Coronary angioplasty has revolutionized the treatment of coronary artery disease. Over the past two decades the field has seen numerous innovations in an attempt to perfect the percutaneous management of coronary atherosclerotic disease. The development of coronary stenting was a major advance in preventing elastic recoil and treating dissections following balloon angioplasty.1 Unfortunately, bare-metal stents have been associated with relatively high rates of restenosis requiring additional procedures for target vessel revascularization. This led to the development of the drug-eluting stent, a coronary stent system composed of a drug-eluting polymer layer and an antiproliferative drug to prevent restenosis. The use of drug-eluting stents resulted in a dramatic lowering of restenosis and rates of revascularization, leading to widespread uptake of this technology.2 However, stent thrombosis, both sub-acute and late, remains an issue with drug-eluting stents and necessitates prolonged antiplatelet therapy.
The recent concerns of late stent thrombosis have rekindled an interest in designing a better coronary stent. An ideal stent would have the ability to seal intimal dissections occurring during the procedure and possess sufficient radial force to prevent elastic recoil of the vessel. In addition, it would have the ability to deliver pharmacological agents to prevent restenosis in the first six months following the procedure. Metallic stents are able to fill this role, but at a price. They are thrombogenic and necessitate the use of antiplatelet medication in the short term—and now perhaps in the long term, given the concerns of late thrombosis with drug-eluting stents. Their use has consequences for the normal architecture of the coronary tree as there is often a mismatch between the vessel size and stent due to positive remodeling of the vessel. In addition, stenting can result in jailing of important side branches, as well as presenting an obstacle to future coronary artery bypass graft surgery. In the era of improved non-invasive imaging with computed tomography (CT) and magnetic resonance imaging (MRI) for coronary disease, stents result in vessel artifacts that make coronary assessment very challenging.
The pitfalls of currently available coronary stents have recently brought research into bioabsorbable stents to the forefront in the hope that they might provide all of the features of a metallic stent but disappear from the artery once their job is done, obviating the need for long-term antiplatelet therapy. An ideal bioabsorbable stent would need to have adequate radial force to prevent early elastic recoil and maintain its scaffolding strength for six months to overcome late vessel remodeling and restenosis. In addition, the stent material must be biocompatible so as to prevent vessel irritation, endothelial dysfunction, and chronic vessel inflammation caused by polymers of drug-eluting stents. Such material would ideally result in minimal artifacts to allow for non-invasive imaging modalities such as CT or MRI.
Current bioabsorbable stent programs have focused on either a polymeric stent or a magnesium stent. The polymeric stents are composed of poly-L lactic acid (PLLA), which holds 1,000mmHg of crush pressure and maintains radial strength for approximately one month. Compared with metallic stents, this radial strength is lower and may result in early recoil post-implantation. The bioabsorption rate is relatively slow and may still result in restenosis. Additionally, the stents are radiolucent, which may impair accurate positioning using fluoroscopic guidance. The magnesium stents have potential advantages in terms of higher radial strength due to their metallic nature and biocompatibility as a naturally occurring element in the body. Currently, there are no commercially available bioabsorbable stents; however, various programs are in trial phases with non-randomized results available for review.
The Igaki-Tamai® stent is a coil stent made of PLLA monofilament (molecular mass 183kDa) with a zigzag helical design and a strut thickness of 0.17mm (0.007 inches). The stent has two radio-opaque gold markers to facilitate the identification of both ends of the prosthesis, and delivery balloon inflation is performed with a heated dye at 80°C (almost 50°C at the stent site, as estimated by in vitro experiments) using a 30-second inflation at 6–14atm. This temperature ensures adequate stent expansion within 30 seconds and may minimize vessel injury caused by use of a heated balloon. Once deployed, the stent continues to expand gradually to its original size. When implanted in a vessel smaller than the stent diameter, the residual radial force in the prosthesis will tend to dilate the artery until equilibrium is reached between the elastic resistance of the arterial wall and the dilating force of the PLLA stent.3
A feasibility study utilizing this stent was published in 2000 and enrolled 15 patients having elective angioplasty with the Igaki-Tamai stent. Coronary angiography and intravascular ultrasound (IVUS) were performed before and immediately, one day, and three and six months after the procedure. The procedure was considered successful if residual stenosis was ≤50% and thrombolysis in myocardial infarction (TIMI) grade 3 flow was achieved. Angiographic restenosis was defined as a follow-up diameter stenosis ≤50% by quantitative coronary angiography (QCA).
The percent diameter stenosis decreased from 64% before stenting to 12% after stenting. The mean lumen diameter (MLD) increased from 1.02mm before stenting to 2.59mm afterwards. The percentage of acute stent recoil (defined as maximal inflated balloon diameter minus final MLD divided by maximal inflated balloon diameter x 100) was 22±7% by quantitative coronary angiography (QCA). At one day post-procedure there was no difference in elastic recoil demonstrated on angiography or using IVUS. There were no major cardiac events at 30 days. The three-month target lesion revascularization rate per lesion was 5.3% (one of 19 patients), and the per-patient rate was 6.7% (one of 15 patients). At six months, both the angiographic restenosis rate and the target lesion revascularization rate per lesion were 10.5% (two of 19 patients), and the rates per patient were 6.7%. IVUS continued to show the presence of stent struts at six months.
REVA Bioabsorbable stent
The REVA bioresorbable stent is a polymer stent composed of a tyrosine-derived polycarbonate that also acts as a drug-delivery matrix. This polymer is inherently radio-opaque due to the inclusion of iodine atoms to the polymer, and is therefore visible by fluoroscopy. The stent has a slide-and-lock design, which means its expansion is based on sliding and locking parts rather than material deformation. The stent possesses high radial strength and negligible recoil with standard balloon deployment. Clinical trials are currently under way to evaluate this stent in humans. The REVA Endovascular Study of a Bioresorbable Coronary Stent (RESORB) study was initiated in 2007 and will enrol up to 30 patients at multiple sites in Germany and Brazil. It is a non-randomized study with an initial assessment of major adverse cardiac events (MACE) at 30 days and a follow-up period of five years.4
The BVS everolimus-eluting stent that was originally developed by Guidant is composed of three main components: a poly lactic acid (PLA) backbone, a polymer coating of poly-D,L-lactide, and everolimus, an antiproliferative and anti-inflammatory drug loaded on the polymer. Both the stent and the polymer are bioabsorbable and degrade in response to lactic acid, which is metabolized by the body. The BVS stent consists of hoops of PLLA with a strut thickness of 150μm linked together with bridging segments, and has a crossing profile of 1.4mm. The stent has two radio-opaque metal markers at each end to aid with positioning. The polymer coating of the stent controls the release of everolimus, an immunosuppressant drug, that is also used in the cobalt chromium XIENCE V stent. The majority of the drug is eluted from the polymer within the first 28 days. The stent is bioabsorbed in approximately 18 months and no drug is left behind once the stent has completely degraded. In order to maintain polymer stability, the stent must be stored at a minimum of -20°C.5 The feasibility and safety of this stent were examined in humans in the ABSORB trial. This was a single-arm, prospective, open-label study that enrolled 30 patients from four international centers: Auckland, Rotterdam, Krakow, and Skejby. Patients were eligible if they were above 18 years of age and had a diagnosis of stable, unstable, or silent ischemia. They were required to have a de novo lesion that was between 8 and 14mm in length with a reference vessel diameter of 3.0mm. Exclusion criteria included acute myocardial infarction, poor ventricular function, restenotic lesions, left main coronary artery disease, bifurcation lesions, or visible thrombus in the target vessel.
The composite end-point of the study was cardiac death, myocardial infarction, and ischemia-driven target lesion revascularization. Angiographic end-points, intravascular ultrasound, and derived morphology parameters were assessed at six months and were planned for two years following the initial procedure. Procedural success was achieved in all patients. After one-year of follow-up there was one non-Q-wave infarction and no stent thrombosis. There was no target lesion revascularization at 12 months. Quantitative coronary angiography revealed an in-segment late loss of 0.44mm and asymptomatic binary stenosis in three patients. Intravascular ultrasound analysis showed a significant reduction in stent area as a result of neointimal hyperplasia and possibly due to acute stent recoil or loss of radial support secondary to partial stent absorption.
A subset of patients also underwent optical coherence tomography (OCT) at six months to establish the degradation patterns of the stent, as well as to evaluate strut apposition. At baseline, 5% of stent struts were not apposed to the vessel wall, a finding that was persistent at follow-up and noted to be at the site of side branch take-off. In addition, at follow-up 1% of struts demonstrated late-acquired malapposition.
The issues of reduced stent area and strut malapposition are concerning and represent challenges with a polymeric stent that may lack sufficient radial force initially, and that further decreases with bioabsorption, resulting in recoil of the stent and malapposition at follow-up. Recent two-year follow-up data on the ABSORB cohort were presented by Patrick Serruys at the Transcatheter Therapeutics (TCT) meeting 2008 in Washington. Results showed that at two years there was one ischemia-driven MACE, no cardiac deaths, no stent thrombosis, and no ischemia-driven TLR. Follow-up IVUS was also performed in 28 of the 30 patients with measurements of the vessel, lumen, plaque, and minimal lumen area. Comparisons were made between results immediately following PCI and at six months and two years. Six months after PCI, there was some loss of lumen area and increase in plaque area felt to be secondary to neointimal hyperplasia. At two years, minimal lumen area had increased and plaque area had decreased to levels similar to post-PCI.6
Overall, decreases in vessel area (-3.31%) and increases in plaque area (4.73%) at two years were not statistically significant, while the two-year decrease in lumen area (-9.66%) showed a strong trend compared with post-PCI measurements (p=0.07), and the decrease in minimal lumen area (-12.78%) was statistically significant (p=0.03). In addition, CT evaluation of the remaining stent struts revealed that more than one-third of strut sites had no remaining discernible features.6
Bioabsorbable Metallic Stents
A metallic bioabsorbable stent would be ideal because of high radial strength similar to stainless steel. Magnesium is a good choice for a bioabsorbable stents because of its biocompatibility and biocorrosion properties. In addition, magnesium is not visible by X-ray and as a result does not cause imaging artifacts with CT or MRI. Initial work using magnesium for the construction of coronary stents was carried out by Heublein. In vitro and in vivo studies of the magnesium alloy stent demonstrated that the overall integrity of the stent was preserved at 28 days, but high rates of degradation were evident from 60 to 90 days. Further animal work in porcine coronary arteries demonstrated complete absorption of the stent in 56 days with no evidence of thromboembolic events.7
The first use of magnesium stents in humans was for critical limb ischemia in patients with severe peripheral vascular disease. Twenty patients with severe infrapopliteal stenosis underwent angioplasty and implantation with an absorbable magnesium stent on a compassionate basis. Angiographic success was achieved in all patients, and at three-month follow-up clinical patency was 89.5%.8
The first trial of a magnesium coronary stent was designed to assess the efficacy and safety of this stent in humans. The Clinical Performance and angiographic Results of Coronary Stenting with Absorbable Metal Stents (PROGRESS-AMS) trial used the Lekton Magic bioabsorbable coronary stent (Biotronik, Bulach, Switzerland), which is constructed from a magnesium alloy (WE43) also containing zirconium (<5%), yttrium (<5%), and rare earths (<5%). The stent is sculpted by laser from a single tube of an absorbable magnesium alloy (WE43). The stent design is characterized by circumferential noose-shaped elements connected by unbowed cross-links along its longitudinal axis. The stents is reported to have a high collapse pressure (0.8 bar), low elastic recoil (less than 8%), and minimum amount of shortening after inflation (less than 5%).
The PROGRESS-AMS trial was a non-randomized, consecutive, multicenter feasibility trial. The primary end-point was cardiac death, non-fatal myocardial infarction, or clinically driven target lesion revascularization at four months. Secondary end-points included major adverse cardiac events at six and 12 months and target lesion or target vessel revascularization at four, six, and 12 months. All patients achieved device and procedural success. The study stents could be deployed in the target lesion and achieved a residual diameter stenosis of 12.6%. During the first four months, major adverse cardiac events were recorded in 15 (24%) of 63 patients (95% confidence interval [CI] 14–36%). All major adverse cardiac events were clinically driven target lesion revascularization. Elastic recoil was equal to 7% (15%) and in-segment diameter stenosis after four months was 49% (16%). Serial intra-coronary ultrasound examinations demonstrated only small remnants of the original stent well-embedded in the intima. The ischemia-driven target lesion revascularization rate was 23.8% after four months, and the overall target lesion revascularization rate was 45% after one year.9
Although the study was able to establish both safety and efficacy, the high rates of restenosis and target vessel revascularization were concerning. The results were in fact similar to those seen previously with balloon angioplasty alone. Intra-coronary ultrasound results indicated that the late lumen loss was a combination of neointimal proliferation and elastic recoil of the vessel.
Initial work with bioabsorbable stents has established their feasibility and revealed the further challenges that lie ahead. Both the PLLA and magnesium stent have yet to resolve issues of a bioabsorbable stent with sufficient radial force to prevent acute vessel recoil. Additionally, the high rates of restenosis and target vessel revascularization in patients treated with the magnesium stent suggest that neointimal proliferation is also a major obstacle with this stent. Positive results with the drug-eluting BVS PLLA stent demonstrate low rates of restenosis, but OCT examination highlighted another potential problem of malapposed stent struts. Although this did not translate into clinical events in the ABSORB trial, the low number of patients and limited follow-up suggest that this story may be far from over. The journey toward the ideal bioabsorbable stent continues, fuelled by encouraging results; however, for the moment bioabsorbable stents are far from their goal of replacing bare-metal or drug-eluting stents.