Peripheral Vascular Stents

Number: 0785

Policy

Aetna considers peripheral artery stenting by means of Food and Drug Administration-approved stentsFootnotes for stents* medically necessary in any of the following situations:

• Primary therapy for common iliac artery stenosis and occlusions.
• Primary therapy for external iliac artery stenoses and occlusions.
• Primary therapy for chronic mesenteric ischemia.
• Primary therapy for individuals with symptomatic posterior cerebral or cerebellar ischemia caused by subclavian artery stenosis (subclavian steal syndrome) who are at high-risk of surgical complications.
• Primary therapy for individuals with symptomatic extremity ischemia caused by subclavian artery stenosis (used in cases for stenting of the subclavian artery following percutaneous transluminal angioplasty).
• Salvage therapy for brachiocephalic arteries: subclavian steal syndrome, upper extremity claudication, ischemic rest pain of the arm and hand, non-healing tissue ulceration, and focal gangrene.
• Salvage therapy for common and external iliac arteries for a sub-optimal or failed result from balloon dilation (e.g., persistent translesional gradient, residual diameter stenosis greater than 50 %, or flow-limiting dissection).
• Salvage therapy for femoral, popliteal, and tibial arteries for a sub-optimal or failed result from balloon dilation (e.g., persistent translesional gradient, residual diameter stenosis greater than 50 %, or flow-limiting dissection).
• Salvage therapy for femoral-popliteal arterial lesions for a sub-optimal result from balloon dilation.
• Salvage therapy for infra-popliteal arterial lesions for a sub-optimal result from balloon dilation.

Aetna considers peripheral artery stenting experimental and investigational in any of the following situations (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Celiac artery stenting in the treatment of celiac artery compression syndrome.
• Primary therapy for tibial artery stenosis and occlusions.
• Primary therapy for infra-popliteal lesions.
• Primary or salvage therapy for atherosclerotic reno-vascular disease (e.g., ischemic nephropathy).
• Primary or salvage therapy for aorto-iliac arterial lesions.
• Primary or salvage therapy for popliteal artery aneurysm
• Renal artery stenting for stenosis due to fibromuscular dysplasia or other causes.

Aetna considers the Zilver PTX Drug-Eluting Peripheral Stent medically necessary for the primary treatment of femoropopliteal artery disease.

Aetna considers the Gore Tigris Vascular Stent medically necessary for the primary treatment of superficial femoral artery and proximal popliteal artery diseases.

Aetna considers the Eluvia Drug-Eluting Vascular Stent System medically necessary for the primary treatment of superficial femoral artery and proximal popliteal artery diseases.

Aetna considers the LifeStream balloon-expandable covered stent medically necessary for the primary treatment of iliac artery stenosis.

Aetna considers peripheral venous stents medically necessary for the following indications (not an all-inclusive list):

• Hemodialysis access graft/fistula: stenosis, restenosis, and occlusion; recurrent cephalic arch stenosis (salvage therapy).
• May-Thurner syndrome (e.g., the VENOVO venous stent system )
• Superior vena cava: superior vena cava syndrome, post radiation venous stenosis, and congenital stenosis.

Aetna considers peripheral venous stents experimental and investigational for the treatment of recurrent phlebitis because their effectiveness for this indication has not been established.

Aetna considers biodegradable stents (i.e. bioabsorbable and bioresorbable) experimental and investigational for the treatment of peripheral arterial disease because their effectiveness has not been established.

Aetna considers the Eluvia Drug-Eluting Vascular Stent System experimental and investigation for the treatment of iliac artery stenosis because its effectiveness has not been established.

Footnotes for stents* All drug-eluting arterial stents and polytetrafluoroethylene (PTFE)-covered arterial stents (e.g., the Atrium Medical iCast stent), other than the Gore Viabahn PTFE-coated stent and the Zilver PTX-Drug-Eluting stent, are considered experimental and investigational for treatment of peripheral vascular diseases because their effectiveness for this indication has not been established.

Background

1. functional, and
2. organic. 

Functional PVD does not involve defects in the structure of the blood vessels; is usually transient and related to spasm of the vessels (e.g., Raynaud's disease).  It can be triggered by smoking, cold temperatures, emotional stress, or working with vibrating machinery.  Organic PVD is caused by inflammation and tissue damage in the blood vessels (e.g., peripheral artery disease [PAD]).  It is caused by fatty build-ups in arteries that block normal circulation; and is more common than functional PVD.

Peripheral artery disease affects 3 major arterial segments:

1. aorto-iliac arteries,
2. femoro-popliteal (FP) arteries, and
3. infra-popliteal (primarily tibial) arteries. 

The disease is usually classified based on claudication, rest pain, or degree of tissue loss due to chronic ischemia.  Peripheral artery disease is an important cause of morbidity that affects up to 10 million people in the United States.  Physicians can identify patients who are at risk for the disease with a questionnaire and the ankle brachial index (ABI).  The ABI can be attained by measuring the blood pressure (BP) at the brachial artery and at the posterior tibialis artery by means of sonography.  The ankle systolic BP is divided by the brachial BP, both measured in the supine position.  Normally, the ratio is more than 1; in severe disease, it is less than 0.5.  More than 70 % of patients diagnosed with the disease remain stable or improve with conservative management.  Those who do not improve may undergo contrast angiography or magnetic resonance angiography, which may be used in planning for surgery or percutaneous intervention.  In particular, patients with critical limb ischemia (CLI) should undergo interventions for re-vascularization.  Re-vascularization methods have entailed surgical as well as endovascular approaches.  Surgical bypass, atherectomy, and endarterectomy have been used to restore peripheral circulation.  However, the invasiveness and complications of surgical interventions have resulted in the development of endovascular procedures.  Percutaneous transluminal angioplasty (PTA) and/or stenting have been employed as primary and salvage therapy for PAD (De Sanctis, 2001; Ouriel, 2001; Balk et al, 2008; AHA, 2009).

 There are 2 basic types of stents:

1.  balloon-expandable (BE), and
2. self-expandable (SE). 

The former uses an angioplasty balloon to expand and set the stent within the arterial segment (e.g., the Palmaz stent); although it has been supplanted by the next generation of SE stents for arterial occlusive lesions.  Self-expanding stents may have benefits in longer occlusive lesions as primary therapy, especially in the FP segment, where PTA and BE stents may be associated with higher rates of re-stenosis and failure.  The SE stent depends on the unique properties of a memory metal (e.g., nitinol) or alternatively the weave of the stent, to assume a pre-configured shape within the vessel lumen.  The Wallstent, an example of the latter, is composed of elgaloy, a variant of stainless steel, and the radial force induced by the weave density determines expansion.  The SE stent may be post-dilated to ensure strut apposition to the arterial wall.  The patency rates of SE stents appear to be superior to BE stents (Balk et al, 2008).

New materials have been added to conventional stents in an attempt to improve their effectiveness.  The standard stent (whether BE or SE) is bare-metal, with no added materials.  Covered stents use a synthetic fabric, such as polytetrafluoroethylene (PTFE), which covers the metal component of the stent and acts as an exoskeleton.  However, animal studies did not support the proposed advantage of the covered stent that it lowers the incidence of neointimal hyperplasia, which can hasten re-stenosis.  While the incidence of neointimal hyperplasia was reduced in the mid-portion of the graft, it was comparable to that of controls at the proximal and distal ends of the covered stent.  One major advantage of a stent graft is that a longer infra-inguinal lesion can be treated.  In theory, the synthetic fabric of the covered stent excludes the atherosclerotic plaque from the lumen.  In addition, the combination of the nitinol exoskeleton and the fabric cover yields a flexible, but structurally stable device, which is particularly advantageous in the femoro-popliteal segment (Balk et al, 2008).

Drug-eluting stents (DES) that usually contain sirolimus (rapamycin) have been used "off-label" for patients with PVD.  Other treated stents have been developed such as the Carbostent, which has a thin coating of carbon designed to reduce its interaction with platelets.  "Off-label" use of stents is problematic because the device does not follow the conventional Food and Drug Administration (FDA) approval process.  Randomized controlled trials (RCTs) are underway, one that compares PTA alone to PTA and a biliary stent in the superficial femoral and proximal popliteal arteries; another RCT has been performed, which examines a bare nitinol biliary stent in the same anatomical segment.  Neither of these trials has yet been published in peer-reviewed journals (Balk et al, 2008).  The National Institute for Health and Clinical Excellence's guideline on "Lower limb peripheral arterial disease: Diagnosis and management" (2012) recommended the use of bare metal stents where stenting is indicated for intermittent claudication because of a lack of evidence of superior clinical outcomes with DES. 

There is no consensus on the diagnosis or treatment of renal artery stenosis (RAS).  The consequences of renal ischemia are hypertension, neuroendocrine activation, and renal insufficiency, which can result in acceleration of atherosclerosis, further renal dysfunction, myocardial infarction (MI), heart failure, stroke, and death.  Whether re-vascularization improves clinical outcomes when compared with optimal medical therapy is unclear.

There is insufficient evidence of the effectiveness of stenting over percutaneous transluminal angioplasty (PTA) for renal artery stenosis.  An assessment prepared for the Agency for Healthcare Research and Quality (2007) concluded that "[o]verall, there is insufficient evidence to determine whether angioplasty with stenting is better treatment for [atherosclerotic renal artery stenosis] than aggressive medical therapy alone."  The report also concluded that there is no difference in the long-term kidney function of people who have angioplasty compared with people who have medical therapy alone."  The report also noted that there is insufficient evidence to determine whether angioplasty reduces the number of antihypertensive medications required after the procedure, and there is no research about how angioplasty and medical therapy compare in treating people who have acutely decompensating hemodynamic and kidney function.

The American Heart Association (AHA)'s symposium on atherosclerotic peripheral vascular disease – intervention for renal artery disease (Rocha-Singh et al, 2008) stated that the treatment of atherosclerotic renal artery disease is evolving and remains controversial.  Renal artery stenting is widely available and frequently used to treat patients with renal artery stenosis and poorly controlled hypertension and/or renal insufficiency.  However, it is still unclear if percutaneous re-vascularization adds incremental value to optimal medical therapy to prevent the adverse consequence of renal artery disease.  Accordingly, the AHA recommended that physicians enroll hypertensive patients with atherosclerotic RAS into the CORAL trial to acquire outcomes and selection data.

More recently published systematic evidence reviews (e.g., Kumbhani et al, 2011) have found no significant differences in clinical outcomes in persons with renal artery stenosis managed with stenting and persons managed medically. Ongoing clinical trials such as the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) trial will ultimately help to determine the best strategies to limit the morbidity and mortality associated with renal artery stenosis.

Cooper and colleagues (2006) stated that the Cardiovascular Outcomes in Renal Atherosclerotic Lesions Trial (CORAL) is a randomized clinical study contrasting optimal medical therapy alone to stenting with optimal medical therapy for patients with atherosclerotic RAS on a composite cardiovascular and renal endpoint: cardiovascular or renal death, MI, hospitalization for congestive heart failure, stroke, doubling of serum creatinine, and need for renal replacement therapy.  The secondary endpoints evaluate the effectiveness of re-vascularization in important subgroups of patients and with respect to all-cause mortality, kidney function, renal artery patency, microvascular renal function, and BP control.

Tuttle and colleagues (1998) reported their 5-year experience with the intra-vascular stent for the treatment of ostial RAS.  A total of 129 patients (63 men and 66 women) and 148 arteries were included in this study.  The mean age of the patients was 71 +/- 10 years; 98 % were hypertensive and 57 % had renal dysfunction.  Angiographical characteristics of RAS were unilateral in 78 %, bilateral in 15 %, and single kidney in 7 %.  The technical success rates were 98 % for stent versus 11 % for percutaneous renal angioplasty (PTRA) in the ostial location.  The stent re-stenosis rate (angiographical) was 14 % at 8 +/- 5 months.  Systolic and diastolic BPs were as follows: baseline, 158 +/- 3 and 84 +/- 2 mm Hg; 6 months, 149 +/- 3 and 81 +/- 2 mm Hg; 12 months, 149 +/- 3 and 79 +/- 2 mm Hg; and 24 months, 135 +/- 3 and 79 +/- 2 mm Hg.  Follow-up values were significantly lower than baseline (p < 0.05).  The number of medications for hypertension initially decreased from 2.2 +/- 0.1 at baseline to 1.6 +/- 0.1 and 1.8 +/- 0.1 at 1 and 3 months, respectively (p < 0.05).  By 6 months, however, the number of medications had increased and was not significantly different from before stent placement.  Renal function was stable in the group as a whole: Cockroft-Gault creatinine clearance (C-G CrCl) at baseline was 40 +/- 2 ml/min; at 6 months, 36 +/- 3 ml/min; at 12 months, 39 +/- 3 ml/min; and at 24 months, 39 +/- 4 ml/min.  When stratified by degree of renal function, values were similarly stable.  Patients with a baseline serum creatinine level of 2 mg/dL or less had C-G CrCl values as follows: baseline, 53 +/- 3 mg/dL; 6 months, 43 +/- 4 mg/dL; 12 months, 46 +/- 4 mg/dL; and 24 months, 52 +/- 5 mg/dL.  Those with a baseline serum creatinine level greater than 2 mg/dL had C-G CrCl values as follows: baseline, 26 +/- 2 mg/dL; 6 months, 31 +/- 4 mg/dL; 12 months, 32 +/- 6 mg/dL; and 24 months, 23 +/- 3 mg/dL.  Of 8 patients who were dialysis-dependent, 4 (50 %) recovered renal function with a mean serum creatinine level of 2.3 +/- 0.5 mg/dL at 15 +/- 6 months (range of 9 to 24 months).  The authors concluded that stent placement for the treatment of atherosclerotic ostial RAS has a high success rate and a low rate of re-stenosis.  Control of hypertension improves in most patients.  Renal function stabilizes or improves in the majority of patients, even those with severe renal failure.  The authors reported that these favorable outcomes are maintained long-term.

In a prospective non-randomized trial, Zähringer et al (2007) evaluated the patency of sirolimus-eluting stents (SES) compared to bare-metal stents (BMS) in the treatment of atherosclerotic RAS.  A total of 105 consecutive symptomatic patients (53 men; mean age of 65.7 years) with RAS were treated with either a bare-metal (n = 52) or a drug-eluting (n = 53) low-profile Palmaz-Genesis peripheral stent at 11 centers.  The primary endpoint was the angiographical result at 6 months measured with quantitative vessel analysis by an independent core laboratory.  Secondary endpoints were technical and procedural success, clinical patency [no target lesion re-vascularization (TLR)], BP and anti-hypertensive drug use, worsening of renal function, and no major adverse events at 1, 6, 12, and 24 months.  At 6 months, the overall in-stent diameter stenosis for BMS was 23.9 % +/- 22.9 % versus 18.7 % +/- 15.6 % for SES (p = 0.39).  The binary re-stenosis rate was 6.7 % for SES versus 14.6 % for the BMS (p = 0.30).  After 6 months and 1 year, TLR rate was 7.7 % and 11.5 %, respectively, in the BMS group versus 1.9 % at both time points in the SES group (p = 0.21).  This rate remained stable up to the 2-year follow-up; but did not reach statistical significance due to the small sample.  Even as early as 6 months, both types of stents significantly improved BP and reduced anti-hypertensive medication compared to baseline (p < 0.01).  After 6 months, renal function worsened in 4.6 % of the BMS patients and in 6.9 % of the SES group.  The rate of major adverse events was 23.7 % for the BMS group and 26.8 % for the SES at 2 years (p = 0.80).  The authors concluded that the angiographical outcome at 6 months did not show a significant difference between BMS and SES.  Renal artery stenting with both stents significantly improved BP.  They stated that future studies with a larger patient population and longer angiographical follow-up are needed to determine if there is a significant benefit of DES in treating ostial RAS.

Corriere et al (2008) retrospectively examined peri-procedural morbidity and early functional responses to primary renal artery angioplasty and stenting (RA-PTAS) for patients with atherosclerotic reno-vascular disease (RVD).  Consecutive patients undergoing primary RA-PTAS for hemodynamically significant atherosclerotic RVD with hypertension and/or ischemic nephropathy were identified from a prospectively maintained registry.  Hypertension responses were determined based on pre- and post-intervention BP measurements and medication requirements.  Estimated glomerular filtration rate (eGFR) was used to determine renal function responses.  Both hypertension and renal function responses were assessed at least 3 weeks after RA-PTAS.  Stepwise multi-variable regression analysis was used to examine associations between BP and renal function responses to RA-PTAS and select clinical variables.  A total of 110 primary RA-PTAS were performed on 99 patients with atherosclerotic RVD with a mean angiographical diameter-reducing stenosis of 79.2 +/- 12.9 %.  All patients had hypertension (mean of 3.4 +/- 1.3 anti-hypertensive agents).  Mean pre-intervention eGFR was 49.9 +/- 22.7 ml/min/1.73 m(2), and 74 patients had a pre-intervention eGFR of less than 60 ml/min/1.73 m(2).  The technical success rate for RA-PTAS was 94.5 %.  The peri-procedural complication rate was 5.5 %; there were no peri-procedural deaths.  Statistically significant decreases in mean systolic BP (161.3 +/- 25.2 mm Hg versus 148.5 +/- 25.2 mm Hg post-intervention, p < 0.0001), diastolic BP (78.6 +/- 13.3 mm Hg versus 72.5 +/- 13.5 mm Hg post-intervention, p < 0.0001), and number of anti-hypertensive agents (3.3 +/- 1.2 versus 3.1+/- 1.3 post-intervention, p = 0.009) were observed.  Assessed categorically, hypertension response to RA-PTAS was cured in 1.1 %, improved in 20.5 %, and unchanged in 78.4 %.  Categorical eGFR response to RA-PTAS was improved in 27.7 %, unchanged in 65.1 %, and worsened in 7.2 %.  Multi-variable stepwise regression analysis revealed associations between pre- and post-intervention systolic BP (p < 0.0001), diastolic BP (p < 0.0001), and eGFR (p < 0.0001), as well as a trend toward improved diastolic BP response among patients managed with staged bilateral intervention (p = 0.0589).  The authors concluded that primary RA-PTAS for atherosclerotic RVD was associated with low peri-procedural morbidity and mortality but only modest early improvements in BP and renal function.  They stated that results from ongoing prospective trials are needed to assess the long-term outcomes associated with RA-PTAS and clarify its role in the management of atherosclerotic RVD.

The American Heart Association (AHA)'s symposium on atherosclerotic peripheral vascular disease – intervention for renal artery disease (Rocha-Singh et al, 2008) had the following statements:

• The treatment of atherosclerotic renal artery disease is evolving and remains controversial.
• Renal artery stenting is widely available and frequently used to treat patients with RAS and poorly controlled hypertension and/or renal insufficiency.  However, it is still unclear if percutaneous re-vascularization adds incremental value to optimal medical therapy to prevent the adverse consequence of renal artery disease.  Accordingly, the AHA recommended that physicians enroll hypertensive patients with atherosclerotic RAS into the CORAL trial to acquire outcomes and selection data.
• In patients with declining renal function due to ischemic nephropathy, when obstructive renal artery disease affects the entire renal mass, renal artery stenting can be expected to either improve or stabilize renal function in the majority of patients and reduce the risk of developing volume overload; however, this potential benefit must be weighed against the potential risk of worsening renal function due to procedure-related athero-embolization or contrast-induced nephropathy, other adverse events, and renal in-stent re-stenosis (ISR).  Thus, additional research in this area is needed.
• Newer technologies have been applied to treatment of renal ISR, but none has been shown to be superior in limited case-series reports.  Use of a PTFE-covered BE stent (iCast Covered Stent, Atrium Medical Corp, Hudson, NH; or Graft Master Stent, Abbott Vascular Devices, Santa Clara, CA) is another potential method to treat renal ISR, although neither device is approved for this indication, nor is there evidence to support their use.
• Drug-eluting stents reduce ISR at 12 months in coronary arteries.  The efficacy of a sirolimus DES in the renal circulation has been studied in a small feasibility study, the GREAT trial (Palmaz Genesis Peripheral Stainless Steel Balloon Expandable Stent in Renal Artery Treatment), in which 6-month follow-up data demonstrated a decrease in renal ISR from 14 % in the BMS group to 6.7 % in the DES cohort on the basis of follow-up angiography.
• New technology, devices, and medications are promising, but no data support their routine use for the treatment of renal ISR, and further investigation is recommended.

In a randomized clinical trial, Bax and colleagues (2009) examined the safety and effectiveness of stent placement in patients with atherosclerotic renal artery stenosis (ARAS) and impaired renal function.  Randomization was centralized and computer- generated, and allocation was assigned by e-mail.  Patients, providers, and persons who assessed outcomes were not blinded to treatment assignment.  A total of 140 patients with creatinine clearance less than 80 ml/min per 1.73 m(2) and ARAS of 50 % or greater were included in this study.  Stent placement and medical treatment (n = 64) or medical treatment only (n = 76).  Medical treatment consisted of anti-hypertensive treatment, a statin, and aspirin.  The primary end point was a 20 % or greater decrease in creatinine clearance.  Secondary end points included safety and cardiovascular morbidity and mortality.  Forty-six of 64 patients assigned to stent placement had the procedure.  Ten of the 64 patients (16 %) in the stent placement group and 16 patients (22 %) in the medication group reached the primary end point (hazard ratio [HR], 0.73 [95 % confidence interval [CI]: 0.33 to 1.61]).  Serious complications occurred in the stent group, including 2 procedure-related deaths (3 %), 1 late death secondary to an infected hematoma, and 1 patient who required dialysis secondary to cholesterol embolism.  The groups did not differ for other secondary end points.  Many patients were falsely identified as having RAS greater than 50 % by non-invasive imaging and did not ultimately require stenting.  The authors concluded that stent placement with medical treatment had no clear effect on progression of impaired renal function but led to a small number of significant procedure-related complications.  The study findings favor a conservative approach to patients with ARAS, focused on cardiovascular risk factor management and avoiding stenting.

In a randomized, unblinded trial, the ASTRAL Investigators (Wheatley et al, 2009) examined if percutaneous revascularization of the renal arteries improves patency in atherosclerotic renovascular disease.  A total of 806 patients with atherosclerotic renovascular disease were randomly assigned either to undergo re-vascularization (angioplasty either alone or with stenting) in addition to receiving medical therapy or to receive medical therapy alone.  The primary outcome was renal function, as measured by the reciprocal of the serum creatinine level (a measure that has a linear relationship with creatinine clearance).  Secondary outcomes were blood pressure, the time to renal and major cardiovascular events, and mortality.  The median follow-up was 34 months.  During a 5-year period, the rate of progression of renal impairment (as shown by the slope of the reciprocal of the serum creatinine level) was -0.07x10(-3) liters per micromole per year in the re-vascularization group, as compared with -0.13x10(-3) liters per micromole per year in the medical-therapy group, a difference favoring re-vascularization of 0.06x10(-3) liters per micromole per year (95 % CI: -0.002 to 0.13; p = 0.06).  Over the same time, the mean serum creatinine level was 1.6 micromol per liter (95 % CI: -8.4 to 5.2 [0.02 mg per deciliter; 95 % CI: -0.10 to 0.06]) lower in the re-vascularization group than in the medical-therapy group.  There was no significant between-group difference in systolic blood pressure; the decrease in diastolic blood pressure was smaller in the re-vascularization group than in the medical-therapy group.  The 2 study groups had similar rates of renal events (HR in the re-vascularization group, 0.97; 95 % CI: 0.67 to 1.40; p = 0.88), major cardiovascular events (HR, 0.94; 95 % CI: 0.75 to 1.19; p = 0.61), and death (HR, 0.90; 95 % CI: 0.69 to 1.18; p = 0.46).  Serious complications associated with re-vascularization occurred in 23 patients, including 2 deaths and 3 amputations of toes or limbs.  The authors concluded that they found substantial risks but no evidence of a worthwhile clinical benefit from re-vascularization in patients with atherosclerotic renovascular disease.

Rabbia and Pini (2010) stated that atherosclerotic renovascular disease is an increasingly recognized cause of severe hypertension and declining kidney function.  Patients with atherosclerotic renovascular disease have been demonstrated to have an increased risk of adverse cardiovascular events.  In the past 20 years, renal artery re-vascularization for treatment of ARAS has gained great increase via percutaneous techniques.  However the effectiveness of contemporary re-vascularization therapies in the treatment of RAS is unproven and controversial.  The indication for renal artery stenting is widely questioned due to a not yet proven benefit of renal re-vascularization compared to best medical therapy.  Many authors question the effectiveness of percutaneous renal re-vascularization on clinical outcome parameters, such as preservation of renal function and BP control.  None of the so far published RCTs could prove a beneficial outcome of RAS re-vascularization compared with medical management.

Peixoto et al (2010) noted that the management of ARAS is controversial.  Although it may appear intuitive that restoring normal blood flow to the kidney(s) is the treatment of choice, there are no data showing an obvious advantage of interventional therapy compared with medical therapy.  The authors discussed the most recent advances in the treatment of ARAS with a focus on RCTs comparing medical treatment with angioplasty/stenting, especially in patients with underlying renal dysfunction.  The available data are still of limited quality but provide support against indiscriminate use of interventions, as these treatments appear no better than best medical treatment that focuses on BP control, use of blockers of the renin-angiotensin system, and aggressive cardiovascular risk management.

Steichen et al (2010) systematically reviewed the controlled studies on primary stenting for ARAS.  Studies were included if they compared the outcome of stenting with other treatments, or the outcome associated with different stent characteristics or stenting methods.  Stenting is preferred over angioplasty alone and over surgery when re-vascularization is indicated for ostial ARAS, except in cases of co-existent aortic disease indicating surgery.  Randomized controlled trials showed no significant benefit and substantial risk of renal artery stenting over medication alone in patients with ARAS without a compelling indication.  Improvements in the procedure, such as with distal embolic protection devices and coated stents, are not associated with better clinical outcomes after stent placement for ARAS.  The authors concluded that recent evidence shows that impaired renal function associated with ARAS is more stable over time than previously observed.  Optimal medical treatment should be the preferred option for most patients with ARAS.  Only low-level evidence supports compelling indications for re-vascularization in ARAS, including rapidly progressive hypertension or renal failure and flash pulmonary edema.

Simon (2010) stated that percutaneous intervention has become very popular for treating ARAS, as the use of stents has boosted the rate of technical success and as more cases are being discovered incidentally during angiography of the coronary or other arteries.  Yet, RCTs indicate that the procedure does little in terms of controlling BP and may actually harm as many patients as it helps in terms of renal function.  Needed are better ways to predict which patients will benefit and better ways to prevent adverse effects such as athero-embolism.

Guidelines on management of peripheral artery disease from the American College of Cardiology (Hirsch et al, 2006), discussed in greater detail below, conclude that primary stent placement is not recommended in the femoral, popliteal, or tibial arteries.  In addition, the guidelines state that the effectiveness of stents for the treatment of femoral-popliteal arterial lesions (except to salvage suboptimal results from balloon dilation) is not well established, and the effectiveness of uncoated/uncovered stents for the treatment of infra-popliteal lesions (except to salvage a suboptimal result from balloon dilation) is not well-established.

A Cochrane systematic evidence review of angioplasty versus stenting for superficial femoral artery lesions found most randomized clinical trials meeting inclusion criteria reporting patency rates and ankle-brachial pressure index, with only one trial reporting on quality of life (Twine et al, 2009).  The Cochrane review found a small but statistically significant improvement in primary angiographic and duplex patency at 6 months in patients treated with PTA plus stent over lesions treated with PTA alone.  However, primary angiographic patency was non-significant at 1 year.  A similar but lesser effect was seen for ankle brachial pressure index (ABPI).  The review reported a small improvement in treadmill walking distance in patients with PTA plus stent insertion at 6 months and 1 year, but not at 2 years.  The Cochrane review found only 1 trial reporting quality of life, which showed no significant difference between patients treated with PTA alone or PTA with stent insertion at any time interval.

The Agency for Healthcare Research and Quality's technology assessment of "invasive interventions for lower extremity peripheral artery disease" and systematic review of "studies comparing stent placement to other interventions" (Balk et al, 2008) reached the following conclusions:

1. The cited aorto-iliac surgery studies did not describe the pre-operative anatomy and no clinically relevant outcomes were reported.  The majority of the studies cited for endovascular treatment of the aorto-iliac segment did have anatomical descriptions of the studied patients; however, none used the Trans-Atlantic Society Consensus (TASC) classification;
2. There is a dearth of trials of patients with either aorto-iliac or infra-popliteal disease.  The newer nitinol stents were used by only 3 of the trials (plus 1 RCT of stent versus bypass and 2 RCTs comparing different stents).  The predominant primary outcome of the trials remain patency (variously defined), which has not been adequately demonstrated to be an excellent predictor of clinical outcomes.  True clinical outcomes have frequently been inadequately or incompletely reported and analyzed.

Regarding studies comparing stents to PTA, the AHRQ assessment found "Individual studies did find statistically significantly better clinical outcomes with one intervention or the other, but overall, the trials and other comparative studies failed to provide adequate data to show that any one intervention is superior for any outcome over any other intervention in any group of patients.  However, for the most part, the data can not be said to convincingly show that stent and PTA (or the other comparisons) are equivalent.  The studies are clinically too heterogenous and both individually and collectively too small to accurately estimate relative differences in clinical event rates.  The AHRQ assessment stated: "There is a dearth of trials of patients with either aorto-iliac or infrapopliteal disease …. The primary outcome of the trials remains patency (variously defined), which has not been adequately shown to be an excellent predictor of clinical outcomes."  The assessment found that clinical studies have frequently focused on patency rates, a surrogate endpoint of unclear clinical significance.  The assessment stated: "To be able to assess the true relative value of stent placement compared to PTA, it is important that future trials analyze more clearly defined questions, use greater methodological rigor, and use appropriate clinical outcomes.  This includes clearly defining what the population being analyzed is (by diseased artery, lesion morphology, and clinical severity), and what the intervention and comparator is (preferably analyzing stent to PTA, with minimal crossover, since high rates of secondary stenting make the study results difficult to interpret).  The primary outcomes should be important clinical outcomes, not surrogate outcomes, such as patency (or even ABI)."

Mewissen (2004) assessed the safety and effectiveness of SE shape memory alloy recoverable technology (SMART) nitinol stents in patients with CLI demonstrating type B or type C TASC lesions in the FP arterial segment.  A total of 137 lower limbs in 122 patients with CLI, secondary to TASC A (n = 12) or TASC B/C (n = 125) lesions in the FP artery were treated with the Cordis SMART SE nitinol stents.  The hemodynamic primary stent patency was calculated by life-table methods from the time of intervention, uninterrupted by hemodynamic stent failure.  The mean lesion length was 12.2 cm (range of 4 cm to 28 cm).  The technical success was 98 %.  Within the follow-up period (mean of 302 days), 24 limbs were diagnosed with hemodynamic stent failure.  The hemodynamic primary stent patency rates were 92 %, 76 %, 66 %, and 60 % at 6, 12, 18, and 24 months, respectively.  These data provided objective evidence that endovascular treatment of FP TASC A, B and C lesions using SE nitinol SMART stents in patients with CLI provides favorable safety and durability outcomes.

The Cordis Randomized Iliac Stent Project-US (CRISP-US) trial assessed the performance of the SMART nitinol SE stent and the stainless steel Wallstent for treating iliac artery disease after sub-optimal PTA (Ponec et al, 2004).  This multi-center, prospective, randomized trial comprised 203 patients with CLI who received either the SMART stent (n = 102) or the Wallstent (n = 101) after sub-optimal PTA.  The primary endpoint was a composite of 9-month re-stenosis, 30-day death, and 9-month target vessel re-vascularization (TVR).  Functional, clinical, and hemodynamic assessments were made at hospital discharge and at 1, 6, 9, and 12 months.  The 9-month composite endpoint rate was equivalent for the SMART stent and the Wallstent (6.9 % versus 5.9 %), with low rates of re-stenosis (3.5 % versus 2.7 %), death (2.0 % versus 0.0 %), and re-vascularization (2.0 % versus 4.0 %) in the 2 groups.  Primary patency at 12 months was 94.7 % and 91.1 % with the SMART stent and the Wallstent, respectively.  Functional and hemodynamic improvements were also comparable between the groups.  The acute procedural success rate was higher in the SMART stent group (98.2 % versus 87.5 %; p = 0.002).  The frequency of major adverse events was similar at 1 year (4.9 % versus 5.9 %).  The authors concluded that the performance of the SMART stent was equivalent to that of the Wallstent for treating iliac artery stenosis.  The design characteristics of the SMART stent may contribute to greater procedural success and more accurate stent deployment.

In a double-blind, randomized, prospective trial, Duda and associates (2002) evaluated the effectiveness of the SMART nitinol SE stents coated with a polymer impregnated with sirolimus (rapamycin) versus uncoated SMART stents in superficial femoral artery (SFA) obstructions.  A total of 36 patients were recruited for this study.  All patients had CLI and femoral artery occlusions (57 %) or stenoses (average lesion length, 85 +/- 57 mm).  Patients were eligible for randomization after successful guide-wire passage across the lesion; 18 patients received sirolimus-eluting SMART stents and 18 patients received uncoated SMART stents.  The primary endpoint of the study was the in-stent mean percent diameter stenosis, as measured by quantitative angiography at 6 months.  The in-stent mean percent diameter stenosis was 22.6 % in the SES group versus 30.9 % in the uncoated stent group (p = 0.294).  The in-stent mean lumen diameter was significantly larger in the SES group (4.95 mm versus 4.31 mm in the uncoated stent group; p = 0.047).  No serious adverse events (prolonged hospitalization or death) were reported.  The authors concluded that the use of sirolimus-eluting SMART stents for SFA occlusion is feasible, with a trend toward reducing late loss compared with uncoated stents.  The coated stent also proved to be safe and was not associated with any serious adverse events.

In a follow-up study, Duda et al (2005) expanded the treatable population and limited the lesion lengths so that all lesions could be covered by no more than 2 stents.  A total of 57 patients (29 in the SES group and 28 in the BMS group) with CLI and SFA occlusions (66.7 %) or stenoses (average lesion length of 81.5 +/- 41.2 mm).  Stent implantation followed standard interventional techniques.  The primary endpoint was the in-stent mean lumen diameter at 6 months as determined by quantitative angiography.  Both stent types were effective in re-vascularizing the diseased SFA and allowing sustained patency for at least 6 months.  There was no statistically significant difference between treatment groups in the in-stent mean lumen diameter at 6 months (4.94 +/- 0.69 mm and 4.76 +/- 0.54 mm for SES and BMS groups, respectively; p = 0.31).  Although the diameter of the target lesion tended to be larger and percent stenosis tended to be lower with the SES, there were no statistically significant differences between treatments in terms of any of the variables.  The mean late loss values were 0.38 +/- 0.64 mm and 0.68 +/- 0.97 mm for the SES group and the BMS group, respectively (p = 0.20).  The binary re-stenosis rates, with a cut-off value of 50 % at 6 months, were 0 % in the SES group and 7.7 % in the BMS group (p = 0.49).  Clinical outcomes matched angiographical outcomes with improvements in ABI and symptoms of claudication.  There was no significant difference between treatments in terms of adverse events.  The authors concluded that although there is a trend for greater efficacy in the SES group, there were no statistically significant differences in any of the variables.

Schillinger et al (2006) examined if primary implantation of a SE nitinol (nickel-titanium) stent yielded anatomical and clinical benefits superior to those afforded by PTA with optional secondary stenting.  These investigators randomly assigned 104 patients who had severe claudication or CLI due to stenosis or occlusion of the SFA to undergo primary stent implantation (n = 51) or angioplasty (n = 53).  Re-stenosis and clinical outcomes were assessed at 6 and 12 months.  The mean (+/- SD) length of the treated segment was 132 +/- 71 mm in the stent group and 127 +/- 55 mm in the angioplasty group.  Secondary stenting was performed in 17 of 53 patients (32 %) in the angioplasty group, in most cases because of a sub-optimal result after angioplasty.  At 6 months, the rate of re-stenosis on angiography was 24 % in the stent group and 43 % in the angioplasty group (p = 0.05); at 12 months the rates of re-strenosis on duplex ultrasonography were 37 % and 63 %, respectively (p = 0.01).  Patients in the stent group were able to walk significantly farther on a treadmill at 6 and 12 months than those in the angioplasty group.  The authors concluded that in the intermediate-term, treatment of SFA disease by primary implantation of a SE nitinol stent yielded results that were superior to those with the currently recommended approach of balloon angioplasty with optional secondary stenting.

Kickuth et al (2007) assessed the primary success and short-term patency associated with a new 4-F sheath-compatible SE nitinol stent after failed conventional angioplasty of distal popliteal and infra-popliteal lesions in severe lifestyle-limiting claudication (LLC) and chronic CLI.  A total of 35 patients with Rutherford category 3 to 5 disease (CLI, n = 16; LLC, n = 19) underwent PTA and stent implantation.  Indications for stent placement were residual stenosis, flow-limiting dissections, or elastic recoil after PTA.  Before and after the intervention and during the 6-month follow-up, clinical investigation, color-flow and duplex Doppler ultrasonography, as well as digital subtraction angiography were performed.  Technical success, primary patency at 6 months, clinical improvement as defined by Rutherford with clinical and hemodynamic measures, and complications were evaluated.  A total of 22 patients underwent distal popliteal artery stent placement and 13 underwent tibio-peroneal artery stent placement.  Stent implantation was successfully performed in all patients.  After stent placement, the primary cumulative patency rate for the study group at 6 months was 82 %.  The mean resting ABI at baseline was 0.50 +/- 0.16 and significantly increased to 0.90 +/- 0.17 at 12 to 24 hours after intervention and 0.82 +/- 0.24 at latest follow-up (p < 0.001 for both).  The sustained clinical improvement rate was 80 % at the 6-month follow-up.  The 6-month limb salvage rate regarding major amputation was 100 %.  The rate of major complications was 17 %.  The authors concluded that infra-popliteal application of the new nitinol stent is a safe, feasible, and effective method with good short-term patency rate in the treatment of severe LLC and chronic CLI.

Zeller et al (2008) examined the impact of nitinol stenting of SFA lesions with a maximum length of 10 cm (TASC-II A or B) on 1-year outcomes compared to a historical study cohort from the Femoral Artery Stent Trial (FAST).  A total of 6 study sites enrolled 110 symptomatic patients (75 men; mean age of 68 +/- 9 years).  These patients had a single de novo greater than 70 % SFA lesion that is less than 10 cm long, and they were treated with the SE nitinol Conformexx stent.  The primary study endpoint was binary re-stenosis determined by duplex ultrasound at 12 months.  Secondary 12-month endpoints were TLR, ABI, mean Rutherford category, greater than 1-class change in Rutherford category, and major adverse events.  Data were analyzed according to the intention-to-treat principle and according to the actual treatment received ("on treatment" analysis).  Outcomes were compared to the historical balloon angioplasty (BA) arm and the Luminexx 3 stent arm of the randomized FAST study.  Technical success was achieved in 106 (96 %) patients; at 1 year, the primary endpoint of ultrasound-assessed binary re-stenosis was reached in 14 (23.3 %) of 60 patients (95 % CI: 13.4 % to 36 %).  This re-stenosis rate was lower versus the historical BA (38.6 %, p = 0.057) or Luminexx 3 stent controls (31.7 %, p = 0.284) from FAST.  The clinically driven TLR was 7.4 % (7 of 94 clinically controlled patients), which was also lower compared to 18.3 % (p = 0.098) and 14.9 % (p = 0.267) for the historical BA and Luminexx 3 stent groups, respectively.  The mean Rutherford category was reduced from 2.75 +/- 0.79 to 0.94 +/- 1.38 (p < 0.0001); 85.1 % were improved by at least 1 Rutherford category.  The ABI increased from 0.62 +/- 0.15 to 0.85 +/- 0.20 (p < 0.0001).  The authors concluded that this study of patients with SFA lesions documented favorable outcomes using nitinol stents in TASC-II A or B lesions after 1 year.  The study was under-powered to prove superiority of the Conformexx nitinol stent design compared to historical balloon angioplasty only or Luminexx 3 stent groups.

It should be noted that Medtronic Inc. (Minneapolis, MN), under an investigational device exemption, is sponsoring a clinical trial of its Complete SE stent for the treatment of PAD in the SFA.  The SFA study is a prospective, multi-center, single-arm trial that planned to enroll 178 subjects at up to 30 sites globally.

In a meta-analysis, Mwipatayi et al (2008) reviewed the currently available literature and compared the short-term and long-term results of primary stenting and angioplasty of FP occlusive disease.  All studies that reported data on the long-term results after balloon dilatation or stent implantation were included if at least 1-year primary patency or re-stenosis rate was presented; the study follow-up was at least 1 year and the number of subjects at the start of study was at least 20 patients.  In the meta-analysis, there were a total of 934 patients: 452 patients underwent BA (273 patients were male) and 482 patients underwent stenting (297 patients were male).  Primary patency at 1-year and post-operative ABI post-intervention was used to evaluate the pooled odds ratio (OR) of all studies.  The pooled OR of all studies estimate for the 12-month patency rates was 0.989 (95 % CI: 0.623 to 1.570, p = 0.962) showing no difference in outcome between the 2 groups (SE 0.269 % to 1.025 %).  The pooled OR estimate for the post-operative ABI was 0.869 (95 % CI: 0.557 to 1.357, p = 0.561) showing a slight advantage in favor of the BA group; but the "p" value was not statistically significant (SE 0.282 % to 1.326 %).  The 1-year primary patency rates following BA ranged from 45 % to 84.2 % and at 2 years it varied from 25 % to 77.2 %.  In the stent implantation group, the 1-year primary patency rates varied from 63 % to 90 %, and 2-year primary patency ranged from 46 % to 87 %.  Heterogeneity was seen among studies, and publication bias could not be excluded.  The authors concluded that the results of this meta-analysis suggested that stent placement in the FP occlusive disease does not increase the patency rate when compared with BA alone at 1 year.

Kasapis and colleagues (2009) performed a meta-analysis of RCTs comparing routine stenting (ST) with PTA for symptomatic superficial femoral-popliteal artery (SFPA) disease.  A total of 10 trials were pooled randomizing patients to ST (n = 724 limbs) or PTA with provisional stenting (n = 718 limbs) with a follow-up period of 9 to 24 months.  The mean lesion length was similar in the two groups (45.8 mm in the ST group and 43.3 mm in the PTA group).  These researchers calculated the summary risk ratios (RRs) for immediate technical failure, re-stenosis, and TVR using random-effects models.  The immediate technical failure was higher in the PTA group than in the ST group (17.1 % versus 5.9 %, respectively, RR = 0.28, 95 % CI: 0.15 to 0.54, p < 0.001), with 10.3 % of the PTA patients undergoing stenting because of sub-optimal result.  There was a trend for lower re-stenosis in the ST group (37.6 % in ST versus 45.3 % in PTA, RR = 0.85, 95 % CI: 0.69 to 1.06, p = 0.146), but no difference in the need for TVR (20 % in ST versus 20.2 % in PTA, RR = 0.98, 95 % CI: 0.78 to 1.23, p = 0.89).  In an analysis restricted to nitinol stents, there was a trend towards reduction in TVR (RR = 0.79, 95 % CI: 0.59 to 1.06, p = 0.12).  The authors concluded that despite the higher immediate success, routine stenting was not associated with a significant reduction in the rate of re-stenosis or TVR.  These findings do not support use of routine stenting as the primary endovascular treatment for short SFPA lesions.

Saxon and colleagues (2008) compared the safety and effectiveness of the Viabahn endoprosthesis with that of PTA alone in the treatment of symptomatic PAD affecting the SFA.  From 1998 to 1999, patients with symptomatic SFA PAD were enrolled in a prospective, multi-center randomized study and underwent either PTA alone (n = 100) or PTA followed by stent-graft placement (expanded PTFE [ePTFE]/nitinol self-expanding stent-graft) (n = 97) for stenoses or occlusions of the SFA that were 13-cm long or shorter.  At baseline, there were no significant differences between the PTA and stent-graft treatment groups, including CLI status and treated lesion length.  The stent-graft group had a significantly higher technical success rate (95 % versus 66 %, p < 0.0001) and 1-year primary vessel patency rate at duplex ultrasonography (65 % versus 40 %, p = 0.0003).  A patency benefit was seen for lesions at least 3-cm long.  At 12 months, CLI status was 15 % further improved for the stent-graft group (p = 0.003).  There were no significant differences between treatment groups with regard to the occurrence of early or late major adverse events.  The authors concluded that in this multi-center study, the patency, technical success, and clinical status results obtained with stent-grafts were superior to those obtained with PTA alone.  Drawbacks of this study included the lack of an uncovered stent arm that precluded direct comparisons with nitinol stents, the frequency of minor puncture site hematomas (not requiring therapy) was higher in the stent graft group, and short follow-up period.  Also, the study was stopped with a smaller patient population than was originally planned, which may have limited the power of the study and resulted in a failure to detect significant differences that may have been present.  The authors noted that studies with longer follow-up are needed to define more clearly the durability of stent graft re-vascularization in patients with CLI.  Additionally, more RCTs comparing stent graft and new bioactive stent grafts with other endovascular techniques or with bypass surgery are needed.

Kougias et al (2009) performed a retrospective cohort study of consecutive patients with symptomatic SFA occlusions (greater than 15 cm) who underwent subintimal endovascular intervention, either covered stent (CS) or balloon-only subintimal angioplasty (SIA), in a single institution.  Primary patency was the primary outcome.  Secondary outcomes included complication rates, freedom from re-intervention, and limb salvage rates.  Patency was ascertained with follow-up duplex or clinically.  These investigators evaluated 57 patients in the SIA group and 31 patients in the CS group.  At 1 year the SFA primary patency for the SIA and CS groups was 28 % versus 75 % (p < 0.001), whereas the primary assisted patency was 37 % versus 84 % (p < 0.001), respectively.  Need for bypass was 13 % versus 0 % (p = 0.05) in the SIA and CS groups, respectively.  The authors concluded that placement of a covered stent improves patency after subintimal intervention for long SFA occlusion.  Drawbacks of this study included its retrospective nature, small sample size, and short follow-up period.  Also, not all the patients had confirmed patency with imaging studies.  The authors noted that primary placement of a covered stent is a promising endovascular modality in the treatment of SFA occlusive disease, and more long-term data are needed to ensure durability.

Kawamura et al (2009) compared patency rates following nitinol stenting in subjects with SFA lesions compared to a historical group of subjects with SFA lesions who received stainless steel stents in preceding years.  As the study did not compare stenting with PTA alone, no conclusions can be reached about the value of PTA plus stenting versus PTA in this study.  Although the study suggested that nitinol stent implantation improves primary patency after PTA compared with stainless steel stenting, the lack of randomization and use of non-contemporaneous comparison groups introduces the risk of bias.  In addition, the study did not report on clinical outcomes.

McQuade and associates (2010) compared the treatment of SFA occlusive disease percutaneously with an ePTFE/nitinol self-expanding stent graft (stent graft) versus surgical femoral to above-knee popliteal artery bypass with synthetic graft material.  A total of 100 limbs in 86 patients with SFA occlusive disease were evaluated from March 2004 to May 2005.  Patient symptoms included both claudication and limb threatening ischemia with or without tissue loss.  Trans-Atlantic InterSociety Consensus (TASC II) A (n = 18), B (n = 56), C (n = 11), and D (n = 15) lesions were included.  Patients were randomized prospectively into one of two treatment groups:

1. a percutaneous treatment group (group A; n = 50) with angioplasty and placement of one or more stent grafts, or
2. a surgical treatment group (group B; n = 50) with a femoral to above-knee popliteal artery bypass using synthetic conduit (Dacron or ePTFE). 

Patients were followed for 48 months.  Follow-up evaluation included clinical assessment, physical examination, ABI, and color flow duplex sonography at 3, 6, 9, 12, 18, 24, 36, and 48 months.  Mean total lesion length of the treated arterial segment in the stent graft group was 25.6 cm (SD = 15 cm).  The stent graft group demonstrated a primary patency of 72 %, 63 %, 63 %, and 59 % with a secondary patency of 83 %, 74 %, 74 %, and 74 % at 12, 24, 36, and 48 months, respectively.  The surgical femoral-popliteal group demonstrated a primary patency of 76 %, 63 %, 63 %, and 58 % with a secondary patency of 86 %, 76 %, 76 %, and 71 % at 12, 24, 36, and 48 months, respectively.  No statistical difference was found between the 2 groups with respect to primary (p = 0.807) or secondary (p = 0.891) patency.  The authors concluded that management of SFA occlusive disease with percutaneous stent grafts exhibits similar primary patency at 4-year (48 month) follow-up when compared with conventional femoral-popliteal artery bypass grafting with synthetic conduit.  The authors concluded that this treatment method may offer an alternative to treatment of the SFA segment for re-vascularization when prosthetic bypass is being considered or when autologous conduit is unavailable.  Drawbacks of this study included a small total patient cohort, a single center experience, and that only 64 % (32 to 50 limbs) in the stent graft group and 52 % (26 of 50 limbs) in the surgery group are available for analysis at 4 years.  Also, there were a variety of anti-thrombotic medications – almost all (93 %) of the stent graft group were on combination anti-platelet therapy with aspirin and plavix whereas only about 50 % of the surgery group were on this combination regimen.  Furthermore, the patients enrolled in this clinical trial had relatively mild lesions (more than 70 % were TASC II A and B lesions with mostly intermittent claudications).  It is unclear if the stent graft approach is effective in the more severe lesions.

Lenti et al (2007) reported the findings of a prospective multi-center registry designed to evaluate the safety, effectiveness, and patency of the aSpire SE PTFE-covered stent (Vascular Architects Inc, San Jose, CA) in patients with FP occlusive disease.  The aSpire Registry included 150 patients (166 limbs) enrolled in 16 centers during a 28-month period for medium/long (greater than 3 cm) occlusion (n = 115) or stenosis (n = 51) of the SFA (n = 51) or of the proximal popliteal (n = 115) arteries.  Procedures were performed for intermittent claudication in 92, for rest pain in 33, and for limb savage in 41.  The mean length of arterial segment covered was 107.35 +/- 73.7 mm.  Indications for treatment included 44 type B1, 57 type B2, 47 type C1, and 18 type D lesions according to the TASC classification.  Clinical and ultrasound evaluations were performed at discharge and at 1, 6, 12 months, and yearly thereafter.  Mean follow-up was 13 months (range of 1 to 36).  Primary endpoints were immediate technical success (vessel re-canalization with residual stenosis less than or equal to 30 %) and stent patency.  Initial technical success was obtained in 162 (97.6 %) of 166 procedures.  More than one stent was applied in 48 procedures, for a total of 214 stents.  No peri-procedural deaths occurred.  Procedure-related complications occurred in 22 of 166 procedures, including 6 peripheral embolizations, 7 thromboses, 2 hemorrhages requiring revision, 1 vessel rupture, and 6 vessel dissections.  Life-table estimates of primary patency at 12, 24, and 36 months were 64 %, 59 %, and 59 %, respectively.  A total of 32 re-interventions were performed during follow-up, resulting in secondary patency rates at 12, 24, and 36 months of 74.2 %, 67 %, and 67 %, respectively.  Amputation was required in 6 of 41 patients treated for limb salvage.  At multi-variate analysis, CLI was the only significant predictor of late failure.  The authors concluded that endovascular treatment of SFA occlusive lesions provided interesting results.  Length of lesion and clinical symptoms influence negatively the patency.  The PTFE-covered stent showed good mid-term results, but a number of re-interventions were necessary to obtain an optimal secondary patency.  Risk of patency failure was related to CLI as an indication for the procedure.  These researchers stated that technological and pharmacological improvement and longer follow-up are needed to define the indications for the aSpire PTFE-covered stent.

Dearing et al (2009) reported on the results of peripheral angioplasty and stenting by a single surgeon of primary stenting of the SFA and popliteal artery.  Limitations of this study include the lack of a comparison group and the reporting only of patency rates and not clinical outcomes.  Dosluoglu et al (2009) compared percutaneous balloon angioplasty and stenting versus above knee femoral popliteal bypass with PTFE for TASC C and D lesions and reported better primary and primary assisted patency with PTA and stenting than with surgical reconstruction.  Limitations of this study included its retrospective nature and its reporting solely of patency rates.

The American College of Cardiology/American Heart Association's guidelines for the management of patients with PAD (lower extremity, renal, mesenteric, and abdominal aortic) had the following statements (Hirsch et al, 2005):

• Stenting is effective as primary therapy for common iliac artery stenosis and occlusions
• Stenting is effective as primary therapy for external iliac artery stenoses and occlusions
• Provisional stent placement is indicated for use in the iliac arteries as salvage therapy for a sub-optimal or failed result from balloon dilation (e.g., persistent translesional gradient, residual diameter stenosis greater than 50 %, or flow-limiting dissection)
• Stents can be useful in the femoral, popliteal, and tibial arteries as salvage therapy for a sub-optimal or failed result from balloon dilation (e.g., persistent translesional gradient, residual diameter stenosis greater than 50 %, or flow-limiting dissection)
• Primary stent placement is not recommended in the femoral, popliteal, or tibial arteries
• The effectiveness of stents for the treatment of femoral-popliteal arterial lesions (except to salvage a suboptimal result from balloon dilation) is not well-established
• The effectiveness of uncoated/uncovered stents for the treatment of infra-popliteal lesions (except to salvage a suboptimal result from balloon dilation) is not well-established.

The American Heart Association (AHA)'s symposium on atherosclerotic peripheral vascular disease – lower-extremity re-vascularization (Gray et al, 2008) had the following statements:

• Re-stenosis after endovascular therapy for infra-inguinal PAD remains a major obstacle to widespread adoption of DES as primary treatment of symptomatic PAD.  With the dramatic improvement in re-stenosis rates realized in large-scale prospective, multi-center RCT in coronary artery disease using DES compared with BMS, it seems intuitive that similar technology would result in clinical as well as anatomical benefits in infra-inguinal PAD.  Unfortunately, data evaluating such therapy are limited.
• There is an ongoing clinical trial in the United States, the Zilver-PTX trial (Cook, Inc., Bloomington, IN) in which paclitaxel, which has been shown to dramatically reduce coronary artery ISR, has been placed on the surface of nitinol SE stents, although without a top coat.  This randomized, prospective, multi-center trial comparing a DES with a BMS has completed its feasibility phase and is now enrolling patients in the pivotal segment of the trial.
• Two treatment strategies have shown efficacy for coronary ISR (DES and vascular brachytherapy), however, there is no consensus for the treatment of SFA ISR.
• Further studies with DES for SFA re-stenosis are warranted.
• Anecdotes have been reported about the efficacy of covered stents (i.e., PTFE-covered nitinol stents), but no data exist to suggest that these will provide a break-through.

Sarac and colleagues (2008) stated that percutaneous angioplasty and stenting (PTAS) is emerging as a therapeutic option for patients with chronic mesenteric ischemia (CMI).  This study evaluated patency and mortality, and their relationship between degree of vessel occlusion (stenotic or totally occluded), stent characteristics, and co-morbidities in patients who were treated with PTAS of the visceral vessels for CMI.  A retrospective review was performed of the records of all patients who underwent PTAS of the celiac, superior mesenteric, or inferior mesenteric arteries, or both, for symptomatic CMI between January 2001 and December 2005.  Patient demographics, lesion characteristics (stenosis or occlusion), interventional details, and early and late mortality rates were recorded.  Cumulative mortality and patency rates and factors associated with outcomes were determined using Kaplan-Meier method and Cox proportional hazards modeling.  A total of 87 mesenteric vessels (57 superior mesenteric, 23 celiac, and 7 inferior mesenteric arteries) were treated in 65 patients (29 men and 36 women).  Completely occluded vessels were treated in 18 patients (28 %), and greater than 60 % stenosis was treated in 47 patients (72 %).  Mesenteric angina was the most common symptom (97 %).  For the entire series, the cumulative 1-year results were primary patency, 65 % (95 % CI: 50 % to 80 %); primary assisted patency, 97 % (95 % CI: 92 % to 100 %); secondary patency, 99 % (95 % CI, 96 % to 100 %); and survival, 89 % (95 % CI, 80 % to 98 %).  All deaths occurred less than or equal to 60 days after treatment.  The endovascular treatment of visceral artery occlusion was not associated with diminished patency or survival, irrespective of stent size or number.  Patients requiring bowel resection were less likely to survive than those who did not (odds ratio [OR], 26; 95 % CI: 3.5 to 192; p < 0.001).  One-year primary patency was worse among patients with chronic obstructive pulmonary disease (OR, 3.2; 95 % CI: 1.4 to 7.7; p = 0.009) or who had femoral access (OR, 3.0; 95 % CI: 1.1 to 7.9; p = 0.015).  The authors concluded that for patients with CMI, the results of endovascular treatment of occluded mesenteric arteries are indistinguishable from those treated for stenotic vessels.  Patients requiring bowel resection are less likely to survive, and those with chronic obstructive pulmonary disease or who had femoral access have higher re-intervention rates.

Heiss et al (2008) evaluated the technical and clinical success rates of percutaneous stent re-vascularization in the treatment of CMI.  A total of 17 patients (12 females) with typical symptoms of CMI were treated by percutaneous stent placement for stenoses of the splanchnic arteries (celiac trunk; superior mesenteric artery, SMA; inferior mesenteric artery, IMA).  The primary and secondary technical success, primary and secondary clinical success, and the long-term clinical outcome were determined.  A total of 24 stents were implanted in 21 splanchnic arteries (12 stents in the celiac trunk, 11 in the SMA and 1 in the IMA).  The primary technical success rate was 91 % (19/21 arteries), the secondary technical success rate was 95 % (21/22 arteries).  Clinical follow-up was available for 16 patients.  The primary clinical success rate was 81 % (13/16 patients).  Following 2 secondary interventions, the secondary clinical success rate was 94 % (15/16 patients).  Long-term clinical success was achieved in 15 of 16 patients (94 %) with a mean follow-up of 26 months.  One patient died within 30 days of the intervention and 2 patients demonstrated major complications (1 dissection, 1 stent dislocation).  None of the patients required surgical re-vascularization and none of the patients died due to recurrent mesenteric ischemia.  The authors concluded that percutaneous stent placement for the treatment of CMI can be performed with a high technical and clinical success rate as well as an excellent long-term clinical outcome.

Penugonda et al (2009) discussed stent placement in mesenteric arteries in older patients with an increasingly common diagnosis of CMI.  They reviewed the articles that focused on the treatment of this gastrointestinal disorder by stenting/open surgical re-vascularization to avoid further ischemic episodes and bowel infarction and necrosis.  The advantages of stent placement in mesenteric arteries were discussed in comparison to open surgical re-vascularization.  In summary, the low morbidity and high technical success rate of catheter-based techniques have made this approach the first- line of therapy for CMI due to superior mesenteric artery stenosis for many elderly patients especially high-risk operative candidates.

Peck et al (2010) documented the intermediate-term anatomic and functional outcomes of endovascular mesenteric re-vascularization for symptomatic CMI.  This was a retrospective review of all patients undergoing endovascular treatment of symptomatic CMI from July 2002 to March 2008.  Study endpoints included peri-procedural mortality, major morbidity, patency, symptomatic recurrence, and survival.  Endpoints were analyzed using actuarial methods.  A total of 66 mesenteric arteries (78.8 % stenotic; 21.2 % occluded) were treated in 49 patients.  One or more vessels were treated in each case; however, 4 mesenteric artery total occlusions (3 SMAs; 1 IMA) could not be crossed.  Initial symptom relief was noted in 89.8 % (n = 44) with no change in 5 patients.  Single-vessel treatments were performed in 32 patients (65.3 %) and 2-vessel interventions in 17 (34.7 %).  The 30-day mortality rate was 2.0 % (n = 1).  Major complications occurred in 8 patients (16.3 %).  The mean follow-up duration was 37.4 +/- 2.98 months (range of 0 to 66).  Re-stenosis on follow-up imaging occurred in 64.9 % (n = 24) of the 37 patients who had radiographical surveillance at a mean follow-up interval of 8.5 +/- 1.9 months and was diagnosed most often by Duplex scan or computed tomographic angiography (CTA).  Fourteen patients (28.6 %) developed recurrent symptoms with 13 requiring a re-intervention.  Actuarial 36-month freedom from symptomatic recurrence was 60.9 % +/- 9.4 %.  Two-vessel treatment was protective against symptom recurrence (p = 0.0014) and re-intervention (p = 0.0060) by uni-variate analysis.  A total of 19 re-interventions were required in 14 patients (28.6 %) at a mean of 17 months from the original treatment.  Primary patency at 36 months was 63.9 +/- 8.5 %.  Actuarial survival at 48 months was 81.1 % +/- 6.1 % with no CMI-related deaths in the study cohort.  The authors concluded that intermediate (3-year) follow-up indicates that significant re-stenosis and symptom recurrence are common following the endovascular treatment of symptomatic CMI – 30 % of the cohort required a re-intervention, 1/3 of which were converted to surgical reconstruction.  Similar to the surgical paradigm of 2-vessel re-vascularization, endovascular treatment of multiple mesenteric arteries produced better outcomes.  A first-line endovascular approach to patients with CMI is a reasonable clinical strategy, but close follow-up is mandatory.

Fioole et al (2010) noted that open re-vascularization in patients with CMI is considered the gold standard.  Percutaneous transluminal angioplasty and stenting is often reserved for patients not suitable for open re-vascularization.  In the authors' institute, endovascular re-vascularization is the first-choice treatment.  The purpose of this study was to report the technical and clinical success rates after endovascular re-vascularization as the first-choice treatment in a series of 51 consecutive patients with CMI at a single tertiary vascular referral center.  A retrospective review was performed of all consecutive patients with CMI who underwent PTAS from July 2001 to July 2008.  Only symptomatic patients treated for atherosclerotic CMI were included.  Patency was evaluated using CTA.  Kaplan-Meier curves were used to calculate patency rates of the treated mesenteric arteries.  A total of 60 mesenteric arteries (30 celiac trunks, 24 superior mesenteric, and 6 inferior mesenteric arteries) were treated in 51 patients (26 men).  Major morbidity was 4 %.  After dissection of the SMA (n = 1) and brachial artery (n = 1), respectively, both patients underwent endarterectomy and patch plasty.  In 3 arteries, the lesion could not be crossed endovascularly and they were deemed immediate intention-to-treat failures.  The initial technical success rate was 93 %.  No 30-day mortality was observed.  Median follow-up was 25 months.  During follow-up, 2 patients died from intestinal ischemia.  Complete symptom relief was achieved in 78 % of patients.  Primary 1- and 2-year patency rates were 86 % +/- 5 % and 60 % +/- 9 %, respectively; primary-assisted patency rates were 88 % +/- 5 % and 79 % +/- 7 %, respectively.  During follow-up, 6 patients underwent open re-vascularization due to failure of PTAS.  The authors concluded that the initial technical success rate of PTAS as first-choice treatment of CMI is greater than 90 %.  The 2-year primary patency rate dropped to 60 %, but symptomatic in-stent stenoses could often be treated successfully with renewed endovascular techniques.  Including 1 conversion, 14 % of patients needed open re-vascularization during follow-up.

Loffroy and colleagues (2010) noted that percutaneous transluminal angioplasty with stent placement is now recognized as a minimally invasive means of obtaining good long-term results with an acceptable recurrence rate for the treatment of CMI.  Gibbons and Roberts (2010) stated that endovascular treatment for CMI is growing in popularity because of its lower peri-procedural morbidity and mortality than open surgery.  It is especially suitable for the high-risk surgical candidate and for those who have a poor nutritional state, although endovascular surgery may not be possible in patients with ostial occlusions or heavily calcified vessels.  A positive response to angioplasty is helpful to secure a diagnosis in patients with slightly atypical symptoms.  There are little data at present to suggest that primary stenting is better than angioplasty alone, but insertion of a stent may be valuable as a rescue procedure following dissection, vascular recoil, or thrombosis during angioplasty.  The superior mesenteric artery is probably the most important vessel to treat but, where this is impossible, celiac or inferior mesenteric artery dilatation may have therapeutic benefit.  However, there is some evidence at present favoring multiple, as opposed to single-vessel, angioplasty or stenting.  Long-term patency is better after mesenteric bypass, which may be preferred in the younger and fitter patient.  Treatment of the celiac artery compression syndrome is primarily surgical, but stent insertion may have a role as a secondary procedure where there is a residual stenosis after median arcuate ligament division.  Furthermore, the Society for Vascular Surgery (2009) stated that angioplasty and stenting is used for the treatment of CMI.

Wang et al (2010) stated that endovascular therapy is a treatment option for localized occlusion of the subclavian artery (SA).  In this report the long-term experience with 59 patients was presented.  Between June 1998 and September 2008, these investigators used endovascular therapy to treat 61 subclavian arterial obstructive lesions in 59 patients (46 males and 13 females, 34 to 82 years of age with a mean age (61.9 +/- 11.0 years).  Twenty patients (34 %) had clinical symptoms due to vertebro-basilar insufficiency, 26 (44 %) had disabling arm ischemia, and 13 (22 %) had both symptoms.  These researchers performed all procedures under local anesthesia.  The approaches were from the femoral artery (n = 47), brachial artery (n = 1, involving bilateral subclavian disease) or both (n = 11).  A total of 60 stents were implanted.  All patients were followed-up at 1, 3, 6, and 12 months post-procedure, and annually thereafter.  These investigators achieved technical success in 58 (95.1 %) arteries, all of which were stented.  There were 3 technical failures; 2 were due to the inability to cross over an occlusion, necessitating the switch to an axillo-axillary bypass, and the 3rd was due to shock after digital subtraction angiography and prior to stenting.  Arterial stenosis pre- and post-stenting was 83.6 +/- 10.8 % and 2.5 +/- 12.5 %, respectively (p < 0.01).  Clinical success was achieved in 55 of the 59 patients (93.4 %).  Of the 4 clinical failures, 3 were technical and the remaining patient had a stent thrombosis.  Systolic blood pressure difference between the 2 brachial arteries was 44.7 +/- 18.5 versus 2.2 +/- 3.9) mm Hg (p < 0.01).  Primary patency was 98 % at 12 months, 93 % at 24 months, and 82 % at 5 years.  Five patients were lost to follow-up by 12 months post-stenting.  Significant recurrent obstruction developed in 5 patients with resumption of clinical symptoms.  The overall survival rate was 98.2 % at 12 months, 89.5 % at 24 months, and 84.5 % at 5 years.  The authors concludedthat endovascular therapy for proximal subclavian arterial obstructive lesions is effective and successful.  This minimally invasive treatment may be the first choice of treatment for proximal subclavical arterial obstructive lesions.

Babic et al (2012) studied the initial and long-term results of angioplasty and primary stenting for the treatment of chronic total occlusion (CTO) of the SA.  From January 1999 to February 2010, a total of 56 patients (25 men with a mean age of 58 +/- 8 years) underwent endovascular treatment for CTO of the SA.  Duplex scans and arteriograms confirmed occlusion in all cases.  Indications for re-canalization were subclavian steal syndrome in 33 patients (58.1 %), arm claudication in 13 patients (23.2 %), and coronary ischemia in 7 patients (12.5 %) who had a history of previous coronary artery bypass grafting that included left internal thoracic artery graft.  Three patients (5.4 %) were treated before the scheduled coronary artery bypass surgery, which included left internal thoracic artery graft.  After successful re-canalization, all arteries were stented, and all of the patients were followed-up at 1, 3, 6, and 12 months after surgery and annually thereafter.  Successful re-canalization of the SA was achieved in 46 patients (82.1 %), and the complication rate was 7.1 %.  During follow-up (mean 40 +/- 26 months; range of  2 to 125), the primary patency rates after 1 and 3 years were 97.9 % and 82.7 %, respectively.  At the end of follow-up, 76 % of the arteries showed no evidence of re-stenosis.  Uni-variate analysis failed to identify any variable predictive of long-term patency of successfully re-canalized SA.  The authorsconcluded that percutaneous transluminal angioplasty with stenting of the complete total occlusion of the SA is a safe and effective procedure associated with low risks and good long-term results.

Furthermore, an UpToDate review on "Overview of upper extremity peripheral artery disease" (Mohler, 2012) states that "Options for the treatment of symptomatic subclavian stenosis or occlusion include surgical revascularization (e.g., carotid-subclavian bypass, subclavian transposition) and percutaneous transluminal angioplasty and stenting.  Percutaneous catheter-based treatment is less invasive and associated with lower complication rates, and shorter hospitalization". 

Also, the American College of Cardiology Foundation; American Stroke Association; American Association of Neurological Surgeons; American College of Radiology; American Society of Neuroradiology; Congress of Neurological Surgeons; Society of Atherosclerosis Imaging and Prevention; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society of NeuroInterventional Surgery; Society for Vascular Medicine; Society for Vascular Surgery's guideline on "Management of patients with extracranial carotid and vertebral artery disease" (Brott et al, 2011) stated that percutaneous endovascular angioplasty and stenting is reasonable for patients with symptomatic posterior cerebral or cerebellar ischemia caused by subclavian artery stenosis (subclavian steal syndrome) who are at high-risk of surgical complications.

Jung et al (2010) stated that popliteal artery aneurysms (PAAs) have traditionally been repaired with an open surgical approach.  However, endovascular popliteal artery repair (EVPAR) has been used in selected patients because of its less invasive nature.  These investigators presented their long-term outcomes for EVPAR.  They performed ar etrospective review of all patients who underwent EVPAR at a single academic institution between September 2002 and March 2006.  These patients were evaluated for patency, need for secondary intervention, amputation-free survival, and overall survival.  A total of 15 limbs in 13 patients were treated with EVPAR during the study period.  All EVPAR were performed using the Viabahn^® endoprostheses, with an average of 1.67 stents per limb.  The mean age of the patients was 74.6 years (range of 66 to 84).  Technical success was achieved in 100 % and all limbs had initial post-operative ankle-arm indices of greater than or equal to 1.0.  Mean duration of follow-up was 54 months (range of 42 to 70).  Two patients died of unrelated causes at 3 and 38 months with intact limbs, and 1 patient was lost to follow-up.  Two limbs developed type I or III endoleaks, and were successfully treated with additional endovascular stent placement, resulting in a primary patency rate of 84.6 % and secondary patency rate of 100 %.  There were no instances of limb loss during the follow-up period, yielding both amputation-free survival and overall survival rates of 85.7 %.  The authors concluded that long-term follow-up of this cohort of EVPAR patients suggested that in selected patients, this is a durable technique, capable of achieving excellent patency rates and limb preservation.  Moreover, they stated that further large-scale clinical trials are needed to help define optimal candidates for this technique.

Pulli and colleagues (2012) retrospectively compared peri-operative (less than 30 days) and 2-year results of open and endovascular management of PAAs in a single-center experience.  From January 2005 to December 2010, a total of 64 PAAs in 59 consecutive patients were operated on at the authors' institution; in 43 cases, open repair was performed (group 1), whereas the remaining 21 cases had an endovascular procedure (group 2).  Data from all the interventions were prospectively collected in a dedicated database, which included main pre-operative, intra-operative, and post-operative parameters.  Early results in terms of mortality, graft thrombosis, and amputation rates were analyzed and compared by χ(2) text or Fisher exact text.  The surveillance program consisted of clinical and ultrasonographic examinations at 1, 6, and 12 months and yearly thereafter.  Follow-up results (survival, primary and secondary patency, limb salvage) were analyzed by Kaplan-Meier curves, and differences in the 2 groups were assessed by log-rank test.  There were no differences between the 2 groups in terms of sex, age, risk factors for atherosclerosis, and co-morbidities; PAAs were symptomatic in 48 % of cases in group 1 and in 29 % in group 2 (p = 0.1).  Fifteen patients with mild-to-moderate acute ischemia due to PAA thrombosis underwent pre-operative intra-arterial thrombolysis, 13 in group 1 and 2 in group 2.  In open surgery group, 9 cases were treated with aneurysmectomy and prosthetic graft interposition, and in 7 cases, the aneurysm was opened and a prosthetic graft was placed inside the aneurysm.  In 27 cases, ligation of the aneurysm with bypass grafting (21 prosthetic grafts and 6 autologous veins) was carried out.  In group 2, 20 patients had endoprosthesis placement, whereas in the remaining patient, a multi-layer nitinol stent was used.  There was 1 peri-operative death in a patient of group 2 who underwent concomitant endovascular aneurysm repair and PAA endografting.  Cumulative 30-day death and amputation rate was 4.5 % in group 1 and 4.7 % in group 2 (p = 0.9).  Follow-up was available in 61 interventions (96 %) with a mean follow-up period of 22.5 months (range of 1 to 60).  Estimated primary patency rates at 24 months were 78.1 % in group 1 and 59.4 % in group 2 (p = 0.1).  Freedom from re-intervention rates at 24 months were 79 % in group 1 and 61.5 % in group 2 (p = 0.2); estimated 24-month secondary patency rates were 81.6 % in group 1 and 78.4 % in group 2 (p = 0.9), and freedom from amputation rates were 92.7 % and 95 %, respectively (p = 0.7).  The authors concluded that endovascular treatment of PAAs provided, in the authors' initial experience, satisfactory peri-operative and 1-year results, not significantly different from those obtained with prosthetic open repair in patients with similar clinical and anatomical status.  There is, however, a trend toward poorer primary patency rates among patients endovascularly treated, who also seem to require more frequently a re-intervention. 

Antoniou and associates (2012) noted that endovascular repair of PAAs is an emerging treatment in high-risk surgical patients.  The location in a functionally demanding anatomical area creates limitations in terms of endograft patency.  Technological advancements have been conscripted in an effort to circumvent such constraints.  The multi-layer stent technology effects via hemodynamic modulation.  These investigators employed the multi-layer stent to treat 6 asymptomatic PAAs in 3 patients.  All procedures were successfully accomplished without any complications.  Over a mean follow-up period of 9 months, thrombosis occurred in 2 limbs, and blood flow was restored with thrombolysis, achieving a primary and secondary patency rate at 6 months of 67 % and 100 %, respectively.  Partial or complete thrombosis of the aneurysm sac was achieved in all aneurysms.  The authors concluded that even though the use of the multi-layer stent in PAAs was safe in the short-term, their experience showed that close surveillance is needed.  Furthermore, an UpToDate review on "Popliteal artery aneurysm" (Reed, 2012) does not mention the use of stenting as a therapeutic option.

Dake et al (2011) stated that sustained benefits of drug-eluting stents in femoropopliteal arteries have not been demonstrated. A prospective, multinational, randomized study was designed to compare the 12-month safety and effectiveness of a polymer-free, paclitaxel-coated nitinol drug-eluting stent (DES) with percutaneous transluminal angioplasty (PTA) and provisional bare metal stent (BMS) placement in patients with femoropopliteal peripheral artery disease. In this study patients were randomly assigned to primary DES implantation (n=236) or PTA (n=238) and demographics and lesion characteristics were similar between groups. One hundred twenty patients had acute PTA failure and underwent secondary random assignment to provisional DES (n=61) or BMS (n=59). The 12-month rates of event-free survival and patency in the primary DES and PTA groups were evaluated. Compared with the PTA group, the primary DES group exhibited superior 12-month event-free survival (90.4% versus 82.6%; P=0.004) and primary patency (83.1% versus 32.8%; P<0.001). In secondary evaluations, the primary DES group exhibited superior clinical benefit compared with the PTA group (88.3% versus 75.8%; P<0.001).  The provisional DES group exhibited superior primary patency (89.9% versus 73.0%; P=0.01) and superior clinical benefit (90.5% and 72.3%, P=0.009) compared with the provisional BMS group, and the stent fracture rate (both DES and BMS) was 0.9% (4/457). The authors concluded that femoropopliteal peripheral artery disease treatment with the paclitaxel-eluting stent was associated with superior 12-month outcomes compared with PTA and provisional BMS placement.

Lammer et al (2011) stated that a novel self-expanding drug-eluting stent was designed to slowly release everolimus to prevent restenosis following peripheral arterial intervention. They reported on the first-in-human Superficial Femoral Artery Treatment with Drug-Eluting Stents (STRIDES) trial, which was to evaluate the safety and efficacy of this device for the treatment of symptomatic superficial femoral and proximal popliteal arterial occlusive disease.  One hundred four patients were enrolled at 11 European investigative centers in a prospective, nonrandomized, single-arm trial. Enrolled patients had severe symptomatic vascular disease, including a significant proportion of patients with critical limb ischemia (17%), diabetes (39%), and single-vessel outflow (26%). The mean lesion length was 9.0 ± 4.3 cm and ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and arteriography in 83%. Clinical improvement, defined as a sustained decrease in Rutherford-Becker clinical category, was achieved in 80% of patients and primary patency (freedom from ≥50% in-stent restenosis) was 94 ± 2.3% and 68 ± 4.6% at 6 and 12 months, respectively. Plain radiographic examination of 122 implanted devices at 12 months revealed no evidence for stent fracture. The authors concluded that the everolimus-eluting self-expanding nitinol stent can be successfully implanted in patients with severe peripheral arterial disease with favorable outcomes and clinical improvements observed in the majority of patients.

In November, 2012 the FDA approved use of the Zilver PTX Drug-Eluting Peripheral Stent (Zilver PTX Stent),which is the first drug-eluting stent indicated to re-open a particular artery in the thigh (femoropopliteal artery) when narrowed or blocked as a result of PAD.  The device is contraindicated in patients with stenoses that cannot be dilated to permit passage of the catheter or proper placement of the stent, patients who cannot receive recommended drug therapy due to bleeding disorders, or women who are pregnant, breastfeeding, or plan to become pregnant in the next five years (FDA, 2012).

The Gore Viabahn Endoprosthesis has been approved by the FDA for improving blood flow in patients with symptomatic peripheral arterial disease in superficial femoral artery lesions with reference vessel diameters ranging from 4.8 to 7.5 mm. The Gore Viabahn Endoprosthesis is a flexible, metallic (made from nitinol) stent which is lined with expanded polytetrafluoroethylene [ePTFE]). The device is mounted on the end of a delivery catheter and held in place by a release mechanism. The delivery catheter with the mounted endoprosthesis is inserted in the femoral artery through a puncture in the leg and threaded to the blocked section of the femoral artery. Once the device is positioned within the blocked area, it is freed from the delivery catheter by activation of the release mechanism. The device is expanded within the artery , opening the blocked area to improve blood flow. The delivery catheter is removed from the patient leaving the device within the femoropoplitealartery of the patient. According to the FDA (2012), the Gore Viabahn Endoprosthesis is used in patients who have a blockage within their femoral artery, which is caused by atherosclerotic disease. This blockage can cause pain by preventing adequate blood flow from reaching the lower leg and foot.  According to the FDA, the Gore Viabahn Endoprosthesis should not be used in patients who have a blockage where full expansion of a balloon dilatation catheter has not been achieved or where blockages cannot be dilated sufficiently to allow passage of the delivery system.

Saxon et al (2012) evaluated the performance of a heparin-bonded, expanded polytetrafluoroethylene (ePTFE)-lined nitinol endoprosthesis in the treatment of long-segment occlusive disease of the femoropopliteal artery (FPA).  In a single-arm, prospective, 11-center study (VIPER [Gore Viabahn Endoprosthesis with Heparin Bioactive Surface in the Treatment of Superficial Femoral Artery Obstructive Disease] trial), 119 limbs (113 patients; 69 men; mean age of 67 yrs), including 88 with Rutherford category 3-5 disease and 72 with Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) C or D lesions of the FPA, underwent stent graft implantation.  The mean lesion length was 19 cm; 56 % of lesions were occlusions.  Follow-up evaluations included color duplex ultrasonography in all patients, with patency defined as a peak systolic velocity ratio less than 2.5.  At 12 months, Rutherford category and ankle-brachial index (ABI) were significantly improved (mean category improvement, 2.4; ABI increased from 0.6 ± 0.2 to 0.9 ± 0.19; p < 0.0001).  Primary and secondary patency rates were 73 % and 92 %.  The primary patency for devices oversized less than 20 % at the proximal landing zone was 88 %, whereas the primary patency for devices oversized by greater than 20 % was 70 % (p = 0.047).  Primary patency was not significantly affected by device diameter (5 versus 6 versus 7 mm) or lesion length (less than or equal to 20 cm versus greater than 20 cm).  The 30-day major adverse event rate was 0.8 %.  The authors concluded that the heparin-bonded, ePTFE/nitinol stent graft provided clinical improvement and a primary patency rate of 73 % at 1 year in the treatment of long-segment FPA disease.

Sixt et al (2008) reported that percutaneous transluminal angioplasty is an accepted and successful treatment strategy in obstructive disease of the SA. These researchers evaluated the technical and clinical long-term outcome following endovascular therapy.  These researchers retrospectively analyzed 99 patients (mean age of 65 +/- 10 years) with 100 interventions of the SAs and the brachiocephalic trunk with different etiologies [atherosclerosis (90 %); Takayasu's arteritis (5 %); thrombo-embolism (2 %); external compression (1 %); iatrogenic dissection (1 %) and occlusion after graft implantation in type B dissection (1 %)].  Primary success rate was 97 % (100 % for stenoses and 90 % for total occlusions).  Treatment modalities included balloon angioplasty (PTA) alone (16 %), stent implantation (78 %), rotational thrombectomy (2 %) and atherectomy (1 %).  The primary 1-year patency rate of the whole study cohort was 87 % being not significantly lower after PTA (75 %) compared to stent assisted angioplasty (89 %).  After thrombectomy and atherectomy no relevant restenosis were found.  Multi-variable analysis of 1-year restenosis-free survival revealed younger age (p = 0.03) and stenting (p = 0.04) as independent predictor.  The blood pressure difference between both limbs at baseline was 42 +/- 24 mmHg and dropped to 10 +/- 14 mmHg after the intervention and 15 +/- 20 mmHg after 12 months, respectively (p = 0.01).  The authors concluded that endovascular therapy of SA obstructions of various etiologies offers good acute success rates even in total occlusions; long-term patency rate is in favor of stent placement.

Park et al (2011) stated that since they reported about a landmark technique to re-open an occluded SA, they have faced difficulty in using protection devices in the vertebral artery to protect against thromboembolism from the reversed steal phenomenon after angioplasty and stenting.  Thus, they presented an optimal solution in using a protection device while re-canalizing the occluded SA.  Among 21 cases of stenting for SA steno-occlusion, they applied the landmark technique at the opposite end of an occluded segment in 4 patients and used a protection device in 2 patients.  Because the embolic protection device was placed in the vertebral artery via the brachial artery, optimal angioplasty and stenting via the brachial route were limited.  Therefore, angioplasty via the trans-brachial approach was needed to be followed by stenting through a trans-femoral approach.  They estimated the safe and optimal steps for placement and retrieval of the protection devices in addition to stenting.  The procedure was safely performed when a stent was introduced via the femoral artery and a protection device was used via the brachial artery.  However, in cases when a guide-wire wasn't passed via the transfemoral route, simultaneous use of 2 systems via the brachial route could cause friction of devices or trapping of protection devices in a stent.  When a protection device was trapped in a deployed stent, they retrieved the protection device with a 4F angio-catheter by selectively rotating the catheter tip.  To avoid such procedural difficulty, they recommended using a transbrachial angioplasty followed by trans-femoral stenting while placing the protection device in the vertebral artery via the trans-brachial route.  The authors concluded that if a guide-wire was not passed through using a trans-femoral approach while performing the landmark technique, changing the stenting route from brachial to the femoral artery can be useful after securing the lumen in the occluded SA after angioplasty via the brachial artery.

Chatterjee et al (2013) stated that SA stenosis has long been treated with great success with bypass surgery.  Percutaneous intervention, often used in combination with stent placement, has come into vogue for the past few years as a safe and effective therapeutic modality.  These investigators compared angioplasty alone with angioplasty followed by stent placement by combining available data.  The objective of this study was to perform a review of the available literature to compare the efficacy of percutaneous transluminal angioplasty (PTA) alone with PTA followed by stent placement for proximal SA stenosis.  Successful re-canalization was defined as patency at the end of 1 year, and re-occlusions and re-stenoses were noted as events for the purpose of pooling the data.  The authors searched the Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, PubMed, EMBASE, and CINAHL databases for relevant trials/studies comparing PTA and PTA with stenting.  Review authors independently assessed the methodological quality of studies (focusing on the adequacy of the randomization process, allocation concealment, blinding, completeness of follow-up evaluation, and intention-to-treat analysis) and selected studies for inclusion.  All retrospective observational studies were also included in the analysis in the absence of double-blinded randomized trials for increasing sample size.  All analyses were done using RevMan 5.0.  Odds ratio was calculated using Mantel-Haenszel test with a fixed effect model.  All included studies were assessed by all authors for potential sources of bias.  A total of 8 studies were included in the analysis having 544 participants.  Stenting after PTA was significantly superior to angioplasty alone for treatment of SA stenosis and maintenance of patency at 1 year, as indicated by absence of events (p = 0.004; 95 % confidence interval, odds ratio 2.37 [1.32 to 4.26]) without significant complication rates for either procedure.  The authors concluded that there is evidence in favor of stent placement after angioplasty for successful re-canalization of stenosed SAs and long-term maintenance of patency without significant increase in risk for major complications in subjects.

An UpToDate review on "Overview of upper extremity peripheral artery disease" (Mohler, 2013) states that "Patients who do not have symptoms do not require intervention.  Options for the treatment of symptomatic subclavian stenosis or occlusion include surgical revascularization (e.g., carotid-subclavian bypass, subclavian transposition) and percutaneous transluminal angioplasty and stenting.  Percutaneous catheter-based treatment is less invasive and associated with lower complication rates, and shorter hospitalization".

In a prospective, randomized, single-blind, multicenter study, Lammer and colleagues (2013) hypothesized that endovascular treatment with covered stents has equal risks but higher efficacy than BMS in long FP artery disease.  A total of 141 patients with symptomatic PAD were assigned to treatment with heparin-bonded, covered stents (Viabahn; n = 72) or BMS (n = 69).  Clinical outcomes and patency rates were assessed at 1, 6, and 12 months.  Mean ± SD lesion length was 19.0 ± 6.3 cm in the Viabahn group and 17.3 ± 6.6 cm in the BMS group.  Major complications within 30 days were observed in 1.4 %.  The 12-month primary patency rates in the Viabahn and BMS groups were: intention-to-treat (ITT) 70.9 % (95 % CI: 0.58 to 0.80) and 55.1 % (95 % CI: 0.41 to 0.67) (log-rank test p = 0.11); treatment per-protocol (TPP) 78.1 % (95 % CI: 0.65 to 0.86) and 53.5 % (95 % CI: 0.39 to 0.65) (HR: 2.23 [95 % CI: 1.14 to 4.34) (log-rank test p = 0.009).  In lesions greater than or equal to 20 cm, (TASC class D), the 12-month patency rate was significantly longer in VIA patients in the ITT analysis (VIA 71.3 % versus BMS 36.8 %; p = 0.01) and the TPP analysis (VIA 73.3 % versus BMS 33.3 %; p = 0.004).  Freedom from TLR was 84.6 % for Viabahn (95 % CI: 0.72 to 0.91) versus 77.0 % for BMS (95 % CI: 0.63 to 0.85; p = 0.37).  The ABI in the Viabahn group significantly increased to 0.94 ± 0.23 compared with the BMS group (0.85 ± 0.23; p < 0.05) at 12 months.  The authors concluded that this randomized trial in symptomatic patients with PAD who underwent endovascular treatment for long FP lesions demonstrated significant clinical and patency benefits for heparin-bonded covered stents compared with BMS in lesions greater than or equal to 20 cm and for all lesions in the TPP analysis.  In the ITT analysis for all lesions, which was flawed by major protocol deviations in 8.5 % of the patients, the difference was not significant.

Cooper et al (2014) noted that atherosclerotic RAS is a common problem in the elderly.  Despite 2 randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain.  These researchers randomly assigned 947 participants who had atherosclerotic RAS and either systolic hypertension while taking 2 or more anti-hypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone.  Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end-point of death from cardiovascular or renal causes, MI, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy).  Over a median follow-up period of 43 months (interquartile range: 31 to 55), the rate of the primary composite end-point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1 % and 35.8 %, respectively; HR with stenting, 0.94; 95 % CI: 0.76 to 1.17; p = 0.58).  There were also no significant differences between the treatment groups in the rates of the individual components of the primary end-point or in all-cause mortality.  During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95 % CI: -4.4 to -0.2; p = 0.03).  The authors concluded that renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multi-factorial medical therapy in people with atherosclerotic RAS and hypertension or chronic kidney disease.

The accompanying editorial (Bittl, 2014) of the afore-mentioned study concluded that "The CORAL trial is a definitive test of the usefulness of renal-artery stents for moderately severe atherosclerotic disease.  The trial results send a clear message to patients and referring physicians.  Until new treatments are found to be safe and effective, patients in everyday practice who have moderately severe atherosclerotic renovascular disease and either hypertension or stage 3 chronic kidney disease should receive medical therapy to control blood pressure and prevent the progression of atherosclerosis but should not be corralled into getting a renal-artery stent".

In a Cochrane review, Chowdhury et al (2014) examined the effect of PTA compared with PTA with BMS for SFA stenoses on vessel patency in people with symptomatic (Rutherford categories1 to 6; Fontaine stages II to IV) lower limb PVD.  In addition, these researchers assessed the effectiveness of PTA and stenting in improving quality of life, ABI and treadmill walking distance.  For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialised Register (last searched August 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 6).  Randomized trials of angioplasty alone versus angioplasty with BMS for the treatment of superficial femoral artery stenosis were selected for analysis.  Two review authors independently selected suitable trials, assessed trial quality and extracted data.  Furthermore, these 2 review authors performed assessments of methodological quality and wrote the final manuscript.  The third review author cross-checked all stages of the review process.  These investigators included 3 new studies in this update, making a total of 11 included trials with 1,387 participants.  The average age was 69 years and all trials included men and women.  Participants were followed for up to 2 years.  There was an improvement in primary duplex patency at 6 and 12 months in participants treated with PTA plus stent over lesions treated with PTA alone (6 months: OR 2.90, 95 % CI: 1.17 to 7.18, p = 0.02, 6 studies, 578 subjects; 12 months: OR 1.78, 95 % CI: 1.02 to 3.10, p = 0.04, 9 studies, 858 participants).  This was lost by 24 months (p = 0.06).  There was a significant angiographic patency benefit at 6 months (OR 2.49, 95 % CI: 1.49 to 4.17, p = 0.0005, 4 studies, 329 participants) which was lost by 12 months (OR 1.30, 95 % CI: 0.84 to 2.00, p = 0.24, 5 studies, 384 participants).  Ankle brachial index and treadmill walking distance showed no improvement at 12 months (p = 0.49 and p = 0.57, respectively) between participants treated with PTA alone or PTA with stent insertion.  Three trials (660 participants) reported quality of life, which showed no significant difference between participants treated with PTA alone or PTA with stent insertion at any time interval.  Anti-platelet therapy protocols and inclusion criteria regarding affected arteries between trials showed marked heterogeneity.  The authors concluded that although there was a short-term gain in primary patency there was no sustained benefit from primary stenting of lesions of the SFA in addition to angioplasty.  Moreover, they stated that future trials should focus on quality of life for claudication and limb salvage for critical ischemia.

Humphries et al (2014) evaluated midterm outcomes of balloon-expandable bare-metal stents (BMSs) versus covered balloon-expandable (CBE) stents placed in the common iliac artery (CIA) for aorto-iliac occlusive disease.  All endovascular interventions for symptomatic peripheral arterial occlusive disease performed at a single institution from 2006 to 2012 were reviewed.  Patients undergoing stent placement in the CIA segment were included in the analysis.  Demographic data, TASC classification, stent type, patency, and limb re-interventions were compared.  For treatment of de-novo distal aorta or CIA stenosis, 254 procedures were performed in 162 patients.  Balloon-expandable bare-metal stents were used in 190 arteries; CBE stents were used in 64 arteries.  There was no difference in age, gender, or TASC classification between the 2 groups.  Mean follow-up was 22 ± 16 months.  Primary patency, assisted patency, and secondary patency were significantly better in the BMS group.  Common iliac arteries treated with covered stents were more likely at 1 year or longer to require repeated intervention (HR, 2.5; 95 % CI: 1.2 to 5.3; p = 0.009); TASC classification did not predict need for re-intervention in either group.  Multi-variate analysis revealed dual anti-platelet therapy to be the only other factor to affect patency during long-term follow-up.  The authors concluded that in this study, BMSs had significantly better patency compared with CBE stents for treatment of aorto-iliac occlusive disease.  Moreover, they stated that a randomized trial comparing patency as well as re-stenosis rates with long-term follow-up is needed to determine if there is any benefit from use of covered stents in the aorto-iliac segment.

Marmagkiolis et al (2014) stated that endovascular approach to SFA disease, the most common cause of symptomatic PAD, remains fraught with high failure rates. Newer devices including second-generation nitinol stents, drug-coated stents, drug-coated balloons (DCBs), covered stents, cryotherapy, laser, and directional atherectomy have shown promising results. Clinical equipoise still persists regarding the optimal selection of devices, largely attributable to the different inclusion criteria, study population, length of lesions treated, definition of "patency" and "restenosis," and follow-up methods in the pivotal trials. A prospective protocol was developed. These investigators performed a literature search using PubMed from January 2006 to November 2013. Published articles including endovascular interventions in SFA or popliteal arteries with reported 12-month "primary patency" or "binary restenosis" rates as end-points were included. They identified 6,024 patients in 61 trials reporting 12-month primary patency rates in patients with FP disease. Primary patency rates were (weighted average) 77.2 % for nitinol stents, 68.8 % for covered stents, 84 % for DES, 78.2 % for DCB, 60.7 % for cryoballoon, 51.1 % for laser atherectomy, 63.5 % for directional atherectomy and 70.2 % with a combination of endovascular devices. The authors concluded that the most frequently used endovascular devices yielded various 12-month primary patency rates ranging from 51 % to 85 %. The increased variation in inclusion criteria, length, and complexity of lesions between studies did not allow direct comparison between them. They stated that larger RCTs in specific patient populations comparing those modalities are needed before one can make safe recommendation of the superiority of one device over the other.

Jaff and colleagues (2015) noted that atherosclerotic PAD is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical re-vascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular re-vascularization has evolved over the past 2 decades, from PTA to self-expanding stents, atherectomy, laser angioplasty, and DES. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral-popliteal PAD according to current American College of Cardiology Foundation (ACCF)/American Heart Association (AHF) guidelines. However, re-stenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons have the potential to address this need. Several RCTs of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end-point. The pivotal LEVANT 2 trial was designed in collaboration with the FDA to demonstrate safety and effectiveness in a large population and to obtain FDA approval. A prospective, multi-center, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of FP PAD (LEVANT 2) is the first US-based 2:1 RCT of 476 patients with femoral-popliteal PAD designed to demonstrate superior effectiveness and non-inferior safety of a novel paclitaxel DCB compared with PTA. The primary effectiveness end-point is primary patency at 12 months. The primary safety end-point is composite freedom at 12 months from peri-operative death, index limb amputation, re-intervention, and limb-related mortality. A series of important secondary end-points include physical functioning, quality of life, re-vascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2

1. excluded patients stented after pre-dilation before randomization,
2. incorporated very stringent criteria for bailout stenting,
3. did not count bailout stenting as a target lesion re-vascularization or failure of any end-point,
4. required a blinded clinician to perform clinical evaluations at follow-up, and
5. required clinical assessment before review of duplex ultrasound results.

The authors concluded that the LEVANT 2 represents the first US-inclusive multi-center RCT to evaluate the safety and effectiveness of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy.

An UpToDate review on "Percutaneous interventional procedures in the patient with lower extremity claudication" (Zaetta et al, 2016) states that "Although PTA in the femoropopliteal segment is associated with restenosis, a clear advantage to primary stenting has not been definitively demonstrated in meta-analyses of randomized trials. In general, longer lesions probably benefit from stenting, but whether a self-expanding metal stent or covered stents should be used remains debated.  Local delivery of medical therapies aimed at preventing stenosis using drug-eluting stents has also been tried, as well as the use of biodegradable stents.  The use of drug-eluting stents should be considered experimental therapy".

The iCast Stent

The Atrium Medical iCast stent is a PTFE-coated stent indicated for use in trachea-bronchial strictures. A case-series study by Oderich and colleagues (2013) reported that the iCast coated stent had less re-stenosis than BMS for the treatment of CMI disease.  However, an accompanying discussion (no authors listed, 2013) noted that the differences in rates of re-stenosis may have been due to changes in surgical approach or factors other than the conversion from BMS to PTFE-coated stents

Current guidelines on CMI have no recommendations for PTFE-coated stents as standard of care (Pecoraro et al, 2013).  Furthermore, an UpToDate review on "Chronic mesenteric ischemia" (Tendler and Lamont, 2015) states that "Therapeutic options for patients suspected to have symptoms attributable to chronic mesenteric ischemia include surgical reconstruction and percutaneous transluminal angioplasty (PTA) with or without placement of a stent".  It does not mention PTFE-coated stent as a therapeutic option.  There have been no large RCTs comparing PTA, PTA with stenting, and surgical re-vascularization.  In most patients angioplasty is preferred, with surgery reserved for younger patients with fewer co-morbid conditions.

Recurrent Cephalic Arch Stenosis

Shemesh et al (2008) stated that early recurrent cephalic arch stenosis (CAS) in autogenous arterio-venous (AV) access for hemodialysis is a common problem that requires stenting to prevent thrombosis. Because the results of stenting are unsatisfactory, these researchers compared the effectiveness of stent grafts with bare stents in these patients in a prospective, randomized clinical trial.  All patients who presented with recurrent CAS greater than  50 % within 3 months of successful balloon angioplasty were randomized to have angioplasty and stenting with either a bare nitinol stent or a stent graft.  Outcome was assessed by angiography 3 months later.  Re-stenosis was defined as greater than 50 % narrowing of the stent lumen or of the vessel margin up to 0.5 cm adjacent to the stent.  There were no exclusions.  This study included data on the outcome of 25 consecutive patients with recurrent CAS who were treated from April to August 2006.  At 3 months, 3 patients had died and 1 had undergone a renal transplant.  The 21 patients who had angiography at 3 months had patent stents.  Re-stenosis rates were 7 of 10 (70 %) in the bare stent group and 2 of 11 (18 %) in the stent graft group (p = 0.024).  Life-table analysis at 3 and 6 months showed that primary patency was 82 % in the stent graft group and 39 % in the bare stent group.  One-year primary patency was 32 % in the stent graft group and 0 % in the bare stent group (p = 0.0023).  During a mean follow-up of 13.7 months, 9 patients died, 4 in the bare stent group and 5 in the stent graft group.  Two patients in the stent graft group had received a renal transplant.  The number of interventions per patient-year was 1.9 in the bare stent group and 0.9 in the stent graft group (p = 0.02).  The authors concluded that the use of stent grafts in angioplasty for recurrent CAS significantly improved short-term re-stenosis rates and long-term patency compared with the use of bare stents.  The significant improvement that emerged during the study caused accrual of patients to be halted for ethical reasons.  They stated that the findings of this study changed their usage of stents for venous stenoses in AV accesses by eliminating bare nitinol stents in favor of stent grafts.

Sivananthan et al (2014) stated that AV hemodialysis fistulas (AVFs) serve as a lifeline for many individuals with end-stage renal failure. A common cause of AVF failure is CAS.  Its high prevalence compounded with its resistance to treatment makes CAS important to understand.  Proposed etiologies include altered flow in a fistulized cephalic vein, external compression by fascia, the unique morphology of the cephalic arch, large number of valves in the cephalic outflow tract and biochemical changes that accompany renal failure.  Management options are also in debate and include angioplasty, cutting balloon angioplasty, bare metal stents, stent grafts and surgical techniques including flow reduction with minimally invasive banding as well as more invasive veno-venostomy with transposition surgeries for refractory cases.

Dukkipati et al (2015) stated that CAS is a common complication in maintenance hemodialysis (MHD) patients with brachial artery-cephalic vein fistulas and frequently leads to loss of the functioning brachial artery-cephalic vein fistula. There is paucity of conclusive data to guide appropriate management.  These researchers examined the risk of recurrence of CAS after angioplasty compared to angioplasty after stent placement determined by angiography of the involved upper extremity over time in a contemporary cohort of MHD patients treated in 2 interventional nephrology practices from March 2008 through May 2011.  These investigators retrospectively identified 45 MHD patients with evidence of CAS (age of 60 ± 30 years, 45 % men) on elective angiograms.  The median number of days until another angioplasty was required decreased, starting with a median of 91.5 days after the first, 70.5 days after the second, 85 days after the third, and 56 days after the fourth.  Angioplasty is associated with a faster rate of recurrence of CAS.  The authors concluded that the placement of intra-vascular stent appeared to prolong the patency compared to angioplasty alone.  Moreover, they stated that clinical trials with a larger sample size will better elucidate the value and timing of angioplasty versus stent placement in CAS.

Vasanthamohan et al (2015) performed a systematic review of management of recurrent CAS and associated outcomes in the context of dysfunctional HD access. PubMed, Web of Science, and Cochrane Library were searched to retrieve literature on the management of CAS.  Studies had to focus on management of access stenosis solely in the cephalic arch.  Case reports and literature reviews were excluded.  Studies were categorized by intervention, and primary and secondary patency data were compiled.  Studies were aggregated, and meta-analyses were performed where possible.  A total of 9 papers met the afore-mentioned criteria: 5 were retrospective studies and 4 were prospective studies; CAS management strategies have included PTA, peripheral cutting balloons, surgical cephalic vein transpositions, bare stents, and stent grafts.  Reporting strategies varied between studies.  Meta-analyses showed that results were variable even within studies using the same modality, particularly for PTA.  The authors concluded that no singular, definitive management strategy exists for CAS.  Current studies are limited by being primarily single-center retrospective trials featuring heterogeneous patient populations, interventions, and end-points.  They stated that priorities for future studies should include larger randomized trials, more uniform management strategies and end-points, and a longer duration of follow-up.

An UpToDate review on "Percutaneous intervention for the treatment of stenosis in the arteriovenous access" (Beathard, 2016) states that "Cephalic arch stenosis – The cephalic vein passes though the coraco-clavicular ligament just before it joins the subclavian vein, and is accompanied by the thoracoacromial artery and vein, and lateral pectoral nerve. The unique anatomy appears to predispose to recurrent and resistant stenosis for several reasons … Due to recurrent problems with angioplasty treatment of the cephalic arch, the placement of a stent/stent-graft has been used to salvage the access.  No randomized trials are available comparing angioplasty alone with stent/stent-graft placement for this lesion.  An trial [Shemesh et al, 2008] that compared stent devices randomly assigned 25 patients with recurrent cephalic arch stenosis associated with a brachial-cephalic fistula to angioplasty and either a bare metal stent or a stent-graft.  Among the 21 patients available to undergo angiography at 3-month follow-up, the rate of stenosis greater than or equal to 50 % was significantly higher for stents compared with stent grafts (70 versus 18 %).  Unfortunately, half of the patients were lost to longer-term follow-up".

Bioresorbable Stents in Peripheral Arterial Disease

van Haelst and colleagues (2016) provided an overview of currently available data on the use of bioresorbable stents in lower limb PAD and summarized the needs for future research focus.  These researchers performed a systematic search in the databases of Medline, Embase, and the Cochrane Library.  Studies using pre-defined inclusion and exclusion criteria were included and critically appraised by 2 independent reviewers.  Inclusion criteria were

1. original data on
2. bioresorbable stents in
3. lower limb arteries including the iliac tract. 

Primary end-points were safety and feasibility of bioresorbable stents, including 30-day adverse events (AEs).  Secondary end-points included radial force, bioresorption process, long-term primary and secondary patency, and clinical outcomes, such as amputation rate, Rutherford category, and ABI improvement.  A total of 7 published studies with 316 patients were included, and 5 conference abstracts including 272 patients were assessed.  Median follow-up time was 12 months.  Overall technical success rate was 99 % (range of 95.0 % to 100 %).  The 30-day AE rates were reported in 5.0 % of patients (range of 0 % to 13.3 %); these included 1 death, 2 major amputations, and 7 re-interventions.  Mean primary patency rate was 61.6 % in the femoral arteries (range of 32.1 % to 80.0 %) after 6 to 12 months compared with 50.3 % in below-the-knee lesions (range of 31.8 % to 92.9 %).  Secondary patency rates were 91.5 % (range of 84 % to 97.1 %) and 72.1 % (range of 62.9 % to 100 %), respectively.  The 1-year amputation rate was 3.0 % in the whole group (range of 0 % to 12.4 %).  The authors concluded that experience with the use of bioresorbable stents in PAD is still limited and was examined only in small studies.  They noted that the use of bioresorbable stents in PAD appeared to be feasible and safe; with current published results, they are unable to fully answer all of the questions about the future use of bioresorbable stents in PAD, and use should be limited to study-related cases in PAD.

In a prospective, multi-center, observational registry, Bontinck and associates (2016) evaluated the performance and safety of the bioresorbable REMEDY stent in the treatment of short femoro-popliteal stenosis or occlusion.  The registry was set up of patients in Rutherford-Becker categories 2 to 5 with femoro-popliteal lesions that could be treated with 1 REMEDY stent.  Clinical examination and duplex ultrasound (US) imaging were performed at 1, 6, and 12 months.  The primary end-point was absence of clinically driven TLR at 12 months. Secondary end-points were technical and clinical success, primary and secondary patency rate, clinically driven TLR, major complications, and Rutherford-Becker classification at 6 and 12 months.  The registry enrolled 99 patients between January 2011 and July 2013 in 12 centers in Belgium.  Most lesions were determined as TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) A (n = 80) and located in the superficial femoral artery (n = 91).  There were 19 total occlusions (mean length of 41.3 mm) and 80 stenoses (mean length of 37.5 mm).  Technical success was achieved in 96 patients, and clinical success was obtained in 95; TLR, which equaled target vessel revascularization, was 19 % at 6 months and rose to 33 % at 12 months.  Primary patency was 68 % at 6 months and 58 % at 12 months.  Secondary patency was 85 % at 6 months and 86 % at 12 months.  After 12 months, 2 patients had undergone an amputation.  The authors concluded that the 1-year follow-up results of the REMEDY stent did not meet current standards set by nitinol stents.  They stated that given the significant issues concerning bioresorbable stents in femoro-popliteal arteries, their use outside of clinical trials should be withheld until improvements are made and better data are available.

Biodegradable Stents in Peripheral Arterial Disease

Chu and colleagues (2017) examined the published literature on the use of biodegradable stents in the treatment of PAD.  Systematic review was formulated under the instruction of PRIMSA guideline.  Papers published from January 2005 to March 2015 in English language were included.  Published studies on biodegradable scaffolds or stents in the treatment of PAD were systematically searched and reviewed through a computerized search of PubMed and Ovid Medline and cross-referenced.  Key words include "biodegradable scaffolds", "biodegradable stents", "femoral", "lower limb", "peripheral arterial disease" and "peripheral vascular disease".  All relevant published papers which fulfilled these criteria were reviewed.  On-going studies from other electronic databases were also examined.  A total of 75 non-duplicated publications were identified, but only 6 articles were eligible into the qualitative analysis (1 animal study, 3 case-cohort studies, and 2 randomized studies).  In all, a total of 325 stents were used in 282 patients.  Technical success rates were 100 %.  These studies had a short-to-medium follow-up period up to 58 months.  The primary and secondary patency rates were 60.8 % (range of 32 to 77 %) and 88.4 % (range of 79 to 97 %) respectively.  There were also 4 on-going studies internationally.  The authors concluded that contemporary published literature suggested that biodegradable scaffold/stent is safe and effective in the treatment of PAD, but these studies were heterogeneous and were limited by their study design, relatively small sample size, and short follow-up period; and therefore did not produce a high enough level of evidence to show superiority that leads to a change in current treatment guidelines.

Stenting in Infra-Popliteal Disease

Liu and colleagues (2017) noted that DES have been proposed for the treatment of infra-popliteal arteries disease.  However, the long-term clinical impact of DES treatment in the vascular territory still remains uncertain.  In a meta-analysis, these researchers compared DES versus control therapy in the treatment of infra-popliteal disease.  PubMed, Embase, Cochrane data, CNKI and Wanfang Data were searched until December 20, 2016 for eligible studies according to identical strategies.  Additional data were manually retrieved; STATA ver. 12.0 software were used to meta-analyze the efficacies of DES and control treatment (BMS or PTA) for infra-popliteal arteries disease.  A total of 927 patients from 10 studies (8 RCTs and 2 cohort studies) were assigned to DESs (n = 484) versus control treatment (n = 443).  The results showed that infra-popliteal DES therapy yielded higher primary patency and EFS, while decreased the risk of re-stenosis at 12-months compared to controls significantly.  At 3 years there were no significant differences between 2 groups, pooled RRs and 95 % CI were 1.639 [0.526 to 5.105], p = 0.394; 1.197 [0.432 to 3.317], p = 0.729 and 0.992 [0.960 to 1.024], p = 0.661, respectively.  Subgroup analysis showed that infra-popliteal DES therapy using sirolimus-eluting stents rather than everolimus-eluting stents provided higher clinic benefits.  Infra-popliteal DES therapy yielded no significant difference for TLR, overall survival, Rutherford-Becker class improvement, limb amputation at 12-months and 3-years compared with control treatment.  The authors concluded that the findings of the present meta-analysis indicated the non-superiority of infra-popliteal DES therapy over control therapies (BMS/PTA) at 3 years, although short-term benefits at 12 months after DES therapy were evident.  They stated that further RCTs with longer follow-up are needed to provide the best scientific evidence regarding the preferred endovascular treatment for patients with occlusive disease of infra-popliteal arteries.

Hammad and Prasad (2017) stated that CLI is associated with significant morbidity, mortality, and increased health care expenses.  Re-vascularization has a central role in the treatment of CLI.  Following publication of BASIL (bypass versus angioplasty in severe ischemia of the leg) trial 10 years ago, an "endovascular first" approach had gained momentum and the technologies available for endovascular therapy have exponentially increased.  Both the development of technology and technique have allowed operators to treat complex infra-popliteal lesions which are central to CLI pathology.  The role of atherectomy remains controversial but for calcified lesions it has become an accepted adjunctive tool for plaque modification.  The place of drug delivery technologies requires further trials.  The use of a drug-coated balloon (DCB) makes intuitive sense; however, choice of excipient, lower limit of vessel size, and impact on re-modeling and thrombosis remain uncertain.  The authors concluded that the optimal treatment of infra-popliteal disease remains an area of active investigation.  The end-points in CLI trials continue to be challenging and calibration of patency in relation to wound healing remains a moving target.  In addition, unaccounted variables continue to confound interpretation of CLI trials –including quality and nature of wound care, status of pedal-plantar loop patency, and management of underlying diabetes and other co-morbidities.  These researchers stated that these challenges will also need to be addressed as the CLI field continues to mature in the 21st century.

Peripheral Artery Stenting for Ischemic Nephropathy

Bohlke and Barcellos (2015) stated that the prevalence of atherosclerotic RAS is high; approximately 7 % in individuals older than 65 years and about 50 % in patients with diffuse arterial disease, and it is increasingly frequent in an aging population.  About 10 % to 15 % of atherosclerotic RAS cases led to the development of resistant hypertension and/or ischemic nephropathy.  The management of ischemic nephropathy may include medical therapy and/or re-vascularization.  In the past, re-vascularization required surgical bypass or endarterectomy, accompanied by the morbidity and mortality associated with a major surgical procedure.  During the last few decades, less invasive endovascular procedures such as percutaneous transluminal renal angioplasty (PTRA) with stent placement have become available.  At the same time, new anti-hypertensive and cardiovascular drugs have been developed, which may preclude re-vascularization, at least in some cases.  The indications of each of these therapeutic options have changed over time.  These researchers provided a temporal perspective on the course of technical and scientific advances and the accompanying change in clinical practice for the treatment of ischemic nephropathy.  The latest RCTs, including the CORAL trial, the largest on the subject, as well as a meta-analysis of these studies, have indicated that the best approach is medical therapy alone.  There is evidence that re-vascularization brings no additional benefit, at least in low-risk and stable atherosclerotic RAS.  High-risk patients, especially those with recurrent flash pulmonary edema, could benefit from PTRA and stent placement, but there is no definitive evidence and the therapeutic choice should take into account the risks and potential benefits of the procedure.

Viabahn for the Treatment of Peripheral Artery Occlusive Disease

Johnston and co-workers (2012) stated that optimal selection of a re-vascularization strategy in femoro-popliteal occlusive disease (FPOD) remains controversial.  Among endovascular therapeutic options for FPOD, covered stent placement has become increasingly used.  In a retrospective, single-center study, these researchers examined the influence of clinical, anatomic, and device-related characteristics on the clinical performance of these devices.  This trial included consecutively treated limbs that underwent Viabahn (W. L. Gore, Flagstaff, AZ) stent graft placement for FPOD from 2005 to 2010.  Clinical, anatomic, and device-related characteristics were obtained from review of medical records and angiograms.  End-points were occurrence of any re-intervention, major adverse limb event (e.g., major amputation, thrombolysis/thrombectomy, or open bypass surgery), or thrombolysis/thrombectomy treatment alone.  Uni-variate predictors were calculated and multi-variate models constructed for each clinical end-point using Cox proportional hazards models.  The study cohort included 87 limbs in 77 unique patients, with a median follow-up time of 382 days.  The indication for intervention was claudication in 56 %.  In 25 cases (29 %), the index procedure was a secondary intervention for FPOD, including treatment of in-stent restenosis (ISRs) in 22 cases (25 %).  Lesions treated included 45 % TransAtlantic Inter-Society Consensus (TASC) II D and 58 % chronic total occlusions.  The observed Kaplan-Meier 1-year event rates for re-intervention, major adverse limb event (MALE), and thrombolysis were 43 %, 28 %, and 17 %, respectively.  MALE occurred in 18 patients, 9 of whom presented with acute limb ischemia; no patient underwent major amputation.  Uni-variate predictors of negative outcomes included lack of dual-antiplatelet usage, advanced TASC II classification, smaller implant diameter, increased number of devices used, longer total implant length, and coverage of a patent distal collateral vessel.  Multi-variate analysis demonstrated that the presence of dual-antiplatelet usage was protective against all 3 outcomes, 5-mm device diameter was a risk factor for both re-intervention and MALE, and the use of multiple devices and distal collateral coverage were significant risk factors for thrombolysis events.  The authors concluded that re-intervention was common in the 1st year following Viabahn placement for FPOD, with more than 50 % of the events being a MALE.  Procedural factors such as anti-platelet therapy, stent graft diameter, implant length/number, and distal collateral coverage were strongly associated with adverse clinical outcomes.  These factors should be carefully considered to optimize patient selection and intra-operative decision-making for this procedure.

Geraghty and associates (2013) noted that the predominant mode of bare nitinol stent failure was diffuse ISR, and failure rates correlated to the length and complexity of the treated lesion.  Addition of an expanded polytetrafluoroethylene (PTFE)  lining to a nitinol stent frame, as found in the Viabahn endoprosthesis, mitigated the ingrowth of intimal hyperplasia.  These researchers compared the long-term outcomes of complex superficial femoral artery disease intervention using the Viabahn endoprosthesis to those obtained with bare nitinol stent implantation.  A total of 148 patients with symptomatic complex superficial femoral artery disease (TransAtlantic Inter-Society Consensus I class C and D lesions, accompanied by intermittent claudication or ischemic rest pain) were randomized to endovascular intervention using either bare nitinol stent implantation (76 patients) or non-heparin bonded Viabahn endoprosthesis deployment (72 patients).  Patency, limb hemodynamics, and quality of life (QOL) were evaluated at 1, 6, 12, 24, and 36 months following intervention.  The average treated lesion measured 18 ± 8 cm in length, and 58.8 % of lesions displayed segmental or complete occlusion.  At 3 years, primary patency rates (defined by peak systolic velocity ratio of less than or equal to 2.0 and no target lesion revascularization [TLR]) did not significantly differ between patients treated with the Viabahn stent graft and those who received a bare nitinol stent (24.2 % versus 25.9 %; p = 0.392).  Stent fractures were significantly more common in bare nitinol stents (50.0 %) than in the Viabahn endoprostheses (2.6 %).  Primary-assisted patency rates were higher in those receiving bare nitinol stents than the Viabahn stent graft (88.8 % versus 69.8 %; p = 0.04), although secondary patency rates did not differ between bare nitinol stent and stent graft recipients (89.3 % versus 79.5 %; p = 0.304).  There were no instances of procedure-related mortality or amputation.  The hemodynamic improvement and quality measures improved equally in both groups.  The authors concluded that the long-term outcomes of complex superficial femoral artery disease intervention using the Viabahn endograft and bare nitinol stents were similar.  Although primary patency rates were low in both study arms, excellent primary-assisted and secondary patency rates were achieved, with sustained augmentation of limb perfusion and QOL measures.  Patency rates diminished most rapidly in the 1st year following device implantation.

The authors stated that this study had several drawbacks.  In retrospect, the VIBRANT trial would have been strengthened by the incorporation of a physical functioning end-point.  Future trials would benefit from addition of a supervised-exercise rehabilitation comparison arm.  Over 3 years of surveillance, attrition rates were substantial, albeit similar between treatment groups.  Device iterations progress as clinical trials were conducted, but the pace of innovation should not deter physicians from engaging in careful evaluation of each generation of devices.  Since the study completion, there have been multiple manufacturing changes to the Viabahn device, including addition of a heparin bioactive surface, a contoured proximal edge, and an SFA treatment indication for the 5-mm-diameter device.  In addition, bare nitinol stents with improved flexibility have been released to market, which may reduce the incidence of stent fracture, although these new devices await evaluation in complex lesions comparable to the VIBRANT trial.

Zhang and colleagues (2015) examined the effectiveness of the Viabahn stent-graft in the treatment of superficial femoral artery (SFA) occlusive disease.  These researchers carried out a systematic review and meta-analysis of published studies to evaluate the efficacy of the Viabahn for SFA lesions.  Studies were stratified according to controlled versus uncontrolled design and analyzed using random-effects models.  Outcomes were reported as the RR and 95 % CI.  A total of 4 prospective RCTs, 1 retrospective controlled study, and 9 uncontrolled studies were identified.  In controlled studies, primary patency with the Viabahn was superior to other interventions at 1 year (RR 0.63, 95 % CI: 0.49 to 0.82, p < 0.001) and ankle-brachial index (ABI) improvement was greater at 6 months (mean difference [MD] 0.05, 95 % CI: 0.01 to 0.09, p = 0.01) compared with other interventions.  Subgroup analysis demonstrated a lower incidence of stent fracture in lesions with greater than 15-cm stented lengths.  In uncontrolled studies, ABI improvement was consistently superior at all measurement points during follow-up.  The authors concluded that current evidence suggested that the Viabahn stent-graft was a safe and effective option for symptomatic SFA lesions.  Moreover, these researchers stated that prospective, multi-center RCTs with long-term follow-up are needed to confirm the sustained efficacy of the Viabahn device.

Golchehr and associates (2015) noted that self-expanding covered stents for SFA occlusive disease have undergone an evolution during the years.  Early results of the latest generation, the heparin-bonded Viabahn with a contoured proximal edge, were promising, with reported 1-year primary patency rates of 73 % to 78 % in long lesions. These researchers presented the 3-year outcome of the heparin-bonded Viabahn for SFA occlusive disease.  All patients treated with a heparin-bonded Viabahn in 3 centers between April 2009 and December 2011 were included in the study and retrospectively analyzed.  Clinical state in Rutherford category, ankle-brachial indexes (ABI), and duplex ultrasound (US) scans were the features of follow-up at 6 weeks and 6, 12, 24, and 36 months.  Primary end-points of the study were the 3-year primary, primary assisted, and secondary patency rates.  A total of 73 SFAs in 70 patients were treated with a heparin-bonded Viabahn and included in the study; 54 patients were men (77 %), and the mean age was 70.0 ± 9.1 years.  The mean lesion length was 17.4 ± 7.0 cm, and 84 % were classified TransAtlantic Inter-Society Consensus II types C and D.  The median follow-up was 25 months (range of 2 to 55 months).  The 3-year primary, primary assisted, and secondary patency rates were 59 %, 71 %, and 82 %, respectively, with a 3-year freedom from amputation of 100 %.  The authors concluded that the use of a heparin-bonded Viabahn for SFA occlusive disease was related to patency rates within limits of surgical reconstruction.  The procedure was related to low morbidity and amputation rates.  They stated that the 3-year patency rates were promising but need to be established in comparative studies with both other endovascular options and surgery.

The authors stated that drawbacks of this study were the retrospective design of the study and small sample size, rendering any sub-analysis unreliable.  The small sample size was related to the fact that the use of self-expanding covered stents for SFA occlusive disease was not a widely accepted treatment modality in the Netherlands.  In addition, the entire cohort did not complete the 36 months of follow-up.  These investigators could not exclude a selection bias as patients were treated according to the institutional standards and at the discretion of the surgeon and interventional radiologist.  Unfortunately, a reliable comparison with other treatment modalities was not feasible owing to the retrospective design of the study.  Moreover, an identification of performed alternative treatments for the same indication was not possible with the current hospital registration databases.

In a prospective, multi-center study, Ohki and co-workers (2017) examined 1-year safety, efficacy, and invasiveness outcomes of endovascular stent grafting of symptomatic long lesions (greater than or equal to 10 cm) in the SFA as a substitute for above-knee open bypass surgery.  This trial evaluated heparin-coated stent grafts for the treatment of long SFA lesions in Japanese subjects with peripheral arterial disease (PAD).  Inclusion criteria were Rutherford category 2 to 5 symptoms (grade 5 without active infection), ABI of less than or equal to 0.9, and color flow duplex ultrasound (US)-assessed SFA lesions with cumulative length of greater than or equal to 10 cm and greater than or equal to 50 % stenosis.  Main efficacy and safety outcomes were primary assisted patency and adverse events (AEs), respectively.  Secondary outcomes included primary patency using the surgical bypass definition, that is, blood flow through a device without requiring target lesion revascularization (TLR) to maintain or to restore flow.  For comparison with prior endovascular studies, primary patency-interventional was defined as peak systolic velocity ratio of less than 2.5 without TLR in treated lesions.  Other outcomes included freedom from TLR and Vascular Quality of Life questionnaire scoring.  General anesthesia avoidance and hospitalization duration were compared with historical data from 68 consecutive patients (n = 51 Rutherford 2/3 claudicants and 17 Rutherford 4/5 subjects) who underwent above-knee bypass surgery at study sites between 2002 and 2012 and met study enrollment criteria.  Of 103 enrollees (aged 74.2 ± 7.0 years; 17.5 % women; 97.1 % claudicants), 100 subjects were evaluated through post-operative 12 months.  Average lesion length was 21.8 ± 5.8 cm, and 65.7 % were totally occluded.  The whole-cohort Kaplan-Meier estimated primary assisted patency rate was 94.1 % (95 % CI: 87.3 % to 97.3 %) at 12 months.  The primary patency-surgical rate was 92.1 % (95 % CI: 84.8 % to 96.0 %), the primary patency-interventional rate was 88.1 % (95 % CI: 80.0 % to 93.1 %), and freedom from TLR was 93.1 % (95 % CI: 86.1 % to 96.7 %).  Mean ABI increased from 0.64 ± 0.12 to 0.98 ± 0.12 at 1 month after intervention and 0.94 ± 0 .17 at 12 months (p < 0.0001 at both follow-ups).  Target vessel revascularization, major amputation, or death did not occur through post-operative 30 days.  No life- or limb-threatening intra-operative or peri-operative AEs and no acute limb ischemia cases were observed during follow-up.  Vascular Quality of Life questionnaire score increased from 58.6 % ± 15.7 % to 72.9 % ± 18.6 % at 12 months (p < 0.0001).  No stent fractures were detected.  No stent graft participant required general anesthesia, and median post-operative hospital stay was 2.0 days (mean of 3.4 ± 2.9 days) in the Viabahn claudicant subgroup, values that were significantly lower than the 76.5 % general anesthesia rate (p < 0.0001) and 11.0 days median hospitalization stay (mean of 12.7 ± 5.3 days; p < 0.0001) in the 51 open bypass claudicant subjects.  The authors concluded that stent grafting appeared to be a safe and less invasive alternative to above-knee bypass surgery, providing 88 % to 92 % primary patency at 12 months in long, complex lesions.

The authors stated that the main drawbacks of this study were its single-arm design, relatively small sample size (n = 103), and inclusion of mainly claudicants that limited generalizability across critical limb ischemia (CLI) patients.  Only 1-year results were reported; however, 2-year efficacy results will be collected, and AE assessment and fracture analysis will be conducted through 5 years.  Longer-term multi-national RCTs such as the Surgical versus Percutaneous Bypass (SuperB) study, which directly compares outcomes of stent graft implantation versus bypass surgery for treating long SFA lesions, will provide essential confirmation of these findings in diverse populations.  Device limitations included the necessity for at least 1 patent runoff vessel and unsuitability for across-the-knee applications.  A prior single-center retrospective series showed less favorable results with a population that did not adhere to these limitations, had a larger proportion of CLI patients, and included in-stent restenosis.  Nonetheless, these findings showed that stent grafts could safely provide improvement to patients with extensive PAD through 1 year of follow-up and constitute a viable alternative to above-knee bypass without the morbidity risks inherent to open surgery.

In a systematic review, Hajibandeh and associates (2019) examined the outcomes of different treatment strategies for ISR in patients with peripheral arterial disease (PAD) of the lower limbs.  This systematic review was carried out in accordance with the PRISMA statement standards.  These investigators searched Medline, Embase, CINAHL and the Cochrane Central Register of Controlled Trials to identify RCTs comparing different treatments for ISR in PAD.  Recurrent ISR and freedom from TLR were defined as the primary outcome measures.  They performed an indirect comparison meta-analysis of different treatments.  These researchers identified 4 RCTs that fulfilled the inclusion criteria enrolling a total of 491 patients and another 4 ongoing trials.  Each of the included trials reported 1 of the 4 comparisons: drug-coated balloon angioplasty versus standard balloon angioplasty; treatment with heparin-bonded Viabahn endoprosthesis versus standard balloon angioplasty; excimer laser atherectomy plus standard balloon angioplasty versus standard balloon angioplasty alone; and peripheral cutting balloon angioplasty versus standard balloon angioplasty.  The risk of recurrent ISR at 12 months was significantly higher with standard balloon angioplasty than with drug-coated balloon angioplasty (p = 0.004).  There was no significant difference in the risk of recurrent ISR at 6 months between cutting balloon angioplasty and standard balloon angioplasty (p = 0.73).  Freedom from TLR at 12 months was significantly higher with drug-coated balloon angioplasty (p < 0.001) and treatment with the heparin-bonded Viabahn endoprosthesis (p < 0.001) than with standard balloon angioplasty.  Freedom from TLR at 6 months was also significantly higher with excimer laser atherectomy plus standard balloon angioplasty than with standard balloon angioplasty (p = 0.003).  Tested indirect comparisons revealed large CIs and no statistically significant difference between treatments.  The authors concluded that the findings from individual trials suggested that drug-coated balloon angioplasty, treatment with the heparin-bonded Viabahn endoprosthesis and adjuvant excimer laser atherectomy conferred improved outcomes compared with standard balloon angioplasty.  These researchers stated that ongoing clinical trials may elucidate uncertainties in the optimal management of ISR in this setting.

The authors stated that the reported outcomes of this review should be viewed and interpreted in the context of inherent limitations.  Only 4 RCTs were identified with each of them comparing different treatment strategies.  The included studies had small sample sizes, and 1 of them was a pilot study; thus, their results should be interpreted with caution as the possibility of type 2 error could not be excluded.  The long-term outcomes and cost-effectiveness of treatment strategies for ISR in PAD remain unknown.  The included studies reported mainly technical outcomes, but it remains unknown if such outcomes translate to improved clinical outcomes, such as QOL.  On the other hand, ISR and TLR as outcome measures are very open to bias if the investigators were the same clinicians who interpreted follow-up imaging and/or decided who to intervene on.  In the included studies, outcome adjudication was not independent of the clinical team, subjecting their findings to bias as imaging interpretation could be very subjective, and the decision to re-intervene may be equally so.  The available studies did not provide stratified data according to clinical (claudication or critical limb ischemia) or anatomic (inflow or outflow vessels) severity of the disease.  Indirect comparison analysis produced very wide CIs that did not allow these investigators to draw solid conclusions on the comparative efficacy of different endovascular treatments for ISR in PAD of the lower limbs.  The wide CI estimates were the result of the of direct evidence and large number of RCTs per comparison to inform the treatment network.

LifeStream Balloon-Expandable Covered Stent for the Treatment of Iliac Artery Stenosis

The LifeStream balloon expandable vascular covered stent is indicated for the treatment of atherosclerotic lesions in common and external iliac arteries with reference vessel diameters between 4.5 mm and 12.0 mm, and lesion lengths up to 100 mm.

In a prospective, single-arm study (the BOLSTER trial), Laird et al (2019) examined the performance of the LifeStream balloon-expandable covered stent for the treatment of iliac artery atherosclerotic lesions.  A total of 155 patients were treated at 17 centers in Europe, New Zealand, and the U.S.  The primary end-point was a composite of device- or procedure-related death or MI over the course of 30 days, or TLR, major amputation of the target limb, or re-stenosis through 9-months.  Secondary end-points included primary patency, TLR, sustained clinical success, quality of life (QOL), and major AEs (MAEs).  At 9 months, the primary composite end-point rate was 16.2 % (93.5 % CI: 10.6 % to 23.2 %), primary patency was 89.1 % (95 % CI: 82.6 % to 93.7 %), and freedom from TLR was 96 %.  There was a cumulative clinical improvement of at least 1 Rutherford category from baseline to 9 months of 90.5 % (95 % CI: 84.3 % to 94.9 %); QOL, assessed by using the Walking Impairment Questionnaire (WIQ), demonstrated a mean change in total score from baseline through 9 months of 32.1 ± 26.84; overall, improvements were noted from baseline in each WIQ category; 7 of 150 patients (4.7 %; 95 % CI: 1.9 % to 9.4 %) experienced MAEs, but none was determined to be related to device or procedure.  The authors concluded that the LifeStream balloon-expandable covered stent provided satisfactory 9-month clinical outcomes including a low rate of TLR for the treatment of stenotic and occlusive lesions of the iliac arteries.

Furthermore, an UpToDate review on "Endovascular techniques for lower extremity revascularization" (Dosluoglu, 2020) states that "Common iliac artery lesions are typically treated with balloon-expandable stents or stent-grafts.  Balloon angioplasty of the iliac arteries without stenting is rarely used, except for the most focal lesions; however, stenting would still be required for a focal lesion if there is flow-limiting dissection or residual stenosis of > 30 %.  If the lesions in the common iliac artery extend to the iliac bifurcation and into the aorta, kissing stent-grafts or stents can be used; these elevate the bifurcation and ensure unimpeded flow to both lower extremities …Treat the diseased segment(s) to achieve a patent lumen followed by completion arteriography.  The general goal is to establish in-line flow to the foot.  Lesions are treated from proximal to distal in sequence.  For apparent occlusions, intraluminal crossing is attempted first; however, if this is not successful, subintimal crossing with the aid of a reentry device may be successful.  A variety of devices are available by which to accomplish angioplasty (standard balloon, cutting balloon, atherectomy) and/or stenting (bare metal, covered stent, stent-graft).  The selected devices depend upon the severity of the lesion and its location".

VENOVO Venous Stent System for the Treatment of May-Thurner Syndrome

May-Thurner syndrome (MTS) is caused when the left iliac vein is compressed by the right iliac artery, which increases the risk of deep vein thrombosis (DVT) in the left extremity.

Bondarev et al (2019) identified factors independently associated with disease recurrence after venoplasty and stent placement for MTS.  A total of 59 consecutive patients (age of 47 ± 15 years; 93 % women) were identified who had undergone endovascular stent placement for MTS.  Patient charts were reviewed for demographic data, risk factors for venous thrombosis, co-morbidities, and venous inflow or outflow at 1st follow-up (3 weeks to 6 months after treatment).  Logistic regression was used to identify independent predictors of symptom recurrence or repeat intervention, and multi-variate analysis of variance and receiver operator characteristic curve (ROC) analysis were used to examine relationships between degrees of in-stent stenosis and other variables in the 73 % of patients with available cross-sectional imaging.  Median follow up was 20.7 months (inter-quartile range [IQR], 4.7 to 49.5 months).  All procedures were technically successful.  Disease recurrence, defined as symptom recurrence following initial post-procedural resolution, was observed in 38 % of patients.  No pre-procedural variable was found to be independently predictive of disease recurrence; however, poor venous inflow or outflow were both strongly associated with recurrent disease, with adjusted ORs and 95 % CIs of 38.02 (3.76 to 384.20; p = 0.002) and 7.00 (1.15 to 42.71; p = 0.04), respectively.  Higher degrees of in-stent stenosis were also associated with symptom recurrence, with an area under the curve (AUC) of 0.93 (p = 0.000002) and 39 % to 41 % stenosis being 78 % to 83 % sensitive and 88 % to 92 % specific for symptom recurrence.  The authors concluded that these findings suggested that cross-sectional imaging could help differentiate patients in whom closer follow-up may be needed following venoplasty and stent placement for MTS and also guide counseling regarding prognosis.

Jayaraj et al (2019) noted that MTS patients with lifestyle-limiting symptoms undergo stenting of the iliac vein for relief of compressive disease.  These researchers carried out a retrospective review of contemporaneously entered data of 202 patients who underwent stenting for MTS between 2005 and 2011.  Classification into 3 groups based on luminal area obtained by intra-operative intravascular ultrasound (IVUS) interrogation of the involved femoro-ilio-caval segments was performed.  Normal luminal diameters and areas were defined as 12 mm and 125 mm^2, 14 mm and 150 mm², and 16 mm and 200 mm² in the common femoral, external iliac, and common iliac veins, respectively.  Mild (less than 60 %), moderate (60 % to 89 %), and severe (greater than 90 %) compression groups were defined using the normal values noted previously and observed after stenting to evaluate outcomes.  Kaplan-Meier analysis was carried out to evaluate primary, primary assisted, and secondary patencies.  Visual analog scale (VAS) for pain scores, grade of swelling, and Venous Clinical Severity Score (VCSS) before and after stenting at 6, 24, and 48 months were analyzed using paired t-test and Tukey test.  Logistic regression was used to gauge the impact of multiple variables including degree of stenosis on stent re-intervention.  There were 55 patients who had mild, 87 patients who had moderate, and 60 patients who had severe iliac vein compression.  Baseline demographic characteristics and co-morbidities were similar across all groups.  In addition, there was no statistically significant difference in median baseline VAS score, grade of swelling, and VCSS among the groups.  Compression was treated with angioplasty and stenting encompassing all areas of disease as determined by IVUS.  Stent technique involved use of Wallstent only in 183 patients and Wallstent-Z stent combination in the remainder.  No difference in median stent patency was noted on follow-up.  Clinically, at 48 months, a statistically significant recurrence of pain, swelling, and worsening of VCSS were noted in the severe stenosis group but not in the other 2 groups.  No variable was noted to have an impact on stent re-intervention.  The authors concluded that severity of MTS stenosis was not a predictor of initial clinical symptoms.  Long-term, patients with greater than or equal to 90 % initial MTS stenosis experienced recurrence of symptoms.  The degree of iliac venous stenosis did not appear to affect stent patency.

Jayaraj et al (2020) stated that symptoms of chronic venous insufficiency (CVI) secondary to obstructive ilio-femoral disease are often bilateral.  The impact of ilio-femoral stenting of the more symptomatic lower extremity (LE) on clinical outcomes in the less affected contralateral extremity is unclear.  Such benefit, secondary to off-loading of collaterals, may potentially be of the magnitude that the contralateral extremity does not require intervention.  These researchers carried out a retrospective review of contemporaneously entered electronic medical record data of 368 patients/limbs with initial unilateral ilio-caval stents (240 left and 128 right) placed during a 3-year period from 2015 to 2017.  Patients who underwent simultaneous bilateral stenting or had occlusive disease were excluded.  Of the remainder, the impact of stenting on contralateral leg symptoms was evaluated by analyzing VAS pain score (1 to 10), grade of swelling (1 to 3), and VCSS.  The duration of any improvement and need for intervention on the contralateral side were also appraised.  Kaplan-Meier analysis was used to evaluate stent patency after intervention, whereas paired t-tests were used to examine clinical outcomes.  Of the 368 limbs that underwent stenting with a combination of a Wallstent with a Z stent for stenotic lesions, 304 patients (89 men and 215 women) had contralateral symptoms (200 left and 104 right).  The cause was post-thrombotic syndrome in 229 limbs and MTS or non-thrombotic iliac vein lesion in 75 limbs.  In this contralateral group, at 12 months, the VAS pain score improved from 5 to 0 (p < 0.0001), the grade of swelling went from 3 to 1 (p < 0.0001), and VCSS went from 5 to 3 (p < 0.0001) after stenting of the ipsilateral side.  During the median follow-up of 20 months, 15 contralateral limbs underwent stenting.  Median time to stenting of the contralateral limb after ipsilateral stenting was 9 months.  The median VAS pain score, grade of swelling, and VCSS in this group before stenting were 6.5, 2, and 5 compared with 0 (p < 0.0001), 1 (p = 0.27), and 3 (p = 0.0021), respectively, in those members of the contralateral group who did not require stenting.  Primary and primary assisted patencies at 12 months after contralateral stenting were 78 % and 100 %, respectively.  There were no stent occlusions after contralateral stenting.  The authors concluded that patients with bilateral obstructive ilio-femoral venous lesions often experienced improvement of the contralateral limb symptoms (95 %) after stenting of the worse ipsilateral limb.  Only 15 of 304 (5 %) symptomatic contralateral limbs had to undergo stenting during the follow-up period because of a worsening clinical picture.  Based on this, a staged approach to ilio-femoral stenting in patients with bilateral symptoms focusing initially on the more symptomatic limb was suggested.

Furthermore, an UpToDate review on "May-Thurner syndrome" (Mousa, 2020) states that "Since its inception and use over the last decade, IVUS has become an integral component of the treatment of MTS.  IVUS is useful for determining vessel diameter, aiding accurate stent placement, ensuring full stent expansion, estimating the gain in cross-sectional area, and, with follow-up, identifying the severity of in-stent restenosis … For moderate-to-severe symptomatic MTS in the absence of DVT, treatment is targeted toward reducing the severity of the chronic venous stenosis/occlusion.  We suggest angioplasty and stenting of the affected segment, rather than angioplasty alone".

Eluvia Drug-Eluting Vascular Stent System for the Treatment of Superficial Femoral Artery and Proximal Popliteal Artery Disease

The Eluvia Drug-Eluting Vascular Stent System is indicated for improving luminal diameter in the treatment of symptomatic de-novo or re-stenotic lesions in the native SFA and/or proximal popliteal artery (PPA) with reference vessel diameters ranging from 4.0 to 6.0 mm and total lesion lengths up to 190 mm.

In a randomized, single-blind, non-inferiority study, Gray and colleagues (2018) compared the safety and efficacy of the polymer-coated, paclitaxel-eluting Eluvia stent with the polymer-free, paclitaxel-coated Zilver PTX stent for treatment of femoro-popliteal artery segment lesions.  Patients with symptomatic lower-limb ischemia manifesting as claudication (Rutherford category 2, 3, or 4) with atherosclerotic lesions in the native SFA or PPA were enrolled at 65 centers in Austria, Belgium, Canada, Germany, Japan, New Zealand, and the U.S.  Patients were randomly assigned (2:1) with a site-specific, web-based randomization schedule to receive treatment with Eluvia or Zilver PTX.  All patients, site personnel, and investigators were masked to treatment assignment until all patients had completed 12 months of follow-up.  The primary efficacy end-point was primary patency (defined as a duplex US peak systolic velocity ratio less than or equal to 2.4, without clinically driven TLR or bypass of the target lesion) and the primary safety end-point was major AEs (i.e., all causes of death through 1 month, major amputation of target limb through 12 months, and TLR through 12 months).  These investigators set a non-inferiority margin of -10 % at 12 months.  Primary non-inferiority analyses were carried out when the minimum sample size needed for adequate statistical power had completed 12 months of follow-up.  The primary safety non-inferiority analysis included all patients who had completed 12 months of follow-up or had a major AE through 12 months.  Between December 2, 2015 and February 15, 2017, a total of 465 patients were randomly assigned to Eluvia (n = 309) or to Zilver PTX (n = 156).  Non-inferiority was demonstrated for both efficacy and safety end-points at 12 months: primary patency was 86.8 % (231/266) in the Eluvia group and 81.5 % (106/130) in the Zilver PTX group (difference 5.3 % [1-sided lower bound of 95 % CI: -0·66]; p < 0·0001); 259 (94.9 %) of 273 patients in the Eluvia group and 121 (91.0 %) of 133 patients in the Zilver PTX group had not had a major AE at 12 months (difference 3.9 % 1-sided lower bound of 95 % CI: -0·46]; p < 0.0001).  No deaths were reported in either group; 1 patient in the Eluvia group had a major amputation and 13 patients in each group required TLR.  The authors concluded that the Eluvia stent was non-inferior to the Zilver PTX stent in terms of primary patency and major AE at 12 months after treatment of patients for femoro-popliteal PAD.  These researchers stated that based on these findings, the use of a polymer-coated paclitaxel-eluting stent in patients who require superficial femoral artery or popliteal intervention is a reasonable approach to maximize intermediate-term patency and to maintain hemodynamic and clinical improvement without repeat re-intervention.

Golzar and associates (2020) reported the clinical effect of a drug-eluting stent on femoro-popliteal occlusive disease in patients with long lesions.  The global IMPERIAL Long Lesion sub-study was a prospective, single-arm, multi-center trial of the Eluvia Drug-Eluting Vascular Stent for treating femoro-popliteal lesions of greater than140 mm and less  than or equal to 190 mm in length.  A total of 50 patients (mean age of 68.2 years; 32 men) with long lesions (mean length of 162.8 ± 34.7 mm) were enrolled; 20 patients had diabetes; 14 of the lesions were severely calcified and 16 were occluded.  Primary patency (duplex US peak systolic velocity ratio of less than or equal to 2.4 in the absence of clinically-driven TLR or bypass of the target lesion) and major AEs [30-day all-cause death and 1-year target limb major amputation or TLR] were evaluated at 12 months.  At 12 months, no deaths, target limb amputations, or stent thrombosis had occurred.  The Kaplan-Meier estimate of primary patency was 91.0 % (95 % CI: 82.5 % to 99.6 %). The major AE (MAE)-free rate at 12 months was 93.5 % due to 3 clinically-driven TLRs.  The corresponding Kaplan-Meier estimate of freedom from TLR was 93.9 % (95 % CI: 87.2 % to 100 %).  The authors concluded that the IMPERIAL Long Lesion sub-study showed excellent patency and safety through 1 year among patients with long femoro-popliteal occlusive disease treated with the Eluvia stent.

Eluvia Drug-Eluting Vascular Stent System for the Treatment of Iliac Artery Stenosis

Ontario’s Medical Advisory Secretariat’s evidence-based analysis on "Stenting for peripheral artery disease of the lower extremities" (2010) stated that "Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent.  The OR and their corresponding 95 % CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up.  Both types of stents offer similar immediate success.  Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome.  Further research is needed to confirm its effect and safety". It also noted that "drug-eluting stents are not licensed by Health Canada for peripheral artery disease".

Kalmar and colleagues (2014) examined immediate results and mid-term outcome of the hemoparin-coated (HC) stainless-steel stent (camouflage coating) in the treatment of occlusive lesions of the iliac arteries.  A total of 28 patients were prospectively treated with the use of a HC stent between January 2007 and March 2010.  Clinical examination and color-Doppler US were performed at 1, 3, 6 and 12 months, CTA or magnetic resonance angiography (MRA) at 12 months.  Indication for treatment was a high-grade stenosis of the common iliac and/or external iliac artery.  Successful placement was achieved in all patients.  Significant decrease in translesional pressure gradient (greater than 10 mm Hg) was measured in 27 patients (96 %).  In 1 patient, proximal dissection occurred without flow limitation.  A minor complication (small access site hematoma) occurred in 1 patient (4 %); 2 patients (7 %) were lost to follow-up.  After 12 months, stent patency in CTA, MRA and US was 100 %; 20 patients (77 %) experienced an initial improvement of at least 1 clinical stage.  In 1 patient (4 %), mild intimal hyperplasia without significant stenosis was observed.  In 3 patients (12 %), proximal or distal stenosis occurred.  A non-significant increase of mean ABI following treatment was measured (0.85 ± 0.27 versus 0.75 ± 0.22, respectively; p = 0.328).  The authors concluded that the use of HC stents in patients with iliac artery occlusive disease may lead to a lower rate of intimal hyperplasia and thus to increased patency rates even in heavily calcified vessels.  Moreover, these researchers stated that large, prospective trials are needed to examine the long-term patency rates of the HC coated stents.

Kayssi and associates (2019) noted that stents are placed in the femoro-popliteal arteries for numerous reasons, such as atherosclerotic disease, the need for dissection, and perforation of the arteries, and can become stenosed with the passage of time.  When a stent develops a flow-limiting stenosis, this process is known as "in-stent stenosis".  It is thought that in-stent restenosis is caused by a process known as "intimal hyperplasia" rather than by the progression of atherosclerotic disease.  Management of in-stent restenosis may include performing balloon angioplasty, deploying another stent within the stenosed stent to force it open, and creating a bypass to deliver blood around the stent.  The role of drug-eluting technologies, such as drug-eluting balloons (DEBs), in the management of in-stent restenosis is unclear.  Drug-eluting balloons might function by coating the inside of stenosed stents with cytotoxic chemicals such as paclitaxel and by inhibiting the hyperplastic processes responsible for in-stent restenosis.  In a systematic review, these researchers examined the efficacy of DEB because of the potential for increased expenses associated with DEBs over uncoated balloon angioplasty, also known as plain old balloon angioplasty (POBA).  These researchers examined the safety and efficacy of DEBs compared with uncoated balloon angioplasty in people with in-stent restenosis of the femoro-popliteal arteries as assessed by criteria such as amputation-free survival, vessel patency, TLR, binary restenosis rate, and death.  They defined "in-stent restenosis" as 50 % or greater narrowing of a previously stented vessel by Duplex US or angiography.  The authors concluded that based on a meta-analysis of 3 trials with 263 participants, evidence suggested an advantage for DEBs compared with uncoated balloon angioplasty for anatomical end-points such as TLR and binary restenosis, and for 1 clinical end-point – improvement in Rutherford category post-intervention for up to 24 months.  However, the certainty of evidence for all these outcomes was very low due to the small number of included studies and participants and the high risk of bias in study design.  These researchers stated that adequately powered and carefully constructed RCTs are needed to adequately examine the role of drug-eluting technologies in the management of in-stent restenosis.

An UpToDate review on "Overview of lower extremity peripheral artery disease" (Berger and Davies, 2020) states that "Concern over paclitaxel — Following percutaneous intervention, a number of medical therapies aimed at preventing restenosis, but only local delivery of the drug paclitaxel has been shown to improve the longevity of interventions for lower extremity PAD.  However, the overall safety of paclitaxel-coated balloons and stents placed into the legs of patients with PAD has come into question".

Furthermore, an UpToDate review on "Endovascular techniques for lower extremity revascularization" (Dosluoglu, 2020) states that "A number of medical therapies aimed at preventing restenosis related to percutaneous angioplasty have been tried, but only local delivery of the drug paclitaxel has been shown to improve the longevity of interventions.  The outcomes of reported trials studying paclitaxel-coated devices have overwhelmingly used lesion-oriented outcome measures, such as TLR or primary restenosis, rather than functional or patient-oriented measures, such as increased limb salvage or improved walking distance.  The indications and percutaneous techniques for treating lower extremity peripheral artery disease (PAD) are reviewed separately.  However, the overall safety of paclitaxel-coated balloons and stents placed into the legs of patients with PAD has come into question.  Based on a review of long-term follow-up data from premarket randomized trials, the US Food and Drug Administration (FDA) has urged that health care providers should consider the potential benefits of paclitaxel-coated devices (i.e., reduced reinterventions) in individual patients along with potential risks (i.e., late mortality) before using paclitaxel-coated devices for the treatment of PAD.  The long-term data from the pivotal premarket trials were presented by the FDA at a public meeting of the Circulatory System Devices Panel of the Medical Devices Advisory Committee.  In the FDA's meta-analysis of these trials (1,090 patients), overall mortality at 5 years was significantly increased for patients treated with paclitaxel-coated devices compared with those treated with uncoated devices (19.8 versus 12.7 %, relative risk 1.57, 95 % CI 1.16 to 2.13).  These results confirmed a meta-analysis by Vascular InterVentional Advances (VIVA) clinicians of patient-level data provided by manufacturers (hazard ratio of 1.38, 95 % CI 1.06 to 1.80) and an earlier meta-analysis (mortality risk ratio 1.93, 95 % CI 1.27 to 2.93). Nevertheless, the Panel, the FDA, and others agree that the magnitude of the potential increased mortality should be interpreted with caution given the multiple limitations in the available data (e.g., pooling of studies of different paclitaxel-coated devices that were not intended to be combined, substantial amounts of missing study data, no clear evidence of a paclitaxel dose effect on mortality, and no identified pathophysiologic mechanism for the late deaths).  Recommendations for informed consent, monitoring patients, and adverse event reporting can be found on the FDA website".

Renal Artery Stenting for Stenosis due to Fibromuscular Dysplasia

Schwarzwalder and Zeller (2009) noted that significant RAS is a well-accepted cause of deterioration of arterial hypertension and of renal insufficiency.  Recently, more interest has been focused on the impact of RAS on structural heart disease and patient survival.  Technical improvements of diagnostic and interventional endovascular tools have led to a more widespread use of endoluminal renal artery re-vascularization and extension of the indications for this type of therapy during the past 20 years.  Since the 1st renal artery angioplasties performed by Felix Mahler and Andreas Gruntzig, numerous single-center studies have reported the beneficial effect of percutaneous transluminal renal angioplasty, and since the early 1990's stenting of RAS caused either by atherosclerosis or fibro-muscular dysplasia (FMD).  However, none of the so far published or presented RCTs could prove a beneficial outcome of RAS re-vascularization compared with medical management.  As a result of these negative trials including the recently presented ASTRAL trial, referrals to endovascular renal artery re-vascularization went down and moreover, reimbursement of these procedures became a matter of debate.  The authors summarized the background and the limitations of the so far published and still ongoing controlled trials.  Moreover, they discussed why well-designed registries might give important insight on the impact of endovascular re-vascularization of hemodynamically relevant atherosclerotic RAS.

Henry and associates (2010) stated that RAS is common among patients with atherosclerosis, up to 1/3 of patients undergoing cardiac catheterization; FMD is the next cause of RAS, commonly found in young women.  Atherosclerosis RAS generally progresses overtime and is often associated with loss of renal mass and worsening renal function (RF).  Percutaneous renal artery stent placement is the preferred method of re-vascularization for hemodynamically significant RAS according to ACC and AHA guidelines.  Several randomized trials have shown the superiority of endovascular procedures to medical therapy alone.  However, 2 studies ASTRAL and STAR studies were recently published and did not find any difference between renal stenting and medical therapy.  But these studies have a lot of limitations and flaws as discussed by the authors (poor indications, poor results, numerous complications, failures, poor technique, inexperienced operators, etc.).  Despite these questionable studies, renal stenting keeps indications in patients with: uncontrolled hypertension; ischemic nephropathy; cardiac disturbance syndrome (e.g., "flash" pulmonary edema, uncontrolled heart failure or uncontrolled angina pectoris); solitary kidney.  To improve the clinical response rates, a better selection of the patients and lesions is mandatory with: good non-invasive or invasive imaging; physiologic lesion assessment using transluminal pressure gradients; measurements of biomarkers (e.g., BNP); fractional flow reserve study.  A problem remains after renal angioplasty stenting, the deterioration of the RF in 20 to 30 % of the patients.  Athero-embolism appeared to play an important role and is probably the main cause of this RF deterioration.  The use of protection devices alone or in combination with IIb/IIIa inhibitors has been proposed and appeared promising as shown in different recent reports.  The authors concluded that renal angioplasty and stenting is still indicated but we need: a better patient and lesion selection; improvements in techniques and maybe the use of protection devices to reduce the risk of RF deterioration after renal stenting.

Yang and co-workers (2016) noted that RAFMD is a non-atherosclerotic cause of RAS often affecting the young; PTRA is the treatment of choice but there are few studies of the outcome of the procedure.  This retrospective analysis included 64 patients (56.2 % female; mean age at diagnosis of 28.0 years) with RAFMD who underwent PTRA between November 2003 and August 2015.  Technical and clinical success rates and re-stenosis rates were evaluated.  A total of 76 procedures were performed on 64 RAFMD patients.  Technical success was 96.9 %, as defined by less than 30 % residual stenosis, with stent placement required in 11 patients (17.2 %).  In the short-term (1 month), the majority (79.7 %) had an immediate clinical benefit, with cure of hypertension in 35.9 %, and improvement in hypertension and a lower requirement for anti-hypertensive medications in 43.8 %.  In the long-term (mean of 47.5 months; range of 5 to 141 months), the survival rate was 96.9 %, freedom from re-stenosis was 84.4 %, and 76.6 % of patients showed a sustained clinical benefit (cure rate 40.6 %, improvement rate 35.9 %); 8 patients were treated with a 2nd procedure and 2 had a 3rd procedure, with 50 % of these patients showing an improvement in hypertension.  The authors concluded that PTRA for symptomatic RAFMD was safe and clinically successful; more than 50 % of patients experienced an immediate clinical benefit with sustained long-term effects.  For patients with re-stenosis, there was a good response to a 2nd PTRA.

Plouin and colleagues (2017) stated that FMD commonly affects the renal and cervical arteries but has been described to affect other vascular beds as well.  The prevalence of and clinical characteristics associated with multi-site FMD (string-of-beds or focal stenoses affecting at least 2 vascular beds) are not known.  In the prospective ARCADIA registry (Assessment of Renal and Cervical Artery Dysplasia), symptomatic patients with RA FMD underwent tomographic- or magnetic resonance-angiography from the aortic arch to the intracranial arteries and those with cervical FMD from the diaphragm to the pelvis.  Of 469 patients (84.0 % women), 225 (48.0 %) had multi-site FMD.  In addition, 86 of 244 patients with single-site disease had dissections or aneurisms affecting other vascular beds, totaling 311 patients (66.3 %) with lesions in greater than 1 vascular bed.  Among patients with a cerebrovascular presentation, the prevalence of RA lesions was higher in patients with than in those without hypertension (OR, 3.4; 95 % CI: 1.99 to 6.15).  Among patients with a renal presentation, the prevalence of cervical lesions was higher in patients with bilateral than in those with unilateral RA lesions (OR, 1.9; 95 % CI: 0.99 to 3.57). The authors concluded that FMD is a systemic arterial disease.  At least 2 vascular beds were affected by dysplastic stenoses in 48.0 % of cases and by dysplastic stenoses, aneurysms, and dissections in 66.1 % of cases.  They stated that RA imaging should be proposed to hypertensive patients with a cerebrovascular presentation; cervical artery imaging should be considered in patients with a renal presentation and bilateral RA lesions.

Furthermore, an UpToDate review on "Treatment of fibromuscular dysplasia of the renal arteries" (Olin, 2018) states the following:

The 2 options for re-vascularization include percutaneous transluminal angioplasty (PTA, typically without placing a stent) or surgery.

Percutaneous transluminal angioplasty (PTA) is typically performed without placement of stent (unlike PTA for atherosclerotic renal artery stenosis).  In general, stents are only placed when a dissection results from the performance of PTA or in the rare instance in which a perforation of the renal artery occurs during angioplasty.  There are several reasons why a stent should not be used as 1st-line endovascular therapy in patients with FMD:

• Patients do very well with angioplasty alone, so there is no reason to place a stent.  If the lesion is so fibrotic that the pressure gradient cannot be obliterated with an angioplasty, a stent will not correct this problem (and stent deformation will likely occur).  Such patients should be referred for surgery.
• Patients with renal FMD usually have stenoses in the mid and distal portions of the artery rather than at the ostium or proximal portion (as occurs with atherosclerosis).  Should surgical re-vascularization become necessary due, e.g., to in-stent restenosis, patients may require more complex branch repair to bypass the occluded stent since the stent often covers the renal artery up to the point of the first intrarenal branch.
  
  
  
  

The above policy is based on the following references: