minimally invasive coronary revascularization by percutaneous transluminal coronary angioplasty was introduced in the late 1970s for the management of symptoms of coronary artery disease . however , percutaneous transluminal balloon coronary angioplasty alone was fraught with problems , including a major risk of abrupt early closure , late restenosis due to elastic recoil , constrictive remodeling , and intimal hyperplasia . the development of the bare - metal stent ( bms ) enabled a reduction in the risk of early procedural complications , abrupt closure , and restenosis . however , the bms introduced a new and device - specific iatrogenic condition , ie , in - stent restenosis , causing late loss , mainly due to excessive neointimal proliferation within the stented segment . coronary stents virtually eliminate elastic recoil and negative remodeling , but promote neointimal hyperplasia.1 in - stent restenosis due to neointimal formation is the main limitation of the bms , and frequently leads to a subsequent revascularization procedure . by inhibiting neointimal hyperplasia , the drug - eluting stent ( des ) dramatically reduces angiographic restenosis and the need for new revascularization , without increasing the risk of stent thrombosis during the first year and need for prolonged dual antiplatelet therapy.2 cypher and taxus stents have been demonstrated to achieve a dramatic reduction in the rate of angiographic restenosis and the need for new revascularization procedures in a variety of clinical and angiographic scenarios . however , the possibility of a slight increase in risk of very late ( > 1 year after implantation ) stent thrombosis , as well as the necessity of long - term dual antiplatelet therapy , has limited the use of these devices and are used in up to two - thirds of procedures . another problem with the first - generation des is that the stainless steel stent platform may make it difficult to use these devices in very complex lesions ( eg , severe tortuosity and calcified lesions ) . these limitations have led to the development of second - generation des , which has included more flexible stent platforms , different drugs , and/or different polymers . rapamycin ( sirolimus ) , a macrolide immunosuppressant inhibitor of m - tor ( mammalian target of rapamycin ) , inhibits growth factor - dependent proliferation of hematopoietic and nonhematopoietic cells ( vascular smooth muscle cells and fibroblasts ) via cell - cycle arrest in the late g1 phase . rapamycin has been shown to inhibit vascular smooth muscle cell proliferation and migration in vitro and inhibit neointimal growth in balloon - injured rat carotid and porcine coronary arteries.3 there are six limus family - related drugs that have been studied in des , ie , sirolimus , everolimus , biolimus , zotarolimus , tacrolimus , and pimecrolimus . sirolimus , everolimus , biolimus , and zotarolimus bind to the fkbp 12-binding protein and have a similar effect , but tacrolimus and pimecrolimus bind to the fkbp 506 complex.4 in this review , the clinical evidence for the everolimus - eluting coronary stent ( ees ) is revised . like the other des , the ees has three components , ie , the antiproliferative drug everolimus , a stent platform , and a release system , ie , the polymer . everolimus ( certican ; novartis , basel , switzerland ) is an analog of sirolimus ( a second derivate of the limus family with a single minimal alteration in the hydroxyl in position 40 of the molecular structure , alkalinized with a 2-hydroxyethyl group , without chemical modification ) resulting in increased solubility in several organic solvents and galenic excipients , and it has been useful in the prevention of allograft rejection after organ transplantation.1,4,5 the everolimus - fkb12 complex interferes with fkb12-rapamycin associated protein , a regulatory protein that controls cell metabolism and proliferation through the phosphorylation of p70 s6 kinase and 4e - bp1 . consequently , fkb12-rapamycin associated protein inhibition arrests the cell cycle at the late g1 stage . everolimus absorbs into local tissue rapidly and possesses longer cellular residence time and activity . in vitro studies have shown that the immunosuppressive activity of everolimus is two- to fivefold lower than that of sirolimus.1,5,6 oral everolimus 0.75 or 1.5 mg is given twice daily for immunosuppression after renal or cardiac transplantation . other studies have demonstrated that the immunosuppressive efficacy and incidence of adverse effects for everolimus are correlated with blood concentration . the adverse event profile of everolimus includes hypercholesterolemia , anemia , thrombocytopenia , leucopenia , infections , and renal , gastrointestinal , and neurologic disorders.7 however , everolimus is almost always undetectable in blood 30 days after ees implantation . wiemer et al showed in a pharmacokinetic study that only when a patient received the maximum of four stents was it possible to achieve a drug concentration similar to that with oral treatment within a short period after stent implantation , with a maximal concentration of 2.79 ng / ml.7 for most patients , whole blood concentration initially increased to reach a maximum at about 1060 minutes after stent implantation . thereafter , whole blood concentration decreased biphasically , with an initially fast distribution/ elimination phase followed by a slower elimination phase . the biphasic distribution is the result of initial distribution to the tissues and subsequent elimination from blood . because blood concentrations increase rapidly after stent placement , the initial release of everolimus from the stent must be higher than the net drug distribution to tissues and its clearance from blood . at peak concentration , release of drug from the stent equals its distribution to the tissues and clearance from the blood . after the peak , clearance of everolimus from blood is higher than its release from the stent , and everolimus concentration decreases . apparently the high release from the stent is only temporary because no steady - state or plateau concentration is observed.7 different coronary stents have been developed containing everolimus as an antiproliferative agent . the platform of the xience v ( promus ) stent , the most widely studied and used ees , is a l-605 cobalt chromium expandable balloon stent remarkably similar to its bms equivalent , the multi - link vision ) , the main characteristics of which are low strut thickness ( 81 m ) , high flexibility and deliverability , an acceptable compliance , recoil , and risk of plaque prolapse , and overall good radio - opacity.1 the polymer coating of xience v is formed by two layers , ie , a thin primer adhesion layer of poly(n - butyl methacrylate ) and a drug reservoir of poly(vinylidene fluoride - co - hexafluoropropylene ) . the layer of everolimus  polymer matrix is applied to the surface of the stent and loaded with 100 g of everolimus per centimeter of stent surface area with no top - coat polymer layer . eighty percent of the stent drug is released during the first month , and all the drug is released within four months . the coating thickness is lower for the xience v ( 5.3 m ) than for the cypher ( 7.2 m ) or taxus ( 15.6 m ) stents.1,5 in the future ( first use to underscore restenosis reduction with everolimus ) i and future ii trials , the ees platform was the s - stent manufactured by biosensors ( newport beach , ca ) . this is a stainless steel , tubular stent , with everolimus coated onto the s - stent with a bioabsorbable poly - l - lactic acid polymer ) in a 1:1 ratio , with approximately 70% of drug release in 30 days and 85% in 90 days . more recently , the promus element stent has been developed , with a novel stent platform made of a platinum alloy with thin struts ( 81 m ) , and using fluorinated copolymer ( vinylidene fluoride - co - hexafluoropropylene ) as a permanent polymer . finally , the bioabsorbable everolimus - eluting stent ( bvs ) is composed of a poly - l - lactic acid backbone , coated with a bioabsorbable polymer containing everolimus , and expected to be totally metabolized and absorbed in the human body . the ees has been shown to decrease neointimal proliferation significantly at six months compared with the bms in the future i and future ii trials . in the single - center future i trial , 42 patients were randomized in a 2:1 ratio to the ees or the bms . after the future i trial , the subsequent multicenter future ii enrolled 64 patients , using a reverse randomization scheme ( 1:2 ratio for ees versus bms , respectively ) to equalize the ees and bms arms when the two studies were combined . inclusion and exclusion criteria for the two studies were identical except for the inclusion of diabetic patients in future ii . all patients received aspirin 325 mg / day and a clopidogrel 300 mg loading dose immediately and after 75 mg / day for six months . at six - month follow up , ees in - stent late lumen loss decreased by 78%94% , resulting in a significant 34%42% increase in minimum lumen area compared with the bms across all vessel sizes as assessed by intravascular ultrasound . there were no cases of in - stent restenosis with the ees at any vessel size but eight cases with the bms ( five in small vessels ) . no stent thrombosis , aneurysm formation , or incomplete late stent apposition was observed in any group . the ees appears to be effective for treatment of de novo coronary lesions in decreasing neointimal proliferation at six - month follow - up compared with the bms , regardless of vessel size.1,8 the spirit i trial was a single - blind randomized trial performed in nine centers . the inclusion criteria were stable or unstable coronary disease , with the exclusion of overt myocardial infarction , plus the presence of a single de novo coronary lesion 3.0 mm in diameter as assessed by quantitative coronary angiography , that could be covered by an 18 mm stent . notably , no patient with unprotected left main , chronic total occlusion , bifurcation lesion , or in - stent restenosis could be included . patients were thus randomized to the xience v stent versus a matching multi - link vision stent . a single stent , 3.0 mm in diameter , 18 mm long , was used in the study . follow - up was by clinical assessment , quantitative coronary angiography , and intravascular ultrasound at six months . the primary endpoint was angiographic in - stent luminal late loss , which was 0.10 mm for the ees and 0.87 mm for the bms ( p < 0.01 ) . binary angiographic restenosis ( > 50% stenosis at follow - up ) was detected in 0% and 25.9% of patients allocated to the ees and bms , respectively ( p < 0.01 ) . concerning clinical efficacy , the spirit i trial suggested beneficial effects of the xience v stent in terms of target vessel failure ( 3.8% versus 21.4% , p = 0.102).2 in the two year follow - up results of spirit first , in - stent late loss was 0.10  0.23 mm for the ees versus 0.84  0.36 mm for the bms ( p < 0.01 ) . no major device - related adverse cardiac events were reported , and there was no stent thrombosis with either the ees or the bms over two years . data from these trials comparing the ees and bms show that the ees has among the lowest in - stent late loss values . this is of great clinical importance , since in - stent late loss is related with the clinical benefit of a given des , without comprising safety . in the absorb study , the safety and efficacy of the bvs was assessed in 30 patients undergoing intervention for native coronary artery stenosis . this stent is made of poly - l - lactic acid that provides support and has a coating of poly ( d , l - lactic acid ) that serves as a reservoir of everolimus . the composite endpoint of this study was cardiac death , myocardial infarction , and ischemia - driven target lesion revascularization . the stent became dislodged in two patients , and in one the site was treated with a cypher stent , whereas in the other a new bvs stent was deployed . one patient had a non - q wave infarction in association with a revascularization procedure . angiographic in - stent late loss at six months was 0.44 ( 0.35 ) mm and was mainly due to a mild reduction of the stent area ( 11.8% ) , as measured by intravascular ultrasound.9 at two years , the device was safe , with no cardiac deaths , ischemia - driven target lesion revascularizations , or stent thromboses recorded , and only one myocardial infarction ( non - q wave ) . at two years , in - stent late loss was 0.48  0.28 mm.10 the investigators detected transient but long - term effective scaffolding of the vessel , device bioabsorption , complete strut apposition , potential late lumen enlargement associated with decreased plaque burden , and restoration of normal vasomotion . clinicians should note that the lesions treated in this study represent only the simplest seen in current clinical practice , and the radial strength of this stent will require further testing in more complex lesions . the findings of this preliminary report need to be confirmed in larger prospective studies , but bioabsorbable stents may indeed be unique for treatment of flow - limiting plaque , by not only eliminating the obstruction , but also restoring vascular integrity.11 there have been some trials comparing the xience v stent with other des types , mainly with the taxus stent . in the spirit ii trial , 300 patients in europe and the asia pacific region were randomized 3:1 to the xience v ( n = 223 ) or taxus ( n = 77 ) . inclusion criteria were a maximum of two lesions with a diameter between 2.5 and 3.75 mm and length < 28 mm . the primary endpoint was six - month in - stent late loss of 0.12 for the ees and 0.37 for the taxus ( p < 0.001 ) . binary restenosis was detected in 1.3% versus 3.5% , respectively ( p = 0.194 ) , and target lesion revascularization in 2.7% versus 6.5% ( p = 0.157 ) , and stent thrombosis occurred in 0.5% versus 1.3% ( p = 0.448 ) for the ees and taxus , respectively.1,12,13 the spirit iii trial recruited patients with similar features to those enrolled in spirit ii , and was a prospective , multicenter , randomized , single - blind , controlled clinical trial done at 65 us and 12 japanese sites . a total of 1002 patients with either one or two de novo native coronary artery lesions were randomized in a 2:1 ratio to the ees ( n = 669 ) or taxus ( n = 333 ) . the primary endpoint was six - month in - segment late loss , which was significantly lower in ees patients ( 0.14  0.41 versus 0.28  0.48 mm , p < 0.001 ) . in - stent late loss ( 0.16  0.41 versus 0.30  0.53 mm , p < 0.001 ) , and the rate of binary angiographic restenosis ( 2.3% versus 5.7% , p = 0.083 ) were also lower with the ees . the hazard curves for events between one and two years continued to diverge , and at the end of two years of follow - up , patients treated with the ees had a significant 32% reduction in target vessel failure rate and a 45% reduction in major adverse cardiac events.1,17 more recently , two larger studies comparing the ees and the taxus stent have been presented , both of them with the same clinical endpoints , ie , target lesion failure at one year for spirit iv and major adverse cardiac events at one year in the compare trial . the number of patients included was 3687 in spirit iv ( 2:1 randomization ) and 1800 in compare ( 1:1 randomization ) . in spirit iv , target lesion failure at one year occurred in 3.9% versus 6.6% for the ees and taxus , respectively ( p < 0.01 ) . in compare , the rate of major cardiac events at one year was 6.2% versus 0.1% for the ees and importantly , the rate of stent thrombosis was significantly lower for the ees in both trials ( 0.2% versus 0.8% , p < 0.01 , in spirit iv , and 0.7% versus 2.6% , p < 0.01 , in compare ) . in both trials , this reduction in the one - year rate of stent thrombosis was mainly due to a reduction in the incidence of thrombosis in the first month after stent implantation . although this may be partly explained by differences in the stent platform between both types of des , it remains speculative.1,1416 another recently presented trial is the randomized isar - test-4 ( the intracoronary stenting and angiographic results : test efficacy of 3 limus - eluting stents-4 ) study . a substudy of this trial compared ees ( n = 652 ) with the sirolimus - eluting cypher coronary stent ( n = 652 ) . the primary endpoint was the incidence of major cardiac events at one year , which was 13.6% and 15.2% for the ees and cypher , respectively ( p = 0.46).17 the results of these head - to - head trials evaluating the efficacy of the ees demonstrates that the ees is superior to the taxus in terms of angiographic ( in - stent late loss , binary angiographic restenosis ) , and clinical ( revascularization , cardiac events ) outcomes . the only trial comparing both of these des have no data showing superiority or inferiority of either type of stent . apart from these trials the spirit v study is a prospective , open - label , single - arm registry evaluating the performance of the xience v stent in real life . within this study , there is a randomized substudy of 300 diabetic patients who are being randomized to the ees or taxus stent ( 2:1 design ) , with in - stent late loss at nine months as the primary endpoint.1 the spirit women is a registry for the xience v coronary stent in female patients that also includes a randomized substudy comparing the ees and taxus stent.18 the excellent ( efficacy of xience / promus versus cypher in reducing late loss after stenting ) trial is a prospective , randomized , open - label , 2  2 factorial - designed multicenter trial testing whether the ees is noninferior to the sirolimus - eluting stent ( 3:1 randomization ) in reducing late loss at nine months and to test whether a six - month duration of dual antiplatelet therapy is noninferior to a 12-month duration of dual antiplatelet therapy in preventing the occurrence of target vessel failure . approximately 1400 patients will be enrolled at 17 centers in korea.9 the cibeles ( non - acute coronary occlusion treated by everolimus - eluting stent ) trial is an ongoing randomized study in spain and portugal comparing the ees and the sirolimus - eluting stent in 208 patients with chronic coronary occlusions . the primary endpoint is in - stent late loss at nine months.19 other head - to - head trials evaluating the efficacy of the ees include best ( 1776 patients with multivessel disease comparing the ees with coronary artery bypass grafting in korea ) , sort - out ( 2678 patients , allcomers , comparing the ees and ees in denmark ) , examination ( 1500 patients with st - segment elevation comparing the ees and bms in spain ) , twente ( 1400 patients , allcomers , comparing the ees with the endeavor in the netherlands ) , and xami ( 800 patients with st - segment elevation comparing the ees with the sirolimus - eluting stent in the netherlands).18,20 the ees has been demonstrated to be effective in reducing neointimal hyperplasia and restenosis in comparison with the bms . several head - to - head randomized trials have demonstrated consistently that the ees is more effective than the pes in reducing not only angiographic restenosis , but also cardiac events during follow - up . some recent studies have shown a reduced risk of stent thrombosis at one year with the ees in comparison with the pes . ongoing trials will provide more information about the efficacy of the ees in comparison with the ses.20,21
bare metal stents enabled a reduction in the risk of early procedural complications and restenosis in comparison with balloon angioplasty alone , but introduced a new and device - specific iatrogenic condition , ie , in - stent restenosis due to increased neointimal hyperplasia . 
 sirolimus- and paclitaxel - eluting stents reduce restenosis and the need for new revascularizations in comparison with bare metal stents , although at the cost of a slight increase in the risk of late stent thrombosis and a need for prolonged dual antiplatelet therapy . 
 everolimus is an analog of sirolimus with an increased solubility . in this review , 
 the currently available evidence for everolimus - eluting stents is revised , including randomized trials against bare metal stents , and head - to - head trials comparing this stent with other drug - eluting stents .