Biodegradable polymeric coatings facilitate drug delivery to the vessel wall and are then resorbed without any long-term sequelae. Since their introduction in the year 2004,18 many DES with biodegradable polymers have been developed, particularly after it was hypothesized that this technology would potentially reduce the risk of very late ST (VLST), an adverse event which has been associated with durable-polymer DES. The randomized ISAR-TEST 4 trial was conducted to test the noninferiority of a biodegradable-polymer rapamycin-eluting stent (RES; Yukon Choice PC, Translumina; Hechingen, Germany) to a durable-polymer DES (ie, the first generation Cypher sirolimus-eluting stent [SES] or the second generation Xience V everolimus-eluting stent [EES]), with respect to clinical outcomes. A total of 2603 patients were enrolled in the trial. At 3-year follow-up, there were no significant differences in a composite of cardiac death, target-vessel myocardial infarction (MI), and target lesion revascularization (TLR) (RES 20.1% vs DES 20.9%, P=.59), as well as the incidence of definite/probable ST (RES 1.4% vs DES 1.9%, P=.51).19 Longer-term clinical follow-up is required to evaluate the potential superiority of RES over the traditional DES in reducing the risk of VLST.

The next major step forward may be metallic stent structures which allow for appropriate drug-elution kinetics without the use of polymers. Several devices have been designed to test this approach by incorporating drugs into a microporous or nanoporous surface of the stent (Table 2). The efficacy of a polymer-free SES (SES-PF; Yukon Choice, Translumina) was investigated in the ISAR-TEST 3 trial.25,26 The SES-PF (201 patients) was compared to a SES with a biodegradable polymer (202 patients, SES-BP; Yukon Coice PC, Translumina) and a SES with a permanent polymer (202 patients, SES-PP; Cypher, Cordis; Miami Lakes, Florida, United States). At 2 years, there were no significant differences in death, MI (SES-PF 6.5%, SES-BP 5.9%, and SES-PP 6.4%), TLR (SES-PF 13.4%, SES-BP 8.4%, and SES-PP 10.4%), and definite/probable ST (SES-PF 1.0%, SES-BP 0.5%, and SES-PP 1.0%). Patients undergoing paired angiography at 6 months to 8 months and at 2 years (302 patients), demonstrated a lower delayed LLL in the SES-PF (-0.01 mm) group. as compared to both the SES-BP (0.17mm) and the SES-PP (0.16 mm) (P<.001) groups. The absence of delayed LLL in the SES-PF group may indicate a lower propensity for stent-vessel wall interactions, owing to less inflammatory or hypersensitive reactions. Recently, the 5-year clinical outcomes in the ISAR-TEST trial have been reported.27 There were no statistically significant differences in ST events between SES-PF and the first generation TAXUS paclitaxel-eluting stent (PES) (SES-PF 0.5% vs PES 1.6%, P=.32). Extended follow-up data may further support the durability, safety, and efficacy of the SES-PF.

BioFreedom Stent

The BioFreedom stent (Biosensors Inc.). is a 316L stainless steel, polymer-free stent that is coated with biolimus A9 (Fig. 1). Preclinical studies have reported lower injury scores; lower numbers of struts with fibrin, granulomas, and giant cells; significantly lower percentage of diameter stenosis; and greater endothelialization with the BioFreedom stent at 180-day follow-up as compared to the Cypher SES.28 The first-in-man (FIM) trial enrolled 182 patients who were randomized to receive either BioFreedom with SD sirolimus (15.6µg/mm), BioFreedom with low dose (LD) sirolimus (7.8µg/mm), or TAXUS Liberté PES. At 12 months, the in-stent LLL was 0.17mm in the BioFreedom SD arm (P<.0001 vs PES), 0.22mm in the BioFreedom LD arm (P=.21 vs PES), and 0.35mm in the PES arm. There were no ST events and no differences in major adverse cardiac events (MACE) including all-cause death, MI, and emergent bypass surgery or TLR at up to 36 months (BioFreedom SD 11.9%; BioFreedom LD 18.1%, and PES 10.0%).29 Currently, a randomized LEADERS FREE trial has been planned to examine the noninferiority (a composite of cardiac death, MI, and ST) and superiority (clinically driven TLR) of the BioFreedom stent to BMS in >2400 elderly patients with dual antiplatelet therapy for 1 month after stent implantation.

Figure 1.

The surface of the polymer-free BioFreedom stent. A scanning electron microscopy image shows the micropores impregnated with biolimus A9 only in the albuminal side of the strut.

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VESTAsync Stent

The VESTAsync stent (MIV Therapeutics; Atlanta, Georgia, United States) combines a stainless steel platform with a nanoporous, hydroxyapatite (biocompatible crystalline derivative of calcium phosphate) surface coating that is impregnated with 55µg of sirolimus mixture (Fig. 2). It is expected that sirolimus will be completely released within the first 3 months after the implantation, and that the hydroxyapatite will be stable over 4 months. The safety and efficacy of the VESTAsync stent was evaluated in the VESTAsync I FIM trial. A total of 15 patients with single de novo coronary artery lesions were enrolled. In-stent LLL was 0.36mm at 9 months, with no MACE reported at up to 1-year follow-up.30 Recently a randomized VESTAsync II trial has been reported.31 The patients treated with the VESTAsync stent (50 patients) showed a significantly lower in-stent LLL compared to those treated with BMS (25 patients) at 8 months (VESTAsync 0.39mm vs BMS 0.74mm, P=.03). No evidence of ST was reported at up to 2-year follow-up.

Figure 2.

The polymer-free VESTAsync sirolimus-eluting stent system. The scanning electron microscopy images of microporous hydroxyapatite coating (A), cross section of the hydroxyapatite coating (B), final coating including the hydroxyapatite filled with sirolimus formulation (C), and cross section of the final coating (D). A schematic representation of the surface coating (E).

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Magnesium (Mg) is the fourth commonest cation within the human body. It is essential for the synthesis of over 300 enzymes, and is a cofactor for ATPase. A high dose infusion of Mg can cause vasodilatation and the development of collaterals during ischaemia. The degradation of Mg produces an electronegative charge that results in the stent being hypothrombogenic.45

The first generation absorbable metallic stent (AMS-1, Biotronik; Berlin, Germany) was composed of 93% Mg and 7% rare earth metals. In the porcine model, the AMS-1 was shown to be rapidly endothelialized, and largely degraded into inorganic salts at 60 days, with little associated inflammatory response.46 The PROGRESS AMS trial was a signle-arm FIM study, which assessed the efficacy and safety of this stent in 63 patients with single de novo lesions.47 No evidence of death, MI, or ST was reported at up to 12-month follow-up. Disappointingly, the TLR rate was 23.8% at 4 months and 45% at 12 months. The in-stent LLL was 1.08mm and the vasodilator function, after the nitroglycerin administration, appeared to be restored in the stented segment at 4-month angiographic follow-up.48 IVUS data suggested that the increased LLL was attributed to an increased neointimal formation and insufficient radial strength of the Mg alloy, due to rapid stent degradation resulting in vessel recoil. Consequently, new stents have been developed, namely AMS-2 and AMS-3. The AMS-2 stent was designed to address excessive vessel recoil seen with AMS-1. It provided prolonged mechanical integrity by using a different Mg alloy, which not only had a higher collapse pressure, but also a slower degradation time. In addition, the strut thickness was reduced from 165µm to 125µm, and the cross-sectional shape of the strut altered from rectangular to square. These modifications facilitated prolonged mechanical integrity, improved radial strength, and resulted in reduced neointimal proliferation in animal studies. The AMS-3 stent (ie, drug-eluting AMS [DREAMS]) was designed to incorporate a bioresorbable matrix for the controlled release of paclitaxel with the AMS-2 platform. This device was evaluated in the BIOSOLVE-I trial (46 patients), and demonstrated an in-stent LLL of 0.64mm at 6 months and 0.52mm at 12 months. The rate of TLF was 7.0% at up to 12-month follow-up, due to 2 clinically driven TLRs and 1 periprocedural MI.49 The second generation DREAMS has a modified stent platform and sirolimus as its antiproliferative drug. The BIOSOLVE-II study aimed to assess the safety and efficacy of this device will be initiated in the year 2013.

The backbone of Absorb BVS (Abbott Vascular; Santa Clara, California, United States) is made of PLLA. The coating consists of poly-D, L-lactide (PDLLA), which is a random copolymer of D-lactic acid and L-lactic acid with lower crystallinity than the backbone PLLA. The PDLLA coating controls the release of the antiproliferative drug everolimus. The first generation Absorb BVS (1.0) was tested in 30 patients who were enrolled in the ABSORB FIM (cohort A) trial. Multiple modality imaging was assessed in this trial, and the results can be summarized as follows: a) partial bioresorption of the polymeric struts; b) late lumen enlargement between 6 months and 2 years; c) restoration of vasomotion and endothelial function at 2 years; d) sustained scaffolding of plaque deformability documented with palpography, and e) feasibility of noninvasive imaging with multislice computed tomography.50,51 Five-year clinical follow-up is available in 29 patients.52 Only 1 patient experienced a non-Q wave MI related to the treatment of a non-flow-limiting stenosis at 46 days after Absorb BVS implantation. There were no ST events in the entire period and no MACE between 6 months and 5 years, resulting in an overall MACE rate of 3.4% at 5 years. Late scaffold shrinkage was the primary reason for an increased in-stent LLL (0.44mm) at 6 months. Lumen area was reduced by 16.6%, whilst the late recoil was 11.7%.53 In order to enhance the radial strength of the struts and to reduce late recoil, the strut design and the manufacturing process of the polymer were modified in the second generation Absorb BVS (1.1). Firstly, the new design had in-phase zigzag hoops linked by bridges that allowed for a more uniform strut distribution. This new scaffold design reduced maximum circular unsupported surface area that provided for more uniform vessel wall support and drug delivery. Secondly, a modified manufacturing process resulted in a slower hydrolysis (in vivo degradation) rate of the polymer, thus allowing for prolongation of its mechanical integrity.54

The Absorb BVS 1.1 was evaluated in 101 patients in the ABSORB cohort B trial. This cohort was divided in 2 subgroups: the first group (B1) underwent invasive imaging with quantitative coronary angiography, IVUS, and OCT postprocedurally, at 6 months, and at 24 months; whereas the second group (B2) underwent invasive imaging postprocedurally, at 12 months, and at 36 months. In the entire cohort B population, the overall MACE rate was 9.0%, including 3 non-Q wave MIs and 6 ischemia-driven TLRs, without cardiac death during the 2-year follow-up. There were no possible, probable, or definite scaffold thromboses despite dual antiplatelet therapy rates of 97% at 6 months, 81.2% at 12 months, and 24.8% at 24 months.

For the cohort B1 population, serial multimodality imaging results are currently available.55 Serial angiographic analyses showed that in-scaffold LLL of 0.16mm at 6 months increased to 0.27mm at 2 years. Notably, serial IVUS analyses demonstrated that the mean lumen area increased, whereas the minimum lumen area remained stable between 6 months and 2 years (Fig. 6). Percentage hyperechogenic area, a more sensitive parameter to measure degradation of polymeric material, decreased from 25.3% postprocedurally to 20.4% at 6 months and to 13.8% at 2 years. Similar to IVUS, serial OCT investigation confirmed the progressive increase in mean scaffold area from 7.47mm2 postprocedurally, to 7.70mm2 at 6 months, and 8.24mm2 at 24 months.

Figure 6.

Serial changes in intravascular ultrasound measurements over postprocedure, 6 months, and 2 years after Absorb BVS implantation. NIH, neointimal hyperplasia. IVUS, intravascular ultrasound.

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The promising results of Absorb BVS constitute the proof of concept that this device can adequately revascularize coronary vessels and prevent restenosis. The Absorb BVS acquired the CE mark approval in January 2011, and since September 2012 it is commercially available in different diameters (2.5mm, 3.0mm, and 3.5mm) and lengths (12mm, 18mm, and 28mm). This device is now being evaluated in the ABSORB-EXTEND registry (~800 patients). A pivotal, randomized trial (ABSORB II), comparing Absorb BVS with Xience Prime EES (Abbott Vascular) in 500 patients, is simultaneously ongoing in Europe.

The REVA stent (REVA Medical, San Diego, California, United States) consists of a tyrosine-derived poly carbonate that degrades into water, carbon dioxide, and ethanol. In addition to its radio-opacity, the REVA stent also has a unique “slide and lock” design that provides flexibility. This design maintains the acute lumen gain following stent deployment, and provides additional support to the scaffold during vessel remodeling. The RESORB FIM trial enrolled 27 patients. The in-stent LLL was disappointingly high (1.81mm) and IVUS data showed no vessel recoil as indicated by external elastic lamina area (15.5mm2 postprocedurally and 15.3mm2 at 6 months). There was a high rate of TLR (66.7%) between 4 months and 6 months, mostly due to excessive neointimal hyperplasia.56 The second generation ReZolve stent had a more robust polymer, a “spiral” slide and lock system, and a coating of sirolimus. Furthermore, the ReZolve2 stent had a smaller profile (1.52mm) and achieved approximately 30% increase in radial strength. The safety and efficacy of the ReZolve or ReZolve2 stent is currently under investigation in the RESTORE study (50 patients) that was initiated in December 2011. Preliminary data (26 patients) showed that technical success rate was 85%, due to the delivery failure seen in 4 patients. Two cases with TLR as a primary endpoint were reported at 6-months follow-up.57

DESolve BRS (Elixir Medical; Sunnyvale, California, United States) has a similar PLLA backbone to the Absorb BVS, but it is coated with myolimus (3µg/mm), an mTOR inhibitor macrocyclic lactone, and a sirolimus analogue. Sufficient radial strength was achieved over 3 months and the bioresorption of the scaffold was observed between 1 year and 2 years. The DESolve-I FIM trial (16 patients) demonstrated that the rate of acute recoil was 6.4%, and in-scaffold LLL was 0.19 mm at 6 months.58 In IVUS investigation, the respective mean scaffold area and lumen area was 5.35mm2 and 5.35mm2 postprocedurally, and 5.61mm2 and 5.10mm2 at 6 months (P=no significant). OCT revealed that 98.7% of the struts were covered at 6 months. All patients were clinically followed up to 1 year, and 3 patients experienced MACE including 1 cardiac death, 1 target vessel MI, and 1 TLR. There were no patients with the evidence of ST. The DESolve Nx trial is currently enrolling 120 patients treated with the next generation DESolve Nx stent with novolimus (5µg/mm), which is an active metabolite of sirolimus.59

The IDEAL BRS (Xenogenics Corp.; Canton, Massachusetts, United States) has 2 components: the backbone and the drug layer. The backbone of the device is made of polylactide anhydride mixed with a polymer of salicylic acid and sebacic acid linker. The drug layer consists of salicylate that controls the release of the antiproliferative drug sirolimus. The presence of salicylic acid provides the device with anti-inflammatory properties, which have been confirmed in preclinical studies.60 The IDEAL BRS was tested in a small number of humans (11 patients) in 2008. Although this study has not been fully reported, there was insufficient neointimal suppression and a reduction in lumen area due to inadequate drug dosing and rapid release of the sirolimus.61 The second generation IDEAL BioStent has a higher drug dose, slower drug-release kinetics, and a smaller system profile. The device is currently undergoing preclinical evaluation.

The ART BRS (Arterial Remodeling Technologies; Noisy le Roi, France) is manufactured from a PDLLA amorphous polymer without an antiproliferative drug. This device is 6 Fr compatible, and provides transient scaffolding for 5 months to 7 months. Full resorption occurs within 18 months. The performance of the ART BRS was compared with the BMS in rabbit and porcine models, and no MACE was reported. The acute recoil was comparable to BMS. Interestingly, angiographic analyses demonstrated the phenomenon of late lumen enlargement, as well as increased external elastic lamina area detected by IVUS at 9 months. Based on the results of preclinical studies, the ARTDIVA FIM trial has already commenced and is recruiting patients at 5 sites in France. It aims to evaluate clinical outcomes at 6 months.62

The Xinsorb BRS (Huaan Biotechnology; Laiwu, China) is a fully bioresorbable sirolimus-loaded scaffold that consists of PLLA, poly-lactide-co-glycolide, and poly-L-lactide-co-e-caprolactone. An experimental study evaluated the feasibility of Xinsorb BRS in comparison with the Excel DES (JW Medical; Shandong, China). Sixteen Xinsorb scaffolds and 16 Excel stents were implanted in the coronary arteries of porcine models.63 In vitro drug-elution kinetics indicated that 78% of sirolimus was released from Xinsorb BRS within the first 14 days. Histomorphometry demonstrated a significantly lower percentage diameter restenosis in the Xinsorb BRS compared to the Excel DES (18.6% vs 21.4% at 30 days and 24.5% vs 27.7% at 90 days, respectively). In addition, the struts of the Xinsorb BRS were completely covered by neointima at 90 days.64 Although these preliminary results are encouraging, further extensive preclinical studies are necessary to investigate the safety and efficacy of this device. The company is expecting to organize a FIM trial in the year 2013.

The Amaranth PLLA scaffold (Amaranth Medical; Mountain View, California, United States) and the On-ABS (OrbusNeich, Hong Kong, China) are currently under preclinical evaluation. In addition, there are several other devices that are still under development. These include the Sahajanand BRS (Sahajanand Medical Technologies; Surat, India), the Avatar BRS (S3V; Hyderabad, India), the MeRes BRS (Meril Life Sciences; Vapi, Gujarat, India), and the Zorion BRS (Zorion Medical; Indianapolis, Indiana, United States).