Coronary stent implantation is one of the most important developments in the field of percutaneous coronary revascularisation after the introduction of balloon angioplasty in 1977.1 The treatment of coronary artery disease (CAD) using a bare-metal stent (BMS) is considered effective; however, restenosis occurs in 15–35% of all cases, requiring repeated treatment.2–4 To overcome the restenosis problem, stents coated with drugs, i.e. drug-eluting stents (DES), were developed, resulting in a lower rate of restenosis.4 The DES working principle consists of the local delivery of pharmacological agents leading to the suppression of neointimal growth, which is the main cause of lumen re-narrowing after stent implantation. Therefore, the antiproliferative drugs coated on stents aim to decrease the need for repeat intervention by inhibiting the restenotic process.
DES comprise the stent platform and an antiproliferative (antirestenotic) agent that is frequently loaded with a polymer, which also serves to control the release kinetics and contribute to the effectiveness of a DES. Many studies have shown the efficacy of DES in reducing restenosis rates,5,6 which has been the major limitation of the long-term success of BMS. The first-generation DES decreased the restenosis rates compared with BMS;7,8 however, the main problem with first-generation DES was the incidence of late stent thrombosis, which mostly occurred after the patients were removed from their dual-antiplatelet therapy. Therefore, the recommended duration of the clopidogrel treatment was extended from three months (sirolimus-eluting stent) and six months (paclitaxel-eluting stent) to 12 months.9,10 From human autopsy studies, delayed healing of arteries treated with DES was shown to be a histological predictor of late stent thrombosis.11 Delayed re-endothelialisation was a main factor in extending the usage of dual-antiplatelet therapy to over 12 months.12 Although the second generation of DES further decreases the rate of restenosis, late and very late stent thrombosis are still the most challenging adverse effects of DES.10
The first-generation DES polymer coatings were mostly designed to optimise the durability and release kinetics of drugs, with minimal attention to vascular compatibility. The sirolimus-eluting stent (SES) (Cypher®) has a multilayer coating that includes an initial parylene tie-layer that is applied to the stent surface, followed by a polyethyleneco- vinyl acetate (PEVA) and poly-n-butyl methacrylate (PMBA) mixture that contains the sirolimus drug and, finally, a top coat of PEVA/PMBA (without drug) to control the drug-elution rate.
The paclitaxel-eluting stent (Taxus®) device has a single polymer/paclitaxel drug mixture layer, using the triblock copolymer poly(styrene-b-isobutylene-b-styrene) (SIBS).13 There is a consensus that these permanent coatings may cause late stent thrombosis, especially after drug release has fully eluted.14,15 These events have initiated a trend to use either biodegradable polymer drug carriers or non-polymeric surfaces for direct loading of drugs. As a second-generation DES, the everolimus-eluting Xience V stent carries a new polymer coating using PMBA as a tie-layer to the metal surface and a polyvinylidenefluorohexafluoropropylene (PVDF-HFP) copolymer as the drug carrier layer without top coat.16 This generation of DES has shown a lower restenosis rate and a reduction in late adverse events.17 However, late stent thrombosis is still the main problem in the era of DES.18,19 Biodegradable polymers present an ideal solution providing a controlled drug release.13 Moreover, the degradation of the polymer coating eliminates any potential adverse chronic effects from the presence of the polymer. As a new-generation DES, the Coracto™ rapamycin-eluting stent (RES) incorporates a bioabsorbable polymeric coating that provides controlled drug release. The clinical safety and efficacy of the Coracto RES has been already demonstrated with animal tests and clinical studies. This article aims to give an overview of the data obtained from pre-clinical animal experiments using porcine coronary and rabbit iliac models of stenting and a clinical trial demonstrating the safety and efficacy of the Coracto RES.
Design of the Coracto Rapamycin-eluting Stent
The platform of the Coracto RES is the medical grade 316 LVM stainless steel balloon-expandable Constant stent (Alvimedica Inc., Istanbul, Turkey), which has a tubular, open-cell design, with high flexibility and good radiopacity. The Constant (and also the Coracto RES) is crimped on the Turquoise semi-compliant balloon catheter. The stent delivery system has many advantages, such as good trackability, deliverability and pushability. The strut thickness of the stent is 80μm with 3–4μm of polymer thickness, which is superior to most of the commercially available DES.20 The Coracto RES possesses rapamycin as an antirestenotic drug and a poly(lactic-co-glycolic acid) (PLGA) biodegradable polymer.
Biodegradable synthetic polyesters are a widely investigated group of polymers for different drug-delivery applications;21 they are used as monopolymers and co-polymers in many applications. Among these co-polymers, PLGA has been extensively investigated. Both L- and DL-lactides have been used in copolymerisation with a 25–75% range in composition.22 The stability of PLGA depends on the composition of the homopolymers. PLGA undergoes bulk erosion through hydrolysis of ester bonds and the rate of degradation depends on the lactic acid/ glycolic acid ratio, molecular weight and the shape of the matrix. The polymer of Coracto RES provides controlled release of rapamycin, and degradation of the polymer is completed within eight weeks. The lactic acid and glycolic acid degradation products are subsequently converted to water and carbon dioxide through the action of enzymes, and are then excreted from the body.
Rapamycin is used as an antirestenotic drug in the Coracto RES. With its antiproliferative and immunosuppressive effects, rapamycin inhibits the function of mammalian target of rapamycin (mTOR), which is a regulator of cell metabolism and cell proliferation.1,23,24 This inhibition arrests the cell cycle at G1 phase, reducing the neointimal hyperplasia and therefore decreasing the rate of a restenosis. Since rapamycin is lipid soluble, almost no drug is released into the bloodstream during stent placement and after stent implantation.1 The rapamycin amount is 1.7μg/mm2 for all Coracto RES sizes, with a maximal drug load of the stent of 215μg.
Studies of Coracto Rapamycin-eluting Stent
The goal of the pre-clinical animal experiments was to determine the safety and efficacy of the Coracto RES in vivo. To this end, two in vivo animal models were utilised: the swine coronary and rabbit iliac models. All study protocols were reviewed and approved by the animal care and research committees of the institutions.
Swine Coronary Artery Model
The objective of the swine coronary pre-clinical study was to evaluate the safety and efficacy of Coracto RES in a clinically relevant animal model. Coracto RES was compared with the Constant BMS and a BMS loaded with only the polymer (polymer-only, no drug). After three- and six-month follow-up with 15 and six swine, respectively, control coronary angiography and intravascular ultrasound were performed. Furthermore, histopathological analysis of stented segments was performed to examine the presence of inflammation, fibrin deposition around the stent struts, thrombus and neointimal formation and vessel wall injury by light microscopy. Angiography confirmed Coracto stents conformed well to the natural tortuous structure of the swine coronary arteries. No evidence of stent fracture or stent malapposition was present. Moreover, all stents remained patent for the duration of the study with no signs of thrombus.
Quantitative coronary angiography (QCA) analysis showed that the Coracto RES had a significantly larger minimal lumen and significantly smaller per cent diameter stenosis compared with BMS and polymer-only stents. In-stent late lumen loss (LLL) was 0.14±0.31mm for the Coracto RES, 0.39±0.34mm for BMS and 0.48±0.40mm for polymer-only stent (see Table 1). Although the differences between the study groups were not statistically significant, the Coracto RES group had a numerically lower LLL than the Constant and polymer-only groups. QCA at six-month follow-up showed excellent results for the Coracto RES (see Table 2). In-stent LLL was -0.25±0.13mm. IVUS analysis, performed at three-month follow up, showed significantly larger lumen volume for the Coracto RES, resulting in a significantly smaller neointimal volume (86.3±4.5mm3 for Coracto RES; 79.2±7.3mm3 for Constant BMS; and 75.4±10.9mm3 for polymer-only stent) and volume obstruction compared with Constant and polymer-only stent. Six-month intravascular ultrasound (IVUS) results showed a maintained lumen with no further increase in neointimal hyperplasia (see Table 3).
Near complete re-endothelialisation in the BMS and polymer-only stent groups was revealed after histopathology of the stents, whereas re-endothelialisation was completed three months after Coracto RES. Area stenosis was significantly lower in the Coracto RES compared with the polymer-only stent and the Constant BMS.
A trend towards higher haemorrhagia and fibrin score was observed in the polymer-only stent group and it was significantly higher compared with the BMS group. Six-month histopathology of the Coracto RES revealed a low degree of inflammation, haemorrhagia and fibrin deposition, without evidence of giant cells or stent malapposition (see Table 4). Histomorphometric analysis of the stents showed significant neointimal hyperplasia (>75% area restenosis) in seven out of 27 polymer-only stents, in five of the analysed 30 histological segments of Constant and in none of the Coracto RES.
A rabbit iliac stent model was also conducted to compare Coracto RES with everolimus-eluting (Xience V®, Abbott Vascular, Abbott Park, IL, US) and sirolimus-eluting (Cypher Select®, Cordis, Miami, FL, US) stents and a BMS. The impact of stents on arterial healing and endothelialisation was assessed by scanning electron microscopy (SEM), confocal microscopy and light microscopy at days 14 and 28 post-implantation.
All BMS and DES deployed in the iliofemoral artery of normo-cholesterolaemic rabbits were widely patent without evidence of luminal thrombosis. Assessment of re-endothelialisation at day 14 by means of SEM showed more than 80% surface coverage between struts for all comparator DES and Constant bare-metal control stent. As expected, the percentage of endothelial coverage basedon SEM at 14 days on strut surfaces was significantly greater for bare-metal controls.
Confocal microscopy analysis showed endothelial coverage between struts was significantly greater in Coracto RES compared with the other DES used in this trial. Coracto RES had a significantly higher re-endothelialisation than the Xience V stent and the Cypher DES. However, all DES showed less re-endothelialisation than Constant.
At 28 days, all DES had a significantly increased lumen area, as shown by histomorphometric analysis. The restenosis rates for the Xience V stent and the Coracto RES were significantly lower, while neointimal thickness was significantly reduced for all three DES relative to the BMS. There was a trend towards greater fibrin scores for all three DES.
The safety and effectiveness of the Coracto RES was approved with a clinical trial performed before the CE mark application. In the paragraphs below, data from this trial will be presented and discussed. The clinical study was a multicentre, randomised, prospective study carried out in Germany.25 A total of 95 patients with three-month-old chronic total coronary occlusions (CTO) were enrolled (see Table 5). The participants received either the Constant BMS (n=47) or the Coracto RES (n=48). A total of 253 stents received implants. Dual antiplatelet therapy with clopidogrel 75mg/day plus aspirin 100mg/day was given for six months and was followed only by aspirin 100mg/day indefinitely. Primary end-points of the study were LLL and in-segment restenosis (ISR), as assessed after six months. Target vessel revascularisation (TVR) after six, 12 and 24 months were defined as secondary end-points. The results of the study demonstrated significant differences between the two groups in favour of the Coracto RES. The mean late lumen loss was significantly lower in the RES group than in the BMS group (0.77±0.63mm versus 1.8±0.82mm; p<0.0001) (see Table 6).
No death, myocardial infarction or stent thrombosis occurred in the first six months in either group. After 24 months, none of the patients had myocardial infarction or coronary artery bypass graft (CABG). One patient in the DES group (2%) and two patients in the BMS group (5%) had died of causes unrelated to the target vessel.
The overall risk reduction of restenosis with the Coracto RES compared with the Constant BMS after six months was 71% and the relative risk reduction of TVR after 24 months was 82%.
In the Primary Stenting of Totally Occluded Native Coronary Arteries II (PRISON II) trial comparing a Cypher SES possessing non-biodegradable polymer (Cordis, Johnson & Johnson, Warren, NJ, US) with a BMS in total occlusions, the mean occlusion age was 2.8 months and only 45% of patients met the criteria of CTO.26 In this trial, the Cypher SES reduced the restenosis rate from 41 to 11% in occlusions of about 16mm length and TVR for BMS was necessary in only 22% of patients, underlining a relatively low complexity of disease.
It is well-known that restenosis after stenting is negatively influenced by lesion length, vessel diameter and diabetes.27,28 In the Coracto RES trial, vessel diameter and the presence of diabetes were similar to those in the PRISON trial; however, occlusion length was considerably longer at 36–39mm. As evidence of complexity, restenosis rate was reduced from 60 to 17.4%, and TVR was necessary in 53.3% of the BMS group. These findings are further confirmed by the late lumen loss of 1.0mm versus 0.5mm in the PRISON trial and 1.8 and 0.77mm in BMS and DES, respectively, in the Coracto RES trial. It appears likely that an LLL as low as 0.5mm bears an increased risk of incomplete endothelialisation and stent thrombosis.
After three years of the PRISON trial, none of the patients in the BMS group experienced a stent thrombosis, but stent thrombosis occurred in 5% of the 100 patients who received the Cypher SES.29 By contrast, clopidogrel was used for only six months and no stent thrombosis was observed within 24 months in the group of 48 patients who had received 138 SES in the Coracto RES trial.
As most of the clinical studies performed with stents were conducted in patients who had mild to moderate lesions, our clinical study showed very good results despite all of the enrolled patients possessing only CTO lesions (very severe lesions).
As a new generation of drug-eluting stent, the Coracto RES has many superior properties such as a bioabsorbable polymer with rapamycin providing controlled drug release. The data obtained from animal studies showed greater endothelial recovery in the Coracto RES compared with the everolimus-eluting stents and SES that are currently available.
The presented data from pre-clinical and clinical studies suggest that CORACTO, a rapamycin-eluting stent with a biodegradable polymer, is safe and effective even in patients with complex lesions (CTO). Moreover, the results of the clinical study showed that neither stent thrombosis occurred nor repeat revascularisation was required in patients who received a Coracto RES between six and 24 months even if the dual antiplatelet therapy of the patients was only for six months. Therefore, these results might suggest the use of the Coracto RES especially in patients who are not able to undergo long-term antiplatelet therapy, although this needs to be confirmed in larger clinical trials. Ôûá