STATE-OF-THE-ART PAPER
Current Treatment of Peripheral Arterial Disease
Role of Percutaneous Interventional Therapies
Ehtisham Mahmud, MD*,*,
Jeffrey J. Cavendish, MD
and
Ali Salami, MD*
* Division of Cardiovascular Medicine, University of California, San Diego School of Medicine, San Diego, California
Naval Medical Center, San Diego, California.
Manuscript received October 17, 2006;
revised manuscript received March 12, 2007,
accepted March 14, 2007.
* Reprint requests and correspondence: Dr. Ehtisham Mahmud, Director, Cardiovascular Catheterization Laboratories, University of California, San Diego Medical Center, 200 West Arbor Drive, San Diego, California 92103-8784. (Email: emahmud{at}ucsd.edu).
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Abstract
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Despite advances in medical therapies to help prevent the development of atherosclerosis and improve the management of patients with established peripheral arterial disease (PAD), the prevalence of PAD and associated morbidity remains high. Over the past decade, percutaneous revascularization therapies for the treatment of patients with PAD have evolved tremendously, and a great number of patients can now be offered treatment options that are less invasive than traditional surgical options. With the surgical approach, there is significant symptomatic improvement, but the associated morbidity and mortality preclude its routine use. Although newer percutaneous treatment options are associated with lower procedural complications, the technical advances have outpaced the evaluation of these treatments in adequately designed clinical studies, and therapeutic options are available that may not have been rigorously investigated. Therefore, for physicians treating patients with PAD, an understanding of the various therapies available, along with the inherent benefits and limitations of each treatment option is imperative as a greater number of patients with PAD are being encountered.
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Abbreviations and Acronyms
| | AAA = abdominal aortic aneurysm | | BE = balloon expandable | | BMS = bare-metal stent(s) | | CABG = coronary artery bypass graft | | CAD = coronary artery disease | | CEA = carotid endarterectomy | | CTO = chronic total occlusion | | DES = drug-eluting stent(s) | | LAD = left anterior descending coronary artery | | LIMA = left internal mammary artery | | MI = myocardial infarction | | PAD = peripheral arterial disease | | RAS = renal artery stenosis | | SE = self-expanding | | SFA = superficial femoral artery |
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Atherosclerosis is a systemic disease that affects all major vascular territories. The risk factors associated with the development of atherosclerosis in the coronary arteries are well known and are remarkably consistent for other vascular territories (1,2). In the lower extremities, active smoking, dyslipidemia, and inflammation are associated with progression of large-vessel atherosclerotic disease, whereas only diabetes is associated with progression of small-vessel disease (3). Despite advances in medical therapies to prevent atherosclerosis and better manage patients with established peripheral arterial disease (PAD), the incidence of PAD continues to increase, and associated morbidity remains high, especially as the population ages (4). Over the past decade, percutaneous revascularization therapies for the treatment of patients with PAD have evolved tremendously, and a great number of patients can be offered treatment options that are less invasive than traditional surgical options. Some of these technical advances have outpaced the evaluation of these treatments in adequately designed clinical studies, and therapeutic options are available that may not have been rigorously investigated. Therefore, for physicians treating patients with PAD, an understanding of the various therapies available, along with the inherent benefits and limitations of each treatment option is imperative as a greater number of patients with PAD are being encountered.
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Brachiocephalic and Subclavian Artery Disease
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The primary disease affecting the extracranial aortic arch vessels is progressive atherosclerosis. An endovascular approach to revascularization is preferred for the treatment of atherosclerotic extracranial (noninternal carotid) aortic arch vessel disease (Table 1), although there are no randomized clinical trials directly comparing this approach with contemporary surgery. However, the endovascular approach is less invasive, and a comprehensive review of the published literature demonstrates comparable procedural success (97% vs. 96% surgery), lower procedural complications (6% vs. 16% surgery), lower mortality (0% vs. 2% surgery), and lower major morbidity (stroke: 0% vs. 3% surgery), along with excellent long-term patency (97% at 20 months vs. 84% at 51 months with surgery) (5). Radiation-induced vasculitis and Takayasu’s arteritis affecting these vessels have also been described (1,6,7). Radiation-induced vasculitis is associated with poor wound healing after surgery. Therefore, obstructive disease associated with it is preferentially treated by endovascular techniques (8). In contrast, owing to panvascular inflammation and, often, concomitant aneurysmal disease, treatment for Takayasu’s arteritis is generally surgical, using Dacron grafts as bypass conduits (7).
The proximal left subclavian artery is the most commonly diseased arch vessel with significant stenosis (as determined by a systolic blood pressure difference of >15 mm Hg between the right and left arm), noted in 7.1% of patients referred to a noninvasive vascular laboratory for any indication (9). In patients undergoing coronary angiography and requiring coronary artery bypass graft (CABG) surgery, 5.3% have angiographically significant left subclavian stenosis, whereas 11.5% of patients with known PAD referred for coronary angiography also have angiographically significant left subclavian stenosis (10). In the presence of clinically significant subclavian stenosis, patients can develop upper extremity claudication and subclavian steal syndrome, a reversal of flow in the vertebral artery causing dizziness, vertigo, and, rarely, syncope with upper extremity exertion. In the presence of disease distal to the vertebral artery, patients present with arm claudication only. In contrast, when the innominate artery is affected, patients present with subclavian steal syndrome, often with profound dizziness and/or syncope in the presence of flow reversal in the right vertebral and carotid arteries. The use of the left internal mammary artery (LIMA) during CABG surgery in patients with severe left subclavian stenosis is associated with coronary-subclavian steal syndrome, leading to reversal of flow in the LIMA graft to the left anterior descending coronary artery (LAD) with left arm exertion. These patients often present with angina, particularly with the use of their left arm. If high-grade stenosis of the left subclavian artery is present at the time of CABG surgery, maturation of the LIMA graft to the LAD is also hindered, potentially leading to early graft failure. Therefore, as an increasingly complex group of patients are being referred for surgical revascularization, preoperative subclavian angiography at the time of diagnostic cardiac catheterization to allow adequate treatment of this vessel before CABG surgery is recommended.
Endovascular treatment.
Thoracic aortic arch angiography helps determine the extent of disease affecting the arch and ostia of the great vessels and is always recommended before proceeding with an intervention. Patients with atherosclerotic disease affecting the subclavian artery are best treated with balloon-expandable (BE) stents, as the ostium of this vessel is often calcified and there is significant elastic recoil after balloon angioplasty alone (Fig. 1). The vertebral artery takes off in close proximity to the origin of the left subclavian artery, and the placement of a stent across the vertebral artery is not appropriate in the presence of a contralateral vertebral artery occlusion because posterior cerebral circulation can then be compromised. In such cases, surgery is generally indicated. In a large series of patients with symptomatic subclavian disease treated with stenting, primary success was achieved in 100% of patients with stenotic lesions and 53.8% of patients with a chronic total occlusion (CTO), with the lowest complication rate in patients treated with direct stenting without predilation (11). The subclavian artery is a large-diameter vessel with a high flow rate, and both stent thrombosis and restenosis rates (secondary patency 97.7% at 3 years) are low unless recanalization is attempted for a complete occlusion (11). There are no drug-eluting stents (DES) available for vessels of this diameter, and it is highly unlikely that they will be specifically investigated for this vascular territory, as excellent clinical outcomes are achieved with the current generation of bare-metal stents (BMS). Surgery is reserved primarily for symptomatic subclavian occlusion and involves an extrathoracic carotid-subclavian artery bypass with polytetrafluroethylene or a carotid-subclavian transposition, which as isolated operations have a mortality of 0% to 1% and an excellent long-term patency (12).
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Figure 1 Subclavian Stenting for Subclavian Steal Syndrome
An 83-year-old woman presented with left arm claudication and dizziness with exertion of her left arm. Asymmetric blood pressure measurements were noted in her upper extremities with systolic blood pressure being 30 mm Hg lower in her left arm. (A) Angiography reveals a high grade ostial left subclavian stenosis (arrow) and reversal of flow in the left vertebral artery. (B) There is severe elastic recoil of the left subclavian artery after balloon angioplasty alone and a balloon expandable 9.0 x 28 mm Omnilink (Guidant, Temecula, California) stent is placed. (C) No residual stenosis remains and antegrade flow in the left vertebral artery is immediately restored. Clinical follow-up demonstrated no recurrence of symptoms at 6 months.
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The incidence of hemodynamically significant atherosclerotic disease is lower in the innominate, right subclavian, and common carotid arteries. Endovascular stenting is also the procedure of choice for disease affecting the ostial/proximal stenoses of all these vessels. In the largest series on the subject (13), published almost a decade ago, excellent procedural success (94.3%) with percutaneous treatment of these vessels was reported, albeit with high procedural complications (17.8%) and only 84% patency at 35-month follow-up. A number of investigators (5,14–18) have reported their experiences with contemporary endovascular treatment of the brachiocephalic vessels, with a unifying theme of high initial procedural success (90% to 100%), low major complication rates (0% to 4%), and excellent long-term patency (90% to 100%). The presence of calcified atherosclerotic plaque increases the potential for recoil and restenosis, which is mitigated by the use of BE stents rather than balloon angioplasty alone. Long-term surgical outcomes remain excellent, though this approach is associated with higher periprocedural complications (5). Treatment of symptomatic obstruction involving brachiocephalic vessel bypass grafts (Dacron) has also been described, using BE stents with 100% procedural success and 13.6% restenosis at 29-month follow-up (19).
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Carotid and Intracranial Disease
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Stroke is the third leading cause of mortality and the leading cause of disability in the U.S. (20). Carotid atherosclerosis commonly affects the carotid bulb and extends into the internal carotid artery. It may be associated with 20% of ischemic cerebrovascular events and is one of the treatable causes of initial and recurrent strokes. The NASCET (North American Symptomatic Endarterectomy Trial) (21,22) and ECST (European Carotid Surgery Trial) (23,24) demonstrated that patients with symptomatic carotid stenosis (carotid distribution transient ischemic attack or stroke in the preceding 6 months) and an internal carotid stenosis of 70% to 99% benefit from carotid endarterectomy (CEA) versus medical therapy, with a 2- to 3-year reduction in ipsilateral stroke from 22% to 27% (medical therapy) to 9% to 15% (CEA). Though this benefit was greatest for lesions with >70% stenosis, a subsequent meta-analysis demonstrated that at 5-year follow-up, benefit also existed for lesions with 50% to 69% stenosis (25). In asymptomatic patients, the ACAS (Asymptomatic Carotid Atherosclerotic Study) (26) and ACST (Asymptomatic Carotid Surgery Trial) (27) demonstrated a reduction in ipsilateral stroke and any perioperative death or stroke, from 11% to 12% (optimal medical therapy) to 5% to 6% (CEA) at 5-year follow-up in the presence of a >60% internal carotid artery stenosis. The American Heart Association (AHA) Stroke Council supports these findings and recommends CEA for symptomatic patients with >50% internal carotid stenosis and asymptomatic patients with a >60% stenosis, provided that surgeons can perform CEA with a complication rate <6% in symptomatic patients and <3% in asymptomatic patients (28).
Carotid stenting.
At the time of the initial reporting of results from NASCET and ECST, the first large multicenter randomized clinical trial comparing an endovascular approach to CEA for symptomatic patients with carotid stenosis was also initiated. In the CAVATAS (Carotid and Vertebral Artery Transluminal Angioplasty Study), 504 patients were randomized to carotid balloon angioplasty (with 26% stent use) versus CEA. The risk of death and ipsilateral stroke at 30 days and 3 years was comparable between the 2 strategies, with a higher risk of cranial nerve palsy (8.7% CEA vs. 0% angioplasty, p < 0.0001) but lower risk of restenosis at 1 year (4% CEA vs. 14% angioplasty, p < 0.001) with CEA (29). Despite the lack of randomized controlled trial data demonstrating the superiority of carotid stenting over balloon angioplasty in reducing restenosis, carotid stenting was increasingly undertaken, as it enabled the treatment of arterial dissections and addressed immediate elastic recoil after balloon angioplasty. Three-year restenosis rates with carotid stenting were reported to be <3%, but distal emboli to the brain appeared to result in a prohibitively high risk of stroke (30). With the advent of distal embolic protection devices, it became apparent that microemboli to the brain during carotid stenting could be reduced, as early reports (30–33) indicated a 30-day stroke/death rate with carotid stenting to be 5% to 6% without distal embolic protection but 2% to 3% with the use of these devices. Although these were not randomized comparisons, these data have led to a routine use of distal embolic protection during carotid stenting. Distal embolic protection can be achieved with either filter devices or distal and proximal occlusion devices. Distal occlusion devices are not tolerated by 
5% of patients, and with the easier use of filter devices, along with comparable clinical outcomes, filter devices are predominantly used (34).
Most patients enrolled in clinical trials comparing CEA with medical therapy were deemed to be optimal candidates for CEA and had a low risk of surgical complications (21–27). In patients considered high risk for complications with CEA (Table 2), the optimal treatment strategy had been unclear. In the multicenter SAPPHIRE (Stenting and Angioplasty in Patients at High Risk for Endarterectomy) trial, the investigators randomized 334 high-risk patients to CEA versus carotid stenting with distal embolic protection (35). Patients enrolled in this trial were symptomatic with a >50% stenosis (29%) or asymptomatic with a >80% stenosis in the internal carotid artery, elderly (mean age 73 years), and had a high percentage of coronary artery disease (CAD) (81%). The trial demonstrated noninferiority of carotid stenting with distal embolic protection when compared with CEA in the primary outcomes of death, ipsilateral stroke, or myocardial infarction (MI) at 30 days and ipsilateral stroke and death between 31 days and 1 year (20.1% CEA vs. 12.2% stenting, p = 0.004 for noninferiority) (Fig. 2). A higher risk of cranial nerve palsy (4.9% CEA vs. 0% stenting, p = 0.004) and repeat revascularization (4.3% CEA vs. 0.6% stenting, p = 0.04) was also seen in the surgical group. Multiple registries with various self-expanding stents and distal embolic protection devices have demonstrated similar results for carotid stenting in patients at high risk for CEA (30-day risk of stroke, death, and MI 3.8% to 8.6%) (36–38). Using distal embolic protection and self-expanding (SE) stents, good angiographic results (Fig. 3) and excellent clinical outcomes can be expected. However, it is important to note that these data are applicable to patients at high risk for CEA, the majority of whom were also asymptomatic in the studies.
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Figure 2 1-Year Results of the SAPPHIRE Trial
Major adverse events were defined as a composite of death, stroke, or myocardial infarction within 30 days, or death or ipsilateral stroke between 31 days and 1 year. In the intention-to-treat analysis (A), the rate of event-free survival at 1 year was 87.8% among patients randomly assigned to carotid stenting, compared with 79.9% among those randomly assigned to endarterectomy (p = 0.053). In the actual-treatment analysis (B), the rate of event-free survival at 1 year was 88.0% among patients who received a stent, compared with 79.9% among those who underwent endarterectomy (p = 0.048). I bars represent 1.5 times the standard error. Reproduced with permission from Yadav et al. (35).
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Figure 3 Carotid Stenting in a Symptomatic Patient
An 82-year-old man with a recent transient ischemic attack affecting the right hemisphere of his body, and accelerating angina, was noted to have a high-grade stenosis in the left internal carotid artery by duplex ultrasonography. (A) Angiography reveals a 90% stenosis of the left internal carotid artery. (B) Owing to proximal vessel tortousity, after the sheath is placed in the common carotid artery, tortousity is displaced distally to the internal carotid artery. (C) After placement of a distal embolic protection device Accunet (Guidant, Temecula, California) and treating the lesion with a self expanding 6 to 8 x 40 mm Acculink (Guidant) nitinol stent, 60% residual stenosis remains. (D) After balloon dilation with a 5.0 x 20 mm ViaTrac balloon (Guidant), <30% residual stenosis remains. CC = common carotid artery; EC = external carotid artery; IC = internal carotid artery.
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The results of 2 recent randomized clinical trials (enrolled symptomatic patients not at high risk for CEA) comparing carotid stenting with CEA appear discordant with the results of the SAPPHIRE trial and have called into question the benefits of carotid stenting for some patients (39,40). In the multicenter SPACE (Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy) trial, the investigators randomized 1,200 patients with a transient ischemic attack (TIA) or moderate stroke in the preceding 6 months to carotid stenting versus CEA. The primary end point of death or ipsilateral ischemic stroke at 30 days did not meet the prespecified criteria for noninferiority of stenting to CEA (6.34% CEA vs. 6.84% stenting, p = 0.09 for noninferiority) (39). In the EVA-3S (Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis) trial, 527 patients with a TIA or nondisabling stroke in the preceding 4 months were randomized to carotid stenting versus CEA. The trial was prematurely stopped because of safety concerns; the primary end point of death or any stroke at 30 days was higher in the stenting group (3.9% CEA vs. 9.6% stenting, p = 0.01 for superiority) (40). The limitations in interpreting the results of these trials include the variability in the training of the operators performing carotid stenting, limited use of distal embolic protection devices (27% SPACE; 92% EVA-3S), and the surprisingly low event rate in the surgical arm of EVA-3S. Furthermore, MI rates with either strategy in both trials were not systematically collected and reported. Nevertheless, these data suggest that in symptomatic patients who are not at high risk for cardiovascular complications from CEA and have surgically accessible lesions, the role of carotid stenting remains limited at the present time. In multiple ongoing clinical trials, including the National Institutes of Health-sponsored CREST (Carotid Revascularization versus Endarterectomy Trial), low-risk patients with carotid stenosis are being randomized to carotid stenting with distal embolic protection versus CEA. Until the results of these trials are reported, low-risk patients should likely be treated with CEA, although patient preference may occasionally dictate otherwise. On a precautionary note, results from the lead-in phase of CREST revealed that the 30-day risk of stroke and death was significantly higher for octogenarians treated with carotid stenting (12.1%, age 
80 years vs. 3.2%, age <80 years; p < 0.0001) (41). However, as most octogenarians have also been excluded from CEA trials, the optimal treatment strategy for this population remains unclear.
Plaque characterization.
Though the significance of carotid stenosis is based on either angiographic or Doppler ultrasound data, little attention has been paid to plaque characteristics that may be better predictors of the likelihood of a stroke. For example, a high-grade (>70% stenosis) fibrotic lesion may be less likely to lead to an embolic/ischemic cerebral event compared with a moderate (50% stenosis) lesion that is lipid-rich, friable, ulcerated, and therefore more vulnerable. Surface ultrasound effectively quantifies carotid arterial wall thickening, which is a strong indicator for the presence of CAD (42,43). Furthermore, there is significant correlation between carotid and coronary plaque vulnerability (44,45), with plaque echogenecity assessed by ultrasound with integrated backscatter (IBS) predicting lipid content of plaques (46,47). Echolucent plaques with low IBS values are macrophage-rich (48) and associated with lipid-rich vulnerable lesions (49). Echolucent carotid plaques detected by IBS analysis also predict cardiovascular events in patients with CAD (44), whereas treatment with pravastatin in nonhypercholsterolemic patients with CAD results in a reduction in carotid plaque echogenecity without a change in plaque volume, indicating plaque stabilization (50) (Fig. 4). Using B-mode ultrasound, symptomatic carotid plaques were found to be more echolucent and less calcified than asymptomatic plaques and were also associated with a greater degree of histopathologic plaque necrosis, indicative of plaque instability (51). A reduction in plaque echogenecity and the use of statins are both associated with a lower likelihood of a cerebrovascular event after CEA (52,53), whereas at pathology, unstable plaques are seen more often with CEA in patients who have had a TIA or stroke (54). Assessment of carotid plaque by magnetic resonance imaging in lesions 50% to 79% by ultrasound reveal that vulnerable plaque characteristics, including the presence of thin or ruptured fibrous caps, intraplaque hemorrhage, larger lipid rich/necrotic cores, and larger maximum wall thickness, are associated with the occurrence of future cerebrovascular events (55). Carotid plaque echolucency also predicts an increased likelihood of a stroke during carotid stenting (56), but the role of statins in reducing this before carotid stenting is currently unknown.
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Figure 4 Carotid Ultrasound for Plaque Morphology
(A,B) Representative ultrasound images of atherosclerotic carotid plaques with ultrasound analysis. (A) Regular B-mode image of carotid atheroma as shown by arrowheads. Plaque-intima-media thickness (IMT)max was measured in this mode as shown by an arrow. (B) Integrated backscatter (IBS)-mode image. The red dotted line indicates the region of interest (ROI) in the plaque (intima-media complex), and the blue dotted line indicates the ROI in the adventitia using the manual outline definition mode. Values of cIBS and plaque-IMTmax of this plaque are –19.6 dB and 2.44 mm, respectively. (C,D) Representative IBS images of carotid atheroma from baseline to follow-up. (C) Carotid atheroma at pretreatment. Values of cIBS and plaque-IMTmax of this plaque are –17.8 dB and 2.05 mm, respectively. (D) The same carotid atheroma post-pravastatin therapy (6 months). Values of cIBS and plaque-IMTmax of this plaque are –14.2 dB and 2.10 mm, respectively. CCA = common carotid artery; ICA = internal carotid artery. Adapted with permission from Watanabe et al. (50).
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Intracranial revascularization.
Intracranial atherosclerotic disease affects both the anterior and posterior cerebral circulation with symptoms of a TIA or stroke in the vascular distribution of the affected artery; it accounts for approximately 10% of all strokes. The treatment of intracranial atherosclerosis is predominantly medical, using antiplatelet therapy and aggressive risk factor modification. However, despite optimal medical therapy, recurrent cerebrovascular events (symptomatic patients with a 50% to 99% intracranial stenosis) are reported to be as high as 38.2% over a 2-year period, with the highest recurrence in patients with hemodynamically significant lesions (57). The indications and optimal revascularization techniques for patients with intracranial atherosclerosis remain controversial. There have been a number of case series (57–60) showing the successful use of both BMS and DES in treating patients with middle cerebral, intracranial internal carotid, basilar, and vertebral stenotic disease (Fig. 5). However, the procedural complication rates in some of these series are high (14% neurologic complications) (57,58). No study has yet demonstrated the superiority of the endovascular approach over medical therapy. A consensus document by the American Society of Interventional and Therapeutic Neuroradiology, Society of Interventional Radiology, and the American Society of Neuroradiology recommends that intracranial angioplasty/stenting be reserved for patients with a 50% to 99% intracranial stenosis in whom medical therapy has failed (61). The treatment of acute stroke in thrombolytic ineligible or thrombolytic failure patients with percutaneous revascularization using mechanical thrombectomy, adjunctive stenting, and local delivery of fibrinolytic therapy has been described with relatively good results (62–64) (Fig. 6). We support this approach, but acknowledge that the data supporting it are largely descriptive and have not been subjected to adequately controlled clinical trials. In contrast, the treatment of intracranial aneurysms and arteriovenous malformations with endovascular coiling and local injection of glue, respectively, are well defined and routinely performed (65,66).
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Figure 5 Basilar Artery Stenting for Lightheadedness
A 78-year-old woman presented with episodic lightheadedness, and a complete work-up including magnetic resonance angiography (MRA) of the brain suggested a high-grade stenosis of the basilar artery (BA). (A) Intracerebral angiography confirms a high-grade proximal BA stenosis (arrow) of 95%. (B) After balloon dilation, <30% residual stenosis remains. She had difficulty with her balance and vision for 1 month after the procedure, but then her symptoms completely resolved. (C) Six months later with symptom recurrence, an MRA demonstrated restenosis of the BA, which is confirmed by intracerebral angiography. Note the hypoplastic left vertebral artery (LVA). (D) After placement of a 2.5 x 12 mm Taxus (Boston Scientific, Natick, Massachusetts) drug-eluting coronary stent (thick arrow), <20% residual stenosis remains, and the patient has had no further neurological events at 24-month follow-up. The hypoplastic LVA and the left inferior cerebellar artery (LICA) (thin arrows) both remain patent after stent placement across these vessels. LPCA = left posterior cerebral artery; RPCA = right posterior cerebral artery; RVA = right vertebral artery.
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Figure 6 Intracranial Local Thrombolysis After Iatrogenic Stroke
A 52-year-old man who had undergone a previous renal transplant and coronary artery bypass graft surgery presented with unstable angina. As the graft to the left anterior descending artery (LAD) was occluded, a proximal LAD lesion was stented. Heparin and eptifibatide were used as the antithrombotic and antiplatelet regimen. About 45 min after the procedure, the patient had right hemianopsia, and emergent intracerebral angiography was performed after a computerized tomography scan of the head excluded an intracranial hemorrhage. (A) Anterior circulation angiography: left common carotid angiography with intracranial imaging reveals patent anterior (AC) and middle cerebral (MC) arteries without significant disease of the intracranial internal carotid artery (IC). (B) Posterior circulation angiography: left vertebral angiography with intracranial imaging demonstrates left posterior cerebral artery (PCA) occlusion (arrow). (C) A Tracker catheter (Boston Scientific, Natick, Massachusetts) is placed beyond the occlusion in the left PCA via the vertebral artery approach, and contrast injection through the catheter confirms the patency of the distal vasculature. (D) After local delivery of intra-arterial thrombolytic therapy, flow is restored in the left PCA with the patient leaving the hospital with only a mild residual visual field cut. BA = basilar artery; VA = vertebral artery.
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Renal Artery Stenosis
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Hypertension affects more than 25% of the worldwide adult population (67). Although the vast majority have essential hypertension, it is important to identify patients with secondary treatable causes of hypertension, especially atherosclerotic renal artery stenosis (RAS), the most common cause of renovascular hypertension (68). Clinical clues to the presence of RAS include onset of hypertension before age 30 years or severe hypertension after age 55 years, exacerbation of well-controlled hypertension, malignant hypertension, progressive renal insufficiency, azotemia with initiation of angiotensin-converting enzyme inhibitor therapy, renal atrophy, or cardiac dysfunction (Tables 3 and 4) (69). Noninvasive tools for detecting RAS have sensitivities ranging from 80% to 100%, whereas their specificity varies from 75% to 100% (Table 5) (70). An overview of various noninvasive studies (70) demonstrates that both computed tomographic angiography and magnetic resonance angiography are more accurate than ultrasound or the captopril renal scan in diagnosing RAS, but ultrasound does have the added benefit of providing information regarding renal functional reserve. Furthermore, ultrasound evaluation is often the first screening test as it is inexpensive, does not require contrast, is both sensitive and specific, and provides information regarding kidney size and renal resistive index. A high renal artery end-diastolic velocity (>90 cm/s) and low renal resistive index (<75 to 80) identify patients without microvascular disease or increased resistance in the segmental arteries and who are therefore more likely to derive a clinical benefit from renal artery revascularization (71,72).
In the context of high clinical suspicion, a renal artery angiogram in multiple views is desirable and remains the "gold standard" for the diagnosis of RAS. Among patients undergoing cardiac catheterization and not previously suspected of having atherosclerotic RAS with any of: 1) severe hypertension; 2) unexplained renal dysfunction; 3) acute pulmonary edema with hypertension; or 4) severe atherosclerosis, 39% had renal atherosclerosis, with 14.3% having 50% RAS (73). Traditionally, an angiographic stenosis >70%, a resting pressure gradient of >20 mm Hg across the stenosis, or unmasking of resistive renal artery lesions with intrarenal injection of papaverine or acetylcholine has been required for revascularization (74). In an interesting study, De Bruyne et al. (75) demonstrated increased renin production associated with renal stenoses that had a distal to proximal renal artery pressure drop of >10%, suggesting that this might also identify hemodynamically significant RAS. Medical therapy is, however, preferred over renal revascularization for patients with RAS and advanced renal disease as manifested by chronic renal failure (creatinine >2.5 mg/dl with unilateral RAS), proteinuria (>1 g/day), diffuse intrarenal vascular disease, renal atrophy (kidney length <7.0 cm), or a resistive index >80 (76).
Renal artery balloon angioplasty.
Fibromuscular dysplasia is a nonatherosclerotic, noninflammatory disease that most commonly affects the renal and internal carotid arteries (77). The etiology of this condition remains unknown, but it accounts for 10% of renovascular hypertension and is predominantly diagnosed in young women (77). Percutaneous transluminal renal artery balloon angioplasty (PTRA) is the preferred treatment strategy for renovascular hypertension resulting from fibromuscular dysplasia, but the data supporting this approach are largely descriptive and from the prestent era (78). Although this approach works well for patients with fibromuscular dysplasia, the diagnosis of hemodynamically significant disease by angiography in this condition can be difficult. We have described the use of a pressure measurement wire to obtain pressure gradients throughout the diseased segment in patients with fibromuscular dysplasia, which can be helpful in determining the significance of a specific stenosis and appropriate treatment (Fig. 7) (79).
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Figure 7 Renal Artery Angioplasty for Fibromuscular Dysplasia and Hypertension
A 39-year-old woman presented with poorly controlled hypertension despite being treated with 2 antihypertensive medications. A renal artery magnetic resonance angiogram suggested right renal artery stenosis. (A) Selective right renal artery angiography demonstrating the classic "beaded" appearance of fibromuscular dysplasia. (B) Selective right renal artery angiography after percutaneous transluminal balloon angioplasty (PTA) continues to demonstrate the classic "beaded" appearance of FMD with a minor angiographic change (arrow) just before the renal artery bifurcation. (C) Results of PressureWire measurement depicting the phasic and mean proximal renal artery pressure (Pa), phasic and mean distal renal artery pressure (Pd), and fractional flow reserve (FFR). This figure demonstrates a distal renal artery to proximal renal artery peak-to-peak systolic gradient of 42 mm Hg, mean pressure gradient of 30 mm Hg, and a mean distal to proximal artery pressure ratio of 0.71. (D) After successful PTA, PressureWire measurement reveals a 0 mm Hg residual gradient and a mean distal to proximal renal artery pressure ratio of 1.0. The patient’s hypertension resolved at follow-up examination, and she did not require any antihypertensive therapy. Adapted with permission from Mahmud et al. (79).
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The results of PTRA alone have been disappointing in the treatment of atherosclerotic RAS, which accounts for the vast majority of patients with renovascular hypertension. In the DRASTIC (Dutch Renal Artery Stenosis Intervention Cooperative) trial, 106 patients with atherosclerotic RAS, hypertension despite treatment with 2 antihypertensive medications, and a serum creatinine 
2.3 mg/dl were randomized to PTRA versus medical therapy. This study demonstrated that PTRA offered little benefit over medical therapy for the treatment of hypertension (80). However, major limitations of this study included the enrollment of patients with insignificant RAS, a 44% crossover from medical therapy to PTRA, and low use of stents (20%). Nevertheless, because of the scant data that previously existed on the subject, this study had a broad impact on clinical practice, and enthusiasm for percutaneous revascularization of patients with atherosclerotic RAS diminished.
Renal artery stenting.
The frequent involvement of the ostial renal artery in atherosclerotic RAS leads to high elastic recoil with PTRA and subsequently high restenosis rates of 42% to 47% (81,82). The problem of elastic recoil is alleviated by using BE stents, which provide mechanical scaffolding (Fig. 8). Results from observational studies have demonstrated that renal stenting is safe and effective in reducing blood pressure (83,84). A randomized trial proved the superiority of renal stenting over PTRA for immediate procedural success (88% stent vs. 57% PTRA) and lowering restenosis rates (14% stent vs. 48% PTRA) (85). However, clinical, angiographic, and biomarker criteria that identify individual patients who may respond to renal stenting are limited, although serum brain naturetic peptide >80 pg/ml may be one such marker (86). Concerns have existed regarding the deleterious effects of renal stenting on renal function in patients with chronic renal insufficiency (83). These concerns were largely allayed by recent studies (87,88) demonstrating improvement or stabilization of renal function after unilateral or bilateral renal stenting in patients with atherosclerotic RAS and progressive renal insufficiency.
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Figure 8 Renal Artery Stenting for Renovascular Hypertension
A 69-year-old man with a serum creatinine of 1.7 mg/dl and hypertension (blood pressure 158/97 mm Hg) despite treatment with 4 antihypertensive medications underwent magnetic resonance angiogram, which revealed a left renal artery stenosis. (A) On selective left renal artery angiography, a high-grade left renal artery stenosis of 90% (arrow) in the presence of an accessory left renal artery. (B) After balloon angioplasty, there is evidence of elastic recoil at the ostium and a residual stenosis (arrow) without complete resolution of the pressure gradient across the stenosis. (C) After placement of a 6.0 x 18 mm Herculink stent (Guidant, Temecula, California) in the main renal artery (arrow) and a 3.5 x 13 mm Cypher drug-eluting stent (Cordis, Miami, Florida) in the accessory renal artery, no residual stenosis remains. At 6-month follow-up, the patient had a blood pressure of 130/85 mm Hg and required treatment with 2 antihypertensive medications.
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In patients with RAS and hypertension (BP >140/90 mm Hg) despite treatment with at least 2 antihypertensive medications, renal stenting results in systolic blood pressure reduction of 20 mm Hg and the use of 1 less antihypertensive medication (89). This improvement in blood pressure is maintained at the 2-year interval, but these results were obtained at the expense of a 17.4% restenosis rate. Although brachytherapy and cutting balloon atherotomy have been used successfully for renal artery in-stent restenosis (90,91), long-term outcomes are unknown. The use of coronary DES has also been described for small renal arteries (92), but no well-designed studies to determine adequate doses of the eluting drug for this vessel have been performed. The largest DES is only 3.5 mm in diameter, a size that is inadequate for renal stenting (normal diameter 4 to 7 mm). Distal embolic protection devices have also been used to capture atherosclerotic debris and prevent it from distal embolization during renal stenting (93). Theoretically, this may help preserve renal function. Although surgical revascularization is effective for the treatment of RAS, its role is limited and will likely not be subjected to a randomized clinical trial against renal stenting owing to the higher morbidity and mortality of the surgical approach.
Long-term outcome data after renal stenting using end points such as stroke, MI, heart failure, renal failure, and death need to be obtained. These data are being gathered in the ongoing CORAL (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) study (94). This National Heart, Lung, and Blood Institute-sponsored study is to test the hypothesis that renal ischemia, with its consequent neuroendocrine activation, contributes to adverse cardiovascular and renal events, independently of the blood pressure achieved. The results of this trial are years away, but on the basis of the currently available data, patients with atherosclerotic RAS who are hypertensive (blood pressure 140/90 mm Hg) despite treatment with 2 antihypertensive medications, a serum creatinine <3.0 mg/dl, and a kidney >8 cm in length should be considered for renal artery stenting. In such patients, good procedural outcomes and the long-term benefits of improved blood pressure control and renal function preservation can be expected.
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Aortoiliac and Iliac Disease
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Atherosclerosis affecting iliac or aortoiliac vessels manifests as hip, thigh, or leg claudication and can certainly contribute to critical limb ischemia. Isolated stenosis or occlusion of the terminal aorta is fairly uncommon but can result in the Leriche syndrome with claudication of the upper thighs and buttocks, erectile dysfunction, and diminished femoral pulses. Obstructive atherosclerotic disease of the terminal aorta and the iliac arteries is preferentially treated with endovascular techniques rather than surgery. In 1999, the Trans-Atlantic Inter-Society Consensus (TASC) group developed treatment guidelines for symptomatic lesions in the iliac arteries based on lesion location and characteristics (Table 6) (95). The recommendations were for treating TASC type A to B lesions with an endovascular approach and TASC type C to D lesions surgically. However, with rapid evolution of endovascular techniques, TASC type C and D iliac lesions can be treated percutaneously as well, with long-term patency rates comparable to aortofemoral bypass surgery without the associated morbidity and mortality (96).
Endovascular stenting.
Atherosclerosis affecting the terminal aorta commonly also involves the bifurcation of the common iliac arteries. These bifurcation lesions can be treated using a bilateral retrograde femoral arterial approach. The choice of BE versus SE stents to treat these lesions is determined by a number of factors, including operator preference. Isolated ostial and nonostial common iliac lesions are better treated with BE stents, which are easier to place accurately and have superior radial strength and better radiovisibility. The "kissing stent" technique with BE stents is recommended when there is minimal disease affecting the terminal aorta and the ostia of both common iliac arteries are being treated. Excellent procedural outcomes (100% success without any major adverse events) and long-term patency (primary patency 92% and secondary patency 100% at 20 months) have been reported with this approach, even in a cohort of high-risk patients with disease affecting the terminal aorta and aortoiliac bifurcation (97). In the presence of atherosclerosis affecting the terminal aorta, to minimize the risk of aortic dissection, the "hugging stent" (Fig. 9) technique using 2 SE stents deployed simultaneously from the terminal aorta into each respective common iliac artery may be preferred.
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Figure 9 Iliac Stenting for Claudication
A 68-year-old man presented with severe lifestyle-limiting claudication despite maximum medical therapy including aspirin, cilostazol, atorvastatin, an exercise program, and an aggressive control of all modifiable risk factors including smoking cessation. A noninvasive work-up, including ankle-brachial indices (<0.60 bilaterally) and a magnetic resonance angiogram, suggested severe bilateral aortoiliac and external iliac disease. (A) Abdominal angiography demonstrates bilateral long-segment high-grade disease in the left and right common and external iliac arteries. (B) Kissing balloon angioplasty after placement of 2 self-expanding 9.0 x 100 mm Absolute (Guidant, Temecula, California) stents in the left and right common iliac arteries in the "hugging stent" manner. An additional 8.0 x 56 mm Absolute stent is also placed in an overlapping manner in the left external iliac artery. (C) Final abdominal angiogram reveals no significant residual stenosis and resolution of all resting gradients followed by dramatic symptomatic improvement.
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The iliac arteries, particularly the external iliac artery, have a high rate of dissection and elastic recoil. Therefore, primary stenting is performed in the vast majority of these cases, with few operators still using a provisional stenting strategy. A small randomized trial comparing balloon angioplasty (with provisional stenting) against primary stenting for iliac stenoses demonstrated no difference in procedural success or 2-year clinical outcomes (98). However, a meta-analysis of 14 studies performed since 1990 involving either balloon angioplasty or stenting to treat iliac stenoses revealed higher procedural success with stenting and a 39% lower risk of long-term failure with stenting compared with balloon angioplasty (99). The 3-year assisted patency rate for stenting of occluded iliac arteries is 80% to 90% (96,100), which compares favorably to surgical revascularization (5-year patency of aortobifemoral grafts: 91% for claudication and 88% for critical limb ischemia) without the associated 8.3% surgical morbidity and 3.3% surgical mortality (101). Lower primary patency with endovascular revascularization of iliac arteries has been noted in the presence of diabetes, critical limb ischemia, poor distal runoff, renal insufficiency, and female gender (96,102).
CTOs.
Hydrophilic wires and catheters can be used to traverse CTOs in the peripheral vasculature, but this technique is somewhat limited if the wire becomes subintimal, and entrance to the true lumen beyond the occlusion is not achieved. Recently, true lumen re-entry catheters have become available for treating CTOs in the iliac and superficial femoral arteries, which enable much higher procedural success. In a series of 87 CTOs in the iliac and superficial femoral arteries, the investigators reported failure to recanalize 28% of CTOs with standard techniques, all of which they successfully traversed and treated with the assistance of either the intravascular ultrasound-based Pioneer (Medtronic, Minneapolis, Minnesota) or fluoroscopy-based Outback (Cordis, Miami, Florida) re-entry catheter (103). In another series of 44 patients, controlled blunt microdissection with a novel device developed for this purpose is reported to be successful in recanalizing 91% of CTOs in the iliac and femoral arteries (104). Patients with a noncrossable lesion in the iliac artery or a concomitant large infra-abdominal aneurysm are best treated surgically.
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Abdominal Aortic Aneurysms (AAA)
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Abdominal aortic aneurysm remains a significant cause of morbidity and mortality owing to rupture, thromboembolic ischemic complications, and compression of adjacent structures. Risk factors for the development of an AAA include age, smoking, hypertension, higher body mass index, and alcohol consumption (105). Men with a family history of an AAA in a primary relative or who have smoked are at higher risk for developing an AAA (69). The most recent screening guidelines (Table 7) endorsed by the American College of Cardiology (ACC) and AHA advocate the frequent use of abdominal ultrasound to detect the presence of an AAA in high-risk patients and at least once in low-risk patients over the age of 60 years (69).
Aneurysm size is the single most accurate predictor of the risk of complications. In asymptomatic patients, repair is indicated once the size exceeds 5.5 cm (106). However, in patients with the clinical triad of abdominal and/or back pain, a pulsatile abdominal mass, and hypotension, immediate evaluation is required. The ACC/AHA guidelines also address the indications for the ongoing monitoring and treatment of an AAA (Tables 8 and 9)
(69). Although open surgical repair of AAA remains the standard technique, this operation has substantial morbidity and a perioperative mortality of 4% to 7% (107,108). Endovascular repair results in fewer periprocedural complications, including less blood loss, fewer cardiac and pulmonary complications, and a shorter hospitalization stay, but it is associated with a higher rate of reintervention predominantly to treat endoleaks and maintain graft patency (109–113). With further advances in technology, these complications will likely diminish, and the indications for endovascular repair may further expand.
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Infrainguinal Disease
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Atherosclerosis affecting the lower extremities frequently leads to lifestyle-limiting claudication and can lead to critical limb ischemia. Disease affecting the lower extremity peripheral vessels is most progressive in smokers and diabetics and has the worst outcomes, regardless of therapies, in patients with poor distal arterial runoff (114,115). In patients with claudication, exercise programs increase walking distance (compared with medical therapy), but most studies were performed before contemporary percutaneous revascularization techniques (116). It is quite possible that aggressive medical therapy, smoking cessation, an exercise program, and secondary risk factor modification (Table 10) (117–120) with adjunctive percutaneous revascularization of the infrainguinal vessels would result in an incremental improvement in exercise ability and improved long-term clinical outcomes. In fact, a recent longitudinal study of 300 patients undergoing lower extremity percutaneous revascularization with contemporary medical therapy demonstrates improvement in symptoms, functional status, and quality of life at 3-year follow-up (121). Infrainguinal disease is divided and treated on the basis of 3 anatomic segments.
Common femoral artery.
Atherosclerotic disease affecting the common femoral artery is best treated surgically with an iliofemoral bypass operation or endarterectomy with patch angioplasty (122). As this vessel lies over the hip joint, placement of stents is suboptimal, and restenosis or stent thrombosis can be associated with acute limb-threatening ischemia as circulation to both the superficial femoral artery (SFA) and the profunda femoris can be compromised simultaneously. Common femoral artery stenting, and debulking with rotational atherectomy or extraction atherectomy for patients who are poor candidates for surgery and present with critical limb ischemia or severe lifestyle-limiting claudication, have all been described (123,124). However, acute vessel closure or late restenosis are both associated with the risk of limb loss.
Superficial femoral artery.
Percutaneous treatment of the SFA by balloon angioplasty or stenting is associated with suboptimal long-term clinical outcomes. Short, focal (<5 cm) lesions in the SFA respond well to balloon angioplasty alone, with primary and secondary patency rates comparable to stenting (125). Therefore, endovascular stenting in the SFA is generally indicated only in the presence of a flow-limiting dissection or severe elastic recoil after balloon angioplasty. A recent randomized controlled clinical trial in which patients with long SFA lesions (mean length 13 cm) were enrolled revealed that stenting with SE nitinol stents leads to lower 6-month angiographic restenosis rates compared with balloon angioplasty alone (24% stent vs. 43% balloon angioplasty, p = 0.05) and may be the preferred approach (126). However, in the majority of patients with atherosclerosis of the SFA, the disease is often diffuse, associated with chronically occluded segments, and can involve the region of the adductor canal. This leads to issues of vessel and stent flexion, elongation, and torsion during routine daily activities, which in turn are associated with the development of stent fractures (Fig. 10) (127). Self-expanding drug-eluting nitinol stents have also been investigated for use in the SFA in a randomized clinical trial, but did not reveal a difference in angiographic or clinical outcomes compared with a SE nitinol stent (128).
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Figure 10 Stent Fracture in the Superficial Femoral Artery
Self-expanding nitinol stent 9 months after implantation showing a severe stent fracture in the distal and a moderate stent fracture (arrows; left panel) in the proximal part of the stent. Angiographically, both lesions were associated with a restenosis >50% diameter reduction (arrows; right panel). Reproduced with permission from Scheinert et al. (127).
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A number of devices have recently become available for use in the peripheral vasculature (Table 11); most are used for the treatment of lesions affecting the SFA. These include extraction atherectomy with the SilverHawk (Foxhollow, Redwood City, California), laser atherectomy (Spectranetics, Colorado Springs, Colorado), cutting balloon atherotomy (Boston Scientific, Natick, Massachusetts), and cryotherapy (Boston Scientific). Devices that aid in the recanalization of CTOs include the Pioneer (Medtronic), Outback (Cordis), and Frontrunner (Cordis) catheters. None of these devices has been tested in randomized clinical trials; even the registry outcome data with these devices have not been rigorously controlled or monitored. This has led to a number of these devices being used with unclear long-term benefits. Recently, enthusiasm for the SilverHawk atherectomy device has been noted, and when it is used in the SFA, large amounts of plaque can be retrieved (Fig. 11). This appears to result in low repeat revascularization rates in symptomatic patients who undergo plaque excision (129). Similarly, laser atherectomy may increase limb salvage rates in patients with limb ischemia but is rarely used (130). Cryotherapy appears comparable to balloon angioplasty alone in the treatment of focal SFA lesions, with 9-month repeat revascularization rates of 18% (131).
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Figure 11 Extraction Atherectomy of the Superficial Femoral Artery
A 64-year-old woman with right leg claudication (ankle-brachial index 0.68) despite aggressive medical therapy and an exercise program underwent abdominal angiography with lower extremity runoff. (A) An occluded right superficial femoral artery (SFA) just beyond the ostium is noted with three vessel runoff to the foot via collaterals. (B) The occlusion in the right SFA (arrow) is just beyond the ostium of the vessel. (C) After traversing the stenosis with a 0.035-inch guidewire (Terumo, Japan), the wire is exchanged over an end-hole catheter to a 0.014-inch BMW wire (Guidant, Temecula, California), and atherectomy with a SilverHawk (Foxhollow, California) catheter is performed. (D) Final angiographic result after significant plaque extraction. Duplex ultrasound follow-up at 12 months revealed no evidence of restenosis at the site of atherectomy and the patient remained clinically asymptomatic. CFA = common femoral artery.
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It appears, therefore, that for lesions in the SFA up to 10 cm in length, endovascular stenting with nitinol SE stents or extraction atherectomy both seem reasonable options and are superior to balloon angioplasty alone. However, the roles of stenting, atherectomy, and cryotherapy need to be better defined because the options for the treatment of restenosis in this vessel remain limited. Brachytherapy has been tried and shown to be successful (132) but is not widely available, and long-term benefits are unclear. For long-term success of percutaneous revascularization of the SFA, good in-flow and, at a minimum, single-vessel runoff to the foot are desirable. Surgical femoral-popliteal bypass operation remains an option for patients with chronic limb ischemia.
Below-the-knee.
Obstructive atherosclerotic disease affecting the popliteal and infrapopliteal vessels is treated percutaneously or with medical therapy. For patients with severely symptomatic claudication unresponsive to medical therapy and an aggressive exercise program, infrapopliteal angioplasty, atherectomy, and stenting should be considered. The use of DES has been described for below-the-knee revascularization with a low restenosis rate (133,134). This has also led to the approval in Europe of the BE sirolimus-eluting stent Cypher (Cordis) for this indication. However, there is a paucity of long-term data regarding the benefit of this strategy. In cases of limb salvage where inline flow is required to help heal an ulcer, ischemic area, or infection, aggressive percutaneous revascularization is indicated and has been shown to increase tissue healing and reduce the incidence of amputation resulting in limb salvage (133,135).
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Conclusions
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Tremendous advances were made over the past decade in new techniques and devices for the treatment of atherosclerotic disease affecting the peripheral arterial vessels. Historically, patients with symptomatic PAD were treated medically, with surgical revascularization reserved as an option for advanced disease. There is significant symptomatic improvement with the surgical approach, but the associated high morbidity and mortality preclude its routine use. The newer percutaneous treatment options are associated with much lower procedural complications and good long-term outcomes. Although more randomized clinical trials and registries with independent monitoring need to be performed, the threshold for percutaneous revascularization may also need to be lowered, as a greater number of patients with symptomatic peripheral vascular disease can now be treated with lower procedural risks.
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Footnotes
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The views, opinions, and assertions contained in this work are those of the authors and are not to be construed as official or as reflecting the views of the U.S. Navy, Department of Defense, or the U.S. Government.
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References
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- Pasternak RC, Criqui MH, Benjamin EJ, et al. AHA conference proceedings: Atherosclerotic Vascular Disease Conference: Writing Group I: Epidemiology Circulation 2004;109:2605-2612.[Free Full Text]
- Bhatt DL, Steg G, Magnus Ohman E, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis JAMA 2006;295:180-189.[Abstract/Free Full Text]
- Aboyans V, Criqui MH, Denenberg JO, Knoke JD, Ridker PM, Fronek A. Risk factors for progression of peripheral arterial disease in large and small vessels Circulation 2006;113:2623-2629.[Abstract/Free Full Text]
- Rothwell PM, Coull AJ, Silver LE, et al. Oxford Vascular StudyPopulation-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 2005;366:1773-1783.[CrossRef][ISI][Medline]
- Fields CE, Bower TC, Hoskin T, et al. Takayasu’s arteritis: operative results and influence of disease activity J Vasc Surg 2006;43:64-71.[CrossRef]
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Brachiocephalic and Subclavian...
Carotid and Intracranial Disease
