Percutaneous interventional cardiovascular medicine

Summary

Although stent thrombosis (ST) is less frequent following the introduction of new generation drug-eluting stents (DES) and the evolution in adjunctive pharmacotherapies, it remains the most dreaded and deadly consequence of coronary stent deployment. Specific patient, target lesion, and procedural related factors have been identified which increase risk for ST. Genetic and phenotypic variability in the platelet inhibitory response to clopidogrel may be associated in high on-treatment residual platelet reactivity and/or consequent risk for ST. Inter-individual variability in response to clopidogrel may, at times, be overcome by increasing clopidogrel dose but most often requires switching from clopidogrel to a novel platelet P2Y12 receptor inhibitor. Prevention of ST requires a multifaceted approach which begins with patient risk stratification and choice of stent platform, includes fastidious procedural stent deployment and periprocedural adjunctive pharmacotherapy, and concludes with education and adherence to longer-term dual antiplatelet therapy (DAPT). The optimal duration of DAPT therapy to reduce ST has been investigated in a recent large-scale randomised, placebo controlled clinical trial which compared 30 versus 12 months of DAPT in subjects who had tolerated one year of therapy. Longer duration (30 months) therapy was associated with a significant reduction in both ST and myocardial infarction (MI) not related to ST in addition to an increase in bleeding events. Nevertheless, the majority of ST events occur in patients who are adherent to DAPT therapy. Thus, decisions regarding duration of DAPT therapy must be made in context of the balance between ischaemic event risk reduction and bleeding event risk increase.

Introduction

Stent thrombosis (ST) is a medical emergency often associated with death (20%-40%), MI (50%-70%) or the requirement for urgent repeat revascularisation [1, 2, 3, 4]. The clinical consequences of ST are dependent upon the volume and viability of myocardium at risk, the degree of collateral vessel recruitment and the timeliness of emergency reperfusion therapy. Although drug-eluting stents (DES) reduce angiographic and clinical restenosis compared with bare metal stents (BMS), the incidence of ST has been variable, depending on DES stent type and the time course for ST occurrence may differ as well [5, 6, 7, 8, 9].

The development of standardised definitions for both the time course and probabilistic likelihood of thrombosis following stent deployment by the Academic Research Consortium (ARC) has facilitated comparative analyses across clinical studies and other data sets ( Table 1 ) [10]. Although the ARC definitions add uniformity, they are still an imperfect balance of sensitivity and specificity. “Definite” ST is highly specific but probably underestimates the true frequency of ST, whereas “possible” ST is more sensitive but lacks diagnostic certainty. Most contemporary analyses combine the categories of “definite” and “probable” to provide a balance of specificity and sensitivity. The time course for ST occurrence is categorised as early (either acute or subacute), if within 30 days of stent deployment, and either late (>30 days to one year) or very late (>one year).

Multiple risk factors have been identified which contribute to the genesis of ST ( Figure 1 ) and may vary in importance as a function of time course following stent deployment [11, 12]. Early events may be related to residual target lesion thrombus, plaque prolapse or medial tear, stent malapposition, undersizing and/or underexpansion as well as dual antiplatelet therapy (DAPT) noncompliance or a combination of these factors [2, 12, 13, 14, 15]. Other factors incriminated in the etiology of early and late ST include longer target lesion and/or stent length, overlapping stents, smaller target vessel diameter, depressed left ventricular function and the acuity of the clinical syndrome at presentation [12, 15]. Additional correlates of late/very late ST include younger age, smoking, multivessel disease and vein graft target lesion [16]. Importantly, the antiproliferative properties of DES which are responsible for reducing restenosis (compared with BMS) have also been incriminated in the occurrence of late and/or very late ST following DES particularly in the absence of prolonged (>one year) DAPT therapy. Studies of both animal models and humans have demonstrated delayed endothelialisation and incomplete stent healing with consequent stent strut exposure following DES versus BMS [17, 18, 19]. Although serial angioscopic and optimal coherence tomography (OCT) evaluations as well as autopsy studies have demonstrated a relationship between uncovered DES struts and ST, endoluminal mural thrombus may be present despite neointimal coverage due to inflammation related to the drug delivery polymer [19, 20, 21]. Indeed, differing grades of neointimal stent coverage and luminal thrombus scores have been reported among currently available DES platforms and have been associated with differences in the prevalence of inflammatory cells, including eosinophils, giant cells and fibrin [22, 23, 24]. Non-erodible polymers may precipitate mural thrombus formation by inciting localised inflammation/hypersensitivity reactions and apoptosis of vascular smooth muscle cells [17, 18]. Polymer-related inflammation may also contribute to vessel remodelling and the development of late-acquired incomplete stent apposition (ISA). Late ISA observed by intravascular ultrasound (IVUS) may also be due to gradual dissolution of thrombus or positive vessel remodelling [14, 24].

Although some reports have failed to identify a relationship between late stent malapposition and adverse clinical events, others have documented a direct association between the extent of stent malapposition and the degree of eosinophilic infiltration within thrombus aspirated during percutaneous coronary intervention (PCI) for very late stent thrombosis [24]. This association suggests the presence of a pathogenetic link between a local (Type IVb) hypersensitivity reaction to the polymer utilised in the CYPHER® (Cordis, Miami Lakes, FL, USA), sirolimus-eluting stent (SES) and excessive positive vessel remodelling with stent malapposition and stent thrombosis [24]. Finally, very late stent thrombosis may be a consequence of neoatherosclerosis – the development of yellow plaque and plaque rupture – within a previously deployed stent [25, 26, 27]. Interestingly, neoatherosclerosis appears to occur more frequently and with an accelerated time course following DES compared with BMS. Clinical evidence supports a relationship between the degree of underlying vascular inflammation as reflected in the acuity of the presenting clinical syndrome and the subsequent propensity for risk of ST [28]. Patients who present with an acute coronary syndrome (ACS) and have coronary stent deployment may have a protracted risk for ST regardless of stent type (DES or BMS). However, beyond six to 12 months following stent deployment for ACS, the risk of ST appears to be greatest following either CYPHER® SES or TAXUS® paclitaxel-eluting (PES) DES versus BMS [30, 31, 32] and even less frequent following newer-generation everolimus-eluting stents (EES). Indeed, lower rates of ST have been observed following EES compared with BMS in both randomised trial [34] and meta-analysis of trials [35]. These observations may reflect the fact that first generation (PES and SES) DES struts embedded into the necrotic lipid core of unstable plaque demonstrate incomplete healing and often lack neointimal coverage compared with struts of the same DES embedded in adjacent fibro-calcific plaque [28]. Conversely, the concept that the degree of neointimal thickness as reflected by in-stent late lumen loss may be protective against ST has been questioned by data from randomised clinical trials which demonstrate little or no relationship between angiographic late lumen loss and ST [34, 36]. Indeed, some DES types with the lowest late lumen loss were also associated with the lowest incidence of ST [37]. These observations suggest that the physical presence and degree of neointimal thickness may not confer functional integrity and that chronic endothelial dysfunction and/or residual inflammatory changes may contribute to very late ST [38].

Predictors of stent thrombosis

Multivariable regression analyses from registries and clinical trials have identified multiple risk factors for ST which may be ascribed to being stent, patient, lesion and/or procedural related ( Figure 1 ).

BMS VERSUS DES

Meta-analyses of randomised controlled clinical trials (RCCT) have demonstrated no differences between BMS and DES with respect to the occurrences of death and/or MI at follow-up [5, 6]. A substantial benefit of DES (versus BMS) for reduction in target lesion and/or vessel revascularisation has been demonstrated in both randomised trials as well as clinical registry analyses, particularly when stents are placed for “off-label” indications [6, 39, 40, 41, 42]. Although randomised trials demonstrate similar incidences of death and MI for both stent types, observational (real world) registry experiences demonstrate a consistent 20-25% reduction in mortality favouring DES ( Figure 2 ). The mortality reduction in these non-randomised studies may reflect the effect of confounding due to covariate imbalance (both measured and unmeasured) despite attempts at adjustment [6, 41, 42]. Although prior meta-analyses of RCCT demonstrated similar rates of ST for DES and BMS following either primary (ST-segment elevation myocardial infarction [STEMI]) or elective PCI, [6] subsequent randomised trials, large scale observational studies and network meta-analyses have demonstrated lower rates of ST through two years follow-up for newer DES, particularly EES with a durable fluorocopolymer (PVDF) [33, 34, 37, 43, 44]. A prospective propensity match (55 variables with perfect match on STEMI) comparison in 10,026 subjects enrolled into the Dual Antiplatelet Therapy study demonstrated an increased rate of ST following BMS (2.6%) versus DES (1.7%, p=0.01) through 0-33 months follow-up and a treatment effect (benefit) with longer (30 months) versus shorter (12 months) DAPT therapy that was consistent for both DES and BMS (HR [95% CI] 0.29 [0.17,0.48] and 0.49 [0.15, 1.65] respectively; p interaction=0.42) [44]. The greatest portion of risk difference favoring DES (versus BMS) for ST was observed during the first 12 months of follow-up in the propensity match comparison. The incidence of ST is increased following PCI for “off-label” indications or in patients with diabetes mellitus regardless of stent type. [46, 47]. Beyond one-year follow-up, a small but definite increase in risk for very late ST accompanies first generation CYPHER® SES and TAXUS® PES, particularly when DAPT is discontinued. Indeed, a landmark analysis of pooled patient-level data from the TAXUS® I, II, III, IV and V randomised trials of PES versus BMS with follow-up through five years demonstrates an increased incidence of cardiac death or MI (6.7 vs. 4.5%; p=0.01) and protocol defined ST (0.9 vs. 0.2%; p=0.007) following PES compared with BMS respectively between one and five years of follow-up [48].

FOCUS BOX 1BMS versus DES

Randomised controlled trials, observation studies and meta-analyses have demonstrated increased rates of ST through two to three years follow-up for BMS (versus newer generation DES) with the greatest portion of risk difference favoring DES observed during the first year of follow-up.
The incidence of ST is increased following PCI for both “off label” indications or in patients with diabetes mellitus regardless of stent type
The treatment effect (benefit) of longer (30 months) versus shorter (12 months) duration DAPT therapy for ST reduction appears to be consistent for DES and BMS.

DES VERSUS DES

Rates of ST may differ among currently available DES platforms. In a network meta-analysis, ST was more frequent following TAXUS® PES versus CYPHER® SES [9]. Similar observations have been made from other data sets as well. For example, late ST was observed more frequently following TAXUS® PES than CYPHER® SES treatment through three years follow-up in the non-randomised, cumulative Bern-Rotterdam experience including 8,146 patients [4]. Conversely, the five-year follow-up of the randomised SIRolimus-eluting stent compared with pacliTAXel-eluting stent for coronary revascularisation (SIRTAX) trial demonstrated ST in 4.1% of TAXUS® PES versus 4.6% of CYPHER® SES-treated patients [49]. Similarly, the Bern-Rotterdam registry demonstrated that ST-event rates steadily increase for CYPHER® SES at 0.6% per year [4, 32]. In both the SPIRIT IV and the Comparison of the everolimus-eluting XIENCE V® (Abbott Vascular, Santa Clara, CA, USA) stent with the paclitaxel-eluting TAXUS® Liberté® (Boston Scientific Corporation, Natick, MA, USA) stent in all-comers: a randomised open label (COMPARE) trials, the XIENCE V® EES was compared in a randomised fashion to either the TAXUS® Express® (Boston Scientific Corporation, Natick, MA, USA) or TAXUS® Liberté® PES respectively [36, 50]. In each of these large-scale randomised trials, EES was associated with a significantly lower incidence of ST up to three-year follow-up compared with TAXUS® PES [51]. Each component of ST (early, late, very late) using the ARC definitions was significantly reduced by EES (versus PES). Furthermore, the relative benefit of XIENCE®/PROMUS® EES (versus TAXUS® PES) for reduction in ST is supported by a pooled, patient level analysis of the SPIRIT II, III, IV and COMPARE randomised trials, which compared the XIENCE®/PROMUS® EES with the TAXUS® Express® or Liberté® PES [51, 52]. Multivariable regression analysis of the pooled 6,789 patient cohort (EES, n=4,247; PES, n=2,542) demonstrates that randomly assigned stent type (EES) is an independent predictor of freedom from ST (versus PES) [52]. Subgroup analyses from this pooled data set suggests that the relative benefit of EES (versus PES) for reducing ST may be even more marked in patients treated for ACS (versus stable coronary artery disease [CAD]) [53]. A separate random effects meta-analysis of these four trials also demonstrates a significant reduction in MI (risk ratio [RR] 0.57; 95% confidence intervals [0.45, 0.73]), cardiac death or MI (RR 0.67 [0.54, 0.83]), and stent thrombosis (RR 0.35 [0.21, 0.60]) [54].

These observations are extended by a meta-analysis of 13 randomised trials of various DES involving 17,097 patients which demonstrated a lower incidence of ST following XIENCE®/PROMUS® EES versus other DES types (TAXUS® PES, CYPHER® SES or ENDEAVOR®/Resolute zotarolimus-eluting stent [ZES]; RR 0.55 [0.38, 0.76]) ( Figure 3 ) [55]. This large scale meta-analysis demonstrated relative benefit of EES (versus other DES) for reduction in target vessel revascularisation (RR 0.73 [0.61, 0.87]) and MI (RR 0.79 [0.63, 0.97]) as well. The benefit of EES (versus other DES) for reducing ST was evident regardless of statistical model used for analysis (random or fixed effects), duration of clopidogrel therapy (six vs. 12 months) or duration of clinical follow-up (≤ one year vs. ≥ one year). In addition, a separate landmark analysis at one to three years from the ENDEAVOR® IV (Randomized Comparison of Zotarolimus- and Paclitaxel-Eluting Stents in Patients With Coronary Artery Disease) randomised trial of the ENDEAVOR® (Medtronic, Minneapolis, MN, USA) ZES versus the TAXUS® Express® PES demonstrated a lower incidence of very late (>one year) ST following ENDEAVOR® ZES (0.1 vs. 1.5% respectively; p=0.004) [56]. Although these trials suggest a relative increase in risk for ST associated with the TAXUS® Express® or Liberté® PES in comparison with either of the EES or ZES, each was underpowered for ST as a primary endpoint. Furthermore, in the propensity match analysis of patients enrolled into the Dual Antiplatelet Platelet Therapy trial, the weighted risk difference favoring DES for ST through 0-33 months follow-up was evident for EES, SES and ZES but not for PES ( Figure 4 ).Finally, the incidences of ARC definite and definite/probable ST were relatively increased in the RESOLUTE All-Comers (AC) randomised comparative trial of the ENDEAVOR® RESOLUTE ZES versus the XIENCE®/Promus® (Boston Scientific, Natick, MA, USA) EES following ZES deployment (1.2 vs. 0.3%; p=0.01 and 1.6 vs. 0.7%; p=0.05 respectively) at one-year follow-up [57]. At two-year follow-up of RESOLUTE AC, the difference in ARC definite/probable ST was slightly less marked (1.9 ZES vs. 1.0% EES; p=0.073) [58]. Similarly, in the Dutch PEERS TWENTE randomised comparison of EES and RESOLUTE ZES, definite ST trended higher through two years follow-up (0.1 vs. 0.9% respectively; p=0.12). In aggregate, these data suggest that ST may be less frequent following XIENCE®/PROMUS® EES than other DES platforms although current studies lack the statistical power to be conclusive. The durable fluorocopolymer used in EES (XIENCE®/Promus®) may be more inert and biocompatible than the polymers utilized in either TAXUS® PES or CYPHER® SES. Measures of endothelial and microvascular function may be improved and associated with more rapid and complete endothelial coverage following XIENCE®/Promus® EES. Aggregate data from multiple sources suggests that BMS have a continued low risk for very late ST of approximately 0.15% to 0.2% per year [3, 30, 39, 59]. Late follow-up of almost 10,000 EES-treated patients from the SPIRIT II, III, IV and COMPARE RCCT as well as the XIENCE V® USA registry suggests that the incidence of late or very late ST is between 0.13% and 0.4% and is influenced by the complexity/acuity of the patients treated [60]. The relative thrombo-resistant effects of the XIENCE®/PROMUS® EES fluorocopolymer were also evident in the Evaluation of Xience-VTM stent in Acute Myocardial INfArcTION (EXAMINATION) trial which compared XIENCE®/Promus® EES to the corresponding BMS platform (MULTILINK-VISION™) during primary PCI for STEMI. Freedom from both definite and definite/probable ST was enhanced through two years follow-up following XIENCE®/PROMUS®EES (versus BMS) [61]. Finally, the five year follow-up of the randomised “all-comers” LEADERS trial of a biodegradable polymer biolimus-eluting stent (BES) versus permanent polymer SES (CYPHER®) offers important insights into potential advantages associated with polymer bioresorption. Although the BES demonstrated equivalent safety and efficacy to the SES in this trial, BES performance was superior in ST-segment elevation MI patients and ST rates for BES (versus SES) were lower with divergence of outcomes over five years [62]. Specifically, BES had a lower ST rate than SES through five years that was highly statistically significant in a one to five year landmark analysis (beyond one year). These results are supported by prior OCT analyses at nine months following stent deployment, which demonstrate better stent strut coverage following BES compared with SES [63]. Recent randomised trials and meta-analyses have suggested that although BES have lower rates of late/very late ST than first generation DES (PES, SES) [63], similar or even slightly higher rates are evident in comparison with the newer fluorocopolymer EES platforms [63]. In aggregate, these data suggest that bioresorbable polymer DES have lower risk for late/very late ST than first generation durable polymer DES and BMS and appear comparable to new generation fluorocopolymer EES.

FOCUS BOX 2DES versus DES

Rates of ST may differ between currently available DES platforms and are generally higher following deployment of PES
Large scale randomised trials and meta-analyses of multiple randomised trials have demonstrated lower rates of early, late and very late ST following deployment of XIENCE®/PROMUS® EES, ENDEAVOR®/Resolute ZES and bioresorbable polymer DES
Data from multiple sources suggest that BMS have a continued low risk for very late ST

DUAL ANTIPLATELET THERAPY (DAPT)

Dual antiplatelet therapy with a P2Y12 receptor inhibitor in combination with aspirin is critically important for the prevention of coronary stent thrombosis and is recommended by clinical practice guidelines for six to 12 months after DES and at least one month following BMS implantation in stable ischaemic heart disease (SIHD) [66, 67]. Patients with ACS benefit from 12 months of DAPT therapy whether or not PCI with stent is performed and regardless of stent type (DES or BMS) [68]. These guidelines and U.S. FDA Advisory Panel recommendations [69] are for ≥ six to 12 months of DAPT following DES in all patients without specific contraindications or bleeding risks. Newer generation, more potent P2Y12 receptor inhibitors (prasugrel, ticagrelor) in combination with aspirin further reduce the risk of stent thrombosis through 12-15 months following ACS (compared with clopidogrel plus aspirin) and are associated with a relative increase in major bleeding event risk [70, 71]. Although observational data suggest that the relative risk of DAPT discontinuation for ischaemic events is greatest during the first six months following PCI [72, 73], these observations are complicated by the facts that <1% of persons who discontinue DAPT incur ST and ~80% of ST occur in patients who are DAPT adherent. Using population attributable risk methodology it has been estimated that 68-85% of ST are not ascribed to clopidogrel noncompliance [2, 74, 75]. This suggests that “other factors” such as aspirin and/or clopidogrel resistance, polymer hypersensitivity and/or neoatherosclerosis may be important pathophysiological mechanisms as well. Although non-randomised registry experiences have suggested that discontinuation of clopidogrel within six months following stent deployment, but not thereafter, is a strong predictor of ST, these observations have lacked power to be definitive and extended duration DAPT may also influence non-target-site-related (systemic) ischaemic events as well.

Multiple randomised trials have compared different durations of DAPT therapy following coronary stenting ( Table 2 ). Although these trials differ in design, populations enrolled and durations of therapy compared, they have often combined both safety (bleeding) and efficacy (ischaemia) measures into a single composite primary endpoint in an attempt to accrue power for the assessment of non-inferiority between DAPT treatment durations. This tactic, which obscures directionally divergent changes in measures of different relative value, may confound the accuracy of conclusions. Furthermore, the post-hoc aggregation of underpowered trials with variable study populations, protocols, methodologies and endpoints into meta-analysis often provides results that are proven incorrect by subsequent, adequately powered RCCT [83]. Collectively, these trials compared shorter (three to six months) with longer duration (12-24 months) DAPT therapy on an unblinded basis in relatively small numbers of randomised subjects in context of the specific endpoints being evaluated. In general, the limitations shared by these trials include: (1) lack of power, often due to early study termination and poor enrollment; (2) unbalanced (between unblinded assigned treatment arms) study medication compliance; (3) lower than expected event rates often making the chosen non-inferiority margin inappropriate. For example, in OPTIMIZE, which compared three vs. 12 months of DAPT treatment, the four-fold relative increase in ST (ARC definite/probable definition) associated with shorter duration treatment was counterbalanced by a two-fold increase in major bleeding events associated with longer DAPT treatment [79]. However, the upper bound of the 95% confidence interval surrounding the hazard ratio (HR) for ST associated with three months’ DAPT therapy was 35.5, thus allowing for as much as a 35-fold increase in ST. Furthermore, OPTIMIZE excluded subjects with biomarker positive ACS (greatest risk for ST) from enrollment and evaluated only the ENDEAVOR-ZES DES. Similarly, in ITALIC, which was designed to compare six months versus 24 months of DAPT therapy, very few events were observed (only three [0.16%] ST and 10 [0.45%] MI) which suggests the study population was very low risk and not representative of routine clinical practice [82]. Only the XIENCE V EES DES was evaluated in ITALIC and the study composite primary endpoint of death, MI, urgent target vessel revascularisation, stroke or major bleeding event was assessed at 12 months and was observed in only 1.6 versus 1.5% of the six versus 12 months treatment groups respectively. Finally, the low event rates and sample size in the primary analysis of ITALIC make subgroup analysis (acute coronary syndromes) grossly underpowered to examine potential treatment interactions. Conversely, the Dual Antiplatelet Therapy study was designed in response to a request from the U.S. FDA to manufacturers of coronary stents and was conducted under an investigational device exemption through a public-private collaboration involving the FDA, eight stent and pharmaceutical manufacturers who funded the study and the Harvard Clinical Research Institute (HCRI) [84]. The DAPT study enrolled a broad spectrum of “real world” subjects in 452 sites across 11 countries. Subjects who required chronic anticoagulation or who were poor candidates for DAPT therapy of at least one year duration were excluded. Eligible subjects were treated with an FDA approved BMS or DES (CYPHER SES, ENDEAVOR ZES, TAXUS PES, XIENCE/PROMUS EES) and clopidogrel or prasugrel in labeled approved doses (ticagrelor was not yet FDA approved during trial enrollment). All subjects were enrolled within 72 hours of stent placement and received open-label DAPT for 12 months at which time those subjects who had not incurred a major adverse cardiovascular or cerebrovascular event (MACCE; composite occurrence of death, MI, stroke), repeat revascularisation, or moderate/severe (GUSTO scale) bleeding event and were adherent to thienopyridine therapy were eligible for randomisation. Eligible patients continued taking aspirin and were randomised 1:1 to either continued thienopyridine therapy or placebo (blinded) for an additional 18 months. Randomisation was stratified by stent type (BMS or DES), hospital site, type of thienopyridine drug and present or absence of at least one prespecified clinical or lesion related risk factor for ST. After the end of the randomised treatment period, all patients were followed for an additional three months (months 30 to 33 after enrollment) to assess the impact of thienopyridine discontinuation on the rates of endpoint events. The powered efficacy co-primary endpoint events for the DAPT study included both a stent-related endpoint (ARC definite/probable ST) [10] and a patient-related endpoint (MACCE). The powered safety endpoint is the composite of severe/moderate (GUSTO definition) bleeding events [85]. Bleeding was also evaluated according to the Bleeding Academic Research Consortium (BARC) criteria [86]. The DAPT study enrolled 25,682 patients of whom 22.866 received a DES and 2,816 received a BMS. From these enrolled subjects, 9,961 DES and 1,687 BMS treated patients were randomised at one year to either extended duration (30 months) DAPT therapy or aspirin plus placebo beyond 12 months [86]. By the end of the randomised treatment period (30 months), there was a 71% relative (1% absolute; p<0.001) reduction in ST driven largely by a 74% relative reduction in definite ST ( Table 3A) and a 29% relative (1.6% absolute; p<0.001) reduction in MACCE driven by a 53% relative (2% absolute; p<0.001) reduction in MI in favor of longer duration DAPT therapy. Furthermore, 55% of the MI prevented by longer duration therapy were not related to the stent but occurred in non-stented coronary distributions. The benefit of extended therapy was accompanied by a 0.5% absolute increase in mortality (2.0 vs. 1.5%; p=0.052) and a 61% relative (0.9% absolute; p=0.001) increase in severe/moderate bleeding ( Table 3B). Severe bleeding was not different (0.8 versus 0.6%; p=0.15) and fatal (BARC type 5) bleeding events were rare and not different between the randomly assigned treatment groups. The unexpected finding of an increased number of deaths from any cause during the treatment period in the group continuing to receive thienopyridine was driven by an increase in death from non-cardiovascular causes largely explained by increases in death due to cancer or trauma. Although the rate of cancer diagnosis did not differ significantly after randomisation, the increased relative incidence of death due to cancer in patients treated with continued thienopyridine may reflect a chance imbalance in patients with known cancer before enrollment. In addition, adjusted analyses demonstrated that the magnitude of benefit associated with longer (30 months) duration thienopyridine for reduction in ST or MI was consistent across the four DES types studied including the 4703 (47.2%) subjects treated with EES ( Figure 5 ). Indeed, the adjusted hazard ratios (95% confidence intervals) favoring longer therapy in EES treated patients were 0.38 (0.15-0.97) for ST and 0.63 (0.44-0.91) for MI. Similarly, consistent treatment benefit for ST and MI reduction was observed for both clopidogrel and prasugrel without evidence for a treatment duration by drug type interaction ( Figure 5 ). Subgroup analyses demonstrated consistency of treatment benefit without interaction for most subgroups with the exception of gender and diabetes. Although relative benefit (hazard ratio <1.0) was observed for women (versus men) and for patients with diabetes (versus those without) for both ST and MI, the relative magnitude of treatment benefit associated with prolonged DAPT therapy was greater for men (P interaction 0.04 for ST and 0.03 for MI) and among non-diabetic patients (P interaction 0.08 for ST and 0.004 for MI) ( Figure 6 ). Interestingly, treatment benefit was similar in magnitude whether or not prespecified clinical or lesion risk factors for ST were present. Importantly, prespecified clinical risk factors for ST included biomarker positive ACS (STEMI or non-STEMI).

Despite the magnitude of treatment benefit for ischaemic event reduction favoring longer therapy, a potential limitation of the DAPT study is that only those patients who were adherent to therapy and who did not experience MACCE, revascularisation or moderate/severe bleeding event in the first year underwent randomisation. This study design may have selected for subjects at lower risk for late adverse events. In addition, although the DAPT study did not quantify the net relative effect of ischaemic and bleeding events, a recent decision analysis model suggests that small absolute differences in rates of cardiovascular events may be sufficient to counterbalance bleeding risks [88]. Based on a meta-analysis of published studies, this model predicts a 1.7-fold relative increase in major bleeding with 30 versus 12 months of DAPT therapy (similar to the 1.6-fold increase observed in the DAPT study). This bleeding hazard is counterbalanced by a 78% reduction in ST or a 5% reduction in MACCE for patients with SIHD (compared with a 44% and 2% reduction respectively for patients with ACS). These data suggest that despite the potential limitation of a lower risk population being randomised, the magnitude of benefit associated with prolonged thienopyridine therapy in the DAPT study is adequate to counterbalance the observed bleeding risk. Finally, the DAPT study was prospectively designed to include three month observation periods following thienopyridine discontinuation at both 12 (for subjects randomised to placebo) and 30 months (for subjects randomised at 12 months to extended thienopyridine). Adverse ischaemic events (ST and MI) were observed with increased frequency in the three months following thienopyridine discontinuation in both treatment arms ( Figure 7 ). This observation suggests that the preventative benefit of thienopyridine therapy is realised early and that treatment discontinuation may be associated with ischemic hazard even months to years after coronary stenting.

BARE METAL STENTS

BMS are a commonly used alternative to DES, particularly for patients presenting with ACS or in whom DAPT has perceived increased bleeding risk [89]. Furthermore, BMS are widely perceived to be “safer” and to require a shorter duration of DAPT therapy. The DAPT study was designed to provide insights as to whether the risks of ST and MACCE differ for BMS and DES and whether the optimal duration of DAPT therapy differs for BMS and DES. A prospective propensity match comparison of BMS and DES was incorporated into the DAPT study design and included all enrolled subjects with at least 29 months of follow-up or a ST/MACCE event. The BMS to DES match was 1:many (maximum eight) with subjects matched perfectly with respect to STEMI and for all other variables (total of 55) with a caliper of 0.10. Matching was established on baseline variables without knowledge of subsequent ST/MACCE events which were adjudicated by a central, independent clinical events committee. The hypothesis was that DES are not inferior with respect to ST and MACCE (versus BMS) through 0-33 months follow-up after stent deployment. In addition, the treatment effect of 30 (versus 12) months of DAPT therapy was evaluated in 1687 BMS treated patients who were randomised after one year of treatment (randomisation in the DAPT study was stratified by stent type [DES vs. BMS] at the index PCI). Finally, the consistency of prolonged thienopyridine treatment effect (30 versus 12 months) was compared for randomised DES or BMS treated patients. Among 10,026 propensity match DES (n=8308) or BMS (n=1718) treated patients, ST was more common following BMS ( Table 4 , Figure 8A ) with the greatest portion of benefit (risk difference) accrued during the first year post-PCI. Similarly, MACCE trended less frequent for DES (p=0.053 for difference 0-33 months) with the greatest portion of risk difference evident within the first year (p=0.01 for difference 0-12 months) ( Figure 8B ). Recent randomised trials and meta-analyses of trials have suggested lower rates of ST following new DES when compared to older DES or BMS [37, 43, 90]. In this regard, the risk difference favoring DES (versus BMS) for ST was evident for three types of DES included in the propensity match but not for PES ( Figure 4 ). The risk difference favoring DES (versus BMS) for MACCE was evident across all four DES subtypes. Among 1687 BMS treated patients who were randomised to 30 versus 12 months of DAPT therapy, a 51% relative reduction in definite ST was observed favouring longer treatment. Bleeding risk was increased with longer duration DAPT (severe/moderate bleeding event rate 2.03 versus 0.9%; p=0.07 for 30 versus 12 months respectively) ( Table 5 ). Finally, the magnitude of randomised treatment benefit for reduction in ST among BMS treated subjects was consistent with results observed among DES-treated randomised subjects with no evidence for a treatment duration by stent type interaction (p_interaction 0.42). Thus, the DAPT study results suggest that DES treated subjects have lower rates of ST (0-33 months) and MACCE (0-12 months) compared with BMS treated subjects with the greatest benefit for DES evident during the first year following stent deployment. In BMS treated patients, continued thienopyridine therapy beyond 12 months appears to provide ischaemic benefit in addition to increasing bleeding risk and requires further study.

Although these new data provide support for longer duration thienopyridine therapy for reduction in ST regardless of stent type, considerable data suggest that the vast majority of ST events occur in patients who are adherent to DAPT [75]. Indeed, very late ST may have multiple pathophysiological mechanisms including uncovered stent struts (lack of healing), as well as neoatherosclerosis, stent fracture and restenosis.

PLATELET INHIBITORY RESPONSE

Roughly one quarter of patients undergoing stenting may be relatively “resistant” to the platelet-inhibiting effects of clopidogrel [91]. Furthermore, patients who are poorly responsive to one agent (either aspirin or clopidogrel) are more likely to be hyporesponsive to the other agent and the risk of ischaemic events appears greatest in patients with “dual” resistance [92].

The mechanisms underlying variability in clopidogrel responsiveness (distinct from noncompliance) include genetic variation in specific enzymes involved in clopidogrel absorption and metabolic conversion from pro-drug to active metabolite [93] as well as phenotypic variables such as body mass index, the presence of diabetes, level of glucose control and renal function [93].

Specific genotypes have been demonstrated to be associated with either reduced clopidogrel absorption (TT variant of the ABCB1 or MDR1 gene) or diminished conversion of clopidogrel pro-drug to active metabolite (CYP2C19*2, 3, 4 and 5 alleles) [94]. Active metabolite generation is maximally reduced in CYP2C19*2 homozygotes (*2/*2) and intermediate in heterozygote carriers (*1/*2) of the *2 loss of function (LOF) allele [95, 96]. This gene-dose response relationship for active metabolite generation has been correlated with a gene-dose response for both measured platelet inhibition as well as prevalence of high on-treatment residual platelet reactivity (HPR) and for the occurrence of clinical events such as ST ( Figure 10 ) [97]. This genetically determined limitation in clopidogrel responsiveness may not be overcome by increasing clopidogrel dose. Recent data suggests that the clopidogrel hyporesponsiveness observed in CYP2C19* heterozygotes (but not homozygotes) with respect to the magnitude of platelet inhibition and prevalence of HPR may be “overridden” by progressively increasing the dose of clopidogrel to ≥225mg daily [98]. Whether or not such large daily doses of clopidogrel are safe and effective in mitigating the increased clinical risk for ischaemic events observed in this cohort (25%-30% of the general population) remains to be determined by adequately powered randomised trials.

Recent clinical practice guideline updates [67, 99] recommend an increase in the oral loading dose of clopidogrel from 300mg to 600mg prior to or immediately following either primary or non-primary PCI for STEMI or for elective PCI. Increasing the loading dose of clopidogrel from 300mg to 600mg accelerates the time course and increases the magnitude of platelet inhibition and also reduces the prevalence of clopidogrel resistance [100]. Clinical data in support of the 600mg (versus 300mg) oral loading dose of clopidogrel comes from an analysis of the HORIZONS-AMI trial in which 62% of subjects received a 600mg oral clopidogrel load on a non-randomised basis. Those subjects who received a 600mg load (versus 300mg) experienced a reduction in major adverse cardiovascular events (MACE), especially those who had been randomly assigned to receive bivalirudin, and a reduction in subacute ST to 30 days (1.9% in the 600mg versus 3.2% in the 300mg clopidogrel load; hazard ratio [HR] 0.61 [0.38, 0.96]; p=0.033) [101, 102]. Randomised trial data in support of the 600mg load (versus 300mg) comes from the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA)-6 trial of patients undergoing primary PCI for STEMI [103]. Patients randomly assigned to receive a 600mg load (versus 300mg) enjoyed an event-free survival advantage free from death or MI (p=0.029) and MACE (p=0.027). Finally, in the prespecified but non-randomised PCI subgroup analysis of the CURRENT OASIS 7 trial, subjects randomly assigned to receive a 600mg oral load followed by 150mg daily for seven days and then 75mg daily thereafter (versus 300mg load and 75mg daily thereafter) experienced a marked reduction in the incidence of definite ST [104]. The benefit of increased clopidogrel dosing with respect to reduction in ischaemic events was counterbalanced by an increase in major bleeding events (HR 1.41 [1.09, 1.83]; p=0.009). A meta-analysis of nine studies involving 18,263 patients undergoing primary PCI for STEMI confirmed a reduction in major adverse cardiovascular events (HR [95% CI] = 0.75 [0.63, 0.91]) following 600mg clopidogrel load (compared with 300mg) [105]. Finally, the ischaemic event benefit of 600mg clopidogrel loading dose (versus 300mg) prior to elective PCI in SIHD may be less apparent relative to the increased risk of bleeding [106]. In aggregate, these data suggest that the optimal oral dosing regimen of clopidogrel for primary or non-primary PCI for STEMI appears to be a 600mg load followed by maintenance therapy of 75mg daily. The choice of 600mg (versus 300mg) clopidogrel load prior to elective PCI in SIHD is based more on pharmacodynamics profile than on demonstrated differences in clinical events.

Finally, the novel third-generation thienopyridine, prasugrel, and the non-thienopyridine P2Y12 receptor antagonist, ticagrelor, are not influenced by the genetic polymorphisms which affect clopidogrel metabolism [106, 106]. Neither prasugrel nor ticagrelor efficacy, with respect to primary endpoint events or the relative suppression of ST (compared with clopidogrel) in large-scale randomised trials (TRITON TIMI 38, PLATO), was influenced by CYP2C19 LOF allele carrier status [107, 108]. Indeed, the relative benefit of either prasugrel or ticagrelor for reduction in ST (compared with clopidogrel) was evident and consistent regardless of ACS type (STEMI, non-STEMI), stent type (DES, BMS), diabetic status, creatinine clearance, age (≥ versus <75 years), gender or CYP2C19 LOF allele status [109]. Analysis of ST (ARC definite/probable) in the STEMI cohorts of PLATO (n=7,544) and TRITON TIMI 38 (n=3,534) demonstrates a 26% relative reduction in ST by ticagrelor (HR 0.74 [0.55, 1.00]; p=0.05) and a 42% relative reduction by prasugrel (HR 0.58 [0.36, 0.93]; p=0.02) through the course of the respective trial (12 months PLATO; 15 months TRITON TIMI 38) when compared with clopidogrel [110, 111]. Recent studies suggest a greater degree of inter-individual variability in the magnitude of platelet inhibition during maintenance dose therapy with prasugrel (10mg daily) compared with ticagrelor (90mg twice daily) which may be influenced by CYP2C19 allele status in addition to phenotypic variables. In comparative studies, a more reliable, predictable higher level of platelet inhibition was achieved across a population of patients during maintenance therapy with ticagrelor (versus prasugrel) [112, 113]. Interestingly, pre-treatment with prasugrel in patients undergoing primary PCI for STEMI did not reduce the composite occurrence of cardiovascular death, MI or stroke and increased non-coronary artery bypass graft (CABG) related TIMI major or minor bleeding when compared with a prasugrel loading dose administered at the time of primary PCI [114]. Conversely, pre-hospital (versus in-hospital at the time of PCI) ticagrelor loading was associated with a significant reduction in ST (odds ratio 0.19 [95% CI] 0.04-0.86; p=0.06) to 30 days following PCI for non-ST elevation ACS [115].

FOCUS BOX 3DAPT

The relative risk of DAPT discontinuation is greatest during the first six months following PCI but hazard for both ST and non-ST related MI persists following thienopyridine discontinuation after 30 months of therapy.
Although prior small randomised trials demonstrated no apparent advantage of longer (>six months) DAPT duration following stenting, a recent adequately powered, placebo controlled, blinded randomised trial demonstrated highly significant reductions in ST and MACCE with 30 months of DAPT compared with 12 months.
Prolonged DAPT (30 months) is associated with increased severe/moderate bleeding events (versus 12 months) but fatal bleeding is rare and not different between treatment groups (30 vs. 12 months).
BMS have greater risk for ST (compared with DES) through 33 months follow-up and the treatment effect (benefit) of 30 months DAPT (versus 12 months) for reduction in ST is consistent between stent types (BMS or DES).

DAPT INTERRUPTION/DISCONTINUATION

Observational data suggests that the risk of late and very late ST is greatest in those individuals who discontinue both aspirin and thienopyridine, or in those who discontinue aspirin and have previously discontinued thienopyridine therapy [116]. In addition, the time course for ST occurrence appears to be more abrupt when both aspirin and thienopyridine are discontinued simultaneously. For example, in the RESTART registry, the median time duration between DAPT (both agents) discontinuation and ST was 13 days (interquartile range [IQR] six-61 days) versus 314 days (IQR 79-711 days) following discontinuation of thienopyridine alone [117]. Additional observational data suggests that both the time from stent deployment to DAPT discontinuation for a surgical procedure, as well as the clinical syndrome which prompted stent deployment, influenced the likelihood for occurrence of death and/or ischaemic cardiac events. Those patients who had stent deployment for an ACS and who underwent non-cardiac surgery within 42 days of stent deployment had the greatest risk of adverse events, regardless of stent type (DES or BMS) [118]. Furthermore, approximately 80% of ST occurred within ten days of performance of the non-cardiac surgical procedure [117]. The risk of DAPT cessation for surgical procedures may differ for DES or BMS. For example, the risk of MACE was greatest following BMS deployment when surgery was performed <30 days (odds ratio [OR] 4.0; p<0.001) but remained high when surgery was performed at 31-90 days (OR 1.4; p<0.001) when compared with ≥91 days [119]. Recent large observational series with propensity matching have demonstrated an increased incidence of major adverse cardiovascular events when DAPT is discontinued between six weeks and six months following PCI with a BMS when compared with newer generation DES [120, 121] ( Figure 9 ). This relative hazard of adverse events when DAPT is discontinued for non-cardiac surgical procedures in BMS (versus DES) treated patients is counter to conventional perceptions and consensus guideline recommendations. In aggregate, these data suggests that non-cardiac surgery should be deferred at least six weeks to 90 days following stent deployment, especially in patients treated for ACS, regardless of stent type (DES or BMS). These data also support the practice of abbreviated and partial DAPT discontinuation, if possible, as has been recommended [122]. This practice involves stopping P2Y12 receptor antagonist (clopidogrel or ticagrelor at five days, prasugrel at seven days) before surgery and restarting these agents within 48-72 hours postoperatively. Aspirin (81mg daily) therapy should not be discontinued if at all possible. Consideration may be given to reloading patients at greatest risk for ST (history of ACS, prior bifurcation stenting or vascular brachytherapy) with the P2Y12 receptor inhibitor following the non-cardiac surgical procedure.

FOCUS BOX 4DAPT interruption/discontinuation

The risk of late and very late ST is greatest among individuals who discontinue both aspirin and platelet P2Y12 receptor inhibitor
Both time from stent deployment to DAPT discontinuation for a surgical procedure and the clinical syndrome which prompted stent deployment influence the likelihood of ST or ischemic events
The risk of DAPT cessation for surgical procedures may be less for newer DES (EES, ZES) than for BMS and non-cardiac surgery should be deferred for at least 90 days following stent deployment
Abbreviated and partial DAPT discontinuation (if possible) is recommended for surgical procedures

TREATMENT AND PROGNOSIS FOLLOWING ST

The estimate that 68%-85% of ST is not ascribable to clopidogrel noncompliance [75] and suggests the relative importance of “other factors” such as aspirin and/or clopidogrel non-responsiveness, polymer hypersensitivity, and/or neoatherosclerosis. Alternatively, novel receptors (protease activated receptor [PAR-1]) and pathways may be involved in the pathogenesis of stent thrombosis late following deployment [123]. Observational data suggests that baseline patient demographics may vary significantly according to the timing of ST [117]. Demographic characteristics for late and very late ST (versus early ST) include haemodialysis, end-stage renal disease not on dialysis, chronic total occlusion target vessel and age <65 years. Furthermore, patients with late ST had higher rates of TIMI grade 2/3 flow at the time of ST than did those with early ST (36% vs. 13%; p<0.0001) and very late ST (17%; p<0.0001) while mortality at one year following ST was lower in patients with very late ST (10.5%) compared with those having either early (22.4%; p=0.003) or late ST (23.5%; p=0.009) [117]. Recent data suggest that patients who present with late/very late ST are younger, current smokers, more often have multivessel disease and Type C (modified ACC/AHA criteria) target lesion morphology with longer total stent length deployed and overlapping stents [16]. Interestingly, despite the mortality observed following acute/subacute ST, a relatively lower in-hospital mortality has been consistently associated with late/very late ST (3.8-11.0%) and suggests an predominant underlying pathogenesis of late restenosis/neoatherosclerosis with the potential for development of preconditioning ischaemia and collaterals[16, 117, 124]. Finally, patients who experience ST remain at high risk for recurrence, especially those who have underlying diabetes, depressed left ventricular function, longer total stent length, reduced TIMI flow following ST reperfusion and/or who require additional stent(s) deployment during the emergency PCI procedure [125, 126]. Diagnostic assessment during catheter intervention for ST should include intravascular ultrasound evaluation to assess adequate stent sizing, expansion and apposition, as well as high-pressure re-dilatation with an optimal-sized non-compliant balloon catheter if indicated and re-stenting only for complex/occlusive type marginal endoluminal dissection as necessary. Patients who experience ST despite being compliant with clopidogrel therapy should be switched to either prasugrel or ticagrelor in the absence of specific absolute (history of prior stroke, transient ischaemic attack [TIA]) or relative (age >75 years) contraindications. Elderly or small (<60 kg) patients may be treated with the 5mg daily dose of prasugrel although clinical experience with this dose is relatively limited. The role of clopidogrel dose titration guided by serial platelet function assessment or treatment with triple antiplatelet therapy (aspirin, thienopyridine, cilostazol) in these patients has not been determined. Finally, a recent observation that the PAR-1 receptor antagonist Vorapaxar reduced ST in stable patients when added to aspirin or dual antiplatelet therapy with aspirin and a thienopyridine suggests the need for further study to better define safety and efficacy of alternative strategies for a long term ST prevention [123].

Personal perspective - Dean J. Kereiakes

Despite evolution in DES platform technology and adjunctive pharmacotherapies, stent thrombosis (ST) remains the most dreaded and deadly complication of coronary stent deployment. The etiology of ST is multifactorial and the incidence of ST can be reduced by appropriate patient risk stratification, choice of DES platform, fastidious stent deployment technique with optimal periprocedural adjunctive pharmacotherapy and conscientious management of longer-term platelet inhibitor therapy. Although the risk of ST may diminish over time, hazard persists even years following stent deployment and both pathogenesis as well as prognosis may differ for very late when compared with earlier ST events. Hopefully, the advent of bioresorbable polymers, polymer-free DES and/or bioresorbable vascular scaffolds will further favorably influence both the early and especially long term incidence of ST.

SHOWING 4 COMMENTS

Hemodinamia CMN Siglo XXI
17 January 2021, 03:31
Do you think we should use prasugrel in general except in patients witj contraindications? Thank you Fantastic review,

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Sonia Morcuende
8 March 2021, 12:26
Although the recent ISAR-REACT 5 concluded that prasugrel was superior to ticagrelor in reducing ischemic events after acute coronary syndromes, this was an open-label randomised study with several limitations. Thus, there is no clear and definitive evidence to support a superior antithrombotic efficacy of prasugrel vs. ticagrelor. Moreover, in patients presenting with NSTE-ACS prasugrel should be given after early coronary angiography whereas ticagrelor can be given before. Many healthcare systems cannot provide access to early angiography, and medical therapy alone, is appropriate for selected patients. Nevertheless, prasugrel may be preferred by physicians due to the once daily administration and lower rate of dyspnea-related discontinuation. Thus, compliance to prasugrel could be greater allowing for an enhanced antithrombotic protection that could be particularly relevant when risk factors and mechanisms of stent thrombosis (i.e. procedural issues), are present. Thank you very much for your comment. The editorial team

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Hasan Tokdil
27 March 2021, 15:29
I totally agree, I think ISAR-REACT 5 has investigated the difference between two strategies (time of intervention) in addition to Prasugrel vs. Ticagrelor. This might also be responsible for reducing ischemic events, especially in NSTE-ACS.

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Piera Capranzano
16 April 2021, 12:16
I agree with you, the different administration strategies (prior vs. after coronary angiography) may also have impacted on overall results. Also, this comparison would suggest no potential benefit of routine pre-treatment in NSTE-ACS, supporting current European guidelines recommendations. Thank you very much for your comment. The Editorial Team.

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Stent thrombosis