Looking to the Future - Next-generation Bioactive Stent-graft Technology

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Peripheral arterial disease (PAD) increases in prevalence and incidence with advancing age, and the shifting demographics of an ageing general population is expected to increase the burden of PAD. Thus, there has been an increased focus on how best to manage this burden. If intervention is deemed necessary, surgery remains the gold standard for certain forms of lower-extremity occlusive disease. However, endovascular therapy is gaining greater acceptance.

In treatment for superficial femoral artery (SFA) occlusive disease, surgery demonstrates good long-term patency rates; however, surgery is associated with greater morbidity and mortality. In comparison, while endovascular intervention studies for the SFA have yet to show long-term patency, the technique is associated with less morbidity and mortality. Furthermore, the constantly evolving field of endovascular intervention continues to determine the best material and techniques for recanalisation of the SFA.

Management of Superficial Femoral Artery Occlusive Disease

The Transantlantic Inter-Society Consensus (TASC) has classified four clinically important types of SFA lesion:1

  • TASC type A lesions are a single stenosis ≤10cm in length or a single occlusion ≤5cm in length. Endovascular therapy is the treatment of choice for type A lesions.
  • TASC type B lesions are classed as: multiple lesions (stenoses or occlusions), each ≤5cm; a single stenosis or occlusion ≤15cm not involving the infra-geniculate popliteal artery; single or multiple lesions in the absence of continuous tibial vessels to improve inflow for a distal bypass; a heavily calcified occlusion ≤5cm in length; or a single popliteal stenosis. Endovascular treatment is the preferred treatment for type B lesions.
  • TASC type C lesions are multiple stenoses or occlusions totalling >15cm with or without heavy calcification or recurrent stenoses or occlusions that need treatment after two endovascular interventions. Although surgery is the preferred treatment for good-risk patients with type C lesions, the patient’s co-morbidities, fully informed patient preference and the local operator’s long-term success rates must be considered when making treatment recommendations for type B and type C lesions.
  • TASC type D lesions are classed as chronic total occlusions of the SFA (>20 cm, involving the popliteal artery) or a chronic total occlusion of popliteal artery and proximal trifurcation vessels. Surgery is the treatment of choice for type D lesions.

SFA occlusive disease has clinical characteristics encompassing intermittent claudication of various degrees and critical limb ischaemia (CLI) that may lead to tissue loss or amputation. Recanalisation is frequently necessary to relieve symptoms as well as to save limbs. Although some claudicators may be treated with above-knee (AK) femoropopliteal bypasses, the majority of patients present more advanced PAD with more extensive occlusions, and require bypass to arteries below the knee (BK).

Surgical Intervention

The autologous saphenous vein is established as the bypass conduit of choice for all such instances because of its superior clinical performance and long-term patency compared with synthetic grafts.2 Analysis of the published literature showed one-year primary patency rates of 66 and 81% for expanded polytetrafluoroethylene (ePTFE) and vein BK bypasses, respectively. Small-diameter synthetic conduits have produced historically disappointing results for BK reconstruction, especially when bypassing into an infra-popliteal target vessel.3–5

Unfortunately, use of the patient’s saphenous veins may not be possible in a significant number of cases because of prior use or removal, varicose vein disease or small size and unfavourable anatomy. In addition, the risks of surgery are significantly greater than the risks of an endovascular approach, in terms of not only mortality but also major morbidity (prolonged hospitalisation and delay in return to normal activities). Therefore, the assessment of the patient’s general condition and anatomy of the diseased segment or segments becomes central in deciding which approach is warranted.

Endovascular Intervention

Balloon angioplasty and subintimal angioplasty have been associated with high failure rates, especially with longer SFA segments.6 Moreover, bare nitinol stenting has demonstrated significantly higher primary patency rates versus dilatation alone of SFA lesions.7

However, restenosis due to intimal hyperplasia still remains a problem with bare nitinol stenting, and patency rates remain below those of surgical intervention.8 Patency with bare stents usually fails because of intimal hyperplasia throughout the stented region. Intimal hyperplasia is the outcome of smooth-muscle-cell proliferation and migration into the intima, as well as proteoglycan secretion. These processes are modulated by a complex array of events triggered soon after stent insertion. Platelet activation and thrombus formation take place at the luminal wall. Acute inflammation, formation of granulation tissue and release of chemokines and oxygen free radicals occur in the wall adjacent to the abluminal surface. In addition, the first-generation stents suffered from a high level of fracture owing to the unique forces exerted on the SFA when patients stood or walked.

Drug-eluting Stents

Drug-eluting stents have been assessed as an approach to improve longterm vessel patency. Generally, drug-eluting stents contain antimitotic drugs that attempt to reduce the risk of intimal hyperplasia. However, the Sirolimus-coated Cordis SMART Nitinol Self-expanding stent for the treatment of obstructing superficial femoral artery disease (SIROCCO) I and II trials of sirolimus-eluting stents failed to demonstrate a significant advantage of drug-eluting stents over the bare nitinol controls.9,10

The Rationale for Covered Stents

The GORE VIABAHN® Endoprostheses (WL Gore & Associates, Inc., Flagstaff, AZ) gained US Food and Drug Administration (FDA) indication for the treatment of atherosclerotic disease of the SFA. The ePTFE lining of the VIABAHN endoprosthesis inhibits the ingrowth of intimal hyperplasia. Thus, patency is independent of lesion length and, if the device fails, it is usually at the ends (i.e. edge stenosis). However, experience gained with the VIABAHN device suggests that avoidance of any balloon dilatation outside the endoprosthesis edges and extending the device to relatively disease-free areas of the vessel will help to minimise this effect. The device’s unique construction also imparts favourable mechanical properties well-suited for the SFA (see Figure 1).

A recent study demonstrated that long-term stent-graft patency and clinical success can be achieved in the femoropopliteal artery (FPA) with the VIABAHN endoprosthesis. Patients were followed up for a maximum of 8.5 years after stent-graft placement and no stent fractures were observed despite the use of multiple overlapping stent-grafts in 36.8% of limbs. The data showed durable vessel patency to four years for long TASC C and D lesions treated with the VIABAHN stent graft. One-year primary patency was 76%, with patency of 55% at four years. Results were independent of lesion length and type but dependent on device diameter.11

Another recent study randomised the VIABAHN endoprosthesis versus surgical bypass for AK femoropopliteal lesions. Fifty patients were enrolled in each arm with an average lesion length of 26cm in the VIABAHN stent graft arm. At one year, patencies for the VIABAHN stent graft and surgical bypass were equal at 74%.12

In a study on 32 patients, Hartung et al. found that treating SFA occlusive lesions – with the exception of TASC D lesions – with a VIABAHN stent graft produced satisfactory results for patients with critical or acute ischaemia with bad outflow if concomitant improving procedures were performed.13 This report was expanded by Alimi et al., who conducted a retrospective study to include a larger series of patients.14 From 2000 to 2005, a VIABAHN stent graft was implanted in 102 limbs (95 patients; mean age: 72.1 years, range: 52–94 years) for intermittent claudication (group I, n=50 limbs), critical (group II, n=32) or acute ischaemia (group III, n=20). Lesions treated were TASC A (n=9), B (n=42), C (n=28) or D (n=23), associated with a good (two or three leg arteries, n=60) or a poor (one or no arteries, n=42) runoff. Although the endograft was placed successfully in all cases, three early deaths (3.2%: one in group II and two in group III) and four acute thromboses (4%) occurred. Primary and secondary actuarial patency rates were 97±1.7 and 99±1%, respectively, at one month, 74±4.8 and 84±4.1%, respectively, at one year and 71±9.5 and 79±8.5%, respectively, at three years after a mean follow-up of 30.2 months (range one to 60 months). Long-term primary and secondary patencies were significantly different between TASC C and TASC D lesions. The authors concluded that severity of lesions, rather than pre-operative symptoms or runoff, should mainly be considered before using the VIABAHN endoprosthesis in severe SFA occlusive lesions.

Before using an ePTFE-covered device, good categorisation of the SFA is essential. It is better if the patient has a small part of the proximal SFA patent, which enables a catheter to be inserted into the stump of the SFA correctly. If the SFA is occluded from the beginning, it is not always possible to find a way to re-open the SFA. Accordingly, a centimetre opening at the entry of the artery is essential. Furthermore, having a good popliteal artery in which to land the covered stent is advantageous.

Heparin-bonded Covered Stenting

The most recent development in stent technology is the heparin-bonded covered stent. The GORE VIABAHN endoprosthesis with heparin bioactive surface was recently approved in the US for endovascular intervention of the SFA. The device incorporates Carmeda BioActive Surface (CBAS) technology to bond heparin.15–18 The technology is based on the covalent end-point attachment of heparin to a biomaterial surface, enabling functional heparin bioactivity to be maintained. The end-point attachment mechanism enables the heparin-active site to freely bind antithrombin III. Such CBAS immobilisation has been shown to reduce platelet deposition, decrease inflammatory responses19 and decrease thrombogenicity20 (see Figure 2).

Attaching heparin to implantable medical devices has been attempted before. Heparin coating of extracorporeal circuits21,22 and endovascular stents16 has been successful and is well established, leading to improved patient outcomes. In order to maximise the efficacy at a heparinised prosthetic graft surface, two criteria must be met: long-term drug retention and unimpaired heparin anticoagulant activity.23 Several methodologies have been described and used over the years, but the CBAS technology – which uses covalent end-point linkage to retain heparin on the surface of the device or vascular prosthesis – has been the most commonly used and most effective (see Figure 3).

The PROPATEN Vascular Graft (WL Gore & Associates, Inc.) has been commercially available in the EU since 2002. The graft was used to treat patients requiring a prosthetic femoropopliteal or femorocrural bypass in a multicentre, prospective, non-randomised clinical study.24

All patients had disease limited to the infra-inguinal vasculature. In all, 153 infra-inguinal bypass procedures were performed: 75 (49%) AK and 78 (51%) BK. Thirty-seven (24%) of the BK bypasses had a crural (infra-popliteal) anastomosis. Kaplan-Meier estimates of post-bypass survival at 30 days and one and two years were 97.3, 86.4 and 80.9%, respectively. The overall two-year primary and secondary patency rates were also calculated using the Kaplan-Meier methodology and were 73.6 and 86%, respectively.25 Bypass type did not seem to influence outcome: two-year primary patencies were 76.2% for AK bypasses, 72.6% for BK bypasses and 68.9% for crural bypasses. The corresponding secondary patency rates were 87.5, 87.8 and 79.4%, respectively. Indication for recanalisation (claudication versus CLI) did not have an influence either, but there was a significant difference in patency when comparing good-runoff (two to three patent outflow arteries) with poor-runoff (no to one patent outflow arteries) patients. The primary two-year bypass patency was 86.2% in good-runoff patients and 62% for poor-runoff patients (p=0.0027). There were no differences between these two subgroups in terms of secondary patency (91.5 and 80.8%, respectively). No cases of heparin-induced thrombocytopoenia (HIT) were reported in this study.

Walluscheck et al. in their retrospective study collected the first clinical data for the ePTFE graft with bioactive surface heparin immobilisation.26 Between March 2003 and February 2004, 43 femoropopliteal or femorocrural ePTFE vascular prostheses with bioactive end-point immobilised heparin (Gore Propaten Vascular Graft), using the CBAS technology, were implanted in 40 patients. Twelve prostheses were implanted in AK and 31 in BK positions. The indication for bypass grafting was limb-threatening ischaemia in 88% of the patients. The mean follow-up was 16.6 months. The primary one-year patency was 91% for AK grafts and 92% for BK bypass grafts. The two-year primary patency rate for AK bypass grafts was 68%, and 81% for BK bypass grafts. Limb salvage was achieved in 98%. The peri-operative mortality rate was 0%, but during follow-up 22% of the patients died with patent bypass grafts.

The bioactive heparinised ePTFE graft evaluated in this study provided patency rates comparable to those achieved with autologous vein grafts. The authors suggest that, as luminal heparin bonding not only prevents thromboresistance but also has an impact on protein adsorption, thereby improving hem compatibility, a continuous effect on long-term patency could also be expected.

These are interesting data and, if the technology translates to the covered stent, it could be an important evolution in stent technology. The VIPER trial, a prospective, single-arm, multicentre study, is currently enrolling patients and aims to collect important performance data on the heparinised VIABAHN endoprosthesis in the SFA.


The drive to achieve long-term patency rates associated with stenting comparable to those seen with surgical intervention has led to the continuing evolution of materials and techniques, all aimed at preventing restenosis after interventions in the SFA. Studies with covered stents have produced data on patency rates that are moving towards being comparable to those for surgical procedures, especially in less extensive disease and in the treatment of long-segment disease of the SFA. The ongoing VIBRANT clinical trial is comparing the efficacy of the VIABAHN endoprosthesis with bare nitinol stents in patients undergoing SFA intervention and will provide further important data on the role of the covered stent in treating occlusive SFA disease. Heparin-coated covered stents are a very interesting addition to the field. As clinical data emerge and more experience is gained with the device, important questions will hopefully be answered, such as whether it will be necessary to modify pre-operative and post-operative treatment, and will also help to elucidate the role of heparin-coated covered stents in the treatment of SFA occlusive disease.


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