drug - eluting stents ( des ) have not only improved clinical outcomes compared with bare metal stents ( bms ) , they have vastly enhanced our capability and confidence to tackle increasingly complex patients and lesions traditionally treated with coronary artery bypass graft surgery ( cabg ) [ 13 ] .
this has in turn increased percutaneous coronary interventional ( pci ) procedural volumes worldwide and des use in clinical and angiographic scenarios not initially tested and approved by the u.s .
food and drug administration ( fda ) , otherwise referred to as off - label use .
the result has been justifiable concerns regarding the efficacy and associated risk of des in these situations .
however , these concerns have been continually addressed by carefully collected outcomes analyses from large longitudinal registries , data from randomized controlled trials ( rcts ) , and translational research studies combined with advances in des technology .
importantly , this effort has been a result of unprecedented collaboration between regulatory bodies , industry , and the interventional community . in this review ,
the clinical outcome data of the most recently fda - approved des are critically examined , the resolute zotarolimus - eluting stent ( r - zes , medtronic , inc .
, santa rosa , ca , usa ) , and the unique features of the next iteration of the r - zes built on the integrity platform ( medtronic , inc . , santa rosa , ca , usa ) to further enhance stent flexibility and deliverability , especially in complex lesions
the integrity bms is a new iteration of the driver bms ( medtronic , inc .
, santa rosa , ca , usa ) ; the zotarolimus - eluting version is the resolute integrity stent where integrity bms replaces the driver platform in the new stent .
the integrity stent platform uses a single cobalt chromium wire to form a continuous sinusoidal pattern of crowns and struts wrapped helically around a mandrel with a 0.09  mm strut thickness and a 1.12  mm crossing profile .
this unique manufacturing technology enhances stent flexibility , deliverability , and conformability without sacrificing radial strength .
a study of stent longitudinal distortion tested seven stent platforms including the endeavor driver ( medtronic , inc .
, santa rosa , ca , usa ) , resolute integrity ( medtronic , inc . , santa rosa , ca , usa ) , liberte ( boston scientific , natick , ma , usa ) , omega promus element ( boston scientific , natick , ma , usa ) , multilink 8xience prime ( abbott vascular , santa clara , ca , usa ) , and vision xience v ( abbott vascular , santa clara , ca , usa ) .
the resolute integrity des was more resistant to longitudinal distortion in elongation tests than the omega element or driver stents , and similar to the other stents tested .
the authors note that ideally there must be a balance between stent flexibility and stiffness which has been shown to correlate with the number of connectors between hoops .
the resolute integrity and the driver platform have two connections compared with three for xience v and xience prime stents , but the unique helical single - wire design decreases the longitudinal distortion of the resolute integrity stent thus maintaining a balance between flexibility and longitudinal integrity [ 5 , 6 ] .
radial strength is primarily responsible for creating and maintaining vessel patency and studies have shown it to be an important predictor of clinical performance [ 79 ] .
in - house testing at medtronic has shown equivalence in radial strength between the driver and integrity stents .
performance of the resolute integrity stent platform was compared with five other contemporary stents deployed in an idealized vessel using finite element simulations .
percent malposition of stent struts , defined as the strut distance from the wall > 10  m was least with the resolute integrity platform at 9% and maximal with the promus element stent at 43% .
furthermore , these investigators used finite element analysis correlated with bench testing of radial strength and demonstrated similar radial strength to the promus element stent ( ~0.012  mm / n diameter reduction at given force ) and greater radial strength than the multilink vision ( ~0.16  mm / n ) or xience prime stents ( ~0.018  mm / n diameter reduction ) ( personal communication )
. the r - zes is covered with a proprietary biolinx ( medtronic , inc .
, santa rosa , ca , usa ) tripolymer , a blend of the hydrophilic c19 polymer , polyvinyl pyrrolidinone ( pvp ) and the hydrophobic c10 polymer .
the pvp component results in an overall hydrophilic polymer which enhances the biocompatibility of the stent .
there is an initial release of zotarolimus from the surface of the stent followed by extended drug elution .
nearly 85% of the zotarolimus ( dose density ~1.6  g / mm ) is released by 60  days , and completely by 180  days .
the thin strut , low profile , and continuous sinusoidal design combined with the biocompatible polymer and extended drug release is designed to maximize deliverability and efficacy of this new generation r - zes .
however , the evidence regarding its long - term safety for complex patient subsets also needs to be critically examined . this review will summarize the clinical data for the r - zes and discuss results in the context of complex  real - world  pci
the pubmed database was used to identify all prospective clinical trials for the r - zes and the everolimus - eluting stent ( ees ) for the past 5  years .
related presentations for the past 2  years were obtained from the transcatheter cardiovascular therapeutics , american college of cardiology , and pcronline websites .
the pubmed database was also searched for preclinical data using a zotarolimus - eluting stent , biolinx polymer , coronary stent design , and coronary stent performance search terms .
the first - in - man r - zes experience ( resolute study ) was a 139 patient , multicenter , prospective study examining 9-month in - stent late loss and target lesion revascularization ( tlr ) in stenotic de novo lesions in coronary vessels with reference vessel diameter between 2.5 and 3.5  mm in diameter and 14  mm to 27  mm in length .
the study required a 4-month angiographic and intra - vascular ultrasound ( ivus ) follow - up in the first 30 patients and a 9-month follow - up in the remainder .
complex patients with recent myocardial infarction , left ventricular ejection fraction ( lvef ) < 30% and ostial , bifurcation , heavily calcified , or left main lesions were excluded .
dual anti - platelet therapy ( dapt ) with aspirin and clopidogrel was prescribed for 6  months post - pci , and aspirin continued indefinitely thereafter .
the 9-month in - stent late lumen loss was 0.22    0.27  mm .
tlr rates at 9  months , 1 , 2 , and 4  years were 0.0% , 0.8% , 1.5% , and 2.3% , respectively . the academic research consortium ( arc)-defined definite and probable stent thrombosis ( st ) events at 4  years remained at 0.0% [ 12 , 13 ] . though this experience was restrictive and may not reflect  real - world 
des use , it certainly set the best - case reference of r - zes performance .
the results from the single - arm resolute us trial ( r - us ) , which included 1,402 patients with 1- or 2-vessel coronary artery disease from 116 us centers with lesions suitable for 2.254.0  mm r - zes was reported in april 2011 .
though the main analysis was performed on a prespecified group of single - lesion patients treated with 2.53.5  mm r - zes , a 241 patient cohort received the 2.25  mm r - zes or had two lesions treated .
the overall ( 2.254.0  mm ) target lesion failure ( tlf ) rate was 4.7% , and rates of cardiac death , myocardial infarction ( mi ) , and tlr were 0.7% , 1.4% , and 2.8% , respectively . the 12-month rate of st was 0.1% . the resolute all - comers ( r - ac ) trial was an international , multicenter rct including 2,292 patients with an open - label random assignment of a wide variety of unrestricted coronary lesions in a 1:1 fashion to either r - zes or ees .
there were no restrictions on the number of lesions , vessels , or number of implanted stents .
most importantly , 1,520 patients were defined as complex based on prespecified definition , with a well - balanced allocation to r - zes ( 764 patients and 1,227 lesions ) and ees ( 756 patients and 1,242 lesions ) groups .
the definition of complex patients is shown in table  1.table  1prespecified definition of complex patients in resolute all - comers trial 
 complex patients criteria 

 ( presence of at least one of the following ) 
 acute myocardial infarction within 72  hleft ventricular ejection fraction < 30%renal insufficiency or failure ( serum creatinine 140  mol / l)treatment of bifurcation coronary lesionstreatment of saphenous vein graft lesionstreatment of arterial graft lesionstreatment of in - stent restenosis lesionstreatment of unprotected left main coronary lesionstreatment of 2 coronary vesselstreatment of coronary lesions 27 
mm in lengthtreatment of > 1 lesion per coronary vesseltreatment of coronary vessels with presence of thrombustreatment of coronary total occlusions prespecified definition of complex patients in resolute all - comers trial   the primary 12-month noninferiority endpoint of tlf , defined as a composite of cardiac death , target vessel mi , and clinically indicated tlr , was met ( r - zes 8.2% vs. ees 8.3% , noninferiority p  <  0.001 ) . the mean syntax ( boston scientific , natick , ma , usa ) score was 16.6    9.4 in the complex r - zes patients , compared with 11.2    7.9 in the simple r - zes patients .
patients with recent acute mi , diabetes mellitus ( dm ) , and lvef < 35% constituted 43.5% , 23.1% , and 3.8% of the complex patient cohort , respectively .
bifurcation , left main , saphenous vein graft , and chronic total occlusion pci were performed in 26% , 3.1% , 3.5% , and 25% of complex patients .
overall , tlf was 6.3% and 9.3% ( p  =  0.015 ) at 1  year for simple and complex patients , respectively .
similarly , target vessel failure ( tvf ) in the entire study , defined as a composite of cardiac death , target - vessel mi , and clinically indicated target vessel revascularization ( tvr ) was 7.1% and 10.4% ( p  =  0.009 ) at 1  year for simple and complex patients , respectively .
a patient oriented 1-year composite endpoint including all cause death , mi , and any repeat revascularization was identified as a secondary clinical endpoint and was also higher for complex patients compared with simple ( 16.1% vs. 11.6% , p  =  0.004 ) . definite or probable st occurred in 2.2% of complex patients and in 1.35% of simple patients , with no difference between the r - zes and ees groups ( p value for interaction  =  0.14 ) .
prespecified 2-year clinical outcomes of the r - ac trial demonstrated sustained safety and efficacy for the r - zes and ees .
the rates of tlf at 3  years were 13.1% for r - zes and 12.4% for ees ( p  =  0.614 ) . additionally , the rates of definite or probable st at 3  years were also low .
rates of definite or probable very late stent thrombosis ( vlst ) were 0.5% for both stents .
dapt use was 84.4 and 83.5% at 1  year for the r - zes and ees groups , respectively ( p  =  0.60 ) . the resolute international trial ( r - int ) trial enrolled an unrestricted cohort of 2,349 patients ,
two - thirds of which were complex with at least one r - zes ( 2.254.0  mm stent diameter ) .
nearly 30% of patients were diabetic and 46% presented with an acute coronary syndrome ( acs ) .
the composite primary endpoint of cardiac death and target vessel mi at 1  year was 4.3% .
the pooled resolute clinical program derived from five r - zes studies ( resolute , r - us , r - ac , r - int and resolute japan ) includes 5,130 patients .
the diabetic cohort was older with expectedly more patients with hypertension , hyperlipidemia , or prior pci . at 2  years , clinically - driven tlr was 4.7% and definite or probable st was 0.9% . in a prespecified analysis of less complex patients with dm , 2-year rates of clinically - driven tlr and definite or probable st for patients with dm ( n  =  861 ) was 4.8% and 0.3% , respectively ( fig .  1 ) . in the nondiabetic cohort ( n  =  1,903 )
these data indicate consistently low event rates and durable clinical outcomes in the higher - risk patients with dm .
based on these data the r - zes is the first des approved by the fda for use in patients with dm.fig . 
1two - year event rates for standard - risk patients with diabetes mellitus ( n  =  861 ) in the pooled resolute global clinical program   st stent thrombosis , tlf target lesion failure , tlr target lesion revascularization , tvf target vessel failure , tvmi target vessel myocardial infarction two - year event rates for standard - risk patients with diabetes mellitus ( n  =  861 ) in the pooled resolute global clinical program   st stent thrombosis , tlf target lesion failure , tlr target lesion revascularization , tvf target vessel failure , tvmi target vessel myocardial infarction the diabetic population included 29.6% of patients with insulin - dependent dm . at 1  year , event rates were significantly higher in patients with insulin - dependent diabetes mellitus iddm compared with those without dm ( tlr 6.3% vs. 2.9% [ p  < 
0.001 ] ; cardiac death or mi 6.6% vs. 3.6% [ p  =  0.003 ] ; st 1.5% vs. 0.7% [ p  =  0.02 ] ) .
the cumulative incidence of tlf , cardiac death , target vessel mi , and tlr was similar for dm patients receiving the r - zes ( 7.8% ) and the ees ( 9.0% ) at 1  year ( p  =  0.96 ) ; there was a trend to lower tlf in the non - dm patients ( r - zes 6.1% ; ees 8.3% ; [ p  =  0.09 ] ) .
one year outcomes for r - zes and ees dm patients were also similar for rates of tlr , cardiac death or mi , and st . these data also indicate to the strength of the resolute pooled clinical program which was conceptualized using similar event definitions , adjudication , and data management methodology across a myriad of r - zes trials .
it is imperative that data from this large and diverse cohort of patients representing a  real - world
 patient population will continue to be the source of important data and guide contemporary pci practice worldwide .
stefanini et al .   compared the r - zes results from the r - ac rct to other rcts with  all comer  patients . in the sirolimus - eluting and paclitaxel - eluting stents for coronary revascularization ( sirtax ) trial , 12-month clinically - driven tlr and definite st rate were 8.9% and 1.9% , respectively . in the limus
eluted from a durable versus erodable stent coating ( leaders ) trial , though only a fifth of the patients had angiographic follow - up , clinically - driven tlr and definite st rates were 5.5% and 2.0% at 12  months , respectively .
the randomized controlled trial of everolimus - eluting stents and paclitaxel - eluting stents for coronary revascularization in daily practice ( compare ) trial reported a 1-year clinically driven tlr of 2% and a definite st rate of 0.4% .
the results from the r - zes trials , especially r - ac , compared very favorably with other all - comer studies , while including a much more complex patient population and lesion categories .
a meta - analysis of 76 rcts with 117,762 patient - years of follow - up found considerable variations in the magnitude of long - term tvr rates ( 3961% ) by des type ( zes - r  =  ees  >  paclitaxel - eluting stent  >  zes  >  bms ) .
overall , there was no long - term increase in death with any of the des . in the r - ac trial ,
r - zes was associated with a higher definite stent thrombosis at 1  year than ees ( 1.2% vs. 0.3% ; [ p  =  0.01 ] ) , while definite or probable stent thrombosis at 2  years were 1.9% and 1.0% ( p 
=  0.08 ) for r - zes and ees , respectively [ 16 , 18 ] however , in the twente trial , definite or probable st rates for r - zes and ees were 0.9% and 1.2% , respectively ( p  =  0.59 ) .
definite st rates were also low ( 0.58% and 0% , respectively [ p  =  0.12 ] ) . comparative data of st across r - zes and ees studies is shown in fig .  2 [ 16 , 20 , 25 , 2734 ] .
it is important to note that these data are not based on direct comparisons and on studies not powered for the low frequency st event .
these data suggest a very low risk of st with r - zes and ees stents and the observed differences are caused by chance.fig . 
arc definite and probable st at 12 months from 10  real - world  clinical trials .
it is important to note that these data are not based on direct comparisons and on studies not powered for the low frequency st event .
arc academic research consortium , compare second - generation everolimus - eluting and paclitaxel - eluting stents in real - life practice , estrofa-2 estudio espanol sobre trombosis de stents farmacoactivos de segunda generacion-2 , isar individualizable drug - eluting stent system to abrogate restenosis , lesson 1 long - term comparison of everolimus - eluting and sirolimus - eluting stents for coronary revascularization , r - int resolute international , risico resolute italian study in all comers , st stent thrombosis stent thrombosis across resolute and everolimus - eluting stent trials . arc definite and probable st at 12 months from 10  real - world  clinical trials .
it is important to note that these data are not based on direct comparisons and on studies not powered for the low frequency st event .
arc academic research consortium , compare second - generation everolimus - eluting and paclitaxel - eluting stents in real - life practice , estrofa-2 estudio espanol sobre trombosis de stents farmacoactivos de segunda generacion-2 , isar individualizable drug - eluting stent system to abrogate restenosis , lesson 1 long - term comparison of everolimus - eluting and sirolimus - eluting stents for coronary revascularization , r - int resolute international , risico resolute italian study in all comers , st stent thrombosis patti et al .  
reported in a 2008 meta - analysis of nine studies comparing des with bms in dm patients , including 1,141 patients , an in - stent restenosis ( isr ) and tlr rates with bms of 41% and 27% , significantly higher than first generation des isr and tlr rates of 8% and 8% , respectively ( p  <  0.0001 for both comparisons ) . in a pooled analysis of ees versus paclitaxel - eluting stent from the spirit and
compare trials , ischemia - driven tlr rates were 6.1% and 5.5% for diabetics in the paclitaxel - eluting and ees recipients , respectively ( p  =  0.60 ) ; it was 6.9% and 3.6% , respectively in nondiabetics ( p  <  0.0001 ) .
, tvr rates in patients with dm with sirolimus - eluting stent and ees were 10.7% and 6.7% at 18  months , respectively .
while this subgroup analysis was not powered to assess these endpoints , these data support the observation that significant strides have been made with respect to pci outcomes in diabetics with complex coronary artery disease revascularized percutaneously with r - zes .
r - zes use in complex patients and lesions is associated with durable efficacy and safety and represents another generational improvement in des technology , which will undoubtedly enhance patient outcomes post - pci .
 the introduction of first - generation drug - eluting stents ( des ) was a major advance in the percutaneous treatment of coronary artery disease , with des significantly reducing the incidence of restenosis and major adverse coronary events compared with bare metal stents . 
 next - generation des now utilizes lower profiles , thinner struts , and other technological advances to help extend their safety and efficacy . 
 importantly , studies of next - generation devices have now gone beyond controlled clinical trials with selected populations to registries and studies with all - comer populations , where more diverse and complex sets of patients and lesions have been managed . 
 thus , a large body of evidence and comparative data about the safety and efficacy of these devices has accumulated . 
 the resolute zotarolimus - eluting stent ( r - zes ; medtronic inc . , santa rosa , ca , usa ) is a next - generation des that uses a novel biocompatible polymer on a cobalt alloy stent platform to extend the duration of drug elution and improve the stent s efficacy . 
 the integrity platform ( medtronic , inc . 
 , santa rosa , ca , usa ) used in the most recent iteration of the r - zes stent further enhances the flexibility and deliverability of the stent in complex lesions by incorporation of a continuous sinusoidal design . in the following review , 
 the clinical data is critically examined for the r - zes and discuss its performance using comparative data currently available for next - generation des .  
 it is concluded that r - zes use in complex patients and lesions is associated with durable efficacy and safety and represents another generational improvement in des technology , which undoubtedly will enhance patient outcomes postpercutaneous coronary interventional . 
Introduction
R-Zes
Methods
R-Zes Clinical Studies
R-Zes Results In Perspective
Conclusion