IJC Heart & Vasculature 23 (2019) 100363 Contents lists available at ScienceDirect IJC Heart & Vasculature journal homepage: http://www.journals.elsevier.com/ijc-heart-and-vasculature XLIMus drug eluting stent: A randomIzed controlled Trial to assess endothelialization. The XLIMIT trial Luca Testa a,⁎, Gaetano Pero a, Mario Bollati a, Matteo Casenghi a, Antonio Popolo Rubbio a, Magdalena Cuman a, Raul Moreno b, Antoni Serra c, Joan Antoni Gomez d, Francesco Bedogni a a Dept. of Cardiology, IRCCS Policlinico S. Donato, Milan, Italy b Hospital La Paz, Madrid, Spain c Hospital de la Santa Creu i Sant Pau, Barcelona, Spain d Hospital Bellvitge, Barcelona, Spain a r t i c l e i n f o a b s t r a c t Article history: Background: Thin strut 3rd generation drug eluting stents offer the potential advantage over the previous gener- Received 18 March 2019 ation of better technical performance and reduced neointimal proliferation parameters, which are linked to mid Accepted 15 April 2019 and late term device failure. Available online 28 April 2019 Aim: To evaluate the performance of the Xlimus sirolimus-eluting stent (SES) against the Synergy everolimus- eluting stent (EES) in terms of device reendothelialization in patients undergoing PCI for coronary artery disease Keywords: (CAD). Clinical trials Drug-eluting stent Methods: XLIMIT is a multicenter randomized controlled trial targeting 180 patients requiring percutaneous cor- Coronary artery disease onary interventions (PCI). Patients will be treated with Xlimus SES or Synergy EES implantation and randomiza- tion will be performed in a 2:1 ratio. The primary endpoint will be the reendothelialization grade of the Xlimus stent in terms of strut coverage and neointimal hyperplasia volume as compared to Synergy. Secondary end- points will be represented by clinical and procedural outcomes. The first patient was enrolled on February 2019. Conclusions: A clearer understanding of the endothelialization process of new generation DES could significantly impact the treatment with dual antiplatelet therapy in the future. Moreover, although not powered for clinical end-points, the XLIMIT trial will provide randomized data in a population with minimal exclusion criteria. Trial registration: ClinicalTrials.gov Identifier: NCT03745053. Registered on November 19, 2018. © 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Specifically, thin strut thickness provides greater conformability and deliverability with lower risk of arterial injury. Moreover, it is responsible Over the last four decades, PCI has become one the most frequently of less shear disturbances, reducing peri-strut inflammation and fibrin de- performed medical procedures worldwide. Most of its success is related position which finally contribute to improved reendothelialization [5]. to its long-term efficacy and safety, which have progressively increased The Synergy everolimus-eluting stent (EES) (Boston Scientific, from balloon angioplasty to bare metal stents and, finally, to drug- Marlborough, MA, USA) and the recently introduced Xlimus sirolimus- eluting stents. eluting stent (SES) (Cardionovum GmbH, Bonn, Germany) are both Of note, the introduction of drug-eluting stents (DES) is probably re- ultra-thin devices (strut thickness of 74 μm for Synergy, 73 μm for Xlimus) sponsible of the most significant improvement in the efficacy of PCI due with an abluminal biodegradable polymer coating that should reduce to the reduction in restenosis rates following the release of anti- acute and long-term thrombogenicity due to rapid reendothelialization. proliferative drugs, which suppress neointimal hyperplasia [1,2]. In addition, Xlimus is characterized by better mechanical properties Since their release, DES technology has undergone a continuous devel- than traditional DESs improving its navigability in tortuous lesions. opment in many of its characteristics such as stent design, strut thickness, Whilst the efficacy of the Synergy stent system has been widely optimal loading, improved kinetics of drugs, and new polymer technol- tested [6–13], there is still no randomized data studying the perfor- ogy. All these improvements led to the current generation of DES [3,4]. mance of the Xlimus, but only a limited size registry [14]. The aim of the XLIMIT randomized controlled trial is to compare the ⁎ Corresponding author at: IRCCS Policlinico S. Donato, San Donato Milanese, Milan, Xlimus SES to the Synergy EES in terms of device reendothelialization Italy. and cardiovascular outcomes in patients undergoing percutaneous cor- E-mail address: luctes@gmail.com (L. Testa). onary intervention. https://doi.org/10.1016/j.ijcha.2019.100363 2352-9067/© 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2 L. Testa et al. / IJC Heart & Vasculature 23 (2019) 100363 2. Methods interventions can be performed to patients with multivessel disease but only using the allocated stent platform. Medical therapy during 2.1. Study population and eligibility criteria the PCI procedure and in the follow-up will follow current practice guidelines [15]. The XLIMIT study is a multicenter randomized controlled trial de- signed to assess the efficacy of the Xlimus SES and to compare it with 2.3. Devices description Synergy EES. The study will enroll 180 patients aged N18 years old with docu- Synergy EES has a thin-strut (74–81 μm) platinum chromium (PtCr) mented coronary artery disease (CAD) and indication to PCI for stable/ metal alloy platform with a 4 μm bioabsorbable polylactic (PLGA) abluminal unstable angina or non-ST elevated myocardial infarction (NSTEMI). polymer which elutes the drug. Elution is complete by 90 days, and polymer Stents will be implanted to treat de novo lesions in vessels with a refer- absorption is essentially complete by 120 days [7–10]. ence diameter (RVD) of 2.5 to 4 mm. Subjects will be required to have The stent platform of the XLIMUS is made of cobalt chromium L 605 either target lesion (TL) ≥70% or a stenosis ≥50% to b70% with abnormal and the stent is available in a 6-, 8-, or 10-cell structure design (closed fractional flow reserve (iFR/FFR), elevated cardiac biomarkers, or objec- cell architecture). It consists of a RX (Rapid Exchange) Delivery System tive evidence of myocardial ischemia (abnormal stress or imaging stress with 140 cm working length. The struts thickness is 73 μm and the 6-cell test). Patients with ST–elevated myocardial infarction, left main disease, design is for stenting of coronary artery diameter of 2.25–2.50 mm, 8- chronic total occlusions (CTO), venous graft disease or in-stent resteno- cell structure is used for stenting of 2.75–3.50 mm artery diameters, sis (ISR) will be excluded per-protocol. and the 10-cell is for larger artery diameter lesions (up to 5 mm). The Patients with known hypersensitivity to Heparin, Aspirin, XLIMUS has an innovative hydrophilic coated shaft and an extra-low Clopidogrel, Ticlopidine, Sirolimus, Everolimus or contrast media, preg- tip profile (crossing profile = 0.90 mm) to access the most tortuous le- nancy, history of bleeding or known coagulation disorders, life expec- sions. The highly biocompatible polylactic acid (PLLA) drug containing tancy of b1 year or unable to undergo all follow-up examinations and release matrix degrades smoothly and provides an optimal release ki- procedures will be also excluded (Table 1 – inclusion and exclusion netic profile. Within 30 days, about 70% of the antiproliferative drug is criteria). distributed into the surrounding arterial tissue of the stent struts, ensur- ing a highly effective inhibition of smooth muscle cell migration and 2.2. Enrollment and procedure proliferation. Elution is complete by 90 days, and polymer absorption is essentially complete by 120 days. Pharmacokinetic study results con- After the identification of the TL, and the collection of patient's writ- firm sustained antiproliferative drug efficacy up to 120 days. ten consent to participate, randomization to Xlimus SES or Synergy EES Xlimus SES will be compared with Synergy EES, a thin-strut (74–81 will be performed using a web-based case report form (CRF) in a 2:1 μm) platinum chromium (PtCr) metal alloy platform with a 4 μm ratio. The same CRF will be used to collect all the demographic and pro- bioabsorbable polylactic (PLGA) abluminal polymer which elutes the drug. cedural data. Prior to the procedure, patients will be adequately pre-medicated according to local standard practices. It is recommended that all patients 2.4. Follow-up and data collection receive aspirin and a loading dose of Clopidogrel 600 mg, or prasugrel 60 mg or ticagrelor 180 mg, unless patients were already taking an an- Follow-up is scheduled at 6 and 12 months after the index proce- tiplatelet for at least 5 days prior to procedure. dure. Visits will include clinical examination, EKG and blood tests. At PCIs will be performed according to general practice and current in- 6 months, patients will also undergo a control coronary angiography ternational guidelines [15]. Any lesion characteristic or localization will with OCT of the target vessel. be allowed for enrollment. The use of iFR/FFR for the assessment of an- All the follow-up data as well as any serious adverse events includ- giographically intermediate lesions is recommended. If clinically indi- ing death, MI, revascularization, stent thrombosis and bleeding will be cated, intravascular ultrasound (IVUS) or optical coherence entered into the CRF. The study will be subject to on-site monitoring tomography (OCT) may be used at operator's discretion. Treatment of to secure the integrity of the data (Fig. 1 – study flow chart). all TL within a single PCI procedure is encouraged; however, staged 2.5. Coronary angiography assessment and OCT analysis Table 1 Inclusion and exclusion criteria. CAD: coronary artery disease; PCI: percutaneous coronary Coronary angiograms will be obtained at baseline, immediately after intervention; LVEF: left ventricular ejection fraction; CTO: chronic total occlusion. stenting, and at 6-months follow-up. Inclusion – Age ≥ 18 years old The images will be analyzed using a validated edge detection system criteria – Documented CAD: stable or unstable angina; NSTEMI by a core laboratory. Minimal lumen diameter (MLD), reference vessel di- – Target de novo lesion in a vessel with a significant stenosis ameter (RVD), and percent diameter stenosis at baseline, post-procedure suitable for PCI and at follow-up will be measured, respectively. Acute gain is defined as – Target lesion is in a vessel with reference diameter between 2.5 mm and 4 mm the difference between the MLD immediately after the procedure and – Patient able to sign written informed consent and willing to the baseline. Late lumen loss is defined as the difference between the participate to follow-up visits and procedures MLD immediately after the procedure and at follow-up. Loss index is de- Exclusion – ST-elevated myocardial infarction fined as the ratio between late lumen loss and acute lumen gain. Angio- criteria – Known hypersensitivity to: heparin, aspirin, clopidogrel, ticlopidine, sirolimus, everolimus, zotarolimus, inox steel and/or graphic restenosis is defined as diameter stenosis ≥50% by quantitative contrast media coronary angiography (QCA) within a previously stented segment – Pregnancy (stent and 5 mm proximal and distal) at the follow-up angiogram. Reste- – History of bleeding or known coagulation disorders nosis patterns will be assessed using the Mehran classification system. – Target vessel PCI in the previous 3 months OCT examinations of target vessel will be performed after – Life expectancy of b1 year – Patients participating to other studies intracoronary administration of 200 μg of nitroglycerin. – LVEF b30% Analyses will be performed every 2 cross-sections (mean distance of – Cardiogenic shock at the time of randomization 0,4 mm) according to conventional definitions derived from expert con- – Left main or venous graft lesion sensus documents [16–19] using an off-line software (LightLab – In-stent restenosis or CTO Consolle, Westford, Massachusetts, USA). Neointimal volume will be L. Testa et al. / IJC Heart & Vasculature 23 (2019) 100363 3 Fig. 1. TVR: target vessel revascularization; TV MI: target vessel myocardial infarction; TLR: target lesion revascularization; ST: stent thrombosis; OCT: optical coherence tomography; NSTEMI: non-ST-elevated myocardial infarction; PCI: percutaneous coronary intervention. calculated in all analyzed cross-sections and volumetric measurements 2.6. Study outcomes will be compared in the two groups. All OCT sequences will be analyzed by an independent and validated The primary endpoint of the trial is the reendothelialization grade of Core laboratory with specific expertise in intravascular imaging. Person- the Xlimus stent in terms of struts coverage and neointimal hyperplasia nel blinded to procedural data and clinical outcome will perform all as- volume as compared to the Synergy stent at 6 months. sessments off-line. Neointimal area calculated at the narrowest luminal area segment of In all the analyzed cross-sections, the assessment of neointimal target vessel will represent the secondary endpoint as well as cardiovas- thickness will be calculated as the difference between the stent contour cular death, target vessel MI or target vessel failure (TVF), target lesion and the luminal contour. Volumetric measurements will be obtained revascularization (TLR), stent thrombosis (ST), device success at 24 h, applying the Simpson rule [20]. target lesion success at 24 h and procedural success at 24 h. Stent with suboptimal strut visualization (i.e. inability of OCT to ad- All clinical end points will be adjudicated by an independent event dress all stent struts in a specific cross-section) in N10% of total stent adjudication committee (EAC) made up of interventional and non- struts will be excluded from final analysis. interventional cardiologists who are not participants in the study. The 4 L. Testa et al. / IJC Heart & Vasculature 23 (2019) 100363 EAC will be in charge of the categorization of clinical events and clinical 2.7.3. Ethical considerations endpoints in the study which are based on protocol. This study is conducted in accordance with the ethical principles of the Declaration of Helsinki (2013). The protocol of this study has been 2.7. Statistical analysis read and approved by the Ethics Committee of participating hospitals. Printed informed consent and detailed information about the study 2.7.1. Sample size determination will be offered to patients before randomization. Sample size determination has been based on data obtained from All information and data of this trial are encrypted and stored in an historical cases in a published database including N1500 lesions [16]. online database accessible only to main researchers and administrators. We assumed a mean value of in-stent neointimal volume formation Patients primarily enrolled have rights to withdraw at any time of 15 ± 7.5% in the Synergy EES group after 6-months, and a clinically point and the reasons will be documented. relevant volume reduction of 4% with the Xlimus SES, leading to a mean of 11%. Thus, aiming for a two-tailed α of 0.05 and 80% power at 3. Discussion a Student's t-test, the required total sample would be of 129 patients (43 in Synergy EES group and 86 in Xlimus SES group). This sample The XLIMIT multicenter trial will test the efficacy and safety of the size has to be increased to 135 patients (45 in Synergy EES group and Xlimus stent compared to the Synergy stent. 90 in Xlimus SES group) to consider potential suboptimal image acqui- The aims of the study can be summarized in the following points: sition in 3% of cases. Finally, foreseeing a 25–30% cumulative rate of drop-outs and patients not performing the 6 months angiographic 1. To assess the Xlimus SES reendothelialization and in-stent neointi- follow-up, it is reasonable to enroll 60 pts. in the Synergy EES group mal hyperplasia volume at 6 months (primary outcome) as com- and 120 in the novel Xlimus SES group to test the superiority hypothe- pared to Synergy EES sis. Moreover, if the superiority hypothesis will not be demonstrated, 2. Support the efficacy of the stent in terms of device, procedural and with 180 patients (60 pts. in the Synergy EES group and 120 Xlimus target lesion success at 24 h (secondary outcomes) SES group) it will be possible to test the non-inferiority hypothesis 3. Demonstrate the safety and efficacy of the implant in terms of cardio- with a one-tailed significance level α of 0.05 (equivalent to a 90% confi- vascular death, target vessel MI, TVF, TLR and ST at 12 months (sec- dence interval), a power of about 0.80 and a non-inferiority threshold of ondary outcomes) 3%, thus assuming that the two treatments are actually equivalent. The non-inferiority of Xlimus SES will be claimed if the upper 90% confi- Durable polymers of first-generation DES were considered one of dence limit of the difference between Xlimus SES and Synergy EES the main causes of stent thrombosis and in-stent restenosis due to per- will be b3%. sistent arterial wall inflammation and delayed vascular healing. Al- though the current durable polymer DES shows less long-term 2.7.2. Statistical methods complications in comparison with precedent technologies, a huge effort Descriptive statistics (arithmetic mean, median, minimum and max- has been put in the development of bioabsorbable polymer stents with imum and standard deviation) will be calculated for quantitative vari- the aim of improving late procedural outcomes [21,22]. ables. Absolute frequencies and percentages will be obtained for Synergy EES is one of the new generation thin strut stents with qualitative variables. Summary statistics will be presented according abluminal bioabsorbable polymer and has shown good clinical and pro- to treatment allocation. 95% confidence intervals will be also provided, cedural results in several studies [7–13]. unless otherwise specified. In the EVOLVE II trial, target lesion failure (TLF) and TLR rates were All statistical tests will be performed at two-sided α = 0.05. 6.7 and 2.6% at 1 year, respectively [8]. Student's t-test or Mann-Whitney U test will be used to compare In the all-comers BIO-RESORT study, the 1-year TLF and TLR rates in quantitative variables depending if they are normally distributed or not; the Synergy arm were 4.0% and 2.0% respectively [11]. χ2 or Fisher's exact tests will be used to compare qualitative variables. In a large registry conducted in Asia, despite the vast majority of pa- The primary endpoint and the neointimal area calculated at the site tients having complex lesions (type B2 or C), 1-year TLF rate was 5.8% of minimal lumen area at 6-month FU, measured with OCT will be ana- and TLR rate 1.3% [23]. lyzed by means of the Student's t-test for the superiority hypothesis. The In another registry of 185 high bleeding risk patients who confidence interval approach will be used for the non-inferiority hy- underwent short dual-antiplatelet therapy (DAPT) (78.4% with discon- pothesis on the primary endpoint. tinuation by 3 months), no stent thrombosis was reported and only The probability of not occurrence of clinical secondary endpoints at three patients required target-vessel revascularization at 1 year [24]. 12 months (cardiac death, target-vessel MI and clinically indicated A sub-study from the Swedish SCAAR registry made a comparison TLR, cardiac death, target-vessel MI, TLR, and ST) will be estimated between Synergy EES and other new generation DES showing that the using the Kaplan-Meier method and compared between the two treat- cumulative rate of restenosis (1.1% vs. 1.0%, adjusted HR: 1.24; 95% CI: ment groups by means of the Log-rank test, followed by the Propor- 0.88–1.75; P = 0.21) and stent thrombosis (0.4% vs. 0.5%, adjusted tional Hazard Cox's model to assess predictive models in consideration HR: 0.97; 95% CI: 0.63–1.50; P = 0.17) up to 1 year were low in both of the baseline characteristics statistically associated with the events the Synergy and other new generation DES group [12]. and the following variables: treatment group, age, gender, number of For what concerns the acute setting, in a recent multicenter registry vessel treated, stent length, number of stents, insulin therapy require- enrolling 1008 patients with ACS treated with PCI and Synergy EES, the ment. Clinically appropriate thresholds will be considered to group primary endpoint (composite of cardiac death, myocardial infarction the quantitative variables in classes. and target lesion revascularization) occurred in 3% of the population With the considered sample size, a satisfactory power value of at at 12 months, confirming the good performance of the device [25]. least 0.80 is obtained at a Log-rank test carried out at 0.05 (two tailed) The Xlimus SES has similar characteristics and structure as the Syn- significance level if the difference in survival probability is at least 0.20 ergy EES, with additional features designed to improve its trackability from a baseline ranging from 0.45 to 0.85. across complex anatomy, such as an innovative hydrophilic-coated The clinical secondary endpoints at 24 h (device success, lesion suc- shaft and an extra-low tip profile (crossing profile 0.90 mm). cess, and procedural success) will be compared by means of the Fisher's The biggest study available on the Xlimus is a prospective registry on exact test. With the considered sample size, a satisfactory power value 200 consecutive patients with 255 complex de novo lesions. The stent of at least 0.80 is obtained for a difference of at least N0.15, considering showed good technical performance with a delivery success rate of a baseline proportion of about 0.80. 98% in patients and in 98.4% of lesions. Xlimus SES was successfully L. Testa et al. / IJC Heart & Vasculature 23 (2019) 100363 5 implanted on the first attempt with a single guidewire in 88% of patients [11] C. von Birgelen, M.M. Kok, L.C. van der Heijden, P.W. Danse, C.E. Schotborgh, M. Scholte, et al., Very thin strut biodegradable polymer everolimus-eluting and and in 81.6% of lesions. Additional techniques to facilitate stent delivery sirolimus eluting stents versus durable polymer zotarolimus-eluting stents in (i.e., buddy wire, anchoring-balloon or child-in-mother catheter) were allcomers with coronary artery disease (BIO-RESORT): a three-arm, randomised, necessary in 18.4% of lesions. Implantation failure was seen in 4 lesions non-inferiority trial, Lancet 388 (2016) 2607–2617. [12] G. Sarno, B. Lagerqvist, G. Olivecrona, C. Varenhorst, M. Danielewicz, K. Hambraeus, (1.6%). Moreover, although the sample size was relatively small, the 9% et al., Real-life clinical outcomes with everolimus eluting platinum chromium stent rate of MACE at 12 months was comparable to what has been reported with an abluminal biodegradable polymer in patients from the Swedish Coronary in other studies on 2nd- and 3rd-generation DES [26,12]. Angiography and Angioplasty Registry (SCAAR), Catheter. Cardiovasc. Interv. 90 (2017) 881–887. [13] J. Escaned, C. Collet, N. Ryan, G.L. De Maria, S. Walsh, M. Sabate, et al., Clinical out- 4. Trial status comes of state-of-the-art percutaneous coronary revascularization in patients with de novo three vessel disease: 1-year results of the SYNTAX II study, Eur. Heart J. 38 (2017) 3124–3134. Recruitment started in February 2019 and is estimated to be com- [14] C. Briguori, G. Visconti, M. Donahue, V. Di Palma, F. De Micco, G. Signoriello, Focaccio, pleted in December 2020. Performance of the XLIMUS sirolimus-eluting coronary stent in very complex le- sions, J. Interv. Cardiol. 29 (6) (2016) 559–568. 5. Conclusions [15] F.J. Neumann, M. Sousa-Uva, A. Ahlsson, F. Alfonso, A.P. Banning, U. Benedetto, R.A. Byrne, J.P. Collet, V. Falk, S.J. Head, P. Jüni, A. Kastrati, A. Koller, S.D. Kristensen, J. Niebauer, D.J. Richter, P.M. Seferovic, D. Sibbing, G.G. Stefanini, S. Windecker, R. The XLIMIT trial will provide insights into the endothelialization Yadav, M.O. Zembala, ESC Scientific Document Group, 2018 ESC/EACTS guidelines process of the Xlimus sirolimus eluting stent compared to the Synergy on myocardial revascularization, Eur. Heart J. 40 (2) (2019) 87–165. [16] F. Prati, E. Romagnoli, F. Burzotta, U. Limbruno, L. Gatto, A. La Manna, F. Versaci, V. everolimus eluting stent. Although not powered for clinical end- Marco, L. Di Vito, F. Imola, G. Paoletti, C. Trani, C. Tamburino, L. Tavazzi, G.S. Mintz, points, a “minimally” selected population is of particular significance Clinical impact of OCT findings during PCI: the CLI-OPCI II study, JACC Cardiovasc. as it will test the real-world performance of the new device. Imaging 11 (2015) 1297–1305. [17] L. RaÃàber, G.S. Mintz, K.C. Koskinas, T.W. Johnson, N.R. Holm, Y. Onuma, M.D. Radu, M. Joner, B. Yu, H. Jia, N. Meneveau, J.M. de la Torre Hernandez, J. Escaned, J. Hill, F. Conflict of interest Prati, A. Colombo, C. Di Mario, E. Regar, D. Capodanno, W. Wijns, R.A. Byrne, G. Guagliumi, Clinical use of intracoronary imaging. Part 1: guidance and optimization of coronary interventions. An expert consensus document of the European Associa- The authors report no relationships that could be construed as a con- tion of Percutaneous Cardiovascular Interventions, EuroIntervention 14 (2018) flict of interest. 656–677. [18] F. Prati, G. Guagliumi, G.S. Mintz, et al., Expert's OCT Review Document, Expert re- view document part 2: methodology, terminology and clinical applications of opti- References cal coherence tomography for the assessment of interventional procedures, Eur. Heart J. 33 (2012) 2513–2520. [1] M.C. Morice, P.W. Serruys, J.E. Sousa, J. Fajadet, E. Ban Hayashi, M. Perin, et al., A ran- [19] G.J. Tearney, E. Regar, T. Akasaka, et al., International Working Group for domized comparison of a sirolimus- eluting stent with a standard stent for coronary Intravascular Optical Coherence Tomography (IWG-IVOCT), Consensus standards revascularization, N. Engl. J. Med. 346 (2002) 1773–1780. for acquisition, measurement, and reporting of intravascular optical coherence to- [2] G.W. Stone, S.G. Ellis, D.A. Cox, J. Hermiller, C. O'Shaughnessy, J.T. Mann, et al., One- mography studies: a report from the International Working Group for Intravascular year clinical results with the slow- release, polymer-based, paclitaxel-eluting TAXUS Optical Coherence Tomography Standardization and Validation, J. Am. Coll. Cardiol. stent: the TAXUS-IV trial, Circulation 109 (2004) 1942–1947. 59 (2012) 1058–1072. [3] S. Bangalore, S. Kumar, M. Fusaro, et al., Short- and long-term outcomes with drug- [20] Y. Sotomi, H. Tateishi, P. Suwannasom, J. Dijkstra, J. Eggermont, S. Liu, E. eluting and bare-metal coronary stents: a mixed-treatment comparison analysis of Tenekecioglu, Y. Zheng, M. Abdelghani, R. Cavalcante, R.J. de Winter, J.J. 117 762 patient-years of follow-up from randomized trials, Circulation 125 (2012) Wykrzykowska, Y. Onuma, P.W. Serruys, T. Kimura, Quantitative assessment of 2873–2891. the stent/scaffold strut embedment analysis by optical coherence tomography, Int. [4] T. Palmerini, G. Biondi-Zoccai, D. Della Riva, et al., Stent thrombosis with drug- J. Cardiovasc. Imaging 32 (2016) 871–883. eluting and bare-metal stents: evidence from a comprehensive network meta- [21] M. Joner, A.V. Finn, A. Farb, et al., Pathology of drug-eluting stents in humans: de- analysis, Lancet 379 (2012) 1393–1402. layed healing and late thrombotic risk, J. Am. Coll. Cardiol. 48 (2006) 193–202. [5] N. Foin, R.D. Lee, R. Torii, et al., Impact of stent strut design in metallic stents and bio- [22] R. Waksman, G. Maluenda, Polymer drug-eluting stents: is the future biodegrad- degradable scaffolds, Int. J. Cardiol. 177 (2014) 800–808. able? Lancet 378 (2011) 1900–1902. [6] S.H. Kang, I.H. Chae, J.J. Park, H.S. Lee, D.Y. Kang, S.S. Hwang, T.J. Youn, H.S. Kim, Stent [23] R. Ananthakrishna, W. Kristanto, L. Liu, S.P. Chan, P.H. Loh, E.L. Tay, et al., Incidence thrombosis with drug-eluting stents and bioresorbable scaffolds: evidence from a and predictors of target lesion failure in a multiethnic Asian population receiving network meta-analysis of 147 trials, J. Am. Coll. Cardiol. Intv. 9 (12) (2016) the SYNERGY coronary stent: a prospective all-comers registry, Catheter. 1203–1212. Cardiovasc. Interv. 7 (2018 Mar). [7] I.T. Meredith, S. Verheye, C.L. Dubois, J. Dens, J. Fajadet, D. Carrié, et al., Primary end- [24] R.L. Noad, C.G. Hanratty, S.J. Walsh, Initial experience of bioabsorbable polymer point results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable everolimus-eluting synergy stents in high-risk patients undergoing complex percu- polymer-coated, everolimus-eluting coronary stent, J. Am. Coll. Cardiol. 59 (2012) taneous coronary intervention with early discontinuation of dual-antiplatelet ther- 1362–1367. apy, J. Invasive Cardiol. 29 (2017) 36–41. [8] D.J. Kereiakes, I.T. Meredith, S. Windecker, R. Lee Jobe, S.R. Mehta, I.J. Sarembock, [25] J.M. de la Torre Hernandez, R. Moreno, N. Gonzalo, R. Rivera, J.A. Linares, G. Veiga et al., Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus- Fernandez, A. Gomez Menchero, B. Garcia Del Blanco, F. Hernandez, T. Benito eluting coronary stent: the EVOLVE II Randomized Trial, Circ. Cardiovasc. Interv. 8 Gonzalez, A. Subinas, J. Escaned, The Pt-Cr everolimus-eluting stent with (4) (2015 Apr). bioabsorbable polymer in the treatment of patients with acute coronary syndromes. [9] I.T. Meredith, S. Verheye, C. Dubois, J. Dens, B. Farah, D. Carrié, et al., Final five-year Results from the SYNERGY ACS registry, Cardiovasc. Revasc. Med. (2018 Oct 18) clinical outcomes in the EVOLVE trial: a randomized evaluation of a novel https://doi.org/10.1016/j.carrev.2018.10.019 (pii: S1553-8389(18)30459-7). bioabsorbable polymer coated, everolimus-eluting stent, EuroIntervention 13 [26] C. von Birgelen, H. Sen, M.K. Lam, et al., Third-generation zotarolimus-eluting and (2018) 2047–2050. everolimus-eluting stents in all-comer patients requiring a percutaneous coronary [10] Y. Han, H. Liu, Y. Yang, J. Zhang, K. Xu, G. Fu, et al., A randomized comparison of bio- intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non- degradable polymer and permanent polymer-coated platinum chromium inferiority trial, Lancet 383 (9915) (2014) 413–423. everolimus-eluting coronary stents in China: the EVOLVE China study, EuroIntervention 13 (2017) 1210–1217.