Restenosis, Stent Thrombosis, and Bleeding Complications · THE PRESENT AND FUTURE STATE-OF-THE-ART REVIEW Restenosis, Stent Thrombosis, and Bleeding Complications Navigating Between

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J O U R N A L O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y VO L . 7 1 , N O . 1 5 , 2 0 1 8

ª 2 0 1 8 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Restenosis, Stent Thrombosis, andBleeding ComplicationsNavigating Between Scylla and Charybdis

Juan Torrado, MD, PHD,a,b Leo Buckley, PHARMD,a Ariel Durán, MD,b Pedro Trujillo, MD,b Stefano Toldo, PHD,a

Juan Valle Raleigh, MD,c Antonio Abbate, MD, PHD,a,d Giuseppe Biondi-Zoccai, MD, MSTAT,e,f Luis A. Guzmán, MDa

ABSTRACT

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The field of interventional cardiology has significantly evolved over 40 years by overcoming several challenges. The

introduction of first-generation drug-eluting stents significantly reduced the rates of restenosis, but at the expense of an

increase of late stent thrombosis. Prolonged antithrombotic therapy reduced rates of stent thrombosis, but at the cost of

increased bleeding. Although the advent of second-generation drug-eluting stents subsequently reduced the incidence

of late stent thrombosis, its permanent nature prevents full recovery of vascular structure and function with accordant

risk of very late stent failure. In the present era of interventional cardiology, the tradeoff between stent thrombosis,

restenosis, and bleeding presents as a particularly complex challenge. In this review, the authors highlight major

contributors of late/very late stent thrombosis while targeting stent restenosis, and they discuss evolutionary advances in

stent technology and antiplatelet therapy, to further improve upon the care of patients with coronary artery disease.

(J Am Coll Cardiol 2018;71:1676–95) © 2018 by the American College of Cardiology Foundation.

A lthough the introduction of bare-metal stents(BMS) significantly reduced balloon angio-plasty–associated complications decreasing

emergency coronary artery bypass grafting surgeryand restenosis, BMS were themselves related with aserious phenomenon, stent thrombosis (ST) (1,2). STconstitutes one of the most catastrophic complica-tions of percutaneous coronary intervention (PCI),typically presenting as a large ST-segment elevationmyocardial infarction (STEMI) or as sudden cardiacdeath, requiring emergency repeat PCI. Theincorporation of dual-antiplatelet therapy (DAPT),as well as parallel improvements in stentdeployment techniques, provided some relief to thiscomplication, especially by reducing early ST events(<30 days) (2,3).

N 0735-1097/$36.00

m the aDepartment of Cardiology, VCU Pauley Heart Center, Virgini

epartment of Cardiology, Clinic Hospital, School of Medicine, Republic

rdiology, Hospital Italiano, Buenos Aires, Argentina; dVictoria Johnson Re

y, Richmond, Virginia; eDepartment of Medico-Surgical Sciences and Bio

ly; and the fDepartment of AngioCardioNeurology, IRCCS Neuromed, Pozzi

scular and Bayer. All other authors have reported that they have no rel

close.

nuscript received October 15, 2017; revised manuscript received January

The massive utilization of BMS revealed anotherlimitation of the device: a progressive loss of thearterial lumen inside the stent seen several monthsafter PCI (4,5). With a more benign course, in-stentrestenosis (ISR) decreased the overall efficacy of thetechnique leading to recurrent angina and need foradditional target lesion revascularization (TLR) pro-cedures (6). The demonstration of neointimal hyper-plasia (NIH) as the main mechanism involved in ISRprompted the introduction of first-generation drug-eluting stents (1G-DES) (7). These stents providedstriking results in reducing ISR, but an unexpectedand worrying increase in late and very late ST(>30 days to 1 year and >1 year, respectively) wasobserved, triggering a reflex increase in DAPT in-tensity and duration (8). However, prolonged

https://doi.org/10.1016/j.jacc.2018.02.023

a Commonwealth University, Richmond, Virginia;

University, Montevideo, Uruguay; cDepartment of

search Laboratory, Virginia Commonwealth Univer-

technologies, Sapienza University of Rome, Latina,

lli, Italy. Prof. Biondi-Zoccai has consulted for Abbott

ationships relevant to the contents of this paper to

17, 2018, accepted February 11, 2018.


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ABBR EV I A T I ON S

AND ACRONYMS

1G-DES = first-generation

drug-eluting stent(s)

2G-DES = second-generation

drug-eluting stent(s)

ACS = acute coronary

syndrome(s)

BA = balloon angioplasty

BES = biolimus-eluting stent(s)

BMS = bare-metal stent(s)

BP-DES = biodegradable

polymer-based drug-eluting

stent(s)

BRS = bioresorbable

scaffold(s)

BVS = bioresorbable vascular

scaffold(s)

CI = confidence interval

CoCr = cobalt chromium

DAPT = dual-antiplatelet

therapy

DES = drug-eluting stent(s)

DT = device thrombosis

EES = everolimus-eluting

stent(s)

HR = hazard ratio

ISR = in-stent restenosis

LST = late stent thrombosis

NA = neoatherosclerosis

NIH = neointimal hyperplasia

OCT = optical coherence

tomography

OR = odds ratio

PCI = percutaneous coronary

intervention

PtCr = platinum chromium

RCT = randomized controlled

trial

Re-ZES = Resolute

zotarolimus-eluting stent(s)

SES = sirolimus-eluting

stent(s)

SM = stent malapposition

ST = stent thrombosis

STEMI = ST-segment elevation

myocardial infarction

TLF = target lesion failure

TLR = target lesion

revascularization

VLST = very late stent

thrombosis

J A C C V O L . 7 1 , N O . 1 5 , 2 0 1 8 Torrado et al.A P R I L 1 7 , 2 0 1 8 : 1 6 7 6 – 9 5 Restenosis, Stent Thrombosis, and Bleeding

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antithrombotic therapies introduced a new hazard inthe form of serious bleeding complications (9).

A major step forward in PCI was achieved with theadvent of current second-generation DES (2G-DES),incorporating more biocompatible or biodegradablepolymers, different drug release formulation, stentplatforms, and designs, with the associated decreasein ISR, ST, duration of DAPT, and bleeding (10,11).Novel stent technologies, however, such as fullybioresorbable scaffolds (BRS), have unfortunatelynot fulfilled the promise of reaching the theoreticalideal of reducing very late stent complications,and much work remains to further optimize thistechnology (11–13).

The story of 40 years of PCI can be illustrated asOdysseus’s ship navigating through a strait, in which2 “sea hazards” are situated close enough to eachother that they posed an unavoidable threat to pass-ing sailors: avoiding Charybdis (e.g., restenosis) couldmean passing too close to Scylla (e.g., thrombosis), aswell as avoiding ST could represent increasing severebleeding. The aims of this review are first to analyzehow late ST has been closely linked to the attemptsto avoid restenosis, and second, to review majoradvances in stent technology and antiplatelet therapyto further reduce the occurrence of ST, while bothmaintaining a powerful antirestenosis effect andaffording the lesser possible bleeding hazards.

For this review, pertinent studies were searched inPubMed/Medline (updated December 2017) using thefollowing terms: stent thrombosis, stent restenosis, an-tiplatelet therapy, drug-eluting stent, biodegradablepolymer, and bioresorbable vascular scaffold. Given thedesign of this work as a narrative review, no formalcriteria for study selection or appraisal were enforced.

ST AS AN “ADVERSE EFFECT” OF

ANTIRESTENOSIS THERAPIES

FROM STAND-ALONE BALLOON ANGIOPLASTY TO BMS.

The first balloon angioplasty (BA) of a coronaryatherosclerotic plaque performed by Andreas Grünt-zig in 1977 (14) marked the birth of the field of inter-ventional cardiology. However, at present, with fewexceptions, BA is rarely preferred as a stand-alonetreatment (Figure 1).

In 1986, BMS were introduced into the therapeuticarsenal representing the second turning point in thehistory of interventional cardiology (15). However,the success of BMS was initially eclipsed with theoccurrence of serious ST episodes. In fact, ST wasoptimally circumvented more than a decade lateronly after 2 paramount advances were simulta-neously achieved. First, old antithrombotic regimens

(including heparin, dextran, warfarin, anddipyridamole) were replaced by a saferDAPT regimen (including aspirin and aP2Y12 receptor inhibitor) (9,16). Second, theunderstanding of the concept of “adequate”stent deployment technique, with optimalimplantation strategy aiming at an absolutelyperfect primary result with no residual nar-rowing, absence of dissections, and completestent expansion and apposition (2,3,17).

Initially, stents were considered a “bail-outprocedure” in the case of abrupt or threat-ened artery closure post-BA, reducing theneed of emergent coronary artery bypassgrafting (17). However, several years later, theBENESTENT (BElgian NEtherlands STENTstudy) and STRESS (Stent Restenosis Study)trials demonstrated that routine electiveplacement of a Palmaz-Schatz stent signifi-cantly reduced the rates of angiographicrestenosis as compared with BA (1,18).Although, current BMS offer improved geo-metric structure, thinner struts [<120 mm])and stronger alloys, the risk of NIH and TLRhave relegated BMS to second-line therapy (7).

LATE/VERY LATE ST WHILE PREVENTING

NIH. NIH is a complex and time-dependentphenomenon that occurs in response to deepvascular injury after BA and stenting. It ischaracterized by inflammation, smooth mus-cle cells migration, proliferation, and pro-duction of collagen fibers in the extracellularmatrix (5,19).

Early efforts to reduce NIH includedintracoronary brachytherapy, which despitepromising data for reducing NIH over mid-term follow-up, were limited by a “latecatch-up phenomenon” and an increase inlate ST (20). Indeed, late ST rates of w10%have been observed, depending on theuse of DAPT (20,21).

A major breakthrough in interventionalcardiology was the introduction of 1G-DES.DES while maintaining the mechanical ad-vantages of BMS are able to effectively deliveran antiproliferative therapy locally to thearterial wall. In fact, 1G-DES rapidly becamethe standard of care resulting in angiographicrestenosis rates of a “single digit number” at 6to 12 months follow-up (4). Unfortunately,like prior advances in PCI, there are 2 sides to
the 1G-DES story: on the one hand, 1G-DES reducedthe need for TLR by at least 50% to 70% (7), but on the

FIGURE 1 Milestones in the Evolution of PCI Over the First 40 Years

1996: Introduction of DAPT to prevent early ST by Schömig1977: First coronary BA byAndreas Grüntzig

2017: FDA raises concern about ABSORBlate ST. Abbott removes stent from market

2008: FDA approval of XIENCE everolimus,and ENDEAVOR zotarolimus-eluting stents

2007: Late ST concerns with 1G-DES firstdescribed by Camenzind (ESC Congress)

2003/04: Introduction of the CYPHERsirolimus and TAXUS paclitaxel-eluting stents

1995: Introduction of “stent deploymentoptimization concept” by Colombo

1994: FDA approval of the Palmaz-Schatz to prevent restenosis post-BA

1986: First coronary BMSimplantation by Sigwart andPuel

1977 1982

*Immediate alleviation ofischemia

†Abrupt vessel closure†Unacceptably high restenosisrates (30 – 50% at 12 months)

*↓BA-associated abrupt vessel closure*↓BA-related restenosis rates

†Restenosis rates still high (20 – 30 % at 12 months)

*↓ISR burden(5 – 15% at 12months)

†Impairedarterial healing†↑LST and VLST

*↓ISR burden (≤5% at12 months)*↓LST and VLST

†Impaired late recoveryof vascular structureand function ?‡

1987 1992 1997 2002 2007 2012 2017 2022

BRS

2016: FDA approval ofABSORB GT1 BVS system

2015: FDA approval ofbiodegradable polymerSYNERGY everolimus-eluting stent

1991: First treatment ofAMI with coronary stentingby Cannon and Roubin

Stand-alone BA

BMS

1G-DES

2G-DES

BP-DES

*Strength of the procedure. †Weakness of the procedure. ‡A definitive role in PCI is not yet established. The intensity of the color and length of the arrows correlate

with interventional procedure utilization. 1G-DES ¼ first-generation drug-eluting stent; 2G-DES ¼ second-generation drug-eluting stent; AMI ¼ acute myocardial

infarction; BA ¼ balloon angioplasty; BMS ¼ bare-metal stent; BP-DES ¼ biodegradable polymer-based drug-eluting stents; BRS ¼ bioresorbable scaffold;

DAPT ¼ dual-antiplatelet therapy; ESC ¼ European Society of Cardiology; FDA ¼ Food and Drug Administration; ISR ¼ in-stent restenosis; LST¼ late stent thrombosis;

PCI ¼ percutaneous coronary intervention; ST ¼ stent thrombosis; VLST ¼ very late stent thrombosis.

Torrado et al. J A C C V O L . 7 1 , N O . 1 5 , 2 0 1 8

Restenosis, Stent Thrombosis, and Bleeding A P R I L 1 7 , 2 0 1 8 : 1 6 7 6 – 9 5

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other, resulted in the creation of a new problem, asignificant increase in the risk of late ST (LST) andvery late ST (VLST) (19,22).

McFadden et al. (23) reported seminal clinical andangiographic evidence of late 1G-DES–related throm-bosis (>6 months) in the setting of DAPT interruption.Importantly, the SORT-OUT II (Comparison of CypherSelect and Taxus Express Coronary Stents) study(N ¼ 2,098) showed that the rate of VLST with 1G-DESremains constant (i.e., at an annual rate of 1.3% afterthe first year) over a 10-year period without evidenceof plateau (24). Based on this safety and efficacyprofile, the interventional community conceived theuse of 1G-DES as a double-edged sword, and LST/VLST as the last remaining obstacle in coronary in-terventions (25).

Delayed re-endothelialization is the primary hy-pothesis of the underlying substrate involved in latethrombotic events in a well-deployed DES (22,23).Even though prolonged DAPT alleviates these events(Figure 2), 3 large prospective optical coherence

tomography (OCT) registries assessing the intravas-cular morphologies of coronary stents of patientsexperiencing ST revealed that stent malappositionand rupture of a neoatherosclerotic plaque werehighly prevalent findings, potentially implicated inLST/VLST, in addition to isolated uncovered struts(Table 1) (26–28).

IMPAIRED RE-ENDOTHELIALIZATION AND UNCOVERED

STRUTS. The most widely accepted mechanismexplaining the excess risk of LST/VLST seen with 1G-DES was delayed re-endothelialization due to theantiproliferative effect of the drugs released by thesedevices (19,22). Indeed, evidence of delayed arterialhealing as a contributor to LST/VLST was first seenwith the use of intracoronary brachytherapy (20).Although antiproliferative drugs inhibit NIH by tar-geting smooth muscle cells, they unintentionallydelay or impair endothelial cellular mitosis (i.e., re-endothelialization) required to restore the naturalbarrier between the foreign stent and intravascular

FIGURE 2 Classic Understanding of Restenotic and Thrombotic Complications Following PCI Procedures

Target lesion

BA

Edge dissection Coronaryspasm

Negativeremodeling

Neointimalhyperplasia

Thrombus

Plaquecompressed

Lumen

Arterial wall

Plaque

Plaque

Antiproliferative drug required

Stent

Stent

StentStent

Endothelium

ThrombusUncoveredStruts


Drug elutedDES

Early/late ST (DAPT disruption)*

Thrombus

Thrombus


Stent

Stent

Endothelium†DAPTDiscontinuation

Acute vessel closure

BMS

Early ST*

ISRSevere diffuse ISR

Focal ISRVery late ST

Luminal restenosis

Elastic recoil

Scaffoldrequired

Atheroma plaque

Procedure Periprocedural PCI 6 months FU 12 months FU > 12 months FU

*Technical improvements and strict compliance with DAPT reduced early and late ST. DAPT disruption: cessation of DAPT due to noncompliance or bleeding. †Guideline-

recommended DAPT discontinuation at 12 months may leave uncovered struts (non–re-endothelialized) vulnerable to very late ST (VLST). FU¼ follow-up; abbreviations

as in Figure 1.


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cells, as evidenced in necropsy studies and clinicalinvestigations (19,22).

The presence of >30% uncovered struts/cross sec-tion was identified to be a strong predictor of LST

TABLE 1 Dominant Findings Identified by OCT imaging at the Time of

Study (Year) (Ref. #)Uncovered

Struts Malapposition

PRESTIGE Registry (2017) (27)

LST/VLST (N ¼ 134), % 22 14

PESTO French Registry (2016) (26)

LST/VLST (N ¼ 97), % 10 32

Taniwaki et al.† (2016) (28)

VLST (N ¼ 57), % 12 35

*Other OCT observations at the time of LST/VLST include coronary evaginations, edge r

DES ¼ drug-eluting stent; LST ¼ late stent thrombosis; OCT ¼ optical coherenceThrombosis assessed by OCT; PRESTIGE Registry ¼ PREvention of Stent Thrombosis by an

after DES implantation (29). Findings from OCT andintravascular ultrasound in an in vivo case-controlledstudy, revealed that w80% of patients with LSTexhibited uncovered struts and w70% had >30%

LST/VLST Reported in Large Registries

NeoatherosclerosisSevere

UnderexpansionNIH WithThrombus Other*

27 6 13 18

28 7 5 18

28 7 2 16

elated disease, or no finding identified. †Only DES were included in this registry.

tomography; PESTO French Registry ¼ Morphological Parameters Explaining StentInterdisciplinary Global European Effort Registry; VLST ¼ very late stent thrombosis.



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uncovered struts/section (30). Moreover, evidencederived from angioscopy studies demonstrated that75% of newly formed thrombi attached to the un-covered struts and these uncovered struts may persistin 20% of the patients for up to 2 years (31).

LATE-ACQUIRED STENT MALAPPOSITION. Stentmalapposition (SM) is defined as lack of contact be-tween any strut and the underlying intimal surface ofthe vessel wall in a segment not overlying a sidebranch (32). Highly calcified or fibrotic lesions arecommonly the underlying cause of the inability of anystrut of the stent to get fully and homogeneouslyexpanded and reach the arterial wall (“lever princi-ple”) (33). Additionally, implantation of undersizedstents remains, unfortunately, a frequent cause ofSM. Angiography is particularly limited to detect thisphenomenon for which the use of intravascular ul-trasound or OCT is required (34).

However, an intriguing phenomenon, that is,late-acquired SM, has been observed in a proportionof patients, in which the lack of contact of a strutis identified many months after the index procedurewhen it was not present at the time of theprocedure (34).

Late-acquired SM was first observed after brachy-therapy in BMS-treated segments, and it was hy-pothesized that brachytherapy-associated SM couldbe attributable to an adverse vessel reaction againstthe antiproliferative effect (35). Indeed, late-acquiredSM was also increasingly found in association with1G-DES, as compared with BMS without brachyther-apy (33,36). In a meta-analysis conducted by Hassanet al. (37), the risk of late-acquired SM was 4-foldhigher in DES compared with BMS (odds ratio [OR]:4.36; 95% confidence interval [CI]: 1.74 to 10.94;p ¼ 0.002). A positive remodeling of the vessel out ofproportion to the increase in peristent NIH couldexplain the differential rates of late-acquired SM be-tween BMS and DES (36). The development andgrowth of NIH (which does not occur prominentlywith DES) could be an “adaptive mechanism” to fill inthe gap between the struts and the vessel wall (38).

The importance of SM to the risk of ST relative toother factors remains controversial (34). Late-acquiredSM has been associated with up to a 7-fold greater riskfor ST (OR: 6.51; 95% CI: 1.34 to 34.91; p ¼ 0.02) (37),suggesting a role in the pathogenesis of this adverseevent. (33,34,38). The positive remodeling of thearterial wall may provoke a reduction of blood flowbetween the aneurysmatic wall and the stent strutsserving as a local nidus for thrombus formation byallowing for fibrin and platelet deposition (33).In addition, SM may interfere with healthy arterial

healing. Indeed, the association between late SMand uncovered struts (>30%) is particularly high(28,30,38). However, it has also been postulated thatSM could be only a consequence or marker for othermechanisms primarily causing ST such as delayed re-endothelialization and chronic inflammation (30,33).

LOCALIZED HYPERSENSITIVITY REACTIONS. Othermechanisms potentially implicated in the pathophys-iology of LST/VLST in 1G-DES include chronic inflam-mation and hypersensitivity reactions in response tostent components (39). The foreign stent could triggera localized hypersensitivity vasculitis leading to vesselremodeling, persistent endothelial dysfunction, andfibrin deposition (10,19,39).

Theoretically, allergic reactions can occur againstany DES component, including the stent metal, theantiproliferative agent, or the durable polymer(39,40). Some evidence suggests that the allergenicpotential differs across metals (e.g., nickel vs. chro-mium) (41). Even though still in dispute, the searchfor more biocompatible alloys or specific designmodifications has led to several improvements inmetal scaffolds manufacturing.

Persistent inflammation due to the anti-proliferative drug was also implicated in the patho-physiology of ST in animal models (19). However,considering that drugs eluted by DES promote a localimmunosuppression and also practically disappear3 months after stent implantation, any relationshipbetween antiproliferative drugs and hypersensitivityreactions is unlikely (39,42).

The “polymer matrix hypothesis,” as a trigger oflocalized hypersensitivity reactions, was initially pro-posed by Virmani et al. (39) based on histopathologicalexaminations of an arterial specimen from a patientwho experienced ST 18 months after receiving 2sirolimus-eluting stents (SES). The autopsy revealedan aneurysmally dilated stented artery, with focalmalapposed struts and an extensive inflammatoryinfiltrate (i.e., lymphocytes, macrophages, and eosin-ophils) involving the 3 arterial layers. There were alsostent regions where focal giant cells surrounding afewpolymer remnantswere detected, that had becomeseparated from the stent struts (39). Based on thedogma that stent polymers might not be as benign,DES with biocompatible (nonerodable), biodegrad-able, or directly free of polymer matrix have beenintroduced.

NEOATHEROSCLEROSIS. Nakazawa et al. (43) hy-pothesized that some “thrombogenic events super-imposed to NIH” might be attributable to new plaquegeneration and subsequent rupture within the stent(neoatherosclerosis [NA]). Intravascular imaging and

CENTRAL ILLUSTRATION Pathogenic Mechanisms of Late ST/Very Late ST

Impaired Re-endothelialization Hypersensitivity Reactions

Neoatherosclerosis

Strut Fibrin

HemorrhageInflammatory

cellinfiltration

Neoatherosclerosisplaque

(necrotic core)

Originalplaque

Dysfunctionalendothelium

Lipid-ladenfoamy macrophages

Endothelium

Endothelium

Lack of endothelialcoverage

Malapposeddistance

Bioresorbed strut

StentUncovered strut Covered strut

Strut fractureMalapposed struts

Malapposed strut

Scaffold discontinuity

Thrombusformation

Thrombusformation

Thrombusformation

S T E N TT H R O M B O S I S

Thrombusformation

Thrombusformation

Stent Malapposition Stent Dismantling

Torrado, J. et al. J Am Coll Cardiol. 2018;71(15):1676–95.

More than 1 mechanism can be found in the same arterial segment complicated with stent thrombosis (ST). Stent dismantling occurs in bioresorbable vascular scaffolds

(BVS) as an adverse phenomenon of the bioresorption process. This phenomenon hinders correct strut apposition and re-endothelialization.


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histopathology have confirmed this hypothesis inLST/VLST (43,44).

Importantly, NA and NIH differ, not only in lesioncomposition, but also in onset relative to stentimplantation. Whereas NIH is composed primarily ofproliferative smooth muscle cells and depositionof matrix components, NA lesions are lipid-ladenfoamy macrophage infiltrates with a large necroticcore (43). NA occurs later after stent deployment thanNIH (43,45). Interestingly, the growth and progres-sion of NA plaques may be accelerated in 1G-DES–

versus BMS-treated segments. Foamy macrophageinfiltration was detected at 4 months after 1G-DESimplantation compared with 2 years in BMS, and anecrotic core was observed at 9 months in DES ascompared with 5 years in BMS (43). Yonetsu et al. (45)reported that lipid-laden neointima were detectedtypically at 14 months versus 55 months in DES(mainly 1G-DES) versus BMS, respectively. Theaccelerated course of NA in 1G-DES segments hasbeen associated with an increased endothelialdysfunction with enhanced lipid diffusion (43).

TABLE 2 Overview of Principal Characteristics of 1G- and 2G-DES With Published Large-Scale Randomized Controlled Trial Data

Stent Name(Manufacturer)

FDAApproval

DateDrugEluted

Drug Mechanismof Action

PolymerType

DrugDensity

Kinetic ofDrug-Elution

MetalPlatform

StrutThickness*

(mm)

CYPHER (Johnson &Johnson)

4/2003 Sirolimus Binds to and forms acomplex with theFKBP12, which in turninhibits the mTOR.Blocks progression ofG1 to S in the cell cycle

PEVA andPBMA

1.4 mg/mm2 80%within 30 days;remainder released bythe end of 90 days

SS 140

TAXUS Express2

(Boston Scientific)5/2004 Paclitaxel Binds to b-tubulin, which in

turn stabilizesmicrotubules againstdepolymerization.Blocks cell migrationand proliferation withcell cycle arrest in G0/G1 and G2/M

SIBS 1 mg/mm2 <10% at 30 days;w90%remains sequesteredwithin the polymerformulation withoutfurther measurablerelease

SS 132

TAXUS Liberté(Boston Scientific)

5/2009 SIBS 1 mg/mm2 <10% at 30 days;w90%remains sequesteredwithin the polymerformulation withoutfurther measurablerelease

SS 97

XIENCE V† (AbbottVascular)

7/2008 Everolimus Semisynthetic derivative ofsirolimus with similareffects. Adds morelipophilic properties

PVDF-HFPand PBMA

1 mg/mm2 80%within 30 days;remainder released bythe end of 120 days

CoCr 81

PROMUS Element(Boston Scientific)

11/2011 PVDF-HFPand PBMA

1 mg/mm2 80%within 30 days;remainder released bythe end of 120 days

PtCr 81

ENDEAVOR(Medtronic)

2/2008 Zotarolimus Semisynthetic derivative ofsirolimus with similareffects. Adds morepotent suppression ofthe lymphocyte-mediated localinflammatory reaction

PC 1 mg/mm2 95%within 14 days;remainder released bythe end of 30 days

CoCr 91

RESOLUTE(Medtronic)

2/2012 C10, C19,and PVP

1 mg/mm2 w70%within 30 days;remainder released bythe end of 120 days

CoCr 91

*Based on a 3-mm stent, without adding the polymer thickness. †XIENCE V (Abbott Vascular) and PROMUS (Boston Scientific) are identical stents sold by the respective companies under different brandnames.

1G-DES ¼ first-generation drug-eluting stent(s); 2G-DES ¼ second-generation drug-eluting stent(s); C10 ¼ polybutyl methacrylate; C19 ¼ polyhexyl methacrylate, polyvinyl acetate; CoCr ¼ cobaltchromium alloy; FKB12 ¼ FK-binding protein 12; mTOR ¼ mammalian target of rapamycin; PBMA ¼ poly n-butyl methacrylate; PC ¼ phosphorylcholine; PEVA ¼ polyethylene-co-vinyl acetate;PtCr ¼ platinum chromium alloy; PVDF-HFP ¼ polyvinylidene fluoride co-hexafluoropropylene; PVP ¼ polyvinyl pyrrolidone; SIBS ¼ poly(styrene-b-isobutylene-b-styrene); SS ¼ stainless steel.



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The relative risk of developing NA in 2G- versus1G-DES or BMS is still a matter of debate. Yonetsuet al. (45) found that the incidence of NA was lower ineverolimus-eluting stents (EES) (i.e., 2G-DES)compared with 1G-DES and similar to BMS. Similarly,OCT imaging of stents implanted 5 years after STEMIin event-free patients participating in the RE-EXAMINATION (A Clinical Evaluation of EverolimusEluting Coronary Stents in the Treatment of PatientsWith ST-segment Elevation Myocardial Infarction)study revealed comparable NA prevalence in EES andBMS (46). In other OCT studies, however, 2G-DEShave been associated with accelerated NA comparedwith BMS, and were not more protective against NAthan 1G-DES (44,47). It is noteworthy that the in vivodistinction of NA from other types of in-stent lesionscan be extremely challenging, with no absolute

consensus among researchers on the OCT diagnosticcriteria (44,47).

From a pathophysiological standpoint, in-stent NAmust be understood as a mechanism of stent failure,which clinically and angiographically may presenteither as ISR or as LST/VLST (44). Thus, poor strutcoverage, chronic inflammation, late-acquired SM,and NA with associated thrombotic events may entaillate adverse effects of the antiproliferative therapyfor targeting NIH (Central Illustration).

STENT TECHNOLOGY AND ST

1G-DES VERSUS 2G-DES. Drug-eluting stents can bemodified in several manners to optimize efficacy andsafety: 1) the stent metal itself (platform) with itsparticular strut geometry and thickness; 2) the

FIGURE 3 Pooled HRs and CIs Determined by Network Meta-Analysis for Definite ST, Definite/Probable ST, Definite VLST, and Definitive/Probable VLST

B

0.1 1 10Favors Stent 1 Favors Stent 2

Definite or Probable ST D

0.01 0.1 1 10Favors Stent 1 Favors Stent 2

Definite or Probable VLST

A

CoCr-EES vs BMS

CoCr-EES vs PES

CoCr-EES vs SES

PC-ZES vs SES

BES vs BMS

BES vs PES

BES vs SES

CoCr-EES vs BMS

CoCr-EES vs PES

CoCr-EES vs SES

CoCr-EES vs BES

PC-ZES vs SES

0.50 (0.33-0.73)

HR (95% CI)

0.48 (0.34-0.65)

0.52 (0.35-0.72)

0.68 (0.48-1.00)

0.56 (0.32-0.95)

0.53 (0.31-0.89)

0.58 (0.35-0.92)

0.48 (0.29-0.82)

0.42 (0.27-0.64)

0.41 (0.26-0.64)

0.58 (0.31-1.00)

0.55 (0.36-0.93)

HR (95% CI)

0.1 1 10Favors Stent 1 Favors Stent 2

Definite ST C

0.01

SES vs BMS

CoCr-EES vs PES

Re-ZES vs SES

PC-ZES vs SES

BES vs SES

PC-ZES vs PES

BES vs PES

CoCr-EES vs SES

PES vs BMS

SES vs BMS

CoCr-EES vs PES

CoCr-EES vs SES

BES vs SES

PC-ZES vs PES

PC-ZES vs SES

2.30 (1.30-4.10)

0.49 (0.25-0.49)

0.29 (0.07-0.99)

0.22 (0.10-0.44)

0.28 (0.11-0.66)

0.30 (0.12-0.65)

0.39 (0.15-0.93)

0.36 (0.18-0.65)

HR (95% CI)

2.00 (1.00-4.10)

2.90 (1.50-6.30)

0.47 (0.18-0.89)

0.31 (0.11-0.64)

0.35 (0.13-0.78)

0.18 (0.05-0.47)

0.12 (0.04-0.27)

HR (95% CI)

10.1 10Favors Stent 1 Favors Stent 2

Definite VLST

After a median follow-up of 3.8 years, HRs and CIs were assessed for the risk of definitive ST (A), definitive/probable ST (B), definitive VLST (C), and definitive/probable

VLST (D). Only significant differences are shown from the original data analysis. Figure based on data analysis from Palmerini et al. (53). BES ¼ biolimus-eluting stent;

BMS ¼ bare-metal stent; CI ¼ 95% confident interval; CoCr ¼ cobalt chromium; EES ¼ everolimus-eluting stent; HR ¼ hazard ratio; PC-ZES ¼ phosphorylcholine

zotarolimus-eluting stent; PES ¼ paclitaxel-eluting stent; Re-ZES ¼ resolute zotarolimus-eluting stent; SES ¼ sirolimus-eluting stent; other abbreviations as in

Figures 1 and 2.


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pharmacological agent; and 3) the polymer (i.e., drugcarrier), which controls the drug dose and pharma-cokinetic release (Table 2).

Everolimus-based eluting stents are the moststudied 2G-DES. In a pooled analysis of the final3-year outcomes of the SPIRIT trials, cobalt chromium(CoCr)-EES (XIENCE V/PROMUS stents) providedsuperior reductions in TLR (6.0% vs. 8.2%; hazardratio [HR]: 0.72; 95% CI: 0.58 to 0.90; p ¼ 0.004) andST (0.7% vs. 1.7%; HR: 0.45; 95% CI: 0.26 to 0.78;p ¼ 0.003) in comparison with paclitaxel-elutingstents (48). Importantly, all-cause mortality was alsoreduced with the use of CoCr-EES (3.2% vs. 5.1%; HR:0.65; 95% CI: 0.49 to 0.86; p ¼ 0.003) (48). Similartrends were observed when comparing CoCr-EES withSES (49). A meta-analysis of the 2 largest EES studies,the RESET (Randomized Evaluation of Sirolimus-eluting Versus Everolimus-eluting Stent Trial) andSORT OUT IV (Scandinavian Organization for Ran-domized Trials with Clinical Outcome IV) trials, found

that CoCr-EES significantly decreased the risk of TLRand ST, with similar all-cause mortality (50).2G-DES VERSUS BMS. Vessel diameter may alsoaffect the risk of ISR, and it was hypothesized that theuse of BMS in large arteries may avoid the risks of LST/VLST while providing early re-endothelialization.However, the randomized BASKET-PROVE (BaselStent Kosten-Effektivitäts Trial- PROspective Valida-tion Examination) trial, which enrolled patients with3- to 4-mm diameter target arteries, demonstratedthat TVR was significantly reduced with DES (i.e., SESand CoCr-EES) as compared with BMS (3.7% and3.1% vs. 8.9%, respectively; p < 0.001) with nosignificant differences in the rate of death or ST at2-year follow-up (51).

The benefits of 2G-DES are not limited to a short-term antirestenosis effects. In the NORSTENT(Norwegian Coronary Stent Trial) (N ¼ 9,013), patientsreceiving DES (96% 2G-DES, mainly CoCr-EES) wereassociated, not only with lower rates of TVR (16.5% vs.

TABLE 3 Overview of Most Extensively Studied Biodegradable Polymer-Based-DES With Published Large-Scale Registries or Randomized Controlled Trial Data

Stent Name (Manufacturer) Drug Eluted Drug Mechanism of ActionFDA

ApprovedPolymerType

BioMatrix Flex (Biosensors) Biolimus A-9 Semisynthetic sirolimus derivate with 10�higher lipophilicity

No PLA

Nobori† (Terumo) Biolimus A-9 No PLA

Ultimaster (Terumo) Sirolimus See Table 2 No PDLLA and PCL

Yukon Choice PC (Translumina) Sirolimus No PLA and shellac

ORSIRO (Biotronik) Sirolimus No PLLA

MiStent (Micell Technologies) Crystalline sirolimus Crystalline form of sirolimus providesadditional control over drug deliveryand allows the drug to remain in thetissue and to be eluted for longerperiods

No PLGA

DESyne BD (Elixir Medical) Novolimus Semisynthetic sirolimus derivate produceby removal of methyl-group of C16

No PLA

SYNERGY (Boston Scientific) Everolimus See Table 2 Yes PLGA

Combo DTS (OrbusNeich Medical) EPC (anti-CD34antibodies)þ sirolimus

Anti-CD34 antibodies are immobilized onthe surface of the stent and capturecirculating endothelial progenitor cellspromoting differentiation and re-endothelialization

No PLA, PLGA and CAP

*Based on a 3-mm stent. †The only difference between the Biomatrix Flex and the Nobori stent is an ultra-thin non-degradable parylene coating between the stent and the biodegradable polymer on Noboristent (to promote polymer attachment to the struts), which do not have the Biomatrix Flex.

BES¼biolimus-elutingstent;CAP¼k-caprolactone;EPC¼endothelial progenitor capture;PLA¼polylacticacid;PCL¼poly-L-lactide-co-e-caprolactone;PDLLA¼poly-D, L-lactic acid;PLGA¼poly(D,L-lactide-coglycolide); PLLA¼ poly-L-lactic acid; other abbreviations as in Table 2.

Continued on the next page



1684

19.8%; p< 0.001), but also with lower rates of ST (0.8%vs. 1.2%; p ¼ 0.0498) at 6-year follow-up, as comparedwith BMS (52). Moreover, data from multiple ran-domized controlled trials (RCTs) assessing the efficacyand safety of different DES (1G- and 2G-DES) and BMSwere combined in a network meta-analysis with morethan 50,000 patients. Accordingly, EES (particularlyCoCr-EES) proved to be the safest stent in terms of STin the long term, even as compared with BMS (53).

CoCr-EES has even demonstrated similar outcomesas BMS with respect to ST at 5-year follow-up in theEXAMINATION (Everolimus-Eluting Stents VersusBare-Metal Stents in ST-Segment Elevation Myocar-dial Infarction) all-comers trial of STEMI patients,which is a challenging clinical scenario to test newintracoronary devices due to the highly thromboticmilieu (54).

The improved safety profile of 2G-DES (i.e., EES orZES) with no thrombotic “late catch-up phenomenon”is not fully understood but has been attributed to thelower thrombogenic structure of their design withCoCr (or platinum chromium [PtCr]) platforms,thinner strut thickness (81 mm), and more biocom-patible durable polymer coatings (10) (Table 2). In thecase of CoCr-EES, the inert or nonerodable polymeris composed of vinylidene fluoride and hexa-fluoropropylene monomers, which might inducehealthier endothelialization of the stent andmore thrombo-resistance and hemocompatibility, as

suggested by laboratory tests and OCT examinations(54,55).

This body of evidence led to a paradigm shift and arevolutionary change of interventional cardiologypractice (10). Since 2010, >75% of implanted stentsduring PCI in the United States are 2G-DES (56) and arewidely preferred over BMS in most clinical scenariosincluding diabetes, left-main coronary artery disease,multivessel disease, heart failure, and STEMI (57).COMPARISON BETWEEN 2G-DES. Two additional2G-DES, that is, the Resolute zotarolimus-elutingstent (Re-ZES) (Medtronic Cardiovascular, Dublin,Ireland) and the PtCr-EES (PROMUS Element, BostonScientific, Natick, Massachusetts), have been intro-duced in the interventional practice. The RESOLUTEAll Comers (Randomized, Two-arm, Non-inferiorityStudy Comparing Endeavor-Resolute Stent WithAbbot Xience-V Stent) trial (N ¼ 2,292) compared theefficacy and safety of the gold standard CoCr-EESversus Re-ZES (58). At 5-year follow-up, eventhough a trend toward less definite ST favoring CoCr-EES was observed (0.8 vs. 1.6%; p ¼ 0.084), bothstents demonstrated similar rates of TLR, definite/probable ST, and all-cause mortality (58).

The HOST-ASSURE (Harmonizing Optimal Strat-egy for Treatment of Coronary Artery Stenosis–Safety & Effectiveness of Drug-Eluting Stents &Anti-platelet Regimen) trial randomized all-comerpatients from South-Korea undergoing PCI

TABLE 3 Continued

Polymer CoatingPolymer

Thickness (mm)Bioresorption

KineticsDrug

Concentration/Density Kinetics of Drug ElutionMetal

PlatformStrut

Thickness (mm)*

Abluminal 10 6–9 months 15.6 mg/mm 45% within 1 month SS 120

Abluminal 10 6–9 months 15.6 mg/mm 45% within 1 month SS 120

Abluminal 15 3–4 months 3.9 mg/mm w100% within 3–4 months CoCr 80

Abluminal 5 3 months 1.25 mg/mm2 w100% within 1 month SS 87

Circumferential 7 12–24 months 1.4 mg/mm2 80% within 3 months and w98% at 12 months CoCr 60

Circumferential 10 3 months 2.44 mg/mm2 100% within 9 months CoCr 64

Circumferential <3 6–9 months 5 mg/mm 90% within 3 months CoCr 81

Abluminal 4 4 months 1 mg/mm2 50% within 2 months and w100% at 3 months PtCr 74

Abluminal 3–5 <3 months 5 mg/mm w95% within 1 month SS 100


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(N ¼ 3,755) to either PtCr-EES or Re-ZES (59). At1-year post-PCI, PtCr-EES was noninferior to Re-ZES,with respect to ST (0.7% vs. 0.3%, respectively;p ¼ 0.340) (59). Similarly, no differences in rates oftarget lesion failure (TLF) or ST were observed inthe DUTCH PEERS (Durable Polymer-Based STentCHallenge of Promus ElemEnt Versus ReSoluteIntegrity) Randomized Trial (TWENTE II) of PtCr-EES versus Re-ZES at 2-year follow-up (60).

The PtCr-EES has the same drug and polymer asCoCr-EES on a denser alloy stent platform, which wasmanufactured mainly to enhance radiopacity, radialstrength, and fracture resistance (61). PtCr-EES andCoCr-EES were found to be comparable in outcomesin the 3-year follow-up report of the PLATINUM (aProspective, Randomized, Multicenter Trial to Assessan Everolimus-Eluting Coronary Stent System [PRO-MUS Element] for the Treatment of Up to Two deNovo Coronary Artery Lesions) trial (61).

In line with previous studies, 2 meta-analysescomparing the efficacy and safety of 2G-DES(including Re-ZES, CoCr-EES, and PtCr-EES) havefound no major differences in ST or restenosis sur-rogates among them (53,62).

BIODEGRADABLE POLYMER-BASEDDESVERSUS DURABLE

POLYMER-BASED DES. As discussed previously, oneputative mechanism implicated in the increasedrisk of LST/VLST observed after DES includechronic inflammation or hypersensitivity reactionspotentially triggered by the presence of a durablepolymer. To overcome these limitations, polymerfree- and biodegradable polymer-based DES weredeveloped.

The LEADERS (Limus Eluted From A Durable VersusERodable Stent Coating) trial (N ¼ 1,707) compared theefficacy and safety of the first biodegradable polymer-based DES (biolimus-eluting stent [BES]) (BioMatrixFlex, Biosensors, Newport Beach, California), against adurable polymer DES (i.e., SES) (63). The BES containsbiolimus A-9, a semisynthetic sirolimus analogue with10� higher lipophilicity, into a biodegradable poly-lactic acid biocompatible-polymer on a flexiblestainless-steel stent platform. In the final 5-yearreport, a significant reduction in VLST favoring BESover SES was observed (0.6% vs. 2.2%; respectively;rate ratio: 0.26; 95% CI: 0.10 to 0.68; p ¼ 0.003) (63).However, when BES was compared with CoCr-EES inthe BASKET-PROVE II and COMPARE II (ComparisonBetween the Durable Polymer Coated Everolimus-Eluting Xience/Promus Stent and the BiodegradablePolymer Coated Biolimus-Eluting Nobori Stent in All-Comer Population) trials, no differences in safety andefficacy outcomes were observed at 2- and 5-yearfollow-up, respectively (64,65).

Furthermore, a critical large-scale network meta-analysis (N ¼ 52,158), investigating the relativesafety and efficacy profile of different types of DES(including BES) and BMS, found that although ratesof TVR were similar between CoCr-EES/PtCr-EES andBES, almost all types of stents, including BES, hadhigher rates of ST than CoCr-EES/PtCr-EES at me-dian follow-up of 3.8 years (53). This evidenceplaced these 2G-DESs as the gold standard andbenchmark comparators for stent trials (53)(Figure 3). Important to mention, BES is not avail-able in the United States.



1686

Additional biodegradable-polymer based DES weredeveloped by introducing several modifications onthe stent manufacturing process (e.g., strut thickness,polymer biodegradation kinetics and coating, drugrelease kinetics) and are under clinical investigation(66–69) (Table 3, Online Table 1). The second biode-gradable polymer-based DES most extensively eval-uated in clinical practice is the SYNERGY stent(Boston Scientific), a novel thin-strut (74 to 81 mm)PtCr alloy stent that elutes everolimus from an ul-trathin and very rapidly biodegradable polymer ma-trix (70). The EVOLVE II (A Prospective RandomizedInvestigation of a Novel, Bioabsorbable Polymer-Coated, Everolimus-Eluting Coronary Stent) trial(N ¼ 1,684) was a noninferiority trial designed toassess the safety and efficacy of the SYNERGY stentagainst PtCr-EES. This study showed no differences inTLF or ST rates at 12 months between both stents (70).Due to these findings, the SYNERGY stent receivedFood and Drug Administration approval in 2015.BVS VERSUS “PERMANENT METALLIC” DES. Thenext chapter in interventional cardiology has beenopen with the evaluation of fully BRS. These newdevices, recognized as “the fourth revolution ininterventional cardiology” (71), were designed toapply the necessary mechanical support to preventimmediate and late recoil, and once resorbed, toliberate the artery of theoretical disadvantagesimposed by the inherent nature of a permanent“foreign body,” restoring its physiological integrity(endothelial function, vasomotion, and return ofpulsatility) (72).

The ABSORB GT1 Bioresorbable Vascular Scaffold(BVS) system (Abbott Vascular, Santa Clara, Califor-nia) is the most extensively studied device of BRS.This device has evolved since initial clinical experi-ence with the first prototype of its kind (BVS 1.0),which was limited by evidence of shrinkage at6 months due to a loss of radial force (71). Currently,the scaffold (BVS 1.1) has a 150-mm strut, improveddesign, in-phase zigzag hoops linked by bridges in abody of poly-L-lactide coated with poly-D,L-lactide(71), which controls the release of everolimus(Novartis, Basel, Switzerland).

The ABSORB III (N ¼ 2,008) is the first large ran-domized trial evaluating this revolutionary newconcept (73). The study met its primary endpoint ofnoninferiority of BVS versus CoCr-EES for TLF at1 year (7.8% vs. 6.1%; 95% CI: �0.5 to 3.9; p ¼ 0.007for noninferiority) (73). However, the selectedpre-specified criterion for noninferiority (wided margin of 4.5%) has been criticized as too liberaland may have favored BVS. Furthermore, definite/probable subacute device thrombosis (DT) rate

reported in this study was higher in BVS versus CoCr-EES (0.9% vs. 0.1%, respectively; relative risk: 6.26;95% CI: 0.82 to 48.04; p ¼ 0.040) (73).

Unfortunately, these adverse safety signals havebeen replicated in other studies, such as registriesand meta-analysis of available trials testing BVS, aswell as in the same study when the 3-year follow-updata were reported (11,12,74,75). A large Europeanmulticenter real-world registry (GHOST-EU [Gaugingcoronary Healing with bioresorbable ScaffoldingplaTforms in Europe] registry) (N ¼ 1,189) raised thefirst strong safety alarm revealing a high cumulativeincidence of DT (1.5% at 30 days and 2.1% at6 months) (74). The recent 3-year follow-up of theABSORB III trial reaffirmed the increase in DT withBVS (2.3% vs. 0.7%, respectively; p ¼ 0.01) (75).Furthermore, in an individual patient-data–pooledmeta-analysis of the ABSORB trials, BVS was associ-ated with increased rates of TLR and DT between 1and 3 years, and cumulatively through 3-year follow-up compared with CoCr-EES (12). Importantly, refer-ence vessel diameter <2.25 mm was an independentpredictor of DT and TLF (75). Additionally, theanticipated benefit of restoring vasomotor reactivitywas not demonstrated in longer follow-up studiesevaluating the angiographic response (i.e., changes inmean lumen diameter) to intracoronary nitrate (76).

Given these safety concerns, even though the Foodand Drug Administration approved the use of theABSORB GT1 BVS System in July 2016, later in 2017, itreleased a concern statement followed by the stentcompany (Abbott Vascular) removing the device fromthe world market on September 2017. The ongoing,large-scale (N ¼ 2,610) ABSORB IV trial promisesdefinitive, long-term (7-year follow-up) benefit-riskassessment on the use of BVS versus CoCr-EES(NCT02173379).

It is important to point out that the assumedadvantage of BVS over metallic DES would theoreti-cally accrue only once the device is fully resorbed(within 2 to 4 years) (71). In the attempt to overcomesome of the first-generation device limitations, otherBRS, either based in polymeric or metallic (magnesiumor iron alloy) platforms, areunder clinical investigation(Online Table 2): thinner strut devices with increasedradial force to allow better or easier delivery; moreflexible and greater strut resistance to preventdevice fracture; better visibility to improvedeployment; and probably more important, fasterreabsorption rate andmore biocompatible compoundsto decreased both the need for very prolonged DAPTand late and very late DT risk, are some of the new goalson device developments under active clinical investi-gation. Although some encouraging initial small


https://www.clinicaltrials.gov/ct2/show/NCT02173379


FIGURE 4 Very Late BVS Thrombosis Caused by Intraluminal Scaffold Dismantling

(I) Final coronary angiogram of an uncomplicated elective PCI with implantation of a 3.5 � 28-mm BVS in the right coronary artery (white arrows and white dotted line)

of a 61-year-old woman. (II) OCT imaging at proximal scaffold confirmed optimal scaffold implantation. The patient completed 12 months of DAPT. One month later,

the patient presented with inferior STEMI and thrombolysis was administered followed by transfer to PCI-capable center. (III) Coronary angiogram showed haziness at

the proximal segment of the BVS (white arrows). (IV): OCT imaging showed intraluminal scaffold dismantling at the proximal segment of the BVS with adherent white

thrombi. OCT images at proximal segment of BVS from distal to proximal (A to D). (A) Intraluminal white thrombus with stacked struts at 11 o’clock. (B to D)

Intraluminal scaffold dismantling was shown. Scaffold discontinuities were evidenced by loss of circular struts pattern and intraluminal struts. No evidence of tissue

coverage was detected at the intraluminal struts. Adapted with permission from Chan et al. (80). BVS ¼ bioresorbable vascular scaffold; OCT ¼ optical coherence

tomography; STEMI ¼ ST-segment elevation myocardial infarction; other abbreviations as in Figure 1.


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“first-in-man” studies have been performed, no large-scale clinical trials are still available concerning any ofthese BRS (72).

ADDITIONAL CONSIDERATIONS

OF BVS THROMBOSIS

Ongoing research appears to demonstrate additionalpotential mechanisms involved in BVS thrombosis.Recently, an expert consensus manuscript discussesin depth the factors potentially implicated in theexcess risk of DT with BVS, including the scaffoldfeatures, deployment technique, and patient andlesion selection, among others (77).

Early and late DTs may have been favored due toprocedural challenges and inexperiencewith the use ofthese devices. In a large study of BVS implantation in an

unrestricted patient population, BVS underexpansionwas shown to be an independent predictor of DT (13).Furthermore, the application of a BVS-specific protocolto ensure maximal scaffold dimensions, throughroutine post-dilatation, led to an w70% reduction inthe 12-month risk of DT (from 3.3% to 1.0%) (13).Furthermore, in a subanalysis of the ABSORB trials, anaggressive pre-dilation and optimal post-dilatationtechnique were independent predictors of freedomfrom DT (HR: 0.44; p ¼ 0.03) and TLF (HR: 0.55;p ¼ 0.05) between 1 and 3 years, respectively (78).

A known drawback of this new technology is strutfracture. Unlike metallic stents, the polymeric deviceshave inherent limit of expansion and can break fromoverdilatation (71). Indeed, BVSmust be designedwiththicker and wider struts than CoCr-EES, to improveradial strength, which nevertheless remains about

TABLE 4 Natural History of Biological and Mechanical Behavior of BVS

Revascularization Restoration Resorption

Timing First months after implantation First months to 2–4 yrs >2–4 yrs

Bioresorptionprocess (mass loss)*

Low bioresorption High bioresorption Bioresorption completed

Mechanical support Appropriate lumen support Poor (weakening of the scaffold) None

Antiproliferative activity High Decreased or none† None

Expected advantages � Alleviation of ischemia� Prevent early vessel closure� High flexibility and conformability

(lessens geometric distortion andkeeps normal vessel curvature)

� Early NIH and NA suppression.

� Loss of radial rigidity and mechanicalconstraint with cyclic strain and pulsatilityrecovery.

� Increased responsiveness to vasodilators� Reduced restenosis by NIH residual suppres-

sion and improved endothelial function

� No foreign body remaining� Decreased very late stent failure� Full recovery of vessel functionality� Positive remodeling of the vessel

Observed drawbacks � Vulnerable to implantation issues� Large struts in contact to the vessel

wall and blood� Increased early ST risk

� Increased risk for late-acquired malapposition� Vulnerable to stent fracture and stent

dismantling� Increased subacute, late and very late ST risks

� Increase the risk of very late ST‡

*Progressive molecular weight loss of polymeric scaffolds (followed by mass loss) occurs by hydrolysis and depolymerization, followed by metabolism of lactate into carbon dioxide and water via the Krebscycle, with final collagen and vascular smooth muscle cell replacement. †Drug elution is almost complete at 3 months. ‡Data regarding outcomes of large ongoing trials of late phase are recently available,and benefits of this technology (i.e., over permanent metallic stents) are probably no longer expected in unselected populations.

BVS ¼ bioresorbable vascular scaffold; NA ¼ neoatherosclerosis; NIH ¼ neointimal hyperplasia; ST ¼ stent thrombosis.



1688

one-half of that of BMS (71). Failure to provide appro-priate mechanical support, especially in complex,highly calcified lesions, may predispose to DT. Inaddition, greater protrusion of struts (both length andheight) causes loss of laminar flow and areas of oscil-latory shear stress, promoting platelet activation (77).

Interestingly, using intracoronary OCT imaging, theINVEST (Independent OCT Registry on Very Late Bio-resorbable Scaffold Thrombosis) registry (N ¼ 36)revealed multifactorial mechanisms of very late DT, inwhich scaffold discontinuity (42.1%) was the leadingfinding, followed by malapposition (18.4%) and NA(18.4%) (79). Signs of these problems, described as“late intraluminal scaffold dismantling,” were firstdetected by OCT in a patient experiencing very late DT(at 13 months) (Figure 4) (80). This eventuality occursas a result of the bioresorption process (Table 4)and leads to prolapse of a scaffold segment intothe vessel lumen, strut discontinuities, late stentmalapposition, and incomplete re-endothelialization,all of which serves as a nidus for thrombus formation(Central Illustration) (72,80).

DAPT AND ST

Three large-scale studies demonstrated a temporalassociation between clopidogrel premature discon-tinuation and ST within the first 6 to 9 months afterstent deployment, and no association thereafter (81–83). The median time interval for a ST event afterclopidogrel discontinuation was 9 days (interquartilerange [IQR]: 5.5 to 22.5 days) within the first 6 monthsafter DES implantation, compared with 104 days (IQR:7.4 to 294.8 days) beyond 6 months of index PCI (83).

Loss of protection by clopidogrel therapy rather thana “rebound in platelet reactivity” explains theoccurrence of LST/VLST (82).

However, the large PARIS (Cessation of Dual Anti-platelet Treatment and Cardiac Events After Percu-taneous Coronary Intervention) registry (N ¼ 5,018)found that 74% of ischemic events (including ST)occurred while patients were on DAPT (84). Many ofthese events may have been related to interindividualvariability in the antiplatelet effects of clopidogrel.Supporting this observation, the ADAPT-DES(Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) study found high on-treatment re-sidual platelet activity in nearly one-half of all STevents that occurred while on clopidogrel treatment(85). Indeed, different methods to assess clopidogrel-induced antiplatelet effect (e.g., turbidometric lighttransmittance aggregometry) demonstrated thatroughly w33% of the patient population would bepoor clopidogrel responders (86).

Although “DAPT failure” can be attributed todifferent drug-to-drug interactions and patient char-acteristics, interindividual variability to the responseto clopidogrel due to hepatic cytochrome P450 poly-morphisms (e.g., CYP2C19 reduced-function allele) isperhaps the most important contributor (87).

MORE POTENT P2Y12 ADENOSINE DIPHOSPHATE

RECEPTOR BLOCKERS. In order to overcome theseclopidogrel limitations, more potent P2Y12 adenosinediphosphate receptor blockers, such as prasugrel orticagrelor, have been developed (88). The TRITON–

TIMI 38 (Trial to Assess Improvement in TherapeuticOutcomes by Optimizing Platelet Inhibition With

FIGURE 5 ST and Clinically Significant Bleeding in RCTs

Shorter DAPT Better Longer DAPT Better

P = 0.001

3 or 6 Months Discontinuation

Stent Thrombosis

1

Trial Name Odds Ratio 95% CI

12 Months DiscontinuationDAPT StudyDES-LATEARCTIC-Int.Subtotal

Overall

ISAR-SAFEITALICSECURITYOPTIMIZEPRODIGYEXCELLENTRESETSubtotal

2.28 (1.49 – 3.49)1.95 (0.99 – 3.81)7.16 (0.37 – 138.86)2.22 (1.55 – 3.17)

1.71 (1.26 – 2.32)

1.25 (0.34 – 4.68)7.01 (0.36 – 135.86)0.70 (0.12 – 4.20)1.08 (0.49 – 2.37)1.16 (0.55 – 2.45)6.03 (0.72 – 50.24)0.67 (0.11 – 3.99)1.20 (0.77 – 1.88)Heterogeneity; P = 0.62

Heterogeneity; P = 0.68


Shorter DAPT Better Longer DAPT Better

P < 0.0001

3 or 6 Months Discontinuation

Clinically Significant Bleeding

1

Trial Name

12 Months DiscontinuationDAPT StudyDES-LATEARCTIC-Int.Subtotal

Overall

ISAR-SAFEITALICSECURITYOPTIMIZEPRODIGYEXCELLENTRESETSubtotal

Odds Ratio 95% CI

0.68 (0.52 – 0.90)0.63 (0.46 – 0.87)0.14 (0.02 – 1.17)0.65 (0.52 – 0.81)

0.63 (0.52 – 0.75)

0.46 (0.17 – 1.22)0.71 (0.22 – 2.25)0.52 (0.16 – 1.74)0.71 (0.31 – 1.60)0.55 (0.29 – 1.04)0.50 (0.09 – 2.73)0.50 (0.17 – 1.46)0.57 (0.40 – 0.81)Heterogeneity; P = 0.62



Size of central markers reflects the weight of each study. Reproduced with permission from Giustino et al. (93). RCT ¼ randomized clinical trial; other abbreviations as in

Figures 1 and 3.


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Prasugrel–Thrombolysis In Myocardial Infarction 38)and PLATO (A Study of PLATelet Inhibition and Pa-tient Outcomes) trials were designed to determinewhether prasugrel or ticagrelor, characterized bygreater potency and less response variability, issuperior to clopidogrel for the prevention of ischemicevents and death in patients presenting with an acutecoronary syndrome (ACS) (prasugrel only for thoseundergoing planned PCI) (89,90). Without any sta-tistical difference in all-cause mortality, prasugrel(irreversible thienopyridine and prodrug) providedsuperior reductions in ischemic events at 6 to15 months of treatment, including decrease in ST(2.4% vs. 1.1%; p < 0.001), but at the expense of anincreased risk of major bleeding (89).

On the other hand, ticagrelor (reversible non-thienopyridine, direct-acting antagonist of theadenosine diphosphate receptor P2Y12), significantlyreduced the 12-month primary ischemic endpoint,including ST (1.3% vs. 1.9%; p ¼ 0.009), without anincrease in the rate of overall major bleeding, butwith an increase in the rate of nonprocedure-relatedmajor bleeding (90). In general, these agents arepreferred over clopidogrel in patients with ACS andlow bleeding risk, regardless the antiplatelet response(8,88).

There is a lack of well-powered studies thatcompared antiplatelet power of prasugrel againstticagrelor throughout the maintenance period andresults of small studies have been inconsistent (91).The PRAGUE-18 (Comparison of Prasugrel and

Ticagrelor in the Treatment of Acute MyocardialInfarction) study, the largest RCT to date (N ¼ 1,230)assessing the benefit in clinical outcomes of prasugrelversus ticagrelor, did not find any statistical differ-ence in definite ST (0.5% vs. 0.9%, respectively;OR: 0.56; 95% CI: 0.13 to 2.35; p ¼ 0.428) within30 days (92). Of note, the study enrollment was pre-maturely terminated because of futility (designed tofollow 2,500 subjects with MI for 1 year) (92), andlong-term outcomes are not still available.

SHORT-TERM VERSUS LONG-TERM DAPT DURATION.

Traditionally, themajor role of DAPT in stentingwas toprotect the adverse effects of having a foreign throm-bogenic body inside the artery until full re-endothelialization was completed (i.e., BMS), and fora longer period of time, to “keep safe” the anti-restenotic effects of DES. This would reduce theoccurrence of both early and LST. However, an intensedebate still exists about benefits of using DAPT beyond1-year post-PCI to mitigate the incidence of VLST inpatients with 2G-DES (8,88). Likewise, the optimalDAPT duration in patients with current BVS is un-known and could be longer (8).

Several RCTs with different inclusion criteria,clinical scenarios, and stents have addressed thebenefits of using shorter (3 or 6 months) versus longerdurations (12 or 24 months) of DAPT. In addition,further studies have also compared the clinical ad-vantages of 12 months versus extended (>12 months)DAPT periods (Online Table 3).


FIGURE 6 Proposed Combined Algorithm Using PRECISE-DAPT and DAPT Scores for the Management of DAPT Duration After Stenting

DAPTScore <2

Continue P2Y12receptor inhibitor(up to 18 months)

Stop P2Y12receptor inhibitor

PRECISE-DAPTScore ≥25

ACS

Points0 - 190/260 - 150 - 150 - 25

Index PCI (stent placement)

No significant overtischemic/bleeding

events

12 monthDAPT

6 monthDAPT*

PRECISE-DAPTScore ≥25

SCAD

No Yes No Yes

No Yes

6 monthDAPT

3 monthDAPT

“PRECISE-DAPT Risk Score”

VariablesAge, yPrevious bleeding (no/yes)White blood cell countHemoglobinCreatinine clearance

1000 25

Total score range 0 to 100

10–2 2

Points

–2–1011112

112

“DAPT Risk Score”

Patients characteristics

Procedural characteristics

Age, y≥7565 to <75<65Cigarette smokingDiabetes mellitusPrior PCI or prior MIPaclitaxel-eluting stentCHF or LVEF <30%

MI at presentationStent diameter < 3mmVein graft stent

Total score range –2 to 10

Variables are obtained at or close proximity to the index PCI and added for the final score. Cigarette smoking was defined as smoking within 1 year before PCI. *This

recommendation may be considered if 2G-DES/BP-DES is implanted. For more information, see Yeh et al. (95) and Costa et al. (96). ACS ¼ acute coronary syndrome;

CHF ¼ congestive heart failure; LVEF ¼ left ventricular ejection fraction; SCAD ¼ stable coronary artery disease; other abbreviations as in Figure 1.



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Meta-analyses of these RCTs indicated that DAPTextended beyond 12 months reduces thromboticevents compared with a 12-month regimen, but at theprice of greater risk of major bleeding (Figure 5) (93).Of note, because all cause-death was not clearly pre-vented by prolonged DAPT (or even increased), itseems that thrombotic events amenable to preventionwith prolonged DAPT could be, what was referred to,as “infarctlets” or “strokelets.”

Using data derived from some of these studies,Giustino et al. (93) found a significant interaction be-tween DES generation and DAPT duration on risk of ST.Accordingly, the benefit of prolonging DAPT over 6months in reducing ST rates, was significant in patients

treated with 1G-DES (2.4% vs. 0.6%; p < 0.05), but notwith current 2G-DES (0.6% vs. 0.4%; p ¼ NS) (93).

The recently published SENIOR (Short Duration ofDual antiplatElet Therapy With SyNergy II Stent inPatients Older Than 75 Years Undergoing Percuta-neous Coronary Revascularization) trial further sup-ports this analysis. Among elderly patients (age >75years), who are inherently at high risk of bleeding, astrategy of combining a BP-DES (SYNERGY stent) plusa short DAPT duration (1 and 6 months for stablecoronary artery disease and ACS, respectively) wereequally safe than a BMS plus a similar DAPT durationin terms of ST and bleeding rates, with a significantreduction in TLR at 1-year follow-up (94).

FIGURE 7 Management of Bleeding After Recent Stenting

Acute bleeding

Imaging of clinically suspected SOB

1. Assessment of bleeding entity

General stages of bleeding management

2. Determination ofhemodynamic/neurological condition

3. Stabilization ± AAT†

4. Imaging of clinically suspected SOB

5. Local bleeding control if possible orspecific treatment of SOB ± bloodtransfusions

6. Consider bailout surgery

7. Resume DAPT as soon as possible

Clinically suspected SOB

Intrapericardialbleeding/RPH‡

Consider bloodtransfusions

Stabilization(SBP ≥80 mm Hg)

SBP <80 mm Hgor need for

vasopressors

Bailout surgery

Failure to control bleeding

Endoscopiccontrol/arterialembolization

Endovascularcontrol ±

pericardiocentesis

Fluidresuscitationx 30 min ±

AAT†

Hemodynamically unstable

Patient educationConsider patientadmission

Do notinterrupt DAPT

Compressmechanically

Imaging of SOB Neurologically unstable

Suspicion of ICH

No

No Yes No

Yes

Yes

No Yes

Major bleeding*Minor bleeding*

Ventilatorysupport

±AAT†

DAPTtemporary

interruption

SpecificSOB treatment

Resume DAPT if possible

Neurosurgical evaluation

Urgent brain CT

Withholding 1 or both antiplatelet agents should always be considered as putting the patient at substantial risk for ST. Treat bleeding locally if possible (e.g.,

compression of SOB, endoscopy, endovascular). *Major bleeding includes: intracranial, RPH, bleeding that led to clinically significant disability (e.g., intra-

ocular bleeding with vision loss), bleeding causing hypovolemic shock or severe hypotension, and should be suspected in the presence GP IIb/IIIa use. Minor

bleedings includes: GI, GU tract bleedings, intra-articular, intramuscular, superficial, etc., but not meeting the criteria for major bleeding. †Anti-antith-

rombotic therapy (AAT) may include: stop intravenous infusions (e.g., cangrelor, GP IIb/IIIa inhibitors), antithrombotic antidotes infusion (e.g., protamine,

vitamin K, specific antidotes, fresh frozen plasma, and so on) and platelet transfusion. Unlike anticoagulants, there are no antidotes for platelet inhibitors.

Platelet transfusion has been used extensively to improve platelet function in this setting, but its benefit is unclear. ‡Urgent transfer to cath lab for angi-

ography and endovascular control of bleeding or unnoticed coronary perforation (plus pericardiocentesis). CT ¼ computed tomography; GI ¼ gastrointestinal;

GP ¼ glycoprotein; GU ¼ genitourinary; ICH ¼ intracranial hemorrhage; RPH ¼ retroperitoneal hemorrhage; SBP ¼ systolic blood pressure; SOB ¼ site of

bleeding; other abbreviations as in Figure 1.


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BALANCING ISCHEMIC AND BLEEDING RISK: THE

“DAPT” AND PRECISE-DAPT SCORES. Identifyingsingle patients that could benefit from short, long, orextended DAPT after stenting, rather than a general-ized indication, might be the answer for this safetyand efficacy dilemma. Recently, the DAPT trial

investigators developed the “DAPT Risk Score,”with asimplified prediction for the composite of MI orST (ischemia model) and GUSTO (Global Utilizationof Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries) moderate/severebleeding (bleeding model) in the following 18 months



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after accomplishing safely 12-month DAPT course (95).Within the DAPT study population, a “clear gradientof effect” was observed with a cutoff score of 2(Figure 6).

This strategy, however, cannot be applied earlier,at the time of treatment initiation, to select a shorterthan 12-month treatment duration in patients at highbleeding risk. Overcoming this limitation, a stan-dardized tool (a 5-item risk score) developed byCosta et al. (96) predicts out-of-hospital bleeding inpatients undergoing PCI, and thus helps defineoptimal DAPT duration at the time of stent implan-tation (Figure 6).

These complementary clinical tools may aidclinicians to personalize DAPT durations byidentifying patients who derive net clinical benefitfrom short, long, or extended DAPT following stenting.

MANAGING BLEEDING COMPLICATIONS

AND ST PREVENTION

The prevention of bleeding after stenting has amajor impact in ST prevention and mortality (97).After acute blood loss, there is an increased risk forST, presumably because of the rapid formationof immature, larger, denser, and more reactiveplatelets (98).

Data derived from for the National CardiovascularData Registry found that major bleeding occurs at arate of 1.7% after PCI, about one-half from the siteof arterial access and one-half from nonaccesslocations, most commonly the gastrointestinaltract (99). The progressive incorporation of theradial access in the interventional practice havedramatically reduced the occurrence of majorbleeding (mostly access-related bleeding) ascompared with the femoral access (100). On theother hand, controlling modifiable bleeding riskfactors (e.g., hypertension, concomitant use ofanti-inflammatory drugs, treatment of gastritis) is ofthe utmost significance in preventing nonaccess sitebleeding events at long term (101).

The management of bleeding complications in thepresence of recent stenting always poses a consider-able dilemma. Although aspirin-inhibited plateletaggregation can be restored after 2 to 5 U of platelettransfusion, it is more difficult to restore oraladenosine diphosphate—dependent platelet function(101). In patients receiving clopidogrel or prasugrel,platelet transfusions can restore platelet functiononly 4 to 6 h after the last drug intake (102). In patientson ticagrelor, however, it may take $24 h for drugclearance to allow transfused platelets to restore he-mostatic competence (101). The rapidly reversible

antithrombotic effect of cangrelor would facilitate theimplementation of a rapid hemostasis in case ofbleeding, just by “turning off” the P2Y12 receptorblockage. In addition, this drug allows physiciansto address bleeding more conservative in case ofhigh risk of ST (i.e., avoiding the use of platelettransfusions while keeping the TxA2 pathway inhibi-ted), maintaining the recent deployed stent atleast somewhat protected. In Figure 7, an algorithmfor the management of bleeding complications isproposed.

CONCLUSIONS

The 40-year history of PCI is marked throughout byattempts to reduce ST and ISR. Although 1G-DESreduced BMS-related restenosis, a significantincrease in LST eclipsed this success. Delayedre-endothelialization, chronic inflammation, late-acquired SM and NA are considered the leadingunderlying findings in association with LST/VLST andoccur in relation with the antiproliferative therapy.

The dogma that durable polymers have a majorimplication in increasing LST/VLST rates has beenchallenged with the use of 2G-DES. The remarkablesuperiority of CoCr-EES/PtCr-EES over almostall other DES might lie in the unique favorable prop-erties of permanent fluoropolymers used in thesestents. Thinner struts biodegradable polymer-basedDES may represent an alternative to current 2G-DES.

BVS are still in their infancy, but certainly, openingthe next big chapter in interventional cardiology.However, an increase in DT conspires against the“permanence of these transient-acting devices” in thetherapeutic toolbox. Hopefully, newer generations ofpolymeric BVS, which feature stronger materials,thinner struts, and better reabsorption kinetics willbe soon available.

The tradeoff between bleeding and thromboticevents with prolonged DAPT seems to be morecomplex. With 2G-DES, 6 months of DAPT seems tobe enough to prevent the majority of ST. Theimplementation of PRECISE-DAPT and DAPT scoresmay help clinicians to individualize the decisionregarding duration of DAPT. Cardiologists must beaware how to prevent and manage bleeding compli-cations in the presence of stenting, while minimizingthe risk of ST.

ADDRESS FOR CORRESPONDENCE: Dr. Luis A.Guzmán, Department of Cardiology, VirginiaCommonwealth University, 1200 East Broad Street,5th Floor, West Wing, Room #526, Richmond,Virginia 23298. E-mail: [email protected].

mailto:[email protected]


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KEY WORDS biodegradable polymers,bioresorbable vascular scaffold, bleeding,drug-eluting stent, percutaneous coronaryintervention, stent restenosis, stentthrombosis

APPENDIX For supplemental tables, pleasesee the online version of this paper.























































































































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