Background

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Background

Primary percutaneous coronary intervention (PCI) is considered nowadays as the reperfusion strategy of choice for patients with acute ST-segment elevation myocardial infarction (STEMI) [1], owing to a lower risk of myocardial re-infarction and improved short- and long-term survival compared to fibrinolysis [2]. However, STEMI is still associated with poorer clinical outcomes after PCI, compared to stable CAD (CAD), with higher rates of stent thrombosis and an increased risk myocardial re-infarction persisting throughout long-term follow-up [3-5].

STEMI is most frequently caused by a ruptured coronary artery plaque and is considered as a heightened state of thrombogenicity. Compared to stable CAD lesions, culprit lesions in STEMI are characterized by larger lipid-laden necrotic core, thinner fibrous cap, presence of thrombus, and increased fibrin deposition [6]. Moreover, compared to non-culprit sites, culprit lesions in STEMI after primary PCI are characterized by reduced neo-intimal thickness and increased percentage of uncovered struts, struts with inflammation and struts with fibrin [6]. Therefore, STEMI has been associated with delayed arterial healing after PCI, which has been shown to be a risk factor for device-related adverse outcomes, including late stent thrombosis [6-8], even with newer-generation DESs (DES) [9]. Late adverse clinical events have been linked to a chronic inflammatory reaction [6], at least in part due to the presence of durable polymer coatings, which has been recently also described with newer-generation DES [10]. The large amount of intracoronary thrombus during primary PCI may also predispose to stent malapposition secondary to stent undersizing and later thrombus resolution [6], potentially increasing the likelihood of either stent thrombosis or in-stent restenosis [11]. Consequently, the choice of the optimal stent therapy in patients undergoing PCI for STEMI still remains unresolved.

BMSs have been shown to reduce the risk of infarct-vessel re-occlusion compared with balloon angioplasty alone, but have been associated with in in-stent restenosis due to neo-intimal hyperplasia in up to 20% of patients [12,13]. Furthermore, BMS have not been shown to reduce the rate of mortality and myocardial re-infarction among patients with STEMI [12,13].

First-generation DESs releasing sirolimus or paclitaxel from durable polymers reduce in-stent restenosis and the need for repeat revascularization among patients with STEMI [14-18], but delay vessel healing due to chronic inflammation induced by the presence of a durable polymer [6]. Limus analogues have been shown to be more effective as site-specific agents than paclitaxel to reduce neo-intimal growth and repeat revascularization procedures [19-20]. However, late stent thrombosis remains more frequent with first-generation DESs compared to BMSs, owing to delayed healing and re-endothelialization [19-20]. Furthermore, hypersensitivity reactions from the polymers may further increase the risk of stent thrombosis [21]. These effects may be particularly pronounced in ruptured plaques of STEMI patients due to the direct contact with the necrotic core [6]. Several potential mechanisms for delayed arterial healing and increased risk of stent thrombosis after PCI with first-generation DESs for STEMI have been suggested, including high affinity of the highly lipophilic drugs for the lipid-rich plaques following penetration of the stent struts into the necrotic core, reduced coverage of the lipid-rich avascular necrotic core by migrating and proliferating cells, absence or reduced number of smooth muscle cells in ruptured fibrous caps, delayed smooth muscle cell proliferation and endothelial regrowth with higher drug concentrations, and increased drug uptake by thrombus [6,22].

Second-generation DESs with more biocompatible permanents polymers represent an important breakthrough technology for the treatment of patients with CAD and are associated with improved clinical outcomes, including death, myocardial infarction, stent thrombosis and repeat revascularisation, as compared with BMSs and first-generation DESs in a broad spectrum of patients with CAD [23-24]. Nevertheless, newer-generation DESs with durable polymer have been recently associated with persistent inflammatory reaction and neoatherosclerosis, similar to first-generation DESs, resulting in persistent late adverse clinical events, including an increased risk of thrombosis [10]. Second-generation DESs have been shown to offer better efficacy and safety outcomes, compared to BMSs in patients with STEMI. The EXAMINATION (clinical Evaluation of the Xience-V stent in Acute Myocardial INfArcTION) trial compared the durable polymer EES with BMS in 1’498 patients with STEMI and showed reduction in target lesion revascularisation (3.7% vs 6.8%, p=0.008) but no difference in the composite endpoint of all-cause death, MI and target lesion revascularisation (11.9% vs 14.2%, p=0.19) at 1-year follow-up [25].

Several clinical trials have compared the efficacy and safety of second-generation DESs with more biocompatible permanent polymer with first-generation DESs with permanent polymer in patients with STEMI [26-32]. However, these studies have not been able to show a convincing superiority of second-generation DESs, eluting either zotarolimus or everolimus from a permanent polymer, over first-generation DESs in patients with STEMI. ZEST-AMI compared the efficacy and safety of zotarolimus-eluting stents (n=108) against first-generation SES (n=110) and paclitaxel-eluting stents (n=110) in patients with STEMI [26]. At 12 months, cumulative incidence rates of primary endpoint (MACE, composite of death, MI and ischaemia-driven target vessel revascularisation) in the zotarolimus-eluting, sirolimus-eluting and paclitaxel-eluting stents were 11.3%, 8.2% and 8.2%, respectively (p=0.834). XAMI (XienceV Stent vs. Cypher Stent in Primary PCI for Acute Myocardial Infarction) trial has compared EES against the first-generation SES and reported a lower rate of MACE (composite of cardiac death, AMI or any target vessel revascularisation) with EES (4.0% vs 7.7%, p=0.048) but no significant difference in cardiac mortality (1.5% vs 2.7%, p=0.36) or the incidence of definite/probable stent thrombosis (1.2% vs 2.7%, p=0.21) at 1 year [27]. However, at 3-year follow-up, there was no difference in EES and SES groups for MACE (EES 8.0% vs SES 10.5%, p=0.30), cardiac death (2.5% vs 2.7%, p=0.86) and definite/probable stent thrombosis (2.3% vs 3.2%, p=0.60) [28]. RACES-MI (Randomized Comparison of Everolimus Eluting Stents and Sirolimus Eluting Stent in Patients With ST Elevation Myocardial Infarction) is a prospective, single-center, randomized trial evaluating the benefits of the second-generation EES versus the first-generation SES in 500 patients undergoing primary PCI for acute STEMI ) [29]. The primary endpoint was a major adverse cardiac event at 3-year follow-up. Interestingly, no significant difference was observed between the everolimus eluting-stent and the SES with durable polymers in terms of major adverse cardiac events (16% vs. 20.8%, adjusted hazard ratio [HR]: 0.75 [95% confidence interval (CI): 0.5 to 1.13], p=0.17), cardiac death (4.4% vs. 5.6%, adjusted HR: 0.77 [95% CI: 0.35 to 1.71], p=0.53), recurrent MI (6.4% vs. 10%, adjusted HR:0.62 [95%CI: 0.33 to 1.16], p=0.13), and target vessel revascularization (4.8% vs.4.8%, adjusted HR: 1.00 [95%CI:0.45 to 2.32], p=0.99). However, EES was associated with a significant reduction in stent thrombosis (1.6% vs. 5.2%, adjusted HR: 0.3 [95% CI: 0.1 to 0.92], p= 0.035). STEMI substudies of other trials comparing EES against SES, including Basket-PROVE (the BASKET-Prospective Validation Examination) [30], EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) [31], and SORT-OUT IV (The Scandinavian Organization for Randomized Trials with Clinical Outcome IV) [32], have also shown no significant advantage of EES over SES in patients with STEMI. These data were confirmed in a recent mixed treatment comparison analysis of trial level data from 34’068 patient-years of follow-up from 28 randomized trials [9] demonstrating no significant difference between first- and second-generation des with durable polymer (EES and zotarolimus-eluting stent) in terms of target lesion revascularization among patients with STEMI, despite a reduction in the risk of stent thrombosis, particularly with EESs. In conclusion, second-generation DESs with durable polymer failed to demonstrate in previous studies a clear significant superiority in terms of efficacy and safety, compared with first-generation DESs with durable polymer, in patients with STEMI.

Third-generation DESs with biodegradable polymers have been developed to overcome limitations of second-generation DESs with the potential advantages to be more biocompatible, reduce the risk of late adverse clinical events, including late and very late stent thrombosis, cardiac death, and myocardial infarction and shorten the duration of dual antiplatelet therapy. Newer-generation DESs with biodegradable polymers have been shown to improve long-term clinical efficacy and safety outcomes, as compared to first-generation DP-DES in a broad patient population [33]. However, the potential benefit of BP-DES over new-generation DP-DES for the management of patients with acute STEMI remains debated.

The COMFORTABLE-AMI (Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute STEMI) trial, comparing BES against BMS, demonstrated the superiority of the biodegradable polymer BES to BMS with the identical metallic platform in terms of a significant reduction in the primary endpoint of MACE defined as the composite of cardiac death, target vessel-related MI and ischaemia-driven target lesion revascularisation (4.3% vs 8.7%, p=0.004) and POCE (8.4% vs 12.2%, p=0.04) at 1-year follow-up [34]. Definite stent thrombosis was numerically lower in the BES group (0.9% vs 2.1%, p=0.10), and there was no difference in mortality (2.9% vs 3.5%, p=0.53). Two-year follow-up results were recently reported, showing persistent benefit of BES over BMS [35]. A pooled analysis of the EXAMINATION and COMFORTABLE-AMI trials also showed that newer-generation DES improve safety and efficacy compared with BMS at 1-year follow-up [36]. However, further follow-up is awaited to evaluate the long-term impact of durable polymer newer-generation DES on very late stent thrombosis and its associated clinical impact.

LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) was a 10-center, assessor-blind, non-inferiority, ‘all-comers’ trial randomizing 1’707 patients to treatment with either biodegradable polymer BESs (BES) (n=857) or durable polymer SESs (SES) (n = 850) [33]. The primary endpoint was a composite of cardiac death, myocardial infarction (MI), or clinically indicated target vessel revascularization at 9 months. At 5 years, BES was non-inferior to SES for the primary endpoint but was associated with a significant reduction in the patient-orientated composite endpoint of all-cause death, any MI, and all-cause revascularization (35.1% vs. 40.4%, RR: 0.84 [95% CI: 0.71 to 0.98], p for superiority = 0.023). A significant reduction in very late definite ST from 1 to 5 years was evident with the BES (0.7% vs. 2.5%, RR: 0.26 [95% CI: 0.10 to 0.68], p = 0.003), corresponding to a significant reduction in ST-associated clinical events (primary endpoint) over the same time period. In the post-hoc analysis of the subgroup of patients with acute STEMI (n=275) [37], PCI with BES was associated with a significant reduction of Patient-Oriented Composite Endpoint (POCE, composite of all-cause death, all myocardial infarction and all revascularizations; 24.4% vs 39.3%; RR 0.55, 95% CI 0.36 to 0.85, p=0.006), major adverse cardiac events (MACE, composite of cardiac death, MI and clinically indicated target vessel revascularization; 12.6% vs 25.0%; RR 0.47, 95% CI 0.26 to 0.83, p=0.008) and cardiac death (3.0% vs 11.4%; RR 0.25, 95% CI 0.08 to 0.75, p=0.007), along with a trend towards reduction in definite stent thrombosis (3.7% vs 8.6%; RR 0.41, 95% CI 0.15 to 1.18, p=0.088) at 5-year follow-up, compared with first-generation SES with permanent polymer. This subgroup analysis demonstrated, for the first time, that primary PCI with BES with biodegradable polymer, compared with the durable polymer SES, reduced cardiac death as well as stent thrombosis in a STEMI population at 5-year follow-up.

These data were recently confirmed by the results of a pooled analysis of individual patient data from three randomised trials [38], comparing clinical outcomes of patients with acute STEMI (n=497) undergoing primary PCI with either a biodegradable polymer BES (BES) or a durable polymer SESs at four years. The primary endpoint was a composite of cardiac death, myocardial, or target lesion revascularization. At four years, the primary endpoint was significantly reduced following primary PCI with BES (hazard ratio [HR] 0.59, 95% CI: 0.39-0.90; p=0.01) driven by reduced rates of target lesion revascularization (HR 0.54, 95% CI: 0.30-0.98; p=0.04). Trends towards reduction were seen for cardiac death or MI (HR 0.63, 95% CI: 0.37-1.05; p=0.07) and definite or probable stent thrombosis (3.6% vs. 7.1%; HR 0.49, 95% CI: 0.22-1.11; p=0.09), suggesting superior clinical outcomes following primary PCI with a third-generation DES with biodegradable polymer at four years, compared to first-generation DES with durable polymer.

BIOSCIENCE [39], was a large, prospective, multi-center, single-blind, non-inferiority trial that randomized 2’119 patients with chronic stable CAD or acute coronary syndrome to treatment with the third-generation Orsiro® SES with a biodegradable polymer or the second-generation Xience® EES with a durable polymer. In the pre-specified stratified analysis of the primary endpoint of target lesion failure (cardiac death, target vessel myocardial infarction, clinically-indicated target lesion revascularization at 12 months), the Orsiro® DES was associated with favourable clinical outcome, compared with the Xience® DES in the subgroup of patients with acute STEMI (n=407) with 62% relative risk reduction and 5.4% absolute risk reduction (3·3% vs 8·7%, RR 0·38, 95% CI 0·16–0·91, p=0·024, p for interaction=0·014). Thus, recent data from randomized controlled trials and meta-analyses demonstrate a consistent and strong signal towards a significant reduction in major adverse cardiac events among patients with STEMI undergoing primary PCI with third-generation DESs, compared with both first-generation [33], and second-generation [39], DESs with durable polymer. Importantly, this signal suggesting superiority of third-generation DESs in patients with STEMI has never been demonstrated with second-generation DESs. Third-generation DESs with enhanced biocompatibility may therefore have a particular clinical benefit in high-risk subgroups of patients with delayed vascular healing but these data warrants confirmation in appropriately designed randomized controlled trials. The present trial aims at filling the current gap of evidence by providing randomized data to establish the superior clinical outcome with an ultrathin strut third-generation DES with biodegradable polymer designed to improve vascular healing in patients with STEMI undergoing primary PCI, compared to the current state-of-the art second-generation DES with permanent polymer.

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