Peripheral Arterial Disease

Peripheral Arterial Disease


Most patients with lower extremity PAD are asymptomatic. Approximately 30–50% have intermittent claudication or atypical leg symptoms.13 Patients may be asymptomatic because PAD is either mild, or moderate-to-severe but collaterals are well developed. Patients may also be inactive because of comorbidities that prevent them from experiencing claudication.

Claudication usually remains stable or improves with conservative management. At 5 years, only 20% of patients have progressive claudication, and only 4% progress to critical limb ischemia (CLI).1,4,5This explains why, in the absence of critical limb ischemia, revascularization is only justified for very severe claudication. On the other hand, diabetic patients, patients who continue to smoke, and patients with severely reduced ankle–brachial index (ABI) <0.5 have a particularly aggressive course, with CLI of 10–20% at 5 years.57 In addition, progressive functional decline frequently occurs in these patients and may conceal disease progression.7 Some studies suggest that patients <50 years of age may have a more aggressive course (~40% have unstable, progressive disease with multiple revascularizations and frequent progression to CLI).8,9

As opposed to the relatively benign course from a limb ischemia perspective, patients with PAD have a high rate of cardiovascular events and mortality, that is at least equal to patients with CAD (5–7% yearly risk of cardiovascular death/MI/stroke with 3–5% yearly mortality risk).10,11 The mortality drastically increases in subgroups of moderate PAD (ABI <0.7), and, even more so, severe PAD (ABI <0.5).12 Patients with CLI have a 25% mortality risk at 1 year.

In comparison to isolated CAD, the mortality and event rate is doubled in patients with combined CAD and PAD. Aggressive risk-factor modification and CAD therapy is expected to improve cardiovascular events in PAD. Except for CLI, peripheral revascularization does not clearly reduce mortality or the long-term risk of limb loss.

I. Clinical tips

Typical claudication is described as lower extremity discomfort, fatigue, or weakness initiated with exertion and resolving within 10 minutes of rest. Claudication is consistently reproduced by almost the same walking distance and is worse uphill. It does not occur with prolonged standing per se; it does not occur at rest or at night unless there is also a severe exertional component and signs of CLI on exam. Isolated nocturnal leg cramps without exertional limitation are neuromuscular in origin.

Leg pain is considered atypical when it occurs on exertion but also at rest without signs of rest ischemia. Other atypical symptoms include leg pain that starts with exertion but does not make the patient stop or does not quickly resolve upon cessation of activity. In patients with PAD, those atypical symptoms frequently represent mixed arterial and non-arterial, comorbid pain (PAD combined with neuropathy, spinal stenosis, or arthritis). PAD may not be the primary driver of symptoms (Table 19.1).

Claudication involves the buttocks, hips, and thighs in aortoiliac disease, simulating hip or spinal disease; the thighs in common femoral disease; and the calves in superficial femoral or popliteal disease. Patients with aortoiliac disease sometimes report weakness with walking rather than pain. While isolated internal iliac disease does not usually cause claudication, bilateral internal iliac disease may lead to buttock/hip claudication and erectile dysfunction with a normal ABI; the internal iliac arteries provide gluteal branches that may suffer in case of bilateral disease, depending on the degree of collateralization from the external iliac and common femoral circumflex branches.

Rarely, patients with isolated severe infrapopliteal disease develop foot claudication, which often simulates plantar fasciitis or vasculitic pain (thromboangiitis obliterans). More commonly, these patients present with ischemic, painful distal ulceration.

Isolated superficial femoral artery (SFA) disease with intact common femoral, profunda, and popliteal arteries is less symptomatic than disease in other segments. The profunda femoris, which is rarely diseased, usually provides robust collaterals to the popliteal artery, bypassing the diseased SFA. A diseased profunda particularly increases the risk of progression to CLI.

On physical exam, a normal posterior tibial (PT) pulse or dorsalis pedis (DP) pulse rules out significant PAD with 96% and 92% accuracy, respectively. A normal femoral pulse without bruit rules out aortoiliac PAD with over 90% accuracy. Thus, physical exam is highly accurate in ruling out significantly obstructive PAD. Conversely, only 50% of patients with abnormal femoral pulse or distal pulses have significant PAD; the combination of multiple pulse abnormalities more accurately predicts PAD.3,15 Femoral pulse may be reduced because of body habitus or a deep femoral course. Owing to anatomical variation, DP is absent unilaterally or bilaterally in up to 10% of the population (the anterior tibial artery may quickly taper at the ankle level, giving only a lateral tarsal artery; also, a peroneal perforating branch may be supplying the dorsum of the foot). DP palpation is improved by dorsiflexion of the foot, which prevents DP compression by tendons. PT is absent in 2% of the normal population.

Table 19.1 Differential diagnosis: arterial claudication, neurologic claudication (spinal stenosis), diabetic neuropathy, venous insufficiency.

Arterial claudication Neurologic claudication Diabetic neuropathy Venous insufficiency
Pain type Cramp, tightness, or tiredness; anywhere from buttocks to feet
“Difficulty walking”
Paresthesia, sharp or shooting pain bilaterally
History of back pain
Paresthesia, burning or shooting pain
Starts distally bilaterally and progresses proximally
Walking distance Constant
Worse uphill
Pain not triggered by standing still
Improves with walking uphill
Pain may be triggered by standing still
Pain unrelated to exertion
Occurs at night, at rest
Pain worse at the end of the day rather than after a particular walk
Disturbance with standing No Yes Not necessarily Yes
Relief Walking cessation Sitting, leaning forward Spontaneous Leg elevation
Exam findings Abnormal pulses, femoral bruits
In advanced cases:

  • Pallor that worsens with leg elevation and slowly becomes blue with feet dangling (rubor cyanosis)
  • Cold feet, capillary refill >3 seconds
  • Loss of distal hair, nail dystrophy, skin atrophy
  • Disuse muscle atrophy
Abnormal sense and deep tendon reflexes Hyperkeratosis of the skin and nails
Abnormal sense and deep tendon reflexes
History of DVT
Brown stasis dermatitis, varicose veins

II. Clinical classification of PAD – Critical limb ischemia, acute limb ischemia, atheroembolization

Grossly, there are three clinical forms of PAD: asymptomatic PAD, claudication, and CLI.

A. Rutherford classification

The Rutherford classification is commonly used and incorporates all these clinical forms of PAD into six categories: 0 = asymptomatic; 1–3 = claudication; 4–6 = critical limb ischemia, with 4 = rest pain; 5 = minor tissue loss/skin loss at the digits; 6 = major tissue loss with gangrene.

B. Critical limb ischemia (CLI)

CLI is defined as one of the following (in order of increasing severity): ischemic rest pain, non-healing ulcer, or extensive ulceration with gangrene. CLI is a chronic process that progresses over weeks or months and should be distinguished from acute limb ischemia (Table 19.2). Traditionally, CLI occurs in patients with ABI ≤ 0.4, ankle pressure <50 mmHg, or toe pressure <30 mmHg. However, multiple studies have shown that up to 30% of patients with CLI have normal ABI, 15% of them have elevated ABI, and most have ABI in the mild-to-moderate rather than severe range.16 ABI commonly underestimates the severity of PAD in CLI patients with predominantly infrapopliteal disease. This is related to the fact that tibial arteries are partially non-compressible (creating a falsely normal or elevated tibial pressure), but also to the fact that a substantial proportion of CLI patients have significant pedal/below-ankle disease, sometimes with a “desert” foot (narrow or occluded plantar and metatarsal arteries). Toe-brachial index (TBI) is more reliable than ABI in CLI patients and should be systematically measured in this context. The clinical features of the wound and the low TBI suggest the need for angiography in patients with normal ABI.

Ischemic rest pain is typically a nocturnal pain that forces the patient to wake up and dangle his legs. On physical exam, CLI is characterized by a cool, dry, and fissured skin, lack of hair, dystrophic thick toenails, lack of superficial veins (flat skin), calf atrophy, and dependent rubor cyanosis. Ulcers often occur distally at the toe level and at pressure and friction points (between toes), or at the lateral malleolus level (Table 19.3). An ulcer occurring at another location for another reason may not heal if ischemia is present (mixed ulcer). Dependent rubor is an important marker of rest ischemia. To test for dependent rubor, raise the leg for 30–60 seconds, observe for pallor, then let it down and see how it slowly fills with a dusky red color suggestive of CLI, rather than quickly fills with a normal pink color.

Table 19.2 Acute limb ischemia vs. critical limb ischemia.

Acute limb ischemia Critical limb ischemia
Persistent rest pain
More severe pallor (marble); darker, more mottled cyanosis
Intermittent rest pain (nocturnal) or non-healing ulcer
Sudden onset, progresses over hours or days Progresses over weeks/months
Distal pulses inaudible on Doppler exam Distal pulses audible on Doppler exam
Caused by acute embolization or acute thrombosis, with multiple distal emboli Severe progressive atherosclerosis ± some thrombus
Emergent revascularization required Non-urgent revascularization is required

Table 19.3 Types of lower extremity ulcers.

Ischemic ulcers Neuropathic ulcers Venous ulcers
Painful Painless Achy discomfort
Location: lateral malleolus, tip of toes, friction areas (between toes) Plantar foot, metatarsal heads Medial malleolus
Shape: black, white/pale, or blue, does not bleed Red with increased blood flow Shallow ulcer with red granulating exudative base
Ischemic signs (pallor, cold, cyanosis, capillary refill >3 seconds) Presence of calluses, bone deformities Stasis dermatitis: reddish-brown edematous skin
Absent pulses Neuropathic signs on examination
ABI ≤ 0.5

Some ulcers have mixed neuropathic and ischemic features. Any ulcer or gangrene, whether neuropathic or ischemic, can become infected (wet gangrene). Also, consider the possibility of osteomyelitis with any ulcer.

CLI is associated with a 25% mortality risk at 1 year and a 25% amputation rate, with only 50% amputation-free survival at 1 year. Amputation is required in patients who cannot be revascularized or who present at a stage of deep necrosis. Amputation is associated with the highest mortality (40% at 2 years).

C. Acute limb ischemia (ALI) and acute compartment syndrome

Acute limb ischemia is rest ischemia that develops over hours, sometimes days (occasionally weeks, generally <14 days), and is usually due to: (i) acute embolization from a cardiac or aortic origin (30% of cases), (ii) acute thrombosis of an underlying atherosclerotic stenosis or popliteal aneurysm (60% of cases), (iii) thrombosis in situ from a hypercoagulable state or traumatic injury/dissection, or (iv) graft thrombosis, which mainly occurs when there is obstructive disease at the inflow or outflow of the graft (e.g., disease progression in the common femoral or profunda past an aortofemoral graft; early or late anastomotic stenosis). Regardless of the underlying process, multiple distal emboli are characteristic of ALI. Acute thrombosis generally manifests less severely and less abruptly than acute embolization (days or weeks), as it occurs on top of chronic disease and pre-existing collaterals.

As opposed to ALI, CLI and non-healing ulcers are due to severe progressive atherosclerosis, frequently with some amount of thrombus, and develop over weeks or months (Table 19.2). CLI generally requires revascularization soon (days or 1 week), but not emergently. In ALI, the abrupt occlusion does not allow for the development of robust collaterals, which explains how ALI can lead to limb loss within a few hours (6 hours), dictating emergent reperfusion. In addition, distal embolization is universal in ALI and further accelerates tissue loss. Distal pulses are usually audible on Doppler exam in CLI, but often not in ALI.

CLI progresses at a much slower rate than ALI yet provokes tissue loss and ischemic ulcers at a relatively earlier stage. ALI has the following progression:

  • Stage 1. Rest pain with audible, monophasic distal pulses by Doppler.
  • Stage 2. Very distal sensory loss with inaudible distal pulses by Doppler (“limb threatened”). The skin is initially “marble” white, then becomes dark purple and mottled as it fills with deoxygenated, stagnant blood.
  • Stage 3. Sensory loss beyond toe level or moderate motor loss (“limb immediately threatened”).
  • Stage 4. Profound paralysis and/or major tissue loss (irreversible necrosis of muscles and skin).

Stage 1 dictates urgent revascularization, while stages 2 and 3 dictate emergent revascularization. Stage 4 requires early amputation, followed by revascularization to allow healing of the wound and the remaining viable tissue, limiting the need for a more extensive amputation in the future.

In ALI, stages 1 and 2 may be treated with a local thrombolytic infusion (12–48 hours) delivered through an endovascular approach. After the extensive thrombus burden and emboli are attenuated with thrombolysis, attention is turned towards the endovascular or surgical therapy of underlying/residual stenoses. For stage 3 ALI (motor loss or extensive sensory loss), ischemia needs to be emergently improved and one cannot wait 12–24 hours for thrombolysis to be effective. Surgical revascularization, if feasible, may need to be emergently performed at stage 3; moreover, at this stage, patients have a high risk of reperfusion injury and compartment syndrome and often need prophylactic fasciotomy during surgical revascularization.

D. Atheroembolization

Atheroembolization is embolization of atheromatous cholesterol debris rather than thrombi, and is therefore different from ALI. It typically occurs after angiography or aortic surgery that sloughs off aortic atherosclerotic debris and leads to cholesterol embolization in the small vessels of the kidneys, dermis, lower extremities, and gastrointestinal tract. Yet, ~50% of the cases are spontaneous. Atheroembolism often induces progressive renal failure that develops a week or more after the procedure and is frequently irreversible. It leads to livedo reticularis, “blue toes,” and distal cyanosis or gangrene despite preserved distal pulses, as the ischemia is due to small vessel occlusion. Obstructive PAD may, however, be present and may reduce distal pulses, yet the ischemic findings are generally disproportionate to PAD and ABI. No specific therapy is provided; limb ischemia often improves spontaneously in patients without a severely obstructive underlying PAD. Revascularization may be required in patients with severe PAD to allow healing, but invasive manipulations are better avoided in patients with only mild PAD, as these manipulations may induce further embolization. The role of anticoagulation is unclear (some data suggest benefit while other data suggest harm).

III. Diagnosis of PAD

A. Ankle–brachial index (ABI)

ABI has two purposes: (i) diagnosis of obstructive PAD and its severity; (ii) cardiovascular prognosis (the risk of death/MI of patients with a low ABI approximates or exceeds the risk of patients with CAD) (Table 19.4). If PAD is suspected in a symptomatic patient with an abnormal pulse exam, ABI is first performed, followed by a lower extremity arterial Doppler study if revascularization is considered.

Asymptomatic patients at a high risk of PAD need to be screened with ABI only, particularly if the pulse exam is abnormal (age >65, age 50–70 with diabetes or smoking). A low ABI correlates with increased mortality and dictates more aggressive medical therapy, but not further workup and revascularization, per se.

To calculate ABI, posterior tibial (PT) and anterior tibial (AT) pressures are measured using a well-sized BP cuff and a Doppler stethoscope, then the highest of these pressures is divided by the highest arm pressure.1 ABI testing is ~85% sensitive and 100% specific for angiographically confirmed PAD.1 ABI has the following three pitfalls: (i) ABI may be normal or falsely elevated in calcified, poorly compressible vessels; these vessels are not compressible even if the pressure and flow inside them are low (elderly, longstanding diabetes, or CKD); (ii) ABI may be normal at rest if sufficient collaterals are present; (iii) ABI may also be normal at rest in symptomatic patients with moderate aortoiliac stenoses.

Thus, when ABI is normal at rest but pitfall (ii) or (iii) is suspected, exercise ABI or an arterial Doppler study should be obtained. During exercise, peripheral vasodilatation occurs; a flow-limiting stenosis prevents blood flow from increasing enough to fill the dilated distal vascular space, and thus the distal pressure paradoxically decreases. This process translates into a low exertional ABI (ABI drops ≥ 20%, or >0.2) and explains how DP and PT pulses that are weak but palpable before exercise may become non-palpable after exercise. In fact, post-exertional pulse exam is valuable in the assessment of the PAD patient with only mild pulse abnormality.

Note: normal or elevated ABI in patients with CLI

When arterial non-compressibility is suspected in patients with a normal ABI or elevated ABI ≥ 1.4 (pitfall [i]), arterial Doppler should be done Also, in all CLI patients, regardless of ABI, toe-brachial index (TBI) should be measured, using a special small plethysmograph, as ABI frequently underestimates disease severity in CLI and is normal or high in up to 45% of cases. Medial calcinosis does not typically involve digital arteries, and thus digital arteries remain compressible when pedal arteries are not. TBI <0.6 indicates significant PAD. Patients with significant PAD have pulseless pedal pulses despite the high measured pedal pressure (high pressure yet pulseless). In patients evaluated for leg symptoms, an elevated ABI is associated with significant PAD in 60–70% and CLI in up to 37% of patients.16,17 An elevated ABI has the same negative prognostic implication as a low ABI, more so in the presence of obstructive PAD.16 Even without obstructive PAD, an elevated ABI implies a heavy amount of calcified atherosclerosis and predicts increased cardiovascular mortality.

Note: use of the higher ankle pressure (the higher of the AT and PT pressures) vs. the lower pressure in ABI calculation

The higher pressure correlates with the pressure through the arterial inflow into the best infrapopliteal vessel, and may best correlate with symptoms. A low ABI through only one of AT or PT, with a normal ABI through the other vessel, indicates single-vessel infrapopliteal disease with no significant inflow or femoral disease; this is unlikely to cause symptoms, since only one-vessel runoff to the foot is usually enough to prevent severe symptoms or CLI. However, one study has shown that the use of the lower ABI better correlates with the risk of cardiovascular events, and therefore both numbers should be reported and accounted for.18

B. Ultrasound and Doppler study

A Doppler study is over 95% sensitive and specific for the diagnosis of obstructive stenoses. It is only indicated in patients with severe symptoms who qualify for angiography and revascularization (class I indication). It allows localization of the disease and planning for a potential peripheral intervention. A stenosis is characterized by a focal increase in velocity (>250 cm/s, or >2.5:1 in comparison to the proximal segment), and by a monophasic flow distal to the stenosis (Figure 19.1).

C. Segmental pressures and pulse volume recordings

Rather than just measuring the pressure at the distal ankle (ABI), two BP cuffs are placed across the thigh, and two are placed across the calf. The BP cuff transmits a flow waveform similar to the Doppler waveform, and a pressure waveform (called PVR), similar to the arterial pressure waveform, with a dicrotic notch in normal patients. In PAD, the flow waveform becomes monophasic, and PVR damps and loses its dicrotic notch. It is not as good as duplex study for localizing disease and its extent.

D. CT angiography (CTA)

CTA is particularly helpful when aortoiliac disease is suspected with absent femoral pulses, in which case CTA delineates the disease and allows the planning of a peripheral intervention. CTA has several pitfalls: (i) it may not properly delineate infrapopliteal disease; (ii) heavy calcifications may preclude accurate assessment of the severity of disease; (iii) additional radiation and contrast is used before the eventual angiography or intervention. While a Doppler study has a class I indication before performing angiography, CTA has a class IIb indication.

E. Peripheral angiography is only performed when revascularization is indicated.

Table 19.4 Classification of PAD severity based on ABI.

1–1.3: normal
0.9–0.99: borderline
0.7–0.9: mild PAD
0.4–0.7: moderate PAD
<0.4: severe PAD
>1.3: non-compressible pedal vesselsa

a A high ABI is often associated with significant PAD, particularly in patients with claudication. A high ABI is associated with the same increase in cardiovascular mortality as a low ABI.

Image described by caption.

Figure 19.1 (a) The peripheral arterial pressure has three phases (1, 2, 3). The second phase corresponds to a brief reversal of flow in early diastole before the artery recoils and maintains its pressure. Phases 2 and 3 correspond to an exaggerated and “spread-out” dicrotic notch. (b) The triphasic pressure waveform translates into a triphasic Doppler velocity waveform (sometimes biphasic, with a systolic spike and a diastolic reversal). Distal to an arterial stenosis, the peripheral pressure loses its dicrotic notch and the Doppler loses the early diastolic flow reversal and becomes monophasic. In this case, the arterial volume is reduced past the stenosis and does not allow a backflow in diastole, but rather requires a persistent forward flow throughout diastole. Beside stenosis, this lack of flow reversal may be seen in peripheral vasodilatation.

Across a stenosis, the velocity increases and the flow becomes monophasic, turbulent, with spectral thickening of the waveform (turbulent flow). Beyond the stenosis, the flow is damped and monophasic, with a persistent flow in diastole. Flow may also be monophasic just proximal to the stenosis (e.g., monophasic common femoral velocity when the proximal SFA is occluded).

IV. Medical therapy of PAD

Medical therapy consists of:

  1. Smoking cessation, which reduces the amputation risk 10-fold and the mortality risk by 50%.19 Over 85% of patients who quit smoking have an improvement in symptoms. Bypass graft failure is twice as high in smokers as in non-smokers.
  2. Walking program (30 minutes a day for at least 3 days a week), which improves the walking distance twofold to fourfold within 3 months. Early benefits are seen at 4 weeks.
  3. Aspirin or clopidogrel. In the absence of percutaneous revascularization or prior MI, the combination is not clearly superior to aspirin or clopidogrel monotherapy for the prevention of cardiovascular events.20
  4. Secondary prevention measures that reduce cardiovascular and coronary events: statin and aggressive therapy of hypertension and diabetes.
  5. Cilostazol is a phosphodiesterase inhibitor that increases cAMP levels and induces vasodilatation. It effectively improves walking distance by ~50% and is useful in reducing in-stent restenosis and thrombosis (antiplatelet and antiproliferative effects). It has milrinone-like cardiac effects and is thus contraindicated in HF or recent MI (<6 months).
  6. In VOYAGER PAD trial, a small dose of rivaroxaban, 2.5 mg bid, started early after percutaneous or surgical revascularization (<10 days), on top of aspirin (+/- clopidogrel in 50%, for <6 months), reduced limb events and cardiovascular events by 2.6% at 3 years, mainly acute thrombotic events.21 Indirectly, rivaroxaban may be preferred over clopidogrel after PAD revascularization, particularly as clopidogrel has very limited data in this setting.

V. Revascularization for PAD

A. Indications

Revascularization is indicated for:

  • CLI (absolute indication).
  • Lifestyle-limiting claudication despite a 3-month exercise program, e.g., claudication upon walking <1 block or performing activities of daily living (relative indication).

B. Revascularization modalities: surgical bypass vs. percutaneous therapy

Lower extremity arteries are divided into three segments: aortoiliac, femoropopliteal, and infrapopliteal. The more distal the disease is, the lower the long-term patency is for any revascularization modality (Figure 19.2).

Surgical patency is slightly superior to that achieved with percutaneous revascularization at all levels, particularly for TASC C and D lesions at the femoropopliteal level (e.g., long SFA occlusion). A synthetic graft anastomosed to the popliteal artery below the knee or to a tibial artery is the only exception, as it has a very poor long-term patency, but its short-term patency may still serve to resolve CLI in a patient with no possibility for percutaneous intervention. A poor or small distal runoff reduces the long-term success of both strategies, particularly bypass surgery.

While having a superior long-term patency, historical comparisons show that surgery is associated with a much higher postoperative mortality than percutaneous revascularization (3–5% vs. 0.5%). In addition, surgery has a much higher risk of major periprocedural complications that include cardiovascular, renal, pulmonary, and bleeding complications (8–10% vs. 1–3%).22,23 One randomized comparison of bypass surgery vs. percutaneous revascularization in patients with CLI and infra-inguinal disease has shown that percutaneous revascularization is associated with lower post-procedural complications, morbidity, and costs (BASIL trial). Yet, patients who survived over 2 years had a lower amputation rate with surgery, which suggests that CLI patients who are less sick with fewer comorbidities may benefit from surgery early on. Interestingly, most CLI patients who were screened for this study were either not eligible for surgery because of comorbidities or not eligible for percutaneous therapy because of technical complexity, and ~50% were not eligible for any therapy (with a subsequent high amputation rate).24

In sum, percutaneous revascularization has the advantage of lower periprocedural mortality and complications, is the only option in patients with significant cardiovascular comorbidities or lack of venous conduits, and has a lower but acceptable long-term patency, particularly for TASC A, B, ± C lesions

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Nov 27, 2022 | Posted by in CARDIOLOGY | Comments Off on Peripheral Arterial Disease

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