 mm Hg, TcPO₂ below 30 mm Hg, or flat or minimally pulsatile pulse volume recordings, equivalent to WIfI ischemia grade 3.

Exercise treadmill ABI. A patient with exertional nonjoint leg symptoms and a normal or borderline resting ABI undergoes treadmill exercise ABI testing (Class 1). Ankle and brachial pressures are repeated within 1 to 5 minutes after exercise and until recovery. Criteria vary; the AHA statement accepts a postexercise fall in ankle pressure of more than 30 mm Hg or in ABI of more than 20%. In patients with an abnormal resting ABI, the exercise test documents claudication onset time, peak walking time, and the nature of symptoms, providing a baseline against which exercise therapy and revascularization are judged (Class 2a).

Segmental pressures and pulse volume recordings (PVR). Cuffs from thigh to ankle localize disease by the pressure drop between adjacent levels (Class 2a); a low high-thigh pressure indicates aortoiliac or common femoral disease. Pulse volume recordings, independent of arterial compressibility, flatten distal to an obstruction.

Doppler waveforms. The normal peripheral artery waveform is triphasic: a sharp systolic upstroke, brief early diastolic flow reversal reflecting high peripheral resistance, and late forward flow. Distal to a significant stenosis, the reversal disappears and the waveform becomes biphasic, then monophasic with a delayed upstroke, a rounded peak, and continuous diastolic flow. A monophasic ankle signal with a normal-appearing ABI exposes pressures falsely elevated by calcification.

Screening for peripheral artery disease

Screening with the resting ABI, with or without pulse volume recordings or Doppler waveforms, is reasonable in patients at increased risk of PAD (Class 2a) and is not recommended in patients who are not at increased risk and have no suggestive findings (Class 3: No Benefit). The rationale is that asymptomatic PAD identifies a patient with clinical ASCVD who qualifies for intensive risk reduction and foot care. Population yield below 50 years of age without risk factors is about 1%, and in a national survey about 95% of participants with an abnormal ABI had at least one atherosclerotic risk factor.

The US Preventive Services Task Force reached a different conclusion in 2018. It found the evidence insufficient to assess the balance of benefits and harms of ABI screening in asymptomatic adults (I statement), largely because two trials of aspirin in people with a low screening ABI showed no benefit. The ACC/AHA recommendation applies to defined high-risk groups in whom the result changes treatment intensity.

Duplex ultrasound, CT angiography, MR angiography, and catheter angiography

Anatomic imaging is obtained when revascularization is being considered. Duplex ultrasound, CT angiography (CTA), MR angiography (MRA), or catheter angiography is useful in functionally limiting claudication with an inadequate response to guideline-directed management and therapy (GDMT) including structured exercise (Class 1) and in CLTI (Class 1). Noninvasive imaging may be considered to establish the diagnosis when physiologic testing is inconclusive (Class 2b). CTA, MRA, or catheter angiography performed solely for anatomic assessment in a patient who is not a revascularization candidate exposes the patient to risk without benefit (Class 3: Harm).

Contrast-associated kidney injury. Patients with PAD often have diabetes and chronic kidney disease. Strategies that lower the risk of contrast-associated kidney injury are duplex ultrasound or noncontrast MRA as the first test, minimal contrast volume, carbon dioxide angiography for the aortoiliac and femoropopliteal segments, withholding nephrotoxic drugs, and intravenous isotonic fluid in high-risk patients. In advanced kidney disease, diagnostic angiography combined with treatment in one session can use less contrast than CTA followed by a separate procedure. PRESERVE randomized 5,177 high-risk patients undergoing coronary or noncoronary angiography. Neither intravenous sodium bicarbonate compared with saline nor oral acetylcysteine compared with placebo reduced death, dialysis, or persistent kidney injury at 90 days. When the estimated glomerular filtration rate is below 30 mL/min/1.73 m², MRA uses noncontrast sequences or gadolinium agents with a low reported risk of nephrogenic systemic fibrosis.

Clinical classification: Fontaine and Rutherford

The Fontaine and Rutherford classifications grade chronic limb ischemia by symptoms, and both separate claudication from CLTI. Rutherford added objective hemodynamic criteria. Neither grades wound extent or infection, which the WIfI system addresses.

Rutherford criteria from the 1997 revised reporting standards (treadmill test at 2 mph on a 12% grade for 5 minutes). PVR, pulse volume recording. Fontaine stage II is subdivided into mild (IIa) and moderate to severe (IIb) claudication.

WIfI threatened-limb staging

The Society for Vascular Surgery (SVS) WIfI system grades the threatened limb on three axes: wound extent (W), ischemia (I), and foot infection (fI), each from 0 to 3. Perfusion is one of three determinants of limb threat, which suits the diabetic foot, where a moderate perfusion deficit with a deep infected wound threatens the limb as much as severe ischemia. Expert consensus assigned each of the 64 combinations to one of four clinical stages of 1-year amputation risk and to an estimated benefit of revascularization. Stage correlates with amputation, wound healing time, and amputation-free survival. The Global Vascular Guidelines endorse WIfI staging for every patient with suspected CLTI, repeated after revascularization, foot surgery, or treatment of infection, and the 2024 ACC/AHA guideline recommends objective classification of the threatened limb when primary amputation or palliative care is considered (Class 1) and finds retrospective review of institutional outcomes with limb-threat classification tools useful (Class 2a).

From the SVS WIfI system and the Global Vascular Guidelines (Tables 3.2 to 3.5). Toe pressure or TcPO₂ is used when the ABI is noncompressible. Stage 5 (not in the matrix) denotes an unsalvageable foot.

Stage 1 very low, stage 2 low, stage 3 moderate, and stage 4 high estimated 1-year amputation risk, from the consensus matrix of the SVS WIfI system. The example, W1 I2 fI1, is stage 3 with a high estimated benefit of revascularization. Revascularization benefit assumes that infection is controlled.

GLASS anatomic staging and the PLAN framework

The Global Vascular Guidelines introduced the Global Limb Anatomic Staging System (GLASS) to describe infrainguinal disease in CLTI by its complexity for endovascular treatment. The treating physician selects a target arterial path, the route of in-line flow from groin to ankle, usually through the least diseased tibial artery. The femoropopliteal and infrapopliteal segments of that path are graded 0 to 4, and severe calcification (more than 50% of the circumference, or bulky "coral reef" plaque) raises a segment grade by one. A matrix combines the two grades into stage I, II, or III. Inflow disease is staged separately, and a pedal modifier (P0 to P2) describes the arteries crossing the ankle; P2 denotes that no named artery crosses the ankle into the foot.

GLASS grades and stage matrix from the Global Vascular Guidelines (Figs 5.2 and 5.3, Table 5.3). Expected outcomes of endovascular treatment: stage I, technical failure <10% and 1-year limb-based patency >70%; stage II, technical failure <20% and patency 50% to 70%; stage III, technical failure >20% or patency <50%. SFA, superficial femoral artery; IP, infrapopliteal grade.

Aortoiliac inflow disease is staged I (iliac stenoses, occlusion of the common or external iliac artery but not both, infrarenal aortic stenosis) or II (aortic or combined iliac occlusion, diffuse or small iliac arteries, aneurysm, diffuse in-stent restenosis), with suffix B for common femoral stenosis above 50%.

GLASS is one axis of the PLAN framework: Patient risk, Limb severity (WIfI), and ANatomic complexity (GLASS). An average-risk patient has an anticipated periprocedural mortality below 5% and a 2-year survival above 50%. For average-risk patients with advanced limb threat and complex (GLASS III) disease, the Global Vascular Guidelines favor bypass with autologous vein; less complex anatomy, intermediate limb threat, or high patient risk favors endovascular treatment.

Antiplatelet and low-dose anticoagulant therapy

Antithrombotic therapy in PAD prevents MACE and MALE, which includes ALI and major amputation. In asymptomatic PAD, trials of aspirin after a low screening ABI showed no net benefit. In CAPRIE, clopidogrel reduced the composite of ischemic stroke, myocardial infarction, or vascular death compared with aspirin 325 mg (5.32% compared with 5.83% per year, relative reduction 8.7%), with the largest relative benefit in the PAD subgroup. In EUCLID, ticagrelor was not superior to clopidogrel (10.8% compared with 10.6%), and ALI occurred in 1.7% of each group.

Dual-pathway inhibition. In the PAD population of COMPASS (7,470 patients with stable PAD of the legs or carotid arteries), rivaroxaban 2.5 mg twice daily plus aspirin 100 mg reduced cardiovascular death, myocardial infarction, or stroke compared with aspirin alone (5% compared with 7%, hazard ratio 0.72) and MALE including major amputation (1% compared with 2%, hazard ratio 0.54), at the cost of more major bleeding (3% compared with 2%, hazard ratio 1.61). The excess was mostly gastrointestinal, with no increase in fatal or critical-organ bleeding. VOYAGER PAD randomized 6,564 patients within 10 days of lower extremity revascularization. The same regimen reduced the composite of ALI, major amputation, myocardial infarction, ischemic stroke, or cardiovascular death at 3 years (17.3% compared with 19.9%, hazard ratio 0.85), mainly through fewer ALI events. Thrombolysis in Myocardial Infarction (TIMI) major bleeding was not significantly increased (2.65% compared with 1.87%), whereas International Society on Thrombosis and Haemostasis (ISTH) major bleeding was (5.94% compared with 4.06%). Both trials excluded patients at high bleeding risk.

Vorapaxar. Vorapaxar, an antagonist of the platelet thrombin receptor (protease-activated receptor-1), was tested in 3,787 patients with symptomatic PAD in TRA2°P-TIMI 50. It did not reduce cardiovascular death, myocardial infarction, or stroke (11.3% compared with 11.9%), but it reduced hospitalization for ALI (2.3% compared with 3.9%, hazard ratio 0.58) and peripheral revascularization (18.4% compared with 22.2%), with more moderate or severe bleeding. Vorapaxar is contraindicated after stroke, transient ischemic attack, or intracranial hemorrhage, and its net benefit in PAD is uncertain (Class 2b).

Full-intensity anticoagulation. In WAVE, warfarin added to antiplatelet therapy did not reduce cardiovascular events (12.2% compared with 13.3%) and tripled life-threatening bleeding (4.0% compared with 1.2%).

Lipid, blood pressure, diabetes, and smoking targets in peripheral artery disease

Lipids. High-intensity statin therapy aimed at a reduction in low-density lipoprotein (LDL) cholesterol of 50% or more is indicated in every patient with PAD (Class 1). Adding ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is reasonable when LDL cholesterol remains 70 mg/dL or higher on maximally tolerated statin therapy (Class 2a). Goals, sequencing, and drug choice are covered on the dyslipidemia and LDL-lowering page.

Blood pressure. Antihypertensive therapy is recommended to reduce MACE (Class 1), with a goal below 130/80 mm Hg (Class 1). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are recommended selectively to reduce MACE (Class 1). Beta-blockers do not worsen claudication or limb outcomes and are not contraindicated in PAD; they are used whenever coronary disease, heart failure, or arrhythmia calls for them. Treatment details are on the hypertension page.

Diabetes. Glucagon-like peptide-1 receptor agonists (liraglutide, semaglutide) and sodium-glucose cotransporter 2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) are recommended in PAD with type 2 diabetes to reduce MACE (Class 1). Glycemic control may improve limb outcomes (Class 2b); in EUCLID, each 1% increase in hemoglobin A1c was associated with a 14% higher relative risk of MACE. About half of patients with CLTI have diabetes, and diabetes care is coordinated by the team (Class 1).

Smoking and tobacco. Tobacco users are advised at every visit to quit (Class 1) and are offered a plan that combines varenicline, bupropion, or nicotine replacement with counseling or referral (Class 1). Avoidance of secondhand smoke is recommended (Class 1). Continued smoking accelerates progression and lowers the patency of every type of revascularization.

Other measures. Annual influenza vaccination is recommended (Class 1), and a diet rich in vegetables, fruits, legumes, nuts, whole grains, and fish is beneficial (Class 2a). B-vitamin supplementation for homocysteine, vitamin D supplementation, and chelation therapy do not reduce MACE (Class 3: No Benefit).

Supervised exercise therapy and structured community exercise

Structured exercise is the foundation of treatment for walking impairment in PAD. Supervised exercise therapy (SET) is recommended in chronic symptomatic PAD (Class 1), as is a structured community-based program with behavioral change techniques (Class 1). SET or a structured community program is offered as initial treatment of functionally limiting claudication (Class 1) and after revascularization (Class 1). Nonwalking structured programs such as arm ergometry or recumbent stepping are beneficial (Class 2a), whereas the usefulness of unstructured advice to "go and walk" is uncertain (Class 2b). In a Cochrane review of 32 trials with 1,835 participants, exercise programs improved maximal and pain-free walking distance compared with usual care.

Adapted from the 2024 ACC/AHA guideline, Table 14. Despite Class 1 status and Medicare coverage, 1.3% of Medicare beneficiaries with newly diagnosed claudication enrolled in SET during the first 19 months of coverage, and 5.1% of those enrolled completed all 36 sessions.

Exercise improves walking at least as much as revascularization for claudication. In CLEVER (111 patients with aortoiliac disease), peak walking time at 6 months increased by 5.8 minutes with supervised exercise, 3.7 minutes with stenting, and 1.2 minutes with medical care alone; stenting produced greater gains in patient-reported quality of life. In ERASE, endovascular revascularization plus supervised exercise increased maximal walking distance more than exercise alone (an additional 282 m at 12 months). Walking performance and quality of life are measured at baseline and during follow-up (Class 1) with treadmill claudication onset and peak walking time, the 6-minute walk test, and questionnaires such as the Walking Impairment Questionnaire and the Vascular Quality of Life Questionnaire.

Cilostazol and other drugs for claudication

Cilostazol, a phosphodiesterase-3 inhibitor with antiplatelet and vasodilator effects, is recommended to improve leg symptoms and walking distance in claudication (Class 1). In a Cochrane review of 16 trials with 3,972 participants, cilostazol increased initial claudication distance by a mean of about 26 m compared with placebo, without a demonstrated reduction in cardiovascular events. The usual dose is 100 mg twice daily, taken at least 30 minutes before or 2 hours after breakfast and dinner, reduced to 50 mg twice daily with strong or moderate inhibitors of CYP3A4 (such as ketoconazole, itraconazole, erythromycin, or diltiazem) or with inhibitors of CYP2C19 (such as ticlopidine, fluconazole, or omeprazole). Benefit appears over 2 to 4 weeks and may take up to 12 weeks, so a 3-month trial precedes a judgment of failure. Headache, diarrhea, and palpitations are common.

Cilostazol is contraindicated in heart failure of any severity (Class 3: Harm). The prohibition derives from increased mortality with oral milrinone, another phosphodiesterase-3 inhibitor, in severe heart failure. Cilostazol may also reduce restenosis after femoropopliteal endovascular therapy (Class 2b).

Pentoxifylline does not improve claudication (Class 3: No Benefit), and chelation therapy has no role (Class 3: No Benefit).

Revascularization for claudication by anatomic segment

Revascularization for claudication treats symptoms and does not prevent amputation or cardiovascular events. Its benefits are weighed against procedural risk, restenosis, and repeat procedures in a shared decision (Class 1). It is reasonable when functionally limiting claudication responds inadequately to GDMT including structured exercise (Class 2a). It is not recommended after an adequate response to that therapy (Class 3: No Benefit), and revascularization of asymptomatic PAD solely to prevent progression is harmful (Class 3: Harm). Asymptomatic iliofemoral disease may be treated when access is needed for transcatheter aortic valve replacement, mechanical circulatory support, or endovascular aneurysm repair (Class 2a).

Endovascular devices. Options include plain balloon angioplasty, drug-coated balloons, bare-metal, drug-eluting, and covered stents, atherectomy, and intravascular lithotripsy, selected by lesion location, length, and calcification. In the femoropopliteal segment, paclitaxel-coated balloons and stents reduce restenosis compared with uncoated devices. A 2018 meta-analysis of randomized trials reported higher late mortality after paclitaxel-coated femoropopliteal devices, which led to US Food and Drug Administration warnings. After review of larger patient-level data with longer follow-up, the FDA concluded in July 2023 that the data do not support an excess mortality risk. Atherectomy is used as vessel preparation for heavily calcified or bulky lesions; randomized evidence that it improves clinical outcomes over angioplasty is lacking.

Surgical options. Aortobifemoral bypass, endarterectomy, femoropopliteal and femorotibial bypass, and extra-anatomic (axillofemoral or femorofemoral) bypass are the open procedures, and hybrid procedures combine common femoral endarterectomy with iliac or femoral stenting. Great saphenous vein is the preferred infrainguinal conduit because prosthetic grafts have lower long-term patency.

Chronic limb-threatening ischemia: team care and revascularization strategy

CLTI is defined in the Global Vascular Guidelines as PAD with ischemic rest pain, gangrene, or a lower limb ulcer of more than 2 weeks' duration, with objective hemodynamic evidence of ischemia; venous, traumatic, embolic, and nonatherosclerotic causes are excluded. Suspected CLTI is referred urgently to a vascular specialist, and WIfI and GLASS staging precede the choice of procedure.

The 2024 ACC/AHA guideline recommends evaluation and care by a multispecialty team with expertise in endovascular and surgical revascularization, wound care, podiatric and foot surgery, infectious disease, diabetes, and rehabilitation (Class 1). Surgical, endovascular, or hybrid revascularization is recommended when feasible to minimize tissue loss, heal wounds, relieve pain, and preserve a functional limb (Class 1). The team evaluates revascularization options before any nonemergency amputation (Class 1). Great saphenous vein mapping by duplex ultrasound is recommended in patients who are candidates for both strategies (Class 1). Bypass to the popliteal or infrapopliteal arteries uses autogenous vein when available (Class 1), and prosthetic or cadaveric conduits can be effective when it is not (Class 2a). Restoration of in-line flow, or maximal perfusion, to the wound bed is beneficial (Class 2a). With rest pain alone and multilevel disease, treating inflow disease first is reasonable (Class 2a), whereas tissue loss usually requires inflow and outflow treatment together.

The trials differ in anatomy (BEST-CLI mostly femoropopliteal with or without tibial disease; BASIL-2 infrapopliteal), patient risk, conduit, and endovascular technique, and they are complementary. In BEST-CLI, an adequate vein was a great saphenous vein of at least 3 mm.

The guideline lists factors that shape the first strategy (Table 16). Anatomy favoring surgery includes disease of both the common femoral artery and the profunda origin, multilevel occlusions, long-segment disease involving the below-knee popliteal and tibial arteries, and lesions whose endovascular treatment would compromise a later bypass. Absence of usable vein (for example, after harvest for coronary bypass) and high perioperative risk from coronary disease, heart failure, lung disease, chronic kidney disease, or frailty favor endovascular treatment. Patient preference after shared decision-making completes the decision (Class 1).

Wound care, infection, offloading, and amputation in chronic limb-threatening ischemia

Infection. Foot infection is treated promptly with antibiotics, debridement, and drainage (Class 1). Deep infection, abscess, and osteomyelitis are evaluated with probing of the wound to bone, plain radiographs, and MRI. Severe infection with systemic toxicity is drained or amputated urgently before revascularization.

Wound care and offloading. Wound care after revascularization aims at complete healing (Class 1): serial debridement, a moist wound bed with exudate control, treatment of biofilm, nutrition, glycemic control, and smoking cessation. Pressure offloading is recommended for diabetic foot ulcers (Class 1) and may be considered for nondiabetic ulcers (Class 2b), and customized footwear is recommended after a diabetic foot ulcer has healed (Class 1). Negative-pressure wound therapy has the best supporting evidence among adjuncts. Hyperbaric oxygen may be considered after revascularization for nonhealing diabetic foot ulcers (Class 2b); the Global Vascular Guidelines advise against it in limbs with uncorrected severe ischemia. Cell and gene therapies remain investigational.

No-option CLTI. When no revascularization is possible and the foot has no outflow, the usefulness of prostanoids is uncertain (Class 2b), arterial intermittent pneumatic compression may be considered (Class 2b), and deep venous arterialization, which routes arterial flow into the pedal veins, may be considered for limb preservation (Class 2b).

Amputation. Primary amputation is indicated when life over limb is the prevailing consideration and the limb is the source of instability, such as overwhelming infection or metabolic derangement (Class 1). It is also appropriate for nonambulatory or bedbound patients, limited life expectancy, or tissue destruction that leaves no functional foot, decided with the patient and family (Class 1). The multispecialty team selects the most distal level that will heal and preserve function (Class 1), and minor (inframalleolar) amputation is followed by a customized program of wound care, offloading, and therapeutic footwear (Class 1).

Preventive foot care. Every patient with PAD receives foot self-care education, foot inspection at every visit, and a comprehensive foot evaluation at least annually (all Class 1). Therapeutic footwear is recommended for patients at high risk, such as those with a prior ulcer or amputation, deformity, neuropathy, or poorly controlled diabetes (Class 1).

Acute limb ischemia: causes, categories, and emergency treatment

ALI is a sudden decrease in limb perfusion, present for less than 2 weeks, that threatens viability. Skeletal muscle tolerates complete ischemia for about 4 to 6 hours, so delay determines outcome. The classic findings are the six Ps: pain, pallor, pulselessness, poikilothermia, paresthesia, and paralysis. Sensory loss and motor weakness are the findings that change urgency.

Causes. In patients with known PAD, thrombosis of a stenotic native artery, bypass graft, or stent is the most common cause, and collaterals often blunt the presentation. Embolism from the left atrium in atrial fibrillation or from left ventricular thrombus produces abrupt symptoms with a normal contralateral pulse examination and lodges at bifurcations, most often the common femoral. Other causes are popliteal aneurysm, dissection, trauma and access-site injury, paradoxical embolism, heparin-induced thrombocytopenia, antiphospholipid syndrome, cancer and its therapy, vasculitis, and viral infection including COVID-19.

Rutherford acute limb ischemia categories, as adopted in the 2024 ACC/AHA guideline. Handheld continuous-wave Doppler replaces unreliable pulse palpation; loss of the venous signal marks a limb that may be nonsalvageable.

Initial management. Emergency evaluation by a clinician who can assess viability and deliver treatment is recommended (Class 1). Viability is assessed clinically without noninvasive imaging (Class 1), except after complex prior revascularization (Class 2b) or with suspected aortic dissection. Intravenous unfractionated heparin is given at diagnosis unless contraindicated, regardless of cause or level of occlusion (Class 1); a direct thrombin inhibitor is substituted in heparin-induced thrombocytopenia.

Revascularization. In a salvageable limb, endovascular or surgical revascularization, including catheter-directed thrombolysis, is indicated (Class 1). Category IIb limbs need immediate revascularization, IIa limbs prompt revascularization, and category I limbs allow time for imaging to plan an urgent procedure. Surgical balloon catheter embolectomy suits a fresh embolus at a bifurcation; thrombosis on a diseased artery often needs bypass or patch angioplasty. Endovascular options are catheter-directed thrombolysis and pharmacomechanical or aspiration thrombectomy. TOPAS randomized 544 patients with occlusion of 14 days or less. Amputation-free survival at 1 year was similar with intra-arterial urokinase and with surgery (65.0% and 69.9%), and thrombolysis reduced open operations. Major hemorrhage was more frequent with thrombolysis (12.5% compared with 5.5%), including intracranial hemorrhage in 1.6%. Thrombolysis is most effective for occlusions of less than 14 days, including graft thrombosis, and endovascular or surgical treatment of the culprit lesion it unmasks can be useful (Class 2a). Revascularization of a category III limb is harmful (Class 3: Harm), because reperfusion of necrotic muscle can cause multiorgan failure; primary amputation is performed.

Reperfusion injury and compartment syndrome. Reperfusion releases potassium, myoglobin, and acid, causing hyperkalemia, arrhythmia, acidosis, and pigment nephropathy, and muscle edema raises compartment pressure, most often in the lower leg. Pain on passive stretch, tense compartments, and rising creatine kinase lead to fasciotomy (Class 1). Prophylactic fasciotomy is reasonable for category IIa and IIb limbs (Class 2a), and concurrent amputation can be beneficial after prolonged ischemia (Class 2a).

Cause and secondary prevention. A history and examination directed at the cause (Class 1) and testing for a cardiac source, including electrocardiography, rhythm monitoring, and echocardiography, are useful (Class 2a). Long-term anticoagulation follows embolism from atrial fibrillation, and thrombosis on underlying PAD treated by revascularization is followed by the antithrombotic regimens recommended after any lower extremity revascularization.

Peripheral artery disease in older adults, kidney disease, and diabetes

Older adults. In patients 75 years or older, assessment for geriatric syndromes such as frailty, sarcopenia, malnutrition, and mobility impairment is useful before revascularization and in setting goals (Class 2a). Frailty predicts lower survival after revascularization for CLTI and favors less invasive strategies or palliation in some patients.

Chronic kidney disease and dialysis. Kidney disease raises MACE (hazard ratio about 1.45) and is associated with tibial calcification, noncompressible ABI, CLTI, and amputation. Revascularization for CLTI in patients with kidney disease is associated with lower mortality and amputation than no revascularization, and endovascular treatment carries lower in-hospital mortality than surgery in this group. COMPASS excluded patients with severe kidney disease.

Diabetes. Up to 20% of patients with diabetes older than 40 years, 30% older than 50 years, and 70% older than 70 years have PAD. Neuropathy masks symptoms, and infection is the most frequent trigger of limb loss. Toe pressure with TBI is the routine perfusion test.

Follow-up and surveillance after revascularization

Every patient with PAD has longitudinal follow-up with assessment of limb symptoms, functional status, pulses, the feet, and risk factor control (Class 1), and long-term GDMT is recommended to prevent MACE and MALE (Class 1). Care is coordinated among the clinicians involved (Class 1), and telehealth is an alternative when it matches the urgency of symptoms (Class 2a). After any revascularization, new symptoms or signs lead to ABI and arterial duplex ultrasound (Class 1).

From the 2024 ACC/AHA guideline (Section 12). A failing vein graft found by duplex surveillance is easier to salvage than an occluded one.

The Global Vascular Guidelines define loss of limb-based patency after CLTI revascularization as occlusion, critical stenosis, or reintervention on the target arterial path, or a fall in ABI of 0.15 or more or in TBI of 0.10 or more with recurrent or unresolved symptoms. Restaging with WIfI after revascularization and after treatment of infection identifies limbs that remain at high risk.

European guidance compared with the 2024 ACC/AHA guideline

The 2024 European Society of Cardiology (ESC) guideline on peripheral arterial and aortic diseases agrees on ABI as the first test and on structured exercise, statins, and antiplatelet therapy, and it differs in several points. It sets an LDL cholesterol goal below 55 mg/dL (1.4 mmol/L) with at least a 50% reduction for atherosclerotic PAD (Class 1) and a systolic blood pressure goal of 120 to 129 mm Hg. It assigns rivaroxaban 2.5 mg twice daily plus aspirin a Class 2a recommendation in symptomatic PAD with high ischemic and non-high bleeding risk and after lower limb revascularization, compared with Class 1 in the US guideline. It recommends duplex ultrasound as the first-line imaging test, considers drug-eluting treatment the first-choice endovascular strategy for femoropopliteal lesions (Class 2a), and allows aspirin in asymptomatic PAD only with diabetes (Class 2b), compared with Class 2a single antiplatelet therapy in all asymptomatic PAD in the US guideline.

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