Peripheral arterial disease (PAD) is a common disorder affecting many people in the world. The disease may be defined as impairment of gait and pain in the lower limb muscles, caused by ischemia, which is induced by stenotic or occlusive atheromatous disease in the visceral and lower extremity arteries. PAD affects an estimated 8-12 million individuals in the United States. It is also prevalent in Europe and the Far East. The prevalence of PAD increases with age and affects 12-20% of individuals older than age 65. The risk factors for PAD, such as diabetes mellitus, smoking, and hypertension, are prevalent in the older population. Thus, PAD is a growing public health problem that has been overshadowed by the attention given to coronary artery disease and cerebrovascular disease. Today, more and more patients present with advanced disease and limb-threatening ischemia. Approximately 1% of the population will experience chronic critical limb ischemia. Unfortunately, many clinical medical therapies aimed at reducing cardiovascular risk have little impact on the patient with intermittent claudication, and revascularization is reserved for those with severe disabling symptoms. A variety of revascularization procedures have been developed to treat CLI, and attempts at randomized trials comparing these techniques have begun. This article will deal with endovascular treatment of PAD and will not discuss surgical treatment.

Definition of Peripheral Arterial Disease (PAD)

Peripheral artery disease (PAD) is a major cause of disease and ischemic limb loss, with a prevalence of 5-10% in the general population. It is a marker for widespread systemic atherosclerosis: two-thirds of patients suffering from PAD will also have significant coronary and/or carotid artery disease, placing them at high risk of myocardial infarction or cerebrovascular accident. The economic impact of lower extremity arterial disease is considerable, with annual costs for non-invasive and invasive revascularization procedures, hospital admissions, and amputation care totaling many billions of dollars. This represents one of the highest disease-specific procedural expenditures within allocated funds for Medicare insurance in the USA. At its severest, PAD can result in critical limb ischemia (CLI), an advanced stage of lower-limb ischemia which markedly increases the risk of limb amputation and death. CLI is associated with a one-year mortality rate of up to 25% and a 56% amputation rate within 4 years. In terms of quality of life, patients with CLI suffer more severe functional impairment and faster progression to loss of independence than those with other chronic diseases such as cancer and diabetes. Despite advances in open and endovascular revascularization techniques, many patients with PAD remain untreated, simply due to unawareness of the disease and its severity on the part of the patient and healthcare provider. This underscores the need for increased awareness of PAD, both in terms of public and physician knowledge.

Importance of Interventional Radiology in PAD Treatment

The major point in the introduction is the recognition that treating peripheral arterial disease (PAD) with interventional radiology techniques changes the treatment plan and the most likely positive outcomes for the patient. It is important for all healthcare professionals treating patients with PAD to fully understand the altered approach to patient treatment and how this will impact patient outcomes. As we work through the various treatment options, it is important to be aware of whether a particular treatment is feasible in regards to the specific patient’s disease severity and/or co-morbidities. In some cases, the most appropriate treatment plan will be a referral for surgical or endovascular intervention, and in this case, it is necessary to fully appreciate the expected benefits and potential risks of the intervention specific to each individual patient. This vital understanding will enable reliable and informed advice to the patient on the best management plan for their disease. A thorough understanding of the likely outcomes of treatment will allow patients to have more realistic expectations of their improvement in symptoms and functional capacity. This is an expansive concept which is covered through the discussion on altered prognosis following each treatment and again is something that healthcare professionals must be aware of when seeking to inform and educate patients on treatment options.

Objectives of the Article

To delineate the different percutaneous methods currently available for the treatment of iliac and infrainguinal disease. To provide an evidence-based balanced view of the potential and limitations of endovascular therapy in comparison to surgical revascularization. To set the ideal standard for the performance and reporting of endovascular revascularization procedures, and to readdress the necessity for an accepted angiographic classification of iliac and infrainguinal disease. To provide a detailed review of the wide range of percutaneous recanalization techniques for chronic total occlusions, emphasizing the advantages and disadvantages of each method. To delineate the levels of evidence available for various endovascular treatments and to identify the areas in which more randomized controlled research is required. To stress the considerable importance of informed patient consent, and to highlight the importance of patient-based outcomes when considering revascularization strategy. To review the endovascular and surgical options for critical limb ischemia, and to discuss the potential role of major amputation as a revascularization strategy.

Diagnostic Techniques

In some cases, it can be problematic for patients with critical limb ischemia due to the inability to lie flat and keep still. The quality of MRA can be easily degraded by patient movement. In this case, DSA would be more appropriate for proceeding with intervention.

MRA is an alternative test to CTA and is entirely non-invasive. It is the test of choice for pre-intervention assessment in patients with chronic kidney disease, poor renal function, or allergy to contrast media. MRA has a sensitivity of 91% and specificity of 86% for the detection of hemodynamically significant lower extremity arterial disease, with a positive predictive value of 97% for stenosis.

CTA is a sensitive test for detecting stenosis and occlusions within the arterial system. It can produce a 3-D representation of the vessel to give a visual map of the disease, complementing the range of other tests available. CTA is a useful test prior to interventions for planning purposes. A comparative study of CTA versus DSA in evaluating iliac or femoral artery stenosis severity with color-coded vessel analysis showed greater accuracy and reliability of CTA compared with DSA. However, the level of detail of CTA was not sufficient to assess the nature of the disease in some cases. Additionally, it is not widely available and exposes the patient to ionizing radiation.

Doppler ultrasound is commonly used to diagnose lower extremity conditions. It not only locates the position of the occlusion but also pinpoints its nature by recording waveform data through the site. This is helpful in deciding whether interventional management is indicated or if the patient should just proceed with medical management.

Doppler Ultrasound

Due to its non-invasive nature, Doppler ultrasound has been an attractive choice for evaluating lower extremity arterial disease. Early studies using Doppler waveform analysis for evaluating the severity of arterial stenoses were limited by poor definition of waveform morphologies. This limitation has been largely overcome by more recent advances in ultrasound technology, which allows for high resolution B-mode imaging in conjunction with real-time Doppler waveform analysis. This technical improvement has allowed for better correlation between ultrasound findings and findings at contrast arteriography. Color-flow Duplex imaging combines B-mode imaging and Doppler ultrasound to yield higher sensitivity and specificity for detecting moderate to severe arterial stenosis compared to traditional Doppler ultrasound alone. Utilization of contrast agents with Duplex ultrasound further improves its ability to assess distal run-off vessels. Sensitivity and specificity of 89% and 85% respectively for detection of iliac and femoral artery disease, and 75% and 95% respectively for detection of infrainguinal disease compared favorably with conventional arteriography. Compared to computed tomography or magnetic resonance angiography, lower extremity catheter-based arteriography has enjoyed a long-standing position as the gold standard for anatomic imaging of lower extremity arterial pathology. Advances in ultrasound technology have made possible the development of a virtual arteriogram, which is an anatomic representation of arterial lumen morphology constructed from Doppler ultrasound data. High resolution images of virtual arteriograms closely correlate with corresponding arteriographic images, demonstrating 95% sensitivity and 93% specificity for detecting iliac and femoral arterial stenosis, and 88% sensitivity and 86% specificity for detecting arterial stenoses in the infrainguinal region.

Computed Tomography Angiography (CTA)

CTA is a more recently developed non-invasive modality which has shown increasing promise in imaging the arterial tree throughout the body, especially in the assessment of aorto-iliac disease. CTA involves the acquisition of multiple axial images following the injection of a bolus of contrast material whilst a detector array rotates around the patient. The images are reconstructed to provide multiplanar reconstructions which can give a very detailed representation of the arterial lumen. Subtraction of contrast from non-contrast images also allows the generation of three-dimensional images which are normally displayed as volume rendered or maximum intensity projection images. The majority of studies show CTA to have excellent sensitivity and specificity for detecting significant stenoses in the aorto-iliac region. One published meta-analysis found pooled sensitivity and specificity to be 94% and 97% with 95% CI intervals of 91-96% and 94-98% respectively. This has been achieved using a variety of CTA techniques, for example Burrell et al found 0.5 mm slice thickness CTA using a 4 detector row scanner could detect stenoses of greater than 50% with 95% sensitivity and 96% specificity. More recently there have been promising reports using multislice CTA. One prospective study of 34 patients using 16 slice CTA found only 5 segments had non-diagnostic image quality out of 646 segments studied, with good interobserver agreement for both stenosis and plaque type and size between the CTA and the reference investigations of IVUS and digital subtraction angiography.

Magnetic Resonance Angiography (MRA)

An essential element of MRA examination is coordination of the imaging with patient history and findings on physical examination to create a focused study with specific diagnostic questions.

High-resolution imaging at 1.5T is often adequate for MRA of the lower limb, but imaging of the abdominopelvic and iliofemoral arteries may be improved with the use of a gadolinium chelate that permits imaging at higher field strengths. Due to concerns over nephrogenic systemic fibrosis from gadolinium in patients with significant renal impairment, there is now a preference to use MRA for anatomical localization rather than as a comprehensive examination of patients with advanced renal disease.

Static contrast-enhanced MRA is performed by acquiring separate two-dimensional projection or three-dimensional reconstruction images of static vessel anatomy. Two common types of static MRA now used are contrast-enhanced MRA using a bolus of contrast agent and quiescent interval single shot (QISS). This is a novel noncontrast method which uses a pulse sequence specific for the inflow of unsaturated blood from adjacent venous and arterial circulation to create a constant bright signal from arteries on every image. Static contrast-enhanced MRA using gadolinium is superior to previous noncontrast MRA techniques in providing clear images of the abdominal aorta, major visceral and renal arteries, and distal runoff vessels. Since diseased arteries may have a more rapid clearance of contrast agent, delayed imaging up to five minutes may be required to visualize the entire arterial tree.

Dynamic contrast-enhanced MRA is a two or three-dimensional gradient echo technique utilizing a fast imaging sequence and injection of a gadolinium bolus to obtain a series of images at timed intervals through a single pass of contrast agent. This provides a real-time assessment of arterial flow and may be useful for planning endovascular procedures.

Phase contrast and magnetization transfer MRA have largely been replaced by contrast MRA but may have a limited role in imaging patients with impaired renal function. Velocity-encoded phase contrast MRA is based upon the amplitude of a phase shift imparted to moving spins by gradients, flow velocity being indirectly proportional to the phase shift. High flow velocities or rapid changes in flow direction may result in an inaccurate representation of stenosis severity. These techniques are now primarily used as localizers for flow measurement or angioplasty procedures.

Time-of-flight MRA relies on the inflow of unsaturated blood into the imaging slice to create a signal void from saturation of the inflowing spins. It is most commonly used with a two-dimensional pulse sequence, shorter repetition time and echo time, and thin slices, producing high contrast resolution images of proximal vessels. Problems with the technique include blurring artifact from slow flow or poor slice location, and the absence of a signal void may not indicate vessel patency if there is severe stenosis.

Magnetic resonance angiography (MRA) does not involve ionizing radiation or iodinated contrast agents, utilizing strong magnetic fields and radio waves to provide detailed imaging of the vascular system. It can be performed with or without intravenous contrast agent. Noncontrast MRA techniques include time-of-flight, phase contrast, and magnetization transfer imaging. These methods are more limited in depicting distal vessels in the calf and foot but may provide sufficient information to plan revascularization.

Interventional Radiology Procedures

Currently, the most common form of interventional therapy for intermittent claudication and critical limb ischemia is angioplasty and stenting. It is also the main interventional method of treating stenosis and occlusive lesions as it achieves good immediate technical success rates, generally is minimally invasive, and has accrued a vast amount of knowledge from a decade and a half worth of use. Randomized control trials (RCTs) comparing angioplasty and stenting versus surgical bypass have found that both treatments are equally effective in terms of short-term and long-term mortality and morbidity and that there are no longer any associated risks to using angioplasty and stenting over surgery. This has sparked a shift in preferring angioplasty and stenting as the first choice treatment for PAD in the lower extremities.

Implications of interventional radiology do not just stem from diagnosis but are mainly therapeutic in nature. Interventional therapy is largely utilizing techniques that have been derived from surgical counterparts. A large advantage with interventional techniques is reduced downtimes and less associated trauma when compared with conventional surgical procedures. Several randomized control trials (RCT) have been done comparing the benefit of surgery and interventional therapy. When thinking of interventional therapy, it is important to remember that several modalities can be employed to treat the disease and each patient’s symptoms and disease severity will have different treatment options available.

Angioplasty and Stenting

Percutaneous transluminal angioplasty (PTA) is a technique involving guidewire passage across a stenosis, insertion of a balloon over the wire, inflation of the balloon to compress the atheromatous plaque, and removal of the deflated balloon. This has been shown to be a feasible technique in aorto-iliac, femoro-popliteal, and below the knee disease. The utility of PTA at various lesions has been augmented by the development of precise angioplasty balloons that deliver forceful dilatation at predetermined pressures. This has been an improvement on older techniques that often resulted in vessel dissection or will recoil from plaque compression. Randomized trials provide evidence to support PTA over surgical bypass for stenosis of the femoro-popliteal arteries, while there is Grade C evidence to suggest that PTA is superior to thrombolysis or heparin in patients with critical limb ischemia at this level. Data on aorto-iliac disease shows little long term benefit compared to surgical reconstruction. Below the knee PTA is considered a safe and effective technique with long term clinical improvement in patients with critical limb ischemia. Though there is paucity of data comparing PTA with other techniques.

When treating patients with symptomatic or critical limb ischemia, a key goal of intervention for a stenosis or occlusion is to restore blood flow to the foot. Angioplasty and stenting is a minimally invasive endovascular technique, which can be performed via an antegrade or retrograde approach. Retrograde pedal access for revascularization of the foot has been described, often in critical limb ischemia, and will not be specifically detailed in this review.

Atherectomy

Six main types of atherectomy are performed today, though some are no longer in general use. These are directional or rotational atherectomy (which will not be discussed as it is almost obsolete), laser, orbital, extraction, and photoacoustic.

Currently, 5% of all the arteries treated have atherectomy performed. Although often it is performed in conjunction with adjuvant angioplasty, atherectomy is particularly beneficial in treating more proximal LE lesions, particularly those involving the SFA. Atherectomy has the advantages of rebuilding a more normal arterial structure, reducing complications and distal embolization, and can be repeated at sites of restenosis. Atherectomy offers the potential to be superior to angioplasty, but there has yet to be a properly large-scale controlled trial to compare the two.

Atherosclerotic plaque consists of cholesterol, calcium, fibrin, inflammatory cells, and cellular debris. It may form a fibrous cap or be a loose collection of lipid which may have ulcerations, and it may become organized or form microcalcifications. Regardless of the type and consistency of the plaque, PAD is primarily a result of the atherosclerotic process. Atherectomy attempts to debulk or remove this plaque using a variety of techniques. The goals of atherectomy are to increase arterial lumen diameter, restore blood flow, and enable more effective angioplasty or pharmacological therapy.

Thrombolysis

Studies examining the use of thrombolysis in the peripheral arteries with a specific drug are few, and dosage regimens could influence outcome. Sixteen patients with acute limb ischemia were treated with the standard heparin as well as alteplase and had a 72% limb salvage rate with a mean follow-up of 33 months. Fifty mg of recombinant tissue plasminogen activator over the course of 2 hours was used in a Canadian study and had a 67% success rate. Heparin should be given with thrombolytics as it acts as an anticoagulant, preventing rethrombosis during or after the infusion of the drug. Though not specified, we add the caveats with regard to pharmacomechanical methods of delivering a lytic agent to thrombus with the aim of increasing drug efficacy and decreasing complications and add that as a nascent technology, its evolution is rapid and data is limited but encouraging.

Introduction: Thrombolysis is directed toward focal occlusions usually not amenable to surgical revascularization. It is therefore not surprising that the majority of reports consist of uncontrolled case series with varying patient selection criteria. The drugs used vary widely as well and consist of standard heparin in addition to urokinase and recombinant tissue plasminogen activator. The standard regimen is heparinization with or without the addition of anti-platelet agents for 24 hours before and after thrombolysis. The most common complications are distal embolization or acute progression to total occlusion. Complete or partial lysis of the occlusive lesion occurs in 60-70% of cases depending on the definitions used, although the immediate patency rate is less than 33%. Randomized data for acute limb ischemia does not exist and its use must be individualized based on risk/benefit ratio for the patient.

Embolization

A variety of embolic agents are currently available, which can be delivered transarterially to the site of pathology. These include Gelfoam particles, polyvinyl alcohol (PVA) particles, liquid embolics, and detachable balloons. Gelfoam is a temporary embolic agent that is useful in situations where only short-term vessel occlusion is required, and it has the advantage of being able to be injected through a diagnostic catheter. PVA particles cause irreversible occlusion, and their size can be selected to match the vessel diameter. This is a safe and effective method but does require a microcatheter and an understanding of the vascular anatomy. PVA has been largely superseded by the use of microcoils, which are the current standard for many embolization procedures. In the hands of an experienced operator, coils are precise, quick, and efficient and can be delivered in a variety of coil configurations. More recently, liquid embolics such as N-butyl cyanoacrylate have been used with good results in specific situations, and aneurysm occlusion can be achieved with detachable balloons. Due to the plethora of available devices and embolic agents, it is important to plan each procedure meticulously and to tailor the technique to the demands of the clinical situation and the vascular anatomy.

Embolization is a technique that has been used in peripheral vasculature for over 25 years, but has only recently been modified for the distal vessels. The introduction of microcatheters and coils, in addition to a variety of other devices, has increased the utility of this procedure in the legs and feet. Embolization is indicated for a wide variety of conditions and is often used in situations where surgical intervention is not feasible. These include control of acute arterial hemorrhage, treatment of vascular malformations and tumors, and occlusion of abnormal vessels due to trauma or congenital arteriovenous malformations. This technique can be particularly useful in the diabetic population where limb salvage is the priority. Often these patients have non-reconstructible distal vessels and a high surgical risk. Global results in affected limb salvage rates are as high as 93% and confine to minor amputation in 2% of cases. This compares favorably to the 5-year limb salvage rate following a major amputation, which is only 25%.

Complications and Outcomes

Another major complication of limb PAD interventions is acute or subacute thrombosis of the treated artery. This can occur weeks after the intervention and is usually secondary to neointimal proliferation and/or embolization of plaque or debris. Ischemic rest pain or sudden deterioration of claudication symptoms should prompt urgent assessment. An immediate thrombus overlying a recent stent can sometimes successfully be aspirated with an adapted catheter or thrombectomy device. However intra-arterial thrombolysis (usually overnight) is often required and prolonged dual antiplatelet therapy is essential afterwards. A thrombosis in an artery with a recently successful PTA can sometimes lead to a ‘rescue’ angioplasty of an acute on chronic occlusion. If there is associated critical limb ischemia or embolization of just one limb with a patent contralateral vessel major amputation is a rare but devastating potential outcome.

Vascular access site complications most commonly involve damage to the artery resulting in a dissection and/or pseudoaneurysm. Small dissections are generally of no consequence and if the angioplasty itself extends an intimal tear this can improve luminal dimensions and cause relief of symptoms. However more significant dissections can cause acute or subacute occlusion of the artery and result in recurrence of symptoms or critical limb ischemia. Pseudoaneurysms and arteriovenous fistulae can cause local pain or swelling and rarely significant hemorrhage. During closure of the arteriotomy a hemostatic device can cause plaque exit or embolization, again resulting in acute or subacute occlusion distally in the treated artery. Although increasingly performed the use of closure devices in peripheral artery disease is frequently off-label and the long-term safety and efficacy in this patient group is not well known.

A number of complications can occur with image-guided PTA and stenting. Some are directly related to arterial puncture and sheath placement. Arterial injury can result in large or small hematomas. The majority of large hematomas are self-limiting with a good outcome, although rarely surgery is required for drainage or to gain vascular control if there has been a false aneurysm formation. Small hematomas may cause distal ischemia due to local compression and can usually be managed conservatively. Retroperitoneal hematomas are much less commonly encountered but can be serious, causing hypotension, back pain, or groin swelling. Pelvic sheath placement is a risk factor and predisposing factors such as coagulopathy or antiplatelet agents may increase the risk. Care should be taken in patients with a high risk of bleeding to use the minimum acceptable level of anticoagulation and to monitor platelet function in those on antiplatelet therapy. Trochanteric puncture or crossovers to external iliac or common femoral arteries all have a risk of retroperitoneal hematoma. This can be a significant source of morbidity requiring blood transfusion, embolization or surgical intervention, but usually has a good prognosis if management is prompt and appropriate. If a patient develops generalized abdominal or back pain after an angioplasty it is important to have a high index of suspicion for this potentially serious complication.

Potential Risks and Complications of Interventional Radiology Techniques

With recent advancements in the field, interventional radiology techniques are associated with lower rates of complications than surgical revascularization. In general, the rate of complications from endovascular intervention ranges from 5-10%, with an increase in the risk of adverse events in patients with more severe disease. Specific complications relating to the procedure itself include hemorrhage, vessel dissection, distal embolization, and vessel occlusion. The severity of complications can range from minor injuries to major or life-threatening events. Hemorrhage at the puncture site can usually be managed with local compression; however, severe cases may require surgical repair or blood transfusion. Balloon angioplasty is associated with a 5% risk of vessel dissection. Most cases are minor and can be managed with observation; however, more severe cases may require stent placement or surgical repair. Distal embolization can occur during any endovascular intervention and is a result of atherosclerotic debris or thrombus breaking off during the procedure and traveling down the vessel. It can cause complications ranging from minor ischemia to major tissue loss. Finally, early vessel occlusion can occur following balloon angioplasty or thrombolysis and can cause acute symptoms that necessitate urgent treatment. A later complication is intimal hyperplasia, which can occur following any intervention and is a common cause of restenosis.

Success Rates and Long-term Outcomes of PAD Interventions

For patients with critical limb ischemia (CLI), the need to achieve direct arterial revascularization is paramount. Though aggressive interventional treatment has been shown to increase amputation-free survival rates, there is still high mortality within the first year, more amputations, and no significant improvement in long-term survival rates.

High-risk surgery patients with aortoiliac disease have been offered a promising alternative to surgery with the use of a stent-graft. However, this is a complex procedure and long-term results are still unclear. Atherectomy and laser techniques have not shown improved long-term results compared to PTA and stenting.

For those with milder disease and SFA lesions, PTA with provisional bare metal stenting is also associated with high primary patency and low complications. However, health economic analysis has shown that bypass surgery is a more cost-effective method in the long term. Stents, which have proven to have a higher initial technical success rate compared to PTA, suffer from in-stent restenosis rates of 40-60% after 2 years. Trials comparing stenting to PTA have shown no significant difference in long-term patency rates.

In terms of interventional treatments for PAD, while there are high success rates for relieving ischemic symptoms and avoiding the need for major surgery such as amputation, ultimately the long-term outcomes are not favorable, with restenosis rates being very high. For percutaneous transluminal angioplasty (PTA), the 2-year restenosis rate is as high as 60-70%. Though the repeat procedure can be done, long-term durability for the older patient with significant co-morbidities is not ideal.