percutaneous transluminal coronary angioplasty was introduced by gruntzig in the late 1970s as an alternative to coronary artery bypass graft surgery for coronary revascularization.1 since then , percutaneous coronary intervention ( pci ) has been accepted as a safe , reliable , and effective treatment for coronary artery disease , and its use has spread worldwide .
nevertheless , in - stent restenosis ( isr ) , a complex phenomenon resulting in renewed symptoms , need for re - intervention , and poor patient outcome remained for many years the achilles heel of pci.2 the introduction , a decade ago , of first - generation drug - eluting stents ( dess ) transformed the practice of pci by drastically reducing the rate of this complication.3 the efficacy of dess has largely been demonstrated in large randomized trials , leading to their current widespread use in clinical practice . even in high - risk populations ,
isr incidence does not currently go above 5%10%.46 however , major concerns regarding the long - term safety of these first - generation dess have progressively arisen , especially the increased risk of late / very late stent thrombosis ( st)714 and the need for prolonged dual antiplatelet therapy ( dapt ) with an inherent increase of bleeding complications . aside from patient- and lesion - related factors , delayed re - endothelialization and recovery of endothelial function after stenting as well as inhibition of vascular repair after des implantation ,
all of which promote inflammation and thrombotic pathways , have been implicated in the pathophysiology of late / very late st . of note ,
stent polymer has also been cited as one of the main causes of these late events .
in fact , the persistence of a durable polymer after complete release of the anti - proliferative drug has been shown to be responsible for local hypersensitivity and inflammatory reactions.15 these safety concerns prompted additional research , new trial design , and development of new - generation dess to reduce the rate of this rare but critical event . apart from the progress in stent platforms ( thinner struts and stent designs ) , recent research in this field
has subsequently been focused on the development of new more biocompatible durable polymers or completely biodegradable polymers .
third - generation dess using biodegradable polymers , like the biolimus - eluting stent ( bes ) ( nobori ; terumo corporation , tokyo , japan ) , have been developed to overcome the long - term adverse vascular reactions related to the durable polymer . in this article
we then discuss the results of recent publications investigating the safety and effectiveness of the use of the third - generation bes ( nobori ) for the treatment of coronary artery lesions .
the two major complications of pci , isr and st , have always been the trigger for new stent development.16 indeed , despite the fact that these events are multifactorial , stent  structure  has been suggested to be one of the leading causes of isr and/or st.1721 isr physiopathology has not yet been fully understood .
barotrauma induced by pci is responsible for endothelial denudation and sub - intimal hemorrhages , leading to a local inflammatory response .
this inflammatory process induced by vascular damage is thought to be one of the main contributors to the development of restenosis , by promoting vascular smooth muscular cell proliferation and extracellular matrix formation , resulting in neointimal hyperplasia . beside these mechanical factors ,
other factors have been identified as predictors for isr , including patient - related ( eg , diabetes mellitus , smoking , and renal failure ) and lesion - related ( eg , minimal lumen diameter after pci , severe calcifications , chronic total occlusions , tortuous vessel , and long lesion length ) factors.22 as mentioned above , isr remained the achilles heel of pci until the large use of dess , which were specifically developed to overcome this complication . before the introduction of bare - metal stents ( bmss ) , up to 50% of the patients treated by pci experienced restenosis . even in the bms era , isr remained one of the major limitations of this technique , with an average incidence of 20% , but that could increase up to 35% in complex lesions and diabetic patients.4,5 the introduction , 10 years ago , of first- and then second - generation dess transformed the practice of pci by drastically reducing the incidence of this complication to less than 10%.3 dess prevent restenosis by inhibiting vascular smooth muscle proliferation.2331 unfortunately , they also delay re - endothelialization of stent struts , leading to the potential risk of late / very late st and thereby the need for prolonged dapt . since the appearance of dess , st has become the major safety concern in contemporary pci practice .
st is a rare adverse event ( 1% at 1 year and then 0.5% per year ) but remains associated with high morbidity and mortality rates.32 the overall prognosis is poor : most patients in whom st occurs present with stemi ( st - segment elevation myocardial infarction ) or out - of - hospital death , and up to 30% of those who arrive alive at hospital die within the first month .
numerous factors have been implicated in st physiopathology , but studies have also shown that these predictors vary over time .
these data highlight the complex physiopathology of st , depending on the timing of event occurrence .
acute ( within 24 hours ) and early st ( within 30 days ) are likely related to mechanical issues concerning the stent ( eg , minimum stent area and suboptimal stent expansion ) , inadequate platelet inhibition , or patient prothrombotic factors.33 late ( up to 1 year ) and very late st ( after 1 year ) have been attributed to incomplete vascular healing and/or inadequate neointimal coverage , which in turn , promote inflammation and activation of thrombotic pathways15 and late or acquired stent malapposition .
dapt associating aspirin with an oral p2y12 inhibitor has been shown to be the standard therapy following coronary stenting in order to significantly reduce cardiac events , especially st after pci.34 current guidelines support the use of dapt for 612 months after des implantation.3539 in 2006 , the potential risk of late / very late st after des implantation raised the question of prolonging dapt even beyond the first year.4041 however , prolonged dapt has also clearly been associated with an increased risk of bleeding.4247 availability of new biodegradable polymers and/or stents may shorten the duration of necessary dapt and therefore minimize the risk of major bleeding to which it is associated .
first- and second - generation dess have three major components : the stent platform , the antiproliferative drug , and the polymer .
all of these factors have been subject to modification and have become a target for research and development .
it provides the radial force to prevent vessel occlusion provoked by vessel injury following pci .
cobalt - chromium and later platinum - chromium platforms used in second - generation dess permitted similar stents radial strength all the while enabling a thinner strut design and subsequently significantly improved deliverability and a reduced rate of isr.4849 unfortunately , the presence of a permanent scaffold in the vessel constitutes a stimulus for platelet aggregation and may lead to st in patients with nonoptimal antiplatelet therapy and/or incomplete stent endothelialization .
recently , bioabsorbable platforms that biodegrade over a period of months have been developed , with the purpose of allowing the restoration of a normal vascular physiology and function over time . ultimately , no foreign material is left exposed in the bloodstream
. these stents may also potentially preserve reactive vasomotion and permit expansive remodeling.50 there are several antiproliferative drugs with different modes of action .
the goal of these drugs is to inhibit vascular smooth cell proliferation and migration , without affecting endothelial regeneration , and have anti - inflammatory / anti - thrombotic properties .
inhibitors of the mammalian target of rapamycin ( mtor ) are the dominant class of anti - proliferative drugs used for dess .
the mtor inhibitors are cytostatic drugs resulting in arrest of the cell cycle at the g1 phase . aside from mtor inhibitors ,
tacrolimus , which acts as a calcineurin inhibitor , has also been used in dess and is a cytostatic agent with both antiproliferative and anti - inflammatory activities .
finally , paclitaxel is a taxan drug , which acts as a cytotoxic drug through the stabilization of microtubules .
however , all these antiproliferative agents have shown detrimental local effects on the vascular wall and on endothelial function recovery after stenting.11 new drugs ( biolimus , novolimus , and myolimus ) have been developed and have shown promising results.5152 compared with other mtor inhibitors , biolimus shows better lipophilicity .
agents other than drugs are under investigation to limit restenosis , such as antibody - coated stents ( cd34 antibody - coated stents ) and nucleotide- or peptide - coated stents .
the ultimate goal remains the inhibition of maladaptive neointimal proliferation , all the while promoting vascular healing .
once drug elution has been completed , most polymers exert limited functions and act as a potential trigger for local inflammation and hypersensitivity and subsequently late / very late st .
they promote an inflammatory response and eosinophilic infiltration in the arterial wall , causing hypersensitivity reactions and endothelial dysfunction responsible for delayed healing and lead to st.11,12,22,53 the biocompatibility , composition , formulation , degradation delay of the polymer , pharmacokinetics of the antiproliferative agent released by the polymer , and the management of variation in polymer degradation delay have become new difficult challenges for the development of stent polymers .
an optimal polymer should mimic the endothelial lining in order to prevent late thrombotic complications , thus improving stent safety .
given the issue of polymer - induced inflammation and thrombosis , more biocompatible durable polymers have been developed .
second - generation dess are composed of these polymers , thereby improving arterial healing and potentially reducing the rate of late ischemic events .
the limited function of stent polymers once the drug is eluted has also fuelled research in biodegradable polymers . third - generation dess use polylactic acids ( poly - l - lactic acid and poly d , l - lactide - co - glycolide ) as bioabsorbable polymers .
the bes with biodegradable polymer ( nobori ) is one of these third - generation dess .
finally , another field of research is the development of stents that elute antiproliferative drugs without the need for polymers .
these polymer - free stents could prevent the potential adverse physical effects of the polymer , leading to sustained intima inhibition , improved healing , and a lessened activation of the inflammatory / thrombotic pathways .
safety , efficacy , and deliverability are the main sought - out properties for the development of new dess .
an optimal combination of these components , which are in part interdependent , is necessary for enhancing stent performance .
the bes stent with biodegradable polymer ( nobori ) is one of the third - generation dess ( figure 1 ) . the platform is composed of stainless steel , and the strut thickness is 112 m .
it is coated with a polylactic acid polymer on its abluminal surface , which is metabolized within 69 months to lactic acid , water , and carbon dioxide through interaction with the krebs cycle .
the stent elutes an antiproliferative drug , biolimus ( 15.6 g / mm ) , for up to 30 days .
the coating design of the stent combined with the lipophilicity of the drug is thought to optimize local drug distribution and to reduce its release into the general circulation . at the end
, the nobori stent will leave only a bms in place . the nobori stent has already been compared with first- and second - generation dess with promising results .
the nobori core trial54 reported late - loss with the nobori stent at 9 months , similar to that found using the sirolimus - eluting stent ( ses , cypher ; cordis corporation , bridgewater , nj , usa ) : 0.10 and 0.12 mm , respectively ( p=0.66 )
. however , the use of the nobori stent results in better endothelial recovery , with normal coronary vasodilatation in the adjacent stent segments after implantation , contrasting with the paradoxical vasoconstriction seen with first - generation dess.55,56 the nobori i trial showed non - inferiority to and subsequent superiority of the nobori stent over the paclitaxel - eluting stent ( taxus , boston scientific , maple grove , mn , usa ) : late - loss 0.11 versus 0.32 mm , p<0.001 .
moreover , this trial demonstrated a lower rate of st with the nobori stent after a 9-month follow - up.57 three recent large randomized trials have compared safety and efficacy of this third - generation des with that of first- and second - generation dess with durable polymer ( table 1).58 the sort out v trial59 enrolled 2,468 patients who underwent pci in denmark and randomized them 1:1 using the nobori and cypher stents .
this trial was a multicenter , prospective , non - inferiority trial ( non - inferiority margin chosen at 2% ) comparing the bes using biodegradable polymer with the ses using permanent polymer .
a total of 1,229 patients were assigned to the bes group ( 1,532 lesions ) and 1,239 to the ses group ( 1,555 lesions ) .
the primary endpoint was a composite of safety ( cardiac death , myocardial infarction [ mi ] , and st ) and efficacy ( target lesion revascularization [ tlr ] ) within 9 months of stent implantation ( intention - to - treat analysis ) .
there were 75% male , and only 15% of the patients had a history of diabetes . altogether , 17% had undergone a previous coronary intervention .
the main target vessel location was the left anterior descending ( lad ) artery ( 40.8% ) .
procedure characteristics were similar between the two groups , except for maximum stent pressure , which was significantly higher in the ses group ( 18 versus 16 atm , p<0.0001 ) .
composite primary endpoint occurred in 4.1% of cases in the bes group and 3.1% of cases in the ses group ( one - sided pnon - inferiority=0.06 , and p=0.22 for superiority ) . cardiac death and tlr were not significantly different between the bes and ses groups ( 0.7% versus 1% , p=0.38 ; 3.3% versus 2.1% , p=0.07 ) .
of note , st occurred more frequently in the bes group ( especially within the first month ) , with no clear explanation , and the rate of st was particularly low in the ses group : 0.7% versus 0.2% , p=0.03 .
the authors concluded that the bes did not show non - inferiority when compared with the first - generation ses at 9 months .
the compare ii trial60 was a multicenter , open - label , randomized , controlled , non - inferiority trial ( non - inferiority margin chosen at 4% ) and aimed to compare the safety and efficacy of the bes using biodegradable polymer with a second - generation everolimus - eluting stent ( ees ) using durable biocompatible polymer ( xience v [ abbott vascular , santa clara , ca , usa ] or prime [ boston scientific corporation , natick , ma , usa ] ) .
a total of 1,795 patients ( 2,638 lesions ) received a bes , and 912 patients ( 1,387 lesions ) an ees .
the primary endpoint was a composite of safety ( cardiac death and non - fatal mi ) and efficacy ( tlr ) at 12 months .
there were 74% male , 21.7% diabetics , and 20% had a previous history of mi .
procedure characteristics were not significantly different between the groups but the rate of non - allocated stent implantation was higher in the bes group .
primary endpoint occurred in 5.2% of cases in the bes group and 4.8% in the ees group ( one - sided pnon - inferiority<0.0001 , and p=0.69 for superiority ) .
there was no difference in the rates of cardiac death ( 0.8% in each group , p=0.97 ) and mi ( 2.8% in the bes group versus 2.5% in the ees group ; p=0.63 ) .
the rate of definite st ( 0.7% versus 0.4% , p=0.38 ) and definite / probable st ( 0.8% versus 1% , p=0.58 ) were very low and comparable between the two groups .
target vessel revascularization did not differ between the bes group ( 2.9% ) and the ees group ( 2.6% , p=0.69 ) .
the authors concluded that the bes was shown to be non - inferior to the ees in terms of safety and efficacy at 1-year follow - up after pci .
the 5-year follow - up of the study should answer the question of long - term safety and efficacy of the bes compared with second - generation dess .
the next trial61 was a prospective , multicenter , randomized , open - label , non - inferiority trial ( non - inferiority margin chosen at 3.4% ) comparing the bes ( nobori ) with the ees ( xience v or prime ) in terms of tlr at 1 year .
may to october , 2011 , in 98 japanese centers , 3,235 patients were randomized 1:1 without any exclusion criteria to undergo pci with either the bes or the ees . altogether
, 30% of included patients were over 75 years old , and 46% of the population in each group were diabetic .
efficacy endpoint was any tlr at 1 year , whereas the primary safety endpoint was a composite of death and mi .
primary efficacy endpoint occurred in 4.2% in both the bes group and the ees group ( one - sided pnon - inferiority<0.0001 , and p=0.93 for superiority ) .
the rate of any mi and stroke was similar between the two groups ( 3.3% versus 3.1 [ p=0.77 ] and 1.4% versus 1.5% [ p=0.89 ] ) .
no difference was observed in terms of mortality , 2.6% and 2.5% in the bes and ees groups , respectively , p=0.9 . with regard to the rate of st , the incidence was extremely low , and there was no difference between the bes group and the ees group ( 0.25% and 0.06% , p=0.18 ) .
the angiographic sub - study shows that the difference in in - segment late loss between the two groups was 0.03 mm , demonstrating non - inferiority of the bes , with a margin of 0.195 mm . of note ,
the rate of stent fracture was significantly higher in the bes group ( 3.1% versus 0% ; p=0.004 ) .
the authors concluded in the non - inferiority of the bes over the ees in the setting of stable coronary artery disease .
clinical outcomes were excellent , with a low rate of tlr and extremely low rate of st in each group .
third - generation dess using biodegradable polymer such as the nobori stent have been developed to overcome long - term adverse effects observed with first - generation dess related to the use of durable polymers , and to thereby shorten the duration of dapt and the ensuing risk of hemorrhagic complications .
biodegradable bess should nonetheless possess similar efficacy to actual dess in preventing isr ( lower rate of tlr as compared with bmss ) .
first studies evaluating bes efficacy and safety have shown promising results , with significantly lower in - stent late loss than with paclitaxel - eluting stents , and similar in - stent late loss as sess.54,57 however , the recent compare - ii , sort out v , and next trials , all three of which were sufficiently powered to compare clinical outcomes , showed contrasting results . to date , only the compare - ii and the next trials have evaluated a new third - generation des versus a second - generation des ( xience v or prime ) .
the compare - ii trial demonstrated non - inferiority of the bes relative to second - generation eess , but procedural failure was significantly higher in the bes group.60 by contrast , non - inferiority of the bes relative to the first - generation ses was not shown in the sort out v trial due to a higher risk of early st without a clear explanation for this phenomenon.59 in fact , the rate of st was particularly low in the ses group in this study .
the next trial is the largest trial , to date , evaluating the efficacy and safety of the bes as compared with the ees.61 in this trial , clinical and angiographic outcomes of the bes group were non - inferior to the ees group , and the device implantation success rate was comparable in both groups . of note , a higher rate of stent fracture was seen in the bes group in the angiographic sub - study of the next trial , but its imputability in very late st or tlr is uncertain and needs further exploration . of major importance , all these trials have enrolled low risk patients , and notably a low incidence of diabetics , with relatively simple angiographic lesions ( eg , large vessels , low rate of bifurcations , and lesion length < 20 mm ) .
these facts are critical regarding the interpretation of the results and the low rate of adverse events observed in these three trials : the primary efficacy endpoint was lower than 5% in all studies , and any conclusion must be interpreted with caution , especially in non - inferiority trials .
in addition , a safety comparison of modern dess is challenging . indeed , st , especially very late st , is a rare complication , and although 12-month results of standard trials usually enable safety or efficacy to be assessed , longer follow - up ( 5 years or more ) and large trials are mandatory in the present case in regard of late - event exploration .
the rate of st in the present studies is particularity low ( around 0.5% at 1 year ) , and these trials are not powered enough to evaluate such a low frequency event . finally ,
if present , the expected benefit of third - generation dess like the nobori stent over older dess would logically appear only after 1 year .
to date , no very late st with the nobori stent has been reported in the literature , with the limitation that long - term follow - up is currently only available for very few patients .
the leaders trial was the first randomized study to evaluate bess against durable polymer first - generation dess .
this trial included higher risk patients , and the rate of events was on average twice as high as compared with the compare ii , sort out v , and next trials .
the leaders study compared another third - generation bes ( biomatrix flex , biosensors , newport beach , ca , usa ) with sess .
the only difference between the biomatrix flex and the nobori stent is the presence of an ultra - thin non - degradable parylene coating between the stent and the polymer on the nobori stent to assure polymer attachment to the stent struts , which do not exist on the biomatrix flex. the final 5-year report has just been published62 and demonstrates that the bes is non - inferior to the ses with regard to the primary endpoint ( cardiovascular death , mi , and clinically driven target vessel revascularization ) ( 22.3% in the bes group versus 26.1% in the ses group ; p=0.071 ) .
in addition , even though no significant difference was observed between the bes and the ses in total definite st at 5 years , the bes was associated with a significantly lower rate of very late st and secondary composite endpoint ( all cause death , any mi , any revascularization ) ( 0.6% in the bes group versus 2.2% in the ses group for very late st [ p=0.003 ] , and 35.1% versus 40.4% for secondary composite endpoint [ p=0.02]).62 a recently pooled analysis based on patient individual data from the isar - test 3 , the isar - test 4 , and the leaders trial63 has demonstrated that biodegradable polymer dess ( including : biodegradable polymer bes [ biomatrix flex ] , n=857 ; and biodegradable polymer ses , n=1,501 ) improve safety and efficacy over first - generation sess during long - term follow - up .
the three trials separately showed no differences between bess and dess in the past , highlighting the lack of statistical power of these studies ( taken alone ) to detect relevant differences in very low frequency events such as st . in this meta - analysis ,
the benefit of bess was seen in the rate of st ( 0.2% versus 1.3% , p=0.004 ) , mi ( 1.5% versus 3% , p=0.03 ) , and cardiac death ( 3.9% versus 4.9% , p=0.05 ) . of note
, bess also showed a significant reduction in tlr in this meta - analysis ( 12% versus 13.7% , p=0.029 ) .
these trials were performed with sirolimus first - generation dess as control , and results can not be extended to other second - generation dess .
further studies using second - generation dess as control are required to make any conclusions .
interestingly , such a meta - analysis of trials that have evaluated the nobori stent may carry interesting conclusions in the next future .
bmss and dess have changed the landscape of current pci by significantly reducing the rate of isr .
however , first - generation dess have been associated with a higher rate of late or very late st .
the physiopathology of this rare but serious event is multifactorial , but inflammation and delayed arterial healing , of which the durable polymer may be a putative mechanism , has an important role .
the concept of biodegradable polymer and totally bioresorbable scaffolds looks , in consequence , very interesting .
long - term follow - up is mandatory to see if the implantation of these third - generation dess will improve clinical outcomes with a lower rate of st and mi .
further studies and results of their long - term follow - up would definitely shed light on patient outcomes with the use of such devices .
 first - generation drug - eluting stents have raised concerns regarding the risk of late and very late stent thrombosis compared with bare metal stents and require prolonged dual antiplatelet therapy . despite extensive investigations , 
 the physiopathology of these late events remains incompletely understood . aside from patient- and lesion - related risk factors , 
 stent polymer has been cited as one of the potential causes . 
 in fact , the persistence of durable polymer after complete drug release has been shown to be responsible for local hypersensitivity and inflammatory reactions . 
 third - generation drug - eluting stents with more biocompatible or biodegradable polymers have subsequently been developed to address this problem . in this article , we evaluate and discuss the concept and clinical results ( safety and efficacy ) of a third - generation drug - eluting stent with biodegradable polymer : the nobori stent . 
Introduction
Rationale for new stent development
Stent structure and concept for new development
The BES with biodegradable polymer (Nobori) stent: design and clinical results
Discussion
Conclusion