Biodegradable Stents - A New Era?

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Citation
European Cardiology - Volume 4 Issue 2;2008:4(2):82-84
DOI
http://dx.doi.org/10.15420/ecr.2008.4.2.82

Percutaneous coronary intervention (PCI) deploying metallic stents is now a standard and routine procedure for the treatment of flow-limiting coronary stenosis in patients with ischaemic heart disease and is an alternative to surgery. Stents were invented to overcome limitations of balloon angioplasty coronary dissections, acute and subacute elastic recoil, intimal hyperplasia and negative vessel remodelling. However, the long-term results of bare-metal stents are affected by in-stent restenosis, which can occur in up to 30% of cases, and stent thrombosis, which can be life-threatening. Although neointimal hyperplasia has certainly been delayed with antiproliferative drug-eluting stents (DES), healthy endothelium eventually grows to cover the struts, resulting in stent thrombosis in 0.5–1.5% cases, despite dual antiplatelet agents.1,2 The need for permanent coronary scaffolding and a drug-eluting implant is not justified beyond the first six to 12 months when the process of intimal hyperplasia and acute on chronic recoil is completed. Other drawbacks of the persistence of metallic stents include interference with the ability of non-invasive techniques such as multislice computed tomography or magnetic resonance imaging (MRI) to assess the in-stent patency, occlusion or impaired access to ostia of side branches, impairment of physiological vessel tone reactivity and inability to use the stented segment to anastomose grafts during bypass surgery. To circumvent these issues, biodegradable or absorbable stents have been devised. With time, these are intended to degrade within the coronary artery, akin to dissolving sutures, while providing the vessel with temporary scaffolding until endothelialisation has established. We review these innovative devices and their impact on the future of coronary intervention.

Design and Composition

Biodegradable stents were developed in the 1990s. The main principle in the manufacture of the stent is the provision of polymeric or metallic or combination scaffolding, possibly coated with an antiproliferative drug or gene, all of which degrade in time to restore vessel patency and permit remodelling while maintaining recoil. These stents can be ideal in complex ectatic and anatomically challenged vessels, which once degraded would lend themselves well to non-invasive imaging modalities where a metallic presence is a hindrance. Polymer stents have been used both for scaffolding and as a vehicle for drug delivery and are more flexible than metals. Various polymeric materials have been widely studied: poly-L-lactic acid (PLLA), polyglycolic acid (PGA), poly(D,L-lactide/glycolide) copolymer (PDLA) and polycaprolactone (PCL).

During bioabsorption, these long chains are hydrolysed, phagocytosed and degraded to lactic acid, carbon dioxide and water and eliminated via the Kreb’s cycle. However, degradation times for polymeric stents tend to vary and range from six months to over 24 months.3 Magnesium alloy is commonly used in the construction of biodegradable stents. Histology and spectroscopy in animal studies showed that biocorrosion of the alloy occurs within 56 days of implantation and is replaced by calcium with neointimal hyperplasia that is less pronounced than after conventional bare-metal stenting.4,5

Polymer Stents
The Igaki-Tamai Stent

This is a self-expanding and springy stent made of a high-molecular-weight polymer PLLA monopolymer with a strut thickness of 170μm and a zigzag helical coil design with two radio-opaque markers at either end (see Figure 1). It is 12mm long, is mounted on standard angioplasty balloon catheters and can self-expand in 20 minutes at 37°C. The stent continues to expand gradually to its original size after deployment in vivo or, if the vessel is smaller in diameter, until equilibrium is attained between the circumferential elastic resistance of the arterial wall and the dilating force of the PLLA stent. In the late 1990s, Tamai et al., in their preliminary experience in 15 patients (25 stents), reported a low angiographic restenosis rate of 10.5% with no major adverse cardiac events (MACEs) at six months.6 Thereafter, in their four-year follow-up of 63 lesions in 50 patients, 26 patients were followed up with angiography and intravascular ultrasound (IVUS) at 36 months. Target vessel revascularisation (TVR) was performed in nine patients (18%), with MACE-free survival of 82% at 48 months. The IVUS studies confirmed complete absorption of the stents.7 This appeared promising, but with the advent of DES, high-pressure stent deployment and strong antiplatelet agents with reduced restenosis rates, the results of the study were soon overshadowed.

The REVA Stent

This degradable stent, launched by REVA Medical, is a tyrosine-derived polycarbonate polymer and is composed of elements that slide open and then lock into place, preventing deformation as it expands; it claims to virtually eliminate recoil (see Figure 2). It is radio-opaque by inclusion of iodine atoms to the polymer, has high radial strength and uses standard balloons for deployment. These stents have been deployed successfully in femoral and porcine coronary arteries. Histological evaluation of porcine-stented arteries at 28 days revealed a normal healing response, with a normal foreign body reaction at the tissue–material interface and no acute or chronic inflammation. The rate of resorption can be modified for different needs (coronaries, vulnerable plaques, diabetic lesions and drug delivery). In 2007 REVA Medical commenced the REVA Endovascular Study Of a Bioresorbable coronary stent (RESORB) non-randomised trial, aiming to enrol 30 patients at multiple sites in Germany and Brazil in assessment of MACEs at 30 days and a follow-up period of five years. A second trial is planned to study the safety of a bare (non-coated) and paclitaxel-coated bioresorbable stent in an additional 30 patients.

The Everolimus-eluting Stent

The bioabsorbable everolimus-eluting stent or BVS (Bioabsorbable Vascular Solutions, Abbott Vascular, CA, US) is made up of a combination of two polymers (PLLA semicrystalline polymer coated with poly-D,L-lactide [PDLLA]), both of which are fully bioabsorbable within approximately 18 months. The stent has a crossing profile of 1.4mm, with struts 150μm thick either directly joined or linked by straight bridges (see Figure 3). Both ends of the stent have two adjacent radio-opaque metal markers to assist deployment. The stent has to be maintained at a minimum of -20°C to ensure device stability. Everolimus is an antiproliferative immunosuppressant and achieves 80% of its elution from the polymer within 28 days after implantation, and it completes this process by 120 days with concentrations comparable with those reported with permanent cobalt–chromium implants using everolimus (Xience, Abbott Vascular, Santa Clara, CA, US), which recently obtained US Food and Drug Administration (FDA) approval for clinical use. However, the struts of this polymer stent are much thicker than the struts of the corresponding metallic stents (150 versus 400μm).

In the multicentre, open-label, non-randomised, single-arm Absorb study, Ormiston et al.8 enrolled 30 patients with one de novo short (8mm) coronary artery lesion and treated them with the BVS stent to assess its safety and feasibility. MACEs and stent thrombosis were assessed angiographically with IVUS or optical coherence tomography (OCT) at six and 12 months. At one year, the MACE rate was 3.3%, and no late stent thromboses were recorded. Angiographically, in-stent late loss was 0.44mm and was due mainly to a mild reduction of the stent area (-11.8%) by IVUS. Intimal hyperplasia was non-significant. The presence of a thin layer of intimal coverage on almost all of the struts, as seen on the OCT, was reassuring, but 7% of 671 struts in 13 stents investigated showed malapposition at follow-up. Late-acquired malapposition was also noted in seven of the 25 patients by IVUS, with a reduction in the stent area showing the presence of chronic stent recoil, a phenomenon that is well known with balloon angioplasty or directional atherectomy.9 Acute recoil of the polymer by quantitative coronary angiography was studied by Tanimoto et al.10 in 27 selected patients from Absorb’s study cases with single-vessel coronary artery disease after stent deployment, who were assessed and compared with an equal number of patients using the metallic everolimus-eluting cobalt–chromium stent in the SPITIT I and II trials. There was no significant difference in acute absolute recoil in both groups (0.20 versus 0.13mm), implying that BVS stents have good radial strength compared with their metallic counterparts. A substudy with OCT, performed at mean follow-up of 180 days in 13 stents, documented the presence of a thin layer of intimal coverage on almost all the struts, with 7% of the 671 struts investigated showing malapposition. OCT detected incomplete strut absorption at follow-up, with 3% of struts appearing morphologically unchanged and 30% still present but with an ‘open-box’ appearance, suggesting advanced biodegradation.

Metallic Stents
Magnesium Stents

This stent is a tubular, slotted, balloon-expandable bare-metal stent sculpted by laser from a tube of a biodegradable magnesium alloy and rare earth elements with two radio-opaque markers at either end, as the metal itself is not visible on fluoroscopy.4 It has low elastic recoil (<8%), like stainless steel stents, with minimum shortening after inflation (<5%). The cells are large, with an open mesh design ideal for side-branch access (see Figure 4).

Degradation rates range from 60 to 90 days, with overall integrity remaining at 28 days. The first-in-man application with an absorbable metallic stent was reported by Peeters et al.,11 who enrolled 20 patients with symptomatic critical limb ischaemia undergoing angioplasty at two clinical centres for high-grade (80–100%) atherosclerotic lesions in the proximal infrapopliteal arteries. Procedural success appeared to be excellent, with almost 90% primary patency rate at three-month follow-up.
The clinical PeRformance and angiOGraphic RESults of coronary Stenting with Absorbable Metal Stents (PROGRESS-AMS) trial studied Biotronik’s magnesium stent in 63 patients with a de novo lesion in a single coronary artery with a reference diameter between 3.0 and 3.5mm and a lesion length of 13mm or less.5 The primary end-point – cardiac death, non-fatal myocardial infarction or clinically driven target lesion revascularisation (TLR) rate at four months – occurred in 15 patients (24%). All adverse events were due to TLR, with no deaths or myocardial infarctions. There was one TVR, no acute stent thrombosis and no stent thrombosis at one- year follow-up. Overall, TLR occurred in 27 of 60 patients (45%) and elastic recoil was 7% (standard deviation [SD] 15%) at one year. IVUS was performed in 52 of 63 patients and showed that mechanisms for late loss were the decrease in external elastic membrane volume (42%, -18.9 [SD 45.41mm3]), increase in volume outside the originally encircled stent (13%, -6.06 [SD 23.23]) and neointimal formation (45% of the entire late lumen loss, -20.38mm3 [SD 14.40 mm3]), with no substantial changes in the original plaque volume. IVUS was also a useful tool for the assessment of strut absorption, as echo reflectivity of the stent struts was substantially diminished at follow-up, although their original position could be identified as small circular areas with higher echo reflection than the surrounding tissue but without shadowing. OCT also showed its ability to identify areas of the vessel wall previously occupied by stent struts that underwent total absorption as signal-rich areas. Although only small remnants of struts were visible on serial IVUS, neointimal growth, negative remodelling and chronic recoil accounted for the high restenosis rate. It is likely that the fast degradation of the stent itself had an impact on the results. Modification of the alloy and stent design to prolong degradation, along with antiproliferative drug coating, will be studied in the next generation of these metallic stents.

Combination Stents
Tacrolimus-eluting Cobalt–Chromium Polymer Stent

More recently, a new tacrolimus-eluting stent, Mahoroba™, has been developed (Kaneka Corporation), combining a thin, flexible cobalt– chromium alloy coated with a PDLA polymer incorporating tacrolimus. The balloon-expandable struts are 75μm thick and available in 3x18mm and 3.5x18mm sizes, with the polymer on the abluminal side composed of tacrolimus 0.94μg/mm2 and degradation of the matrix in nine months. The stent consists of two helical coils inter-crossed with two phase-different links on each turn, in which each link deviates diagonally along the longitudinal axis.12 In a porcine model, this stent demonstrated early endothelialisation and reduction of neointimal thickening up to 90 days after implantation.13 Following on from these encouraging results, Serruys et al. are expected to publish their results soon on the four-month angiographic and six-month clinical follow-up in the first-in-man study.

Discussion

The impetus for biodegradable stent use has been the clinical need to maintain vessel patency during the first six to nine months when the vessel is healing, limiting acute and subacute stent thrombosis and preventing recoil. Mechanical properties such as radial force, recoil and the rate and time of degradation have influenced the varied results seen from the initial work. Biological issues such as rate of inflammation and impact of the drug on vessel remodelling have also played a crucial role. It has been suggested that a prolonged degradation time is beneficial to preventing late recoil and vascular remodelling. Although mechanical resistance is desirable, this does not translate into the expected disappearance of the stent a few months from deployment. Chronic recoil is the main mechanism of late lumen loss after balloon angioplasty, accounting for 67–73% reduction of the lumen area at six months.14,15 Struts of the Igaki-Tamai and BVS stents were still visible on IVUS or OCT after six months of implantation, unlike the magnesium stent, which showed only remnants at six-month follow-up. However, if biodegradation requires two to three years, the advantage over conventional DES appears to be unrealistic, except perhaps for the physical absence of the metallic scaffold. For a biodegradable stent, prolonged exposure to a potent antiproliferative drug can be counterproductive, as degradation will then occur when struts are already deeply embedded in the vessel wall.

We still await long-term data (three to four years) to assess the persistent risk of late thrombosis. The absence of late stent thrombosis at four years in the 50 patients (63 lesions) who received the Igaki-Tamai stent is encouraging,7 but these stents promoted a thick rim of intimal thickening, separating the strut protrusion or malapposition seen in the Absorb trial.8 Again, the risk of bulky stent particles embolising distally has not been addressed, and the possible use of late gadolinium-enhanced cardiac MRI would better delineate these events.
It has been suggested that the pro-inflammatory component of the DES has been the polymer rather than the drug itself. PLA polymeric materials have long been used as implants in various orthopaedic surgeries. Local inflammatory and osteolytic foreign-body reactions to the bioabsorbable PGA implants that have a long degradable time (four years) have been well documented in the literature,16,17 possibly related to adverse immunological complement-activating potential,17 but this issue is controversial.18 The Igaki-Tamai clinical programme and the Absorb and PROGRESS-AMS studies have shown the feasibility of implanting such stents and document the absence of stent thrombosis. However, the latter result should be interpreted with caution, as the sample sizes make the studies underpowered for a rare event such as stent thrombosis. In addition, when considering efficacy, in the Igaki-Tamai and PROGRESS-AMS studies the incidence of TLR at one-year follow-up was high, comparable with or higher than that reported with modern bare-metal stents and much higher than DES (6%), which can limit their clinical use.

Conclusion

The challenge with biodegradable stents is the persistent mechanical resistance withstanding acute and chronic recoil and the ability to modulate hyperplasia in the first months of stent implantation while maintaining rapid degradation thereafter. Modified devices with prolonged degradation beyond two to three years tend to lose their advantage over conventional DES. Achieving the right balance between the polymer, drug and degradation will ultimately maintain vessel patency and prevent potentially life-threatening late stent thrombosis. To this end, further continuous research and investment is imperative.

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