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Achtung! Beim aktuellen Update der Software auf dem PC oder der Firmware auf dem Messgerät müssen beide gemeinsam erneuert werden.
Das Design „Black magic“ ist in dieser Version nicht enthalten und wird ab der V5.1 wieder zur Verfügung stehen.

Attention! With the actual update of the software on the PC or the firmware on the measuring device, both have to be renewed together.
The 'Black magic' design is not included in this version and will be available again in V5.1.

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Betriebssysteme / Operating systems / Sistemas operativos: Windows 8, 10

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Betriebssysteme / Operating systems / Sistemas operativos: Windows 8 (64 bit), 10 (64 bit)

Review Article - Interventional Cardiology (2014) Volume 6, Issue 5

Corresponding Author:

AnthonyMathur
Barts & The London NIHR CardiovascularBiomedical Research Unit
LondonChest Hospital, Barts Health NHS Trust,London, E2 9JX, UK
E-mail:[email protected]

Abstract

Percutaneous coronary intervention is currently the most commonly used revascularization procedure. This success is a direct consequence of the improved medium- and long-term target vessel patency achieved with drug-eluting stents (DES). However, DES are associated with stent thrombosis (ST), a rare but potentially catastrophic complication. Early interruption of dual anti-platelet therapy (DAPT) is a major risk factor for ST and guidelines recommend a minimum duration of DAPT of 6 to 12 months post implantation. Recently published observational data suggest that premature DAPT interruption is not associated with ST in patients treated with the second-generation Resolute zotarolimus-eluting stent. This article reviews the background to the development of Resolute DES and reviews recently published data on ST and DAPT interruption.

Introduction

Percutaneous coronary intervention (PCI) iscurrently the most common mode of coronaryrevascularization [1]. The use of drugelutingstents (DES) has improved clinicaloutcomes [2] but safety concerns over stentthrombosis (ST) have been raised [3–5]. Dualanti-platelet therapy (DAPT) is the mainstayof pharmacological treatment for the preventionof ST and contemporary clinical guidelinesrecommend a minimum duration oftreatment ranging from 6 to 12 months postDES implantation [6–11].

Resolute (Medtronic CardioVascular, SantaRosa, CA) and Resolute Integrity (MedtronicCardioVascular, Santa Rosa, CA) are second-generationDES with a biocompatible polymerproviding prolonged zotarolimus elution[12]. Recently published data show thatthere is no increased risk of ST with DAPTinterruption between 1 and 12 months postResolute DES implantation [13].

This article provides the background to thedevelopment of Resolute and Resolute IntegrityDES and reviews the recently publisheddata on ST and DAPT interruption.

Background

the inception of percutaneoustransluminal coronary balloon angioplastyand the pioneering work of Andreas Gruentzigand his co-workers in the 1970s [14],PCI has evolved to became a routine therapeuticmodality [8,11]. In its earliest form,revascularization was achieved with plainballoon angioplasty and was limited byacute vessel closure and a high risk of targetvessel revascularization (TVR) from latelumen loss secondary to negative remodelling[15–18]. The introduction of bare metalstents (BMS) in the 1980s [19] improvedboth acute- and medium-term outcomes andBMS soon became the new standard of care.[20] However, in-stent restenosis (ISR) occursin approximately 30% of lesions treated withBMS [16,21] and is associated with not onlywith the reoccurrence of angina but alsowith myocardial infarction in a small butsignificant subgroup of patients [22]. Theaetiology of ISR is incompletely understoodand currently thought to be caused byan exuberant healing response to vascularinjury [23,24]. ISR with BMS remained the Achilles’ heel of PCI until the development of DES inthe late 1990s [25].

DES share the mechanical scaffolding properties ofBMS and additionally function as delivery platformsfor drugs which modulate the healing response to vascularinjury to prevent ISR. Two drugs became the protagonists:paclitaxel (a chemotherapeutic agent) andsirolimus (rapamycin, a macrolide antibiotic) [26–28].The first generation DES consisted of a BMS platformcoated with a durable (nonbioerodable) polymer thateluted either sirolimus (Cypher) or paclitaxel (TaxusExpress). Randomized controlled trials showed thatfirst-generation DES reduced ISR to less than 10%[29,30], and subsequent meta-analyses suggested thatsirolimus is superior to paclitaxel in reducing TVR andISR [31,32].

Despite substantial progress, ISR remains a problemin a small subgroup of patients treated with DES.The pathophysiology of ISR in DES has recentlybeen reviewed by Dangas et al. [33]; briefly, possiblemechanisms include:

• Biological factors: genetic variants conferringresistance to anti-proliferative drugs [34] andhypersensitivity reactions to components of DES [35];

• Mechanical factors: stent fractures [36], polymerpeeling [37] and non-uniform drug deposition [38];

• Technical factors: stent under-expansion [39].

To address some of the factors predisposing toISR, DES design progressed with the developmentof second-generation DES which are characterized by thinner struts and enhanced polymer biocompatibilityand drug delivery [40,41]. The characteristics ofcommonly used second-generation DES are shown in Table 1 [42]. The rate of TVR at 1 year with second-generationDES is ≤7.5% [43] but some elements ofDES design may predispose to stent thrombosis.

Table 1: Common second-generation drug-eluting stent characteristics.

Resolute & Resolute integrity drug-elutingstents

The Resolute Integrity DES was approved by the USFDA in 2012. Resolute Integrity consists of: cobaltbasedalloy (MP35N) Integrity stent platform, a coatconsisting of Parylene C primer and BioLinx polymerand zotarolimus. Resolute Integrity is the successor ofthe Resolute DES which was based on a Driver modularstent platform whilst Integrity is a continuous pieceof wire with a sinusoidal shape wrapped into a cylinder.With the exception of the stent platform, the two stentshave the same basic technical characteristics. BioLinx isa mixture of three polymers, each with a different function:the hydrophobic C10 controls drug release andprovides rigidity to the mixture; the hydrophilic C19polymer improves biocompatibility and polyvinyl pyrrolidoneprovides short peak in drug release [12,44]. Theactive pharmacological ingredient is zotarolimus, a sirolimusanalogue which shares the same mode of actionas the parent compound, but with a shorter half-life[45]. Resolute and Resolute Integrity stents elute 85% ofzotarolimus within 60 days and drug elution is completeby 180 days [12]. Prolonged drug elution ensures thatzotarolimus provides antiproliferative cover in parallelwith delayed vascular healing [12].

The efficacy and safety of Resolute DES has beenexamined in a number of studies which were part ofthe Medtronic RESOLUTE Global Clinical Program:

• RESOLUTE First In Man was a prospective, non-randomized,multicenter study of 139 patientswith de novo coronary lesions and showed a0.22 ± 0.27 mm in-stent lumen loss at 9 months[46]. At 2 years, there was one case of TVR, onenon-cardiac death and one possible ST [47];

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• RESOLUTE US was a prospective, observationalstudy in the USA designed to evaluate the clinicaleffectiveness of the Resolute DES in 1402 patients[48]. Target lesion failure (cardiac death, myocardialinfarction or clinically-driven target lesion revascularization)was 3.7% at 12 months with ResoluteDES and 6.5% using Endeavour DES historicaldata, meeting the non-inferiority criterion [48];

• RESOLUTE All Comers was a multi-center, single-blind, randomized trial comparing ResoluteDES to Xience V everolimus-eluting stent in 2292patients. Resolute had a similar safety and efficacyprofile to Xience V at 2 years [49,50];

• RESOLUTE International Registry used datafrom 2349 patients and reported a 1-year incidenceof cardiac death and target vessel myocardialinfarction of 4.3% (95% CI: 3.5–5.2%). Definiteand probable ST was observed in 0.9% [51];

• RESOLUTE Japan (ClinicalTrials.gov Identifier:NCT00927940) was designed to examine instentlate lumen loss at 8 months in 100 participants.The results have not been published in peerreviewed journal (PubMed search: February 2014).

Pooled patient-level data from 5130 patients participatingin the Medtronic RESOLUTE Global ClinicalProgram were used to examine Resolute DES inspecific settings:

• Diabetes: the 12-month rate of target lesion failurewas 7.8% in the pre-specified diabetic cohort andwas significantly lower than the performance goalof 14.5% set by the FDA (p < 0.001) [52];

• Overlapping stents: the study reported comparableclinical outcomes in patients with overlapping andnon-overlapping DES [53].

Finally, the TWENTE trial, an investigator-initiatedstudy supported by Abbott Vascular and Medtronic,demonstrated the non-inferiority of Resolute DEScompared with Xience V everolimus DES in a patient-blinded,randomized study which included 1391 patients (the findings were similar to RESOLUTE AllComers) [54].

ST & dual anti-platelet therapy

ST is a serious complication of PCI associatedwith acute myocardial infarction and high mortality[55–59]. Immediately after stent implantation,thrombogenic stent components, coronary dissection,in situ thrombus, stasis, and stent under-expansionmay all contribute to the development of earlyST (<30 days) [60]. Early ST can be effectively preventedby DAPT; aspirin and ticlopidine administrationreduced early ST to <1% [61,62]. With the introductionof clopidogrel, ticolpidine became obsoleteand the most commonly prescribed DAPT regimenis aspirin with clopidogrel [63]. Prasugrel and ticagrelorare alternatives to clopidogrel and may be bettersuited for patients with acute coronary syndromesundergoing stent implantation [64,65].

In 2006 the success of first-generation DES inreducing ISR and target vessel revascularization wasclouded by safety concerns over late (between 30 daysand 1 year) and very late (beyond 1 year) ST [3–5]. Earlyinvestigators used variable definitions of ST whichhampered the generalization and comparability of theresearch findings. Progress was made in 2007 whenthe Academic Research Consortium (ARC) proposedstandardized definitions for ST [66]:

• Definite ST: angiographic or pathologic evidenceof thrombus within a stent;

• Probable ST: any unexplained death within thefirst 30 days post stenting, or myocardial infarctionthat is related to acute ischemia in the territoryof the implanted stent in the absence of any otherobvious cause;

• Possible ST: any unexplained death from 30 dayspost stenting until end of trial follow-up.

ARC ST is also classified according to its temporalassociation with stenting: early (within 30 days), late(between 30 days and 1 year) and very late (beyond1 year) [66].

A number of meta-analyses investigated ST usingthe ARC definitions and reported similarly low rates(<1%) of early and late ST for DES and BMS [67–71].However, the meta-analyses demonstrated that firstgenerationDES were associated with a higher rate ofvery late ST (>1 year) than BMS [67–71]. Data fromlarge registries indicate that the risk of very late STpersists at least 5 years post DES implantation, withan annual ST rate of approximately 0.5% [72,73,58].Two larger network meta-analyses which included studies comparing second-generation DES with eachother or with BMS, demonstrated that very late ARCdefinite ST was lower with everolimus DES thanBMS [2,74]. Even though Resolute DES studies wereincluded in the network meta-analyses [2,74], the relativelysmall number of patients involved make it difficultfor solid conclusions to be drawn with regardsto Resolute DES.

Overall, the available data on ST are reassuringbut extensive DES utilization means that the populationat risk is large and every possible step should betaken to prevent this complication. Risk factors of SThave recently been reviewed by Holmes et al [75] andPalmerini et al [76] and include:

• Patient factors: stenting in acute coronary syndromes,diabetes mellitus, premature DAPT discontinuation,DAPT non-responsiveness, priorbrachytherapy, pro-thrombotic state;

• Lesion factors: lesion/stent length, vessel/stentdiameter, complexity of lesion, saphenous veingraft intervention;

• Procedural factors: stent under-expansion,malapposition, edge dissection;

• Stent factors: hypersensitivity to drug coatingor polymer, incomplete endothelialization, stentdesign, covered stents.

Premature DAPT interruption was identified as astrong predictor of ST following treatment with first-generationDES [56,77,78]. In the absence of data fromrandomized controlled trials examining the impact ofDAPT duration on ST, current international guidelinesrecommend DAPT for 6 to 12 months based on consensusand observational data [6–11]. Even though these recommendationsare reasonable for first-generation DES,the association of ST with DAPT interruption is lessconvincing with second-generation DES and other factorsmay play a dominant role in determining outcomes.The PRODIGY study examined ST relative to DAPTduration in 2013 patients [79]. The patients were randomizedto a second-generation DES, a paclitaxel-elutingstent or a BMS and at 30 days randomized either to 6or 24 months of DAPT with clopidogrel therapy. Treatmentfor 24 months did not confer a mortality benefitand did not reduce ST in second-generation DES [79]. Inanother study, Park et al. randomized 2701 DES recipientswho had been free of major cardiovascular eventsand major bleeding for at least 12 months to receive either clopidogrel plus aspirin or aspirin alone. DAPTfor longer than 12 months did not reduce myocardialinfarction, death from cardiac causes or ST [80]. Finally,the PARIS registry examined adverse cardiac events andtheir relation to DAPT cessation in 5018 patients treatedwith BMS (11%), first-generation DES (15%) and second-generation DES (74%) [81]. The PARIS registryreported that the majority (74%) of a composite of cardiacdeath, definite or probable ST, myocardial infarctionor target-lesion revascularization (MACE) at 2 yearsoccurred whilst on DAPT [81]. The underlying pathologyleading to DAPT interruption may be the dominantplayer in determining cardiac outcomes; DAPT interruption(<14 days) for surgery was not associated witha higher risk of MACE but DAPT disruption for bleedingwas linked to increased MACE (HR: 1·41; 95% CI:0·94–2·12; p = 0·10 and HR: 1·50; 95% CI: 1·14–1.97;p = 0·004 respectively when compared with patients onDAPT). Similar pattern of risk was observed for definiteor probable ST [81].

DAPT interruption & ST with Resolutedrug- eluting stents

Silber et al. recently published a report on the occurrenceof ST in patients treated with Resolute DES who subsequently interrupted DAPT [13]. For this analysisdata were pooled from RESOLUTE-All Comers,RESOLUTE-International, RESOLUTE-Japan andRESOLUTE-US. Of the 4991 subjects who participatedin the aforementioned trials, 95 (2%) patientswere excluded primarily because of missing data onDAPT; the final cohort for this study consisted of 4896patients. The majority of patients were in their seventhdecade of life, 40% had an acute coronary syndromeand the prevalence of diabetes was approximately 30%.Most treated lesions were type B2/C.

All patients were recommended long-term treatmentwith aspirin with co-administration of a thienopyridine(clopidogrel or ticlopidine) for a minimum of 6 monthsand ideally for 12 months post stent implantation.DAPT interruption was defined as treatment discontinuationfor more than 1 day. The outcome of the studywas definite ST or probable ST as defined by the ARC.ST was examined in three groups: patients with continuousDAPT, DAPT interruption in the first monthand DAPT interruption after 1 to 12 months followingstent placement.

In all, DAPT interruption was reported in 1069patients (22%): thienopyridine alone in 62%, aspirinalone in 18% and both anti-platelets in 20%. Medical, dental and surgical procedures were the most commoncauses of temporary DAPT interruption. Interestingly,bleeding was not a cause of DAPT interruptionwithin the first month. Permanent DAPT interruptionoccurred mostly because of physician-directed with-drawalafter a period of 6 months. The reported prevalenceand patterns of DAPT interruption were broadlysimilar to the PARIS observational study [81].

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Within 1 year of treatment with Resolute DES, a totalof 39 (0.8%) ST were observed in 4896 patients. Theoccurrence of ST stratified according to DAPT adherenceis summarized in Figure 1. ST was most commonafter DAPT interruption within the first month poststenting, with a 3.9% cumulative incidence of ST at1 year. There was a single case of definite late ST outof 903 patients who interrupted DAPT between 1 and12 months (1-year cumulative incidence of 0.11%). Thispatient had a prior history of ST and stopped clopidogrel69 days post intervention with ST developing 3 dayslater. There were 32 ST in patients with continuousDAPT, with a 0.84% cumulative incidence of ST at1 year. Very late ST was not observed during the durationof the study. The Kaplan–Meier curves for each prespecifiedgroup is shown in Figure 2. DAPT interruptionbetween 1 and 12 months was not associated with anincreased risk of ST when compared with patients oncontinuous DAPT. The patterns of DAPT interruptionand their relation to ST are shown in Figure 3. Notably,ST was not reported with the simultaneous interruptionof aspirin and thienopyridne. The six ST withinthe first month of stenting occurred in patients withDAPT interruption of >14 days. No ST were reported in patients with prolonged DAPT interruption between1 to 12 months.

Figure 1: Dual anti-platelet interruption and stent thrombosis in patients with resolute drug-eluting stents.DAPTi: Dual anti-platelet therapy interruption; ST: Stent thrombosis (ARC-definite or probable ST).

Figure 2: Cumulative incidence of definite or probable stent thrombosis through 1 year after stent implantation according to dualantiplatelet therapy interruption status.
ST: Stent thrombosis.
Reproduced with permission from [13] © Oxford University Press (2014).

Figure 3: Patterns of dual anti-platelet therapy interruption.DAPTi: Dual anti-platelet therapy interruption; ST: Stent thrombosis (ARC-definite or probable ST).

The reported rates of ST by Silber et al. [13] are inkeeping with the TWENTE trial which tested thenon-inferiority of Resolute against Xience V [54]. In theTWENTE trial five definite or probable late ST (0.5%)were observed in patients treated with Resolute DESwith one ST-related to DAPT interruption [54].

The exact mechanism responsible for the low incidenceof ST with DAPT interruption in Resolute DESis not clear. The authors postulate that their findingsmay be explained by the highly biocompatible nature ofthe BioLinx polymer which provides a minimally pro-inflammatoryhydrophilic surface as shown in a porcinecoronary model [13,44,82]. In humans, optical coherencetomographic studies of Resolute DES have shownimproved early neointimal coverage compared withfirst-generation DES [83,84].

DAPT interruption with other second-generationdrug-eluting stents has also been associated with a lowincidence of ST. Results from the 8061-patient XIENCEV US study showed that the incidence of definite/probableST was 0.8% at 1 year and DAPT interruptionbetween 1 to 12 months was not associated with anincreased risk [85]. A polled analysis of SPIRIT II, SPIRITIII, SPIRIT IV and COMPARE trials also showed thatDAPT interruption after 6 months was not associatedwith ST in patients treated with Xience V stents [86].

Clinical implications

DAPT interruption within 1 year of DES implantationis unavoidable in approximately 15% of patients [81]. Cardiologists and patients commonly face difficultdecisions because of unexpected bleeding and essentialsurgical/dental procedures unforeseen at the time ofcoronary intervention. To minimize the risk of ST withessential surgical procedures, guidelines recommendcontinuing aspirin whenever possible but difficult situationsarise when both aspirin and thienopyridine haveto be discontinued [87].

Data from Silber et al. [13] offer some reassurance thatthe incidence of ST is low following DAPT interruption(including both aspirin and thienopyridine) between 1to 12 months post Resolute DES treatment. This observationshould be interpreted cautiously as it is based onobservational data rather than a randomized controlledtrial examining the optimal duration of DAPT andshould not change the current practice of DAPT for 6to 12 months post DES [6–11]. The results also highlightthat procedural and lesion factors are more important indetermining ST than DAPT duration in the majorityof patients as most ST occurred whilst on DAPT [13],in keeping with the PARIS registry data [81]. An unansweredquestion is whether these data from ResoluteDES can be applied to patients treated with the newerResolute Integrity stent which has a different stentplatform but the same polymer and drug (zotarolimus).

Silber et al. also showed that DAPT interruptionwithin the first month of Resolute DES was associatedwith a higher risk of ST [13] and should thus be avoidedwhenever possible. If absolutely essential, DAPTinterruption should be limited to less than 2 weeks.

Future perspective

With the development of second-generation DES, therisk of ST thrombosis appears to have declined andrandomized controlled trials have shown that DAPTfor 24 months is not beneficial [79,80]. The optimalDAPT duration with second-generation DES needsto be determined in an adequately powered prospectiveclinical trial. However, the low incidence of STmeans makes this challenging as a very large numberof patients will need to be enrolled.

Executive summary

Background

• Stent thrombosis (ST) is an uncommon but serious complication of coronary stenting.

Stent thrombosis & dual anti-platelet therapy

• Dual anti-platelet therapy (DAPT) interruption within the first month of stenting is unequivocally associatedwith a very high risk of ST and should be avoided at all costs.

DAPT interruption with Resolute stents

• Recently published data from the Medtronic RESOLUTE Global Clinical Program indicate that DAPTinterruption between 1 to 12 months of Resolute DES implantation is not associated with a higher risk of ST.

Clinical implications

• Patients treated with Resolute DES should still be advised to continue DAPT for 6 to 12 months post stentingin accordance to international guidelines and can be reassured that DAPT interruption for concurrentmedical/surgical illnesses or bleeding is not likely to lead to catastrophic ST.

Future perspective

• The optimal DAPT duration with second-generation DES needs to be determined in an adequately poweredprospective clinical trial.

References

Papers of special note have been highlighted as:
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