Below-the-Knee Stents and Scaffolds: A Comprehensive Review

Abstract

Below-the-knee intervention of chronic limb-threatening ischemia is an area of increasing interest. Due to lower morbidity and possibly better clinical outcomes, endovascular techniques have become increasingly important in this patient population many of who have limited surgical options. This article serves as a review of existing stent and scaffolding devices utilized for infrapopliteal disease. The authors will additionally discuss current indications and review studies that are investigating novel materials used in treating infrapopliteal arterial disease.

Chronic limb-threatening ischemia (CLTI) or critical limb ischemia is a highly morbid, limb- and life-threatening, late-stage presentation of peripheral arterial disease (PAD). Progression from PAD to CLTI within 5 years has been found to be as high as 21%. ^{1 2} This severe manifestation of PAD is a rapidly growing global health crisis, involving more than 200 million people worldwide. ¹ Mortality and amputation rates within 1 year for untreated CLTI are as high as 22%. ¹

The management of CLTI is multidisciplinary, requiring long-term medical management as well as endovascular or surgical treatment. Treatment for this painful disease process can be evaluated using the WIfI classification, which considers patient wounds, ischemia, and foot infection. There are prominent levels of variability in CLTI management yielding disparities in care. One contributing factor is that guidelines are constantly evolving as new data are published. Additionally, technologies are rapidly advancing as new devices are developed and, in turn, investigated as potential treatments.

Below-the-knee (BTK) intervention of CLTI, while particularly challenging, is an area of rapid development, with constant exploration of new techniques and equipment. While surgical procedures such as grafting, bypass, or amputation were previously the mainstay of treatment, the development of endovascular interventions with fewer associated complications has become more attractive.

Bare Metal Stent

Bare metal stents were first introduced in 1986 to reduce the restenosis seen in plain old balloon angioplasty (POBA) of coronary lesions. ³ Plain percutaneous transluminal angioplasty (PTA) remained the mainstay for endovascular revascularization for BTK disease for decades, until the recent advent of drug-eluting stents (DESs; discussed later). While PTA with BMS introduced a viable treatment to CLTI, patency rates with BMS are poor with only 50% of lesions remaining patent 1 year after intervention with dissection occurring as a common complication; reintervention is frequently required due to recurrence of symptoms. ^{4 5} BMS may also fracture or become crushed in areas of high mechanical stress such as the infrapopliteal area.

BMSs are often made of stainless steel, which provides clear visibility on X-ray, though may be MRI incompatible with a susceptibility to corrosion. More recently, cobalt or nickel-titanium (nitinol) alloys have been used in both coronary and limb revascularization applications. Cobalt alloys are stronger with a small mesh size, thought to reduce risk of thrombosis; nitinol is used in self-expanding stents and offer a high elasticity that is corrosion resistant.

DESs are the preferred device for the treatment of BTK CLTI, though BMS may continue to have limited use. A 2009 systematic review of percutaneous infrapopliteal BMS placement after failed angioplasty resulted in favorable clinical results as compared to angioplasty alone; however, initial findings show that DES may remain superior in this setting due to higher long-term patency rates. ⁵

Drug-Eluting Stents

The development of DES has significantly impacted the landscape of endovascular revascularization. DESs utilize a combination of metal and polymer scaffolding for structural support, and additionally slowly release an antiproliferative agent to improve patency rates.

Initially used for coronary artery stenosis, these stents have become more widely utilized for infrapopliteal disease over the years. The PaRADISE trial (PReventing Amputations using Drug eluting StEnts) was one of the first to elucidate the benefits of DES, with only 6% cumulative incidence of 3-year amputation, and with target lesion revascularization occurring in only 15% of patients. ⁶ DES was directly compared against PTA with BMS in the PADI trial, which found a significantly higher 6-month patency rate in infrapopliteal lesions treated with DES (51.9% for DES and 35.1% for PTA + BMS in a per protocol analysis). ⁷

These initial studies have shown that DESs are associated with improved primary patency when compared to PTA or BMS for short BTK arterial lesions beneath a certain length. The average length of lesions in the PADI trial was 23.1 mm ± 21.8 mm. The ACHILLES trial had a mean lesion length of 27 ± 21 mm. The Destiny I had a mean length of 15.9 mm. In recent years, the role of DES has been investigated for longer lesions. With a mean of 47.4 mm in Destiny II, Bosiers et al demonstrated the effectiveness of everolimus-coated DES in longer lesions up to 10 cm when treating CLTI. ⁸

Giaquinta et al evaluated whether the use of Xience-Prime Everolimus-Eluting Stent (Abbott Laboratories, Abbott Park, IL) is effective for straight line flow for up to 10 cm revascularization for Rutherford-Becker categories 4 and 5 (rest pain or ischemic ulceration, respectively) in patients with CLTI and whether longer length lesions would maintain patency. ⁴ They reported a 1-year primary patency of 88.7%, 3-year primary patency rate of 80.1%, and a 3-year amputation-free survival rate of 93%. They also found a dramatic 94.6% rate of limb salvage for patients with target BTK patency, versus only 40% limb salvage for those without. ³ These findings show significant promise for the role of everolimus-eluting stents to prevent recurrence of CLTI events.

Paclitaxel

Paclitaxel is a common drug used in DES. It stabilizes the microtubule polymer of smooth muscle cells, preventing disassembly for smooth muscle migration and therefore inhibiting atherosclerotic plaque formation. ⁹ The Percutaneous Transluminal Angioplasty and Drug-Eluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI) trial compared two groups: one paclitaxel-eluting DES and the other PTA with or without BMS. Primary amputation rates were significantly lower in the DES group. Primary patency rates were 48% for DES and 35.1% for PTA with or without BMS. ⁷

Sirolimus

Sirolimus was originally designed as a chemotherapeutic drug, inhibiting mTOR to prevent cell cycle progression into the S phase. In DES, sirolimus acts on smooth muscle cells to prevent atherosclerosis. The ACHILLES trial compared sirolimus-eluting stents (SESs; Cypher Select SES; Cordis Corporation, Bridgewater NJ) with PTA, which demonstrated superiority for DES restenosis rate at 1 year over PTA (22.4 vs. 41.9%; p  < 0.0019). ¹⁰ This groundbreaking study showed the promising use of SESs for the treatment of BTK disease. The YUKON-BTK trial went on to find that when randomized patients were broken into a SES group and a BMS group for BTK disease, there was a significant reduction in both amputation (5.3 vs. 22.6%; p  = 0.04) and target lesion revascularization rates (9.2 vs. 20%; p  = 0.06) for the SES group. ¹¹

Everolimus

Everolimus is a semisynthetic macrolide immunosuppressant, which is a modification of the drug sirolimus and acts similarly to prevent smooth muscle proliferation. While initially developed to prevent allograft rejection after organ transplantation, it has been found to be a strong antiproliferative and immunosuppressant agent. ¹² The Drug Eluting STents in the critically ischemic lower leg (DESTINY-I) trial used stents coated with everolimus and found that patients with CLTI who received DES (Xience V; Abbott Vascular, Abbott Park, IL) had significantly better primary patency rates when compared to those with BMS (85 vs. 54%; p  < 0.0001). ¹³

Fig. 1 illustrates a patient undergoing everolimus-eluting stent placement.

Fig. 1.

( a–e ) Left lower extremity angiograms of a 63-year-old woman with left lower extremity critical limb ischemia. Preprocedural angiograms demonstrated multifocal stenoses with extensive collateral vasculature and additional spiral dissection of the popliteal and posterior tibial arteries ( a ). Balloon angioplasty of the posterior tibial (white arrow) and popliteal (black arrow) arteries was performed, with additional angioplasty of the distal superficial femoral artery/popliteal artery ( b ). The posterior tibial artery was stented with two Xience Prime everolimus-eluting stents and additional balloon angioplasty with bare metal stenting in the distal superficial femoral artery/popliteal artery ( c, d ), with post-procedural angiography demonstrating improved patency (D. Arrow = posterior tibial artery).

Self-Expanding DES

In STENTYS PES-BTK-70, Bosiers et al investigated the use of a self-expanding coronary stent. ¹⁴ The STENTYS self-expanding paclitaxel-eluting stent has been shown to have optimal wall apposition in the coronary arteries. Rather than using the typical everolimus-eluting stent that uses a balloon-expandable platform, which are crushable and prone to fracture, they use self-expanding nitinol. Nitinol is more flexible for arterial anatomies susceptible to movement, which is especially true for infrapopliteal lesions. Bosiers et al found the STENTYS self-expanding DES to be safe and effective in the BTK region when treating CLTI. The authors also suggest the use of sirolimus rather than paclitaxel in the future, as it has been shown to have more effective inhibition of neointimal proliferation, especially for longer BTK lesions. ¹⁴

The recently presented SAVAL clinical trial evaluated a novel polymer-based, paclitaxel-eluting, self-expanding stent used in the treatment of infrapopliteal stenosis/occlusion for Rutherford 4 and 5 diseases in critical limb ischemia. This trial enrolled 201 subjects at 39 clinical centers in the United States, Europe, and Japan. This trial did not meet the primary endpoint for efficacy or safety as demonstrated by primary patency at 12 months (68% DES vs. 71% PTA) and freedom from major adverse events at 12 months (91.6% DES vs. 95.3% PTA), respectively. ¹⁵

Tack Implants

PTA in conjunction with stenting has comparable limb salvage and amputation-free survival rates to bypass-grafting, all with fewer complications and recovery time. ¹⁶ One of the most common complications, however, is arterial dissection, due to the mechanics of the intervention. Dilation of the artery may lead to plaque rupture in diseased vasculature leading to intimal splitting and in turn medial dissection. The conventional treatment for post-PTA dissection is stent placement, which can lead to injury, inflammation, and stenosis. As established, this is particularly true for lesions BTK. In 2017, Brodmann et al published a study called Tack Optimized Balloon Angioplasty-Below the Knee (TOBA-BTK), which investigated the use of tack implants rather than stent placement for post-PTA dissection. Technical success of device deployment was 91.4%, and 12-month patency was found to be as high as 77.4%. ¹⁶

Vascular Scaffolding

Drug-Eluting Vascular Scaffold

Drug-eluting resorbable scaffolds (DRSs) were designed with the intention of resolving the foreign body rejection associated with metal stents, as well as their kinetic limitations. Also, metal stents do not allow for vasodilation or constriction. DRSs are made from an absorbable polymer, designed to provide temporary structural support then slowly degrade over time, with the hope of restoring normal vascular structure.

Bioresorbable Scaffold for CAD

The first bioresorbable scaffold (BRS) device was the Igaki-Tamai bioabsorbable scaffold, designed for percutaneous coronary intervention (PCI). Initial trials hinted at a promising alternative to metallic stents, demonstrating absorption of the scaffold within 3 years with no significant inflammatory response seen on histological study. Subsequent iterations were drug-eluting. Gaining increased attention at that time, the Abbott Vascular Absorb DRS, which uses a balloon-expanding mechanism with everolimus similar to drug-eluting metal stents. Initial trials of the Absorb DRS found that it was noninferior to an everolimus-eluting cobalt-chromium metal stent (the Abbott Vascular CoCr-EES), though a follow-up meta-analysis found higher rates of stent thrombosis when compared to the CoCr-EES. ¹⁷ Further findings from the ABSORB II and AIDA trials found that the Absorb BVS was associated with higher morbidity and mortality, including cardiac death and target-vessel MI. ^{18 19} These findings resulted in the withdrawal of the Absorb BVS for coronary artery disease in 2017. ²⁰

Bioresorbable Scaffold for CLTI

Despite these results, there remains interest in using the Absorb DRS in infrapopliteal CLTI. Metallic stents typically risk crushing or breakage in femoral and tibial arteries due to high mechanical stress, and DRS could theoretically be a structurally favorable option. A 2022 single-arm meta-analysis including a total of 155 patients found a pooled 1-year primary patency rate of 90%, with a rate of freedom from clinically driven target lesion revascularization of 96%. ²¹ Further research expanding on these preliminary results will be necessary to compare DRS with standard of care in CLTI; however, these initial findings show promise for the use of DRS in BTK interventions.

Conclusion

Table 1 provides an overview of the currently available stent platforms, and their relative indications, advantages, and disadvantages.

Table 1. Commonly available stent platforms.

Device	Indications	Advantages	Disadvantages
Bare metal stent	Revision of failed balloon angioplasty alone		High restenosis rate Crushing/fracture in high stress areas
Drug-eluting stent	Current standard of care for BTK CLTI	Reduced restenosis rate as compared to BMS	Crushing/fracture in high stress areas
Self-expanding nitinol drug-eluting stent	Infrapopliteal lesions under high mechanical stress	Improved flexibility when compared to balloon-expandable stents	Only available with paclitaxel
Tack implants	Post-PTA dissection	No prior device available to repair dissection
Drug-eluting resorbable scaffold	Infrapopliteal lesions under high mechanical stress	Theoretical restoration of physiologic vasomotion	Limited data available

Abbreviations: BMS, bare metal stent; BTK, below the knee; CLTI, chronic limb-threatening ischemia; PTA, percutaneous angioplasty.

Management of CLTI involves multiple health care specialists and treatments ranging from noninvasive tests, endovascular or surgical treatment, to follow-up for pain control, infection, modification of cardiovascular risk factors, and more. Moreover, BTK endovascular intervention is particularly difficult due to the multifocal, densely calcified, and lengthy nature of the disease. ²² DESs have made groundbreaking differences in the management of infrapopliteal disease. New studies continue to elucidate the role of these stents in a wider array of BTK lesions. All the while, the use of BRSs is proving to be promising, showing longer patency and notably lower numbers requiring target lesion revascularization.