Received: 11 October 2018 Revised: 30 January 2019 Accepted: 23 March 2019 DOI: 10.1002/ccd.28224 CORONARY ARTERY DISEASE Original Studies Comparison of long-term clinical outcomes in multivessel coronary artery disease patients treated either with bioresoarbable polymer sirolimus-eluting stent or permanent polymer everolimus-eluting stent: 5-year results of the CENTURY II randomized clinical trial Andrés Iñiguez1 | Bernard Chevalier2 | Gert Richardt3 | Antoinette Neylon4 | Victor A. Jiménez1 | Ran Kornowski5 | Didier Carrie6 | Raul Moreno7 | Emanuele Barbato8 | Antoni Serra-Peñaranda9 | Vincenzo Guiducci10 | Mariano Valdés-Chávarri11 | Junji Yajima12 | William Wijns13 | Shigeru Saito14 | on behalf of CENTURY II study investigators 1 Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo, Abstract Spain Objectives: To assess the long-term safety and efficacy of a sirolimus-eluting stent with 2 Interventional Cardiology Department, Institut bioresorbable polymer (BP-SES; Ultimaster), in comparison to a benchmark everolimus- Cardiovasculaire Paris Sud, Massy, France 3 Department of Cardiology, Segeberger eluting, permanent polymer stent (PP-EES; Xience), in a prespecified subgroup of patients Kliniken, Bad Segeberg, Germany with multivessel coronary artery disease (MVD) enrolled in the CENTURY II trial. 4 SAOLTA Health Care Group, Galway Background: The use of coronary stenting in high-risk subgroups, like MVD patients, University Hospital and NUI, Galway, Ireland 5 Cardiology Department, Rabin Medical Centre, is rising. The clinical evidence, including long-term comparative analysis of the effi- Petah Tikva, Israel and Sackler Faculty of cacy and safety benefits of different new-generation drug eluting stents, however, Medicine, Tel Aviv University, Tel Aviv, Israel 6 remains insufficient. Department of Cardiology, Rangueil University Hospital, Toulouse, France Methods: Among 1,119 patients (intention-to-treat) enrolled in the CENTURY II 7 Interventional Cardiology Department, La Paz prospective, randomized, single-blind, multicenter trial, a prespecified subgroup of University Hospital, Madrid, Spain 456 MVD patients were allocated by stratified randomization to treatment with 8 Cardiovascular Centre, Onze Lieve Vrouwe Ziekenhuis, Aalst, Belgium and Division of BP-SES (n = 225) or PP-EES (n = 231). The previously reported primary endpoint of Cardiology, Department of Advanced this study was freedom from target lesion failure (TLF: a composite of cardiac death, Biomedical Sciences, University of Naples Federico II, Naples, Italy target vessel-related myocardial infarction [MI] and clinically-indicated target lesion 9 Cardiology Department, Hospital de la Santa revascularization) at 9 months. Creu i Sant Pau, IIB-SantPau, CIBERCV, Results: In this MVD substudy, baseline patient, lesion and procedure characteristics Universidad Autónoma de Barcelona, Barcelona, Spain were similar between the treatment arms. At 1 and 5 years, both BP-SES and PP-EES Abbreviations: (N)IDDM, (non) insulin-dependent diabetes mellitus; (N)STEMI, (non) ST-segment elevation myocardial infarction; ACC/AHA, American College of Cardiology/American Heart Association; ARC, academic research consortium; BARC, bleeding academic research consortium; BP, bioresorbable-polymer; BP-SES, bioresorbable polymer sirolimus-eluting stent; CABG, coronary artery bypass graft; CEC, clinical events committee; CI, confidence interval; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; DMC, data monitoring committee; ITT, intention-to-treat; MI, myocardial infarction; MVD, multivessel disease; PCI, percutaneous coronary intervention; POCE, patient-oriented composite endpoint; PP, permanent-polymer; PP-EES, permanent polymer everolimus-eluting stent; ST, stent thrombosis; TLF, target lesion failure; TLR, target lesion revascularization; TV, target vessel; TVF, target vessel failure; TVR, target vessel revascularization This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any .medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals, Inc. Catheter Cardiovasc Interv. 2020;95:175–184. wileyonlinelibrary.com/journal/ccd 175 176 IÑIGUEZ ET AL. 10 Interventional Cardiology Unit, S. Maria Nuova Hospital, Reggio Emilia, Italy displayed low and comparable rates of TLF (5.3 vs. 7.8%; p = .29 and 10.2 vs. 13.4%; 11 Cardiology Department, Hospital p = .29), and definite or probable stent thrombosis (0.4 vs. 1.3%; p = .33 and 0.9 Universitario Virgen de la Arrixaca, IMIB- Arrixaca, Murcia, Spain vs. 1.7%; p = .43), respectively. Composite endpoint of cardiac death and MI, and 12 Department of Cardiovascular Medicine, The patient-oriented composite endpoint of any death, MI, and coronary revasculariza- Cardiovascular Institute, Tokyo, Japan tions were also similar. 13 The Lambe Institute, NUI Galway, Ireland 14 Conclusions: These results confirm good long-term safety and efficacy of the studied Department of Cardiology and Catheterization Laboratory, Shonan Kamakura bioresorbable polymer stent in this high-risk patient population. General Hospital, Kamakura, Japan KEYWORDS Correspondence clinical trials, complex PCI, coronary artery disease, drug eluting, percutaneous coronary Andrés Iñiguez, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital intervention, stent, stent design/structure/coating of Vigo, Estrada Clara Campoamor, 341, 36312 Vigo, Pontevedra, Spain. Email: andres.iniguez.romo@sergas.es Funding information Terumo 1 | I N T RO D UC T I O N circumferential, biocompatible polymer coating) in terms of freedom from target lesion failure (TLF: a composite of cardiac death, target In recent years, the use of coronary stenting in high-risk subgroups, vessel-related myocardial infarction [MI] and clinically driven target like multivessel disease (MVD) patients, has increased. The treatment lesion revascularization [TLR]), in total study population, at 9 months of MVD patients, by percutaneous coronary intervention (PCI), how- follow-up (primary endpoint).8 Good clinical performance of the two ever, is still challenging. These patients usually have more risk factors stents was recently confirmed also for the long-term, 5-year follow- and comorbidities (e.g., diabetes), as well as overall less favorable up period.9 In this manuscript, we report the 5-year clinical outcomes long-term outcomes. Moreover, the PCI in MVD patients is often of a subgroup of the original CENTURY II trial, consisting of patients 1 more complex and associates with higher procedural risk. Choosing diagnosed with MVD at the time of randomization. the most suitable revascularization strategy for MVD patients requires careful evaluation of both patient and lesion status. The available evi- 2 | METHODS dence suggests that in MVD patients without diabetes and/or with low-anatomical complexity, PCI, and coronary artery bypass grafts 2.1 | Study design and patients (CABG) achieve similar long-term outcomes with respect to survival and the composite clinical outcomes. In MVD patients with intermediate-to- CENTURY II is a prospective, randomized, single-blind, controlled, non- high anatomical complexity, however, evidence from large studies impli- inferiority, multicentre, clinical trial of BP-SES (Ultimaster, Terumo Cor- cates CABG as still the preferred choice over PCI in terms of reducing poration, Japan) and PP-EES (Xience, Abbott Vascular; study registra- mortality and risk of other serious adverse events.2 tion number: UMIN000006940), involving 58 enrolling centers (see list The application of antiproliferative drugs onto bare metal stent scaf- in Supporting Information) from Europe, Japan, and South Korea. Out folds has improved PCI outcomes with respect to restenosis and the need of 1,119 patients, 456 (40.8%) were diagnosed at the time of study for repeat interventions.3,4 Less favorable long-term safety profile, that is, entry with MVD and during randomization, that was stratified for this higher risk of (very) late stent thrombosis (ST),5 however, challenged these characteristic, allocated to treatment with either BP-SES (n = 225) or initially promising results. Due to its association with chronic inflammatory PP-EES (n = 231; Figure 1). MVD was defined as the presence of >50% reactions, delayed arterial healing, poor re-endothelialisation and positive diameter stenosis in two or three major epicardial coronary vessels or remodeling,6 permanent polymer (PP) coating of first generation drug- bypass grafts (as measured by caliper method or coronary angiography eluting stents (DES) became one of the prime targets for redesign. Conse- online). Analysis of this prespecified MVD subgroup was done using quently, several more advanced drug-carriers were developed, including the intention to treat (ITT) approach. Detailed CENTURY II study design bioresorbable polymeric carriers (BP) and biocompatible PP variants, as and methods have been described elswhere.8 In brief, patients with 7 well as nonpolymeric stent surfaces. ischemic heart disease due to stenotic lesions of coronary arteries with In the CENTURY II (Clinical Evaluation of New TerUmo drug- reference vessel diameter suitable for treatment with stents ≥2.5 elUting coRonary stent system in the treatment of patients with coro- and ≤4.0 mm (≤3.5 mm in Japan) were eligible. Patients were randomly narY artery disease) trial, the Ultimaster sirolimus-eluting BP stent (1:1) assigned to PCI with either BP-SES or PP-EES. Randomization was (BP-SES; with abluminal, gradient polymer coating) was shown to be balanced (stratified) for diabetes mellitus, high-risk acute coronary syn- noninferior to the Xience PP everolimus-eluting stent (PP-EES; with drome, and MVD. All patients had to provide a signed written informed IÑIGUEZ ET AL. 177 F I G U R E 1 Study flow chart. Follow-up rates reflect patients with the completed follow-up visit or those who died during the follow-up period. BP-SES, bioresorbable polymer sirolimus-eluting stent; PP-EES, permanent polymer everolimus- eluting stent [Color figure can be viewed at wileyonlinelibrary.com] consent. The study complied with the Declaration of Helsinki and was 2.5 | Endpoints and definitions approved at each participating center by institutional review board and The primary endpoint of CENTURY II study was freedom from target competent authority of each participating country. lesion failure (TLF), a device-oriented composite endpoint consisting of cardiac death, myocardial infarction (MI) not clearly attributable to 2.2 | Procedures a nontarget vessel, and clinically driven target lesion revascularization (TLR) at 9-months. Secondary outcomes included (a) rate of target All coronary interventions were performed according to standard hos- pital practice, while all postrandomization procedural decisions were vessel failure (TVF), defined as composite of cardiac death and MI not left at operators' discretion. Dual antiplatelet therapy (DAPT) was rec- clearly attributable to a nontarget vessel, and clinically driven target ommended for at least 6 months. Clinical follow-up was scheduled at vessel revascularization (TVR); (b) patient-oriented composite end- 1, 4, 9 months, and yearly until the final 5-year control visit. point (POCE) composed of all deaths, all MI and all coronary revascu- larizations; (c) composite of cardiac death and MI (d) rates of cardiac death, MI, TLR, TVR; (e) ST; and (f) rate of bleeding and vascular com- 2.3 | Data management and quality assurance plications according to Bleeding Academic Research Consortium A data monitoring committee (DMC) was responsible for the review (BARC) definitions.10 The endpoints are defined as per Academic of all data and identification of potential safety issues. An indepen- Research Consortium recommendations.11 dent clinical event committee (CEC) reviewed and adjudicated all major endpoint-related adverse and bleeding events. All data on case 2.6 | Statistical analysis report forms were 100% verified on-site versus source documents. Members of DMC and CEC were blinded to patient assignment, while The CENTURY II randomized trial was statistically powered for non- investigators and study personnel were not. inferiority of BP-SES compared to PP-EES regarding the primary end- point of freedom from TLF in the total population at 9-months. The TLF-free rate was 95.64% for BP-SES and 95.09% for PP-EES, dem- 2.4 | Study devices onstrating non-inferiority (p < .0001). Both per-protocol and ITT ana- Detailed technical description of the Ultimaster (BP-SES) and its' com- lyses gave similar results.8 The present analysis is focused on subset 8 parator device Xience (PP-EES) have been previously reported. of MVD patients. Here, categorical variables were compared using the Briefly, Ultimaster uses a thin strut (80 μm) cobalt-chromium platform, chi-squared test (for binary variables) and the Cochran–Mantel– with an abluminal gradient bioresorbable polymer coating, while Haenszel test (for multinomial variables). Continuous variables Xience (PP-EES) platform is also based on cobalt-chromium alloy with were compared using nonparametric test (i.e., Mann–Whitney for PP coating. two-group comparisons) or Kruskal–Wallis test (for multiple group 178 IÑIGUEZ ET AL. comparison). Dichotomous clinical endpoints were tested using the TABLE 1 Baseline patient characteristics chi-squared test. The Kaplan–Meier method was used to estimate BP-SES PP-EES event rates for time-to-event outcomes, while the data were com- n = 225 n = 231 p Value pared using the log-rank test. To explore whether TLF with BP-SES Age, years 65.8 ± 10.4 66.9 ± 11.3 .31 versus PP-EES was consistent across categories of clinical, procedural, Male gender 77.8 84.0 .09 or lesion characteristics, logistic regression analysis with interaction Body mass index, kg/m2 27.3 ± 4.2 26.8 ± 4.2 .27 testing was performed. All analyses were performed, using the SAS Silent ischemia 16.4 16.5 .99 software, version 9.4 (SAS Institute, Inc., Cary, NC). Stable angina 48.9 42.9 .20 Unstable angina 12.0 9.1 .31 3 | RESULTS STEMI 4.9 7.4 .27 NSTEMI 17.8 24.2 .09 3.1 | Patient and procedural characteristics Diabetes mellitus, 37.3 33.3 .37 Four hundered and fifty-six MVD patients were assigned to either IDDM 21.4 18.2 .61 BP-SES (n = 225) or PP-EES (n = 231) treatment-arm (Figure 1). This NIDDM 78.6 81.8 .61 subgroup constituted 40.8% of the total study population (n = 1,119). Dyslipidemia 71.0 71.1 .99 The mean age was 66 years, with 19% females. A relatively high per- Hypertension 74.1 71.2 .49 centage (35%) of diabetes was observed, but this did not differ Smoker, current 19.6 24.3 .23 between treatment arms. No significant differences in proportion of Smoker, previous 48.9 37.6 .02 cardiac risk factors, mean Charlson comorbidity index, nor in the mean Renal insufficiency, 4.0 3.0 .57 SYNTAX score were observed among the two treatment arms. Most Family history of CAD 31.9 32.9 .83 of the patients had stable angina, while 27% presented with the high- History of PCI 44.4 40.3 .37 risk acute coronary syndrome (ST-segment elevation MI [STEMI] and History of CABG 7.1 6.5 .79 non-ST-segment elevation MI [NSTEMI]). On average patients had 2.3 ± 0.5 diseased vessels of which 1.4 ± 0.5 were treated. Overall, History of MI 31.1 32.5 .76 baseline patient characteristics did not differ significantly, aside of the Charlson comorbidity index 1.5 ± 1.8 1.3 ± 1.6 .39 higher frequency of previous smokers in BP-SES arm (Table 1). Vessels diseased 2.3 ± 0.5 2.3 ± 0.5 .16 Altogether, 738 lesions, 364 in BP-SES and 374 in PP-EES study- (LM included) arm were treated. Mean number of detected lesions per patient was Number of vessels diseased .15 (LM included) 3.1 ± 1.4, of which 1.6 ± 0.8 were subjected to coronary stenting. 2 75.1 69.3 Lesion localization was similar between the study groups. More than 80% of lesions were classified as type B2 or C (ACC/AHA classifica- 3 23.6 28.6 tion), while 12.7% represented bifurcation lesion. The frequency of 4 1.3 2.2 ostial localization as well as the level of lesion calcification did not dif- Vessels treated 1.4 ± 0.5 1.4 ± 0.6 .87 fer between the two treatment arms. Only significantly higher pres- Number of vessels treated .76 ence of chronic total occlusion (CTO) lesions was noted in BP-SES 1 59.6 59.3 treated patients (Table 2). Regarding the procedural aspects, the fre- 2 39.1 38.1 quency of pre- and post-dilatations, and utilized access sites were 3 1.3 2.6 similar among the two arms, radial artery being the most frequently SYNTAX score 12.7 ± 8.7 12.3 ± 7.6 .91 used approach (69.1%). Mean total implanted stent number and the Note. Values represent either mean ± SD or % of per patient calculation. total length of the implanted stents per patient were 1.9 ± 1.0 and Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery 37.0 ± 21.3 mm, respectively, and were similar among the two arms. disease; DAPT, dual anti-platelet therapy; LM, left main coronary artery; Overall, baseline lesion and procedural characteristics were largely MI, myocardial infarction; (N)IDDM, (non) insulin-dependent diabetes alike (Table 2). mellitus; (N)STEMI, (non) ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention. DAPT at each time point (1 month, 4 months, 9 months, 1-year, 2-year, 3-year, 4-year, and 5-year follow-up) is shown in Table 3. Pro- portion of patients on DAPT did not differ between the two treat- 1-year (p = .29; Table 4) and 10.2 versus 13.4% at 5 years (p = .29; ment arms during the entire follow-up period. Table 5) in BP-SES and PP-EES arm, respectively (Figure 2). The TVF composite endpoint rates were similar in two arms at 1- and 5-years, as was the incidence of clinically indicated TLR at both time points 3.2 | Medium- and long-term clinical outcomes (Tables 4 and 5). The incidence of all non-TVR and any revasculari- Throughout 5-year follow-up period, the rate of TLF composite end- zation was significantly higher in PP-EES arm only at 1-year follow- point was similar among the two treatment arms: 5.3 versus 7.8% at up (Tables 4 and 5). Rates of cardiac death, MI and definite or IÑIGUEZ ET AL. 179 TABLE 2 Baseline lesion and procedural characteristics TABLE 3 Dual antiplatelet therapy BP-SES PP-EES BP-SES PP-EES npatients = 225 npatients = 231 n = 225 n = 231 p Value nlesions = 364 nlesions=374 p Value DAPT at 1 month 97.8 (218/223) 98.7 (227/230) .45 Lesions detected 3.1 ± 1.5 3.1 ± 1.3 .57 DAPT at 4 months 96.4 (215/223) 96.9 (222/229) .75 Lesions treated 1.6 ± 0.8 1.6 ± 0.8 .93 DAPT at 9 months 85.4 (187/219) 85.0 (187/220) .91 Lesion location .80 DAPT at 1 year 65.6 (143/218) 62.7 (138/220) .53 RCA 30.5 32.4 DAPT at 2 years 29.9 (64/214) 24.4 (52/213) .20 LAD 37.9 34.2 DAPT at 3 years 20.6 (43/209) 16.9 (35/207) .34 CFX 28.3 30.8 DAPT at 4 years 17.1 (35/205) 14.1 (29/206) .40 LM 2.5 2.4 DAPT at 5 years 15.0 (30/200) 13.9 (28/201) .76 Graft 0.8 0.3 Note. Values represent % (number) of patients on DAPT at a given Ostial 7.5 9.9 .24 follow-up time-point. Calcification .32 Abbreviation: DAPT, dual antiplatelet therapy. None/mild 76.2 81.8 At 1 year follow-up, no difference in bleeding rate between the Moderate 16.1 11.6 two groups was noted (Table 4), however, a statistically significant Severe 7.8 6.6 higher rate of bleeding incidence at 5-years follow-up was observed Thrombus present 3.7 3.9 .93 in BP-SES arm (Table 5). Finally, the analysis of possible predictors of Bifurcation 14.8 10.7 .09 TLF, including diabetes, Charlson comorbidity index, Syntax score, and CTO 2.2 0.3 .02 complete versus incomplete revascularization of the coronary tree is ACC/AHA classification .14 shown in Figure 5. The risk of TLF after treatment with BP-SES com- A 3.5 2.8 pared with PP-EES did not differ across categories of these predictors B1 12.1 16.9 (p for interaction >.05). B2 48.9 49.7 C 35.6 30.7 Access site .77 4 | DISCUSSION Radial 69.8 68.4 To the best of our knowledge, the presented data represents unique clin- Femoral 28.9 30.3 ical evidence of long-term safety and efficacy of a bioresorbable polymer Brachial 1.3 1.3 coated sirolimus-eluting stent in the treatment of high risk MVD patients. Pre-dilatation 76.1 76.2 .97 This prespecified substudy of the CENTURY II randomized controlled Post-dilatation 51.0 49.5 .68 trial demonstrates a good 5-year performance, both for bioresorbable Stents implanted per patient 1.9 ± 1.0 2.0 ± 1.1 .30 (BP-SES) and permanent polymer (PP-EES) system. This is evidenced Total implanted stent 36.5 ± 20.1 37.5 ± 22.4 .93 by similarly low rates of composite clinical outcomes, like TLF (10.2 length per patient, mm vs. 13.4%; p = .29), TVF (14.2 vs. 14.7%; p = .88), cardiac death and MI Delivery success per stent 98.3 99.4 .15 (6.7 vs. 10.8%; p = .12), and POCE (27.1 vs. 34.2%; p = .10) up to 5 years Procedure success 97.3 97.8 .73 follow-up, in two study arms, respectively. Moreover, relatively low and Note. Values represent either mean ± SD or % of either per patient or per comparable TLR, TVR, cardiac death, MI, and definite or probable ST lesion calculation. rates, alongside remarkably low (0.4%) very late ST in both treatment Abbreviations: ACC/AHA, American College of Cardiology/American Heart Association; CFX, left circumflex coronary artery; CTO, chronic total arms, add to the overall excellent long-term safety and efficacy profile of occlusion; LAD, left anterior descending coronary artery; LM, left main the two investigated devices. Although in our study, we observed less coronary artery; RCA, right coronary artery. non-TVR in BP-SES versus PP-EES at both 1 year (1.8 vs. 7.4%; p = .005) and 5 years follow-up (8.4 vs. 14.3%; p = .05), this most likely reflects probable ST, both at mid- and long-term follow-up were alike the progression of coronary artery disease itself rather than the actual (Tables 4 and 5). Notably, the rate of very late ST (0.4%) was identi- difference in efficacy between the two compared devices. cal in two study arms (Table 5). The composite safety endpoints of Nowadays coronary artery stenting is increasingly being used to treat cardiac death and MI and POCE during follow-up are presented in the high-risk coronary artery disease patients. Therefore, the evidence of Figures 3 and 4. At 5-years, rate of cardiac death and MI was 6.7% safety and efficacy benefits of different new-generation DES systems is in BP-SES arm compared to 10.8% in PP-EES arm (p = .12; Table 5). needed. The clinical performance and potential benefits of bioresorbable Five-year rates of POCE were 27.1% in BP-SES versus 34.2% in and permanent (second-generation) drug-carriers has been subjected to PP-EES (p = .10; Table 5). scrutiny in numerous studies. While both systems have been shown to 180 IÑIGUEZ ET AL. TABLE 4 Clinical outcomes at 1-year follow-up TABLE 5 Clinical outcomes at 5-year follow-up BP-SES PP-EES BP-SES PP-EES n = 225 n = 231 p Value n = 225 n = 231 p Value All cause death 2.7 (6/225) 2.6 (6/231) .96 All cause death 9.3 (21/225) 10.8 (25/231) .60 Cardiac death 2.2 (5/225) 1.3 (3/231) .45 Cardiac death 4.0 (9/225) 5.2 (12/231) .54 All MI 2.7 (6/225) 3.5 (8/231) .62 All MI 3.1 (7/225) 5.6 (13/231) .19 TV-related MI 1.3 (3/225) 2.2 (5/231) .50 TV-related MI 1.3 (3/225) 2.6 (6/231) .33 Clinically indicated revascularization Clinically indicated revascularization Any revascularization 5.8 (13/225) 9.5 (22/231) .13 Any revascularization 13.3 (30/225) 13.4 (31/231) .98 TLR 2.2 (5/225) 3.9 (9/231) .30 TLR 6.2 (14/225) 6.1 (14/231) .94 TVR 4.9 (11/225) 5.2 (12/231) .88 TVR 10.2 (23/225) 7.8 (18/231) .37 Non-TVR 1.3 (3/225) 4.3 (10/231) .05 Non-TVR 4.9 (11/225) 6.9 (16/231) .36 All revascularizations All revascularizations Any revascularization 7.6 (17/225) 13.9 (32/231) .03 Any revascularization 17.8 (40/225) 22.5 (52/231) .21 TLR 3.1 (7/225) 4.3 (10/231) .49 TLR 8.4 (19/225) 6.9 (16/231) .54 TVR 6.2 (14/225) 6.9 (16/231) .76 TVR 13.3 (30/225) 11.3 (26/231) .50 Non-TVR 1.8 (4/225) 7.4 (17/231) .005 Non-TVR 8.4 (19/225) 14.3 (33/231) .05 Composite endpoints Composite endpoints TLF 5.3 (12/225) 7.8 (18/231) .29 TLF 10.2 (23/225) 13.4 (31/231) .29 TVF 8.0 (18/225) 9.1 (21/231) .68 TVF 14.2 (32/225) 14.7 (34/231) .88 Cardiac death and MI 4.9 (11/225) 4.8 (11/231) .95 Cardiac death and MI 6.7 (15/225) 10.8 (25/231) .12 POCE 12.0 (27/225) 18.2 (42/231) .07 POCE 27.1 (61/225) 34.2 (79/231) .10 Stent thrombosis Stent thrombosis Total 0.4 (1/225) 1.3 (3/231) .33 Total 0.9 (2/225) 1.7 (4/231) .43 Definite 0.4 (1/225) 1.3 (3/231) .33 Definite 0.9 (2/225) 1.7 (4/231) .43 Probable 0.0 (0/225) 0.0 (0/231) – Probable 0.0 (0/225) 0.0 (0/231) – Possible 0.0 (0/225) 0.0 (0/231) – Possible 0.0 (0/225) 0.0 (0/231) – Definite or probable 0.4 (1/225) 1.3 (3/231) .33 Definite or probable 0.9 (2/225) 1.7 (4/231) .43 Bleeding or vascular 8.4 (19/225) 11.7 (27/231) .25 Stent thrombosis (definite or probable) complications Acute 0.0 (0/225) 0.0 (0/231) – Any bleeding 7.6 (17/225) 9.5 (22/231) .45 Subacute 0.0 (0/225) 0.9 (2/231) .16 Bleeding BARC type 2–5 4.9 (11/225) 5.6 (13/231) .72 Late 0.4 (1/225) 0.4 (1/231) .99 Bleeding BARC type 3–5 1.8 (4/225) 1.7 (4/231) .97 Very late 0.4 (1/225) 0.4 (1/231) .99 Note. Values represent % (number); BARC, Bleeding Academic Research Bleeding or vascular 22.2 (50/225) 15.6 (36/231) .07 Consortium; MI, myocardial infarction; TLR, target lesion revascularization; complications TLF, target lesion failure, defined as composite of cardiac death, Any bleeding 19.6 (44/225) 11.7 (27/231) .02 TV-related MI and clinically indicated TLR; TV, target vessel; TVF: target vessel failure, defined as composite of cardiac death, TV-related MI and Bleeding BARC type 2–5 15.1 (34/225) 7.8 (18/231) .01 clinically indicated TVR; TVR, target vessel revascularization; POCE, Bleeding BARC type 3–5 6.7 (15/225) 2.6 (6/231) .04 patient oriented composite endpoint defined as any death, any MI and any coronary revascularization. Note. Values represent % (number); BARC, Bleeding Academic Research Consortium; MI, myocardial infarction; TLR, target lesion revascularization; TLF, target lesion failure, defined as composite of cardiac death, associate with better outcomes than first-generation DES,12,13 in recent TV-related MI and clinically indicated TLR; TV, target vessel; TVF, target vessel failure, defined as composite of cardiac death, TV-related MI and years, it has been debated if their long-term clinical performance is compa- clinically indicated TVR; TVR, target vessel revascularization; POCE, rable or different, and if distinct, in which context benefits can be achieved, patient oriented composite endpoint defined as any death, any MI and any as to provide indication for the use of one over the other system.14 coronary revascularization. To this end, a consensus is emerging that BP-DES are not inferior and, in some contexts, may even be more beneficial, than their con- comparing the performance of various BP- and PP-DES, as due to spe- temporary PP-DES counterparts. This notion, for example, includes cific design differences, they might need to be compared as separate reports of more favorable clinical outcomes of BP-DES in high-risk device entities, rather than as members of larger device families. STEMI patients.15 The caution, however, needs to be taken when Indeed, in their systematic review and network meta-analysis of IÑIGUEZ ET AL. 181 F I G U R E 2 Kaplan–Meier curves of cumulative event rates of target lesion failure (TLF) composite endpoint, up until 5-year follow-up. BP-SES, bioresorbable polymer sirolimus-eluting stent; PP-EES, permanent polymer everolimus-eluting stent [Color figure can be viewed at wileyonlinelibrary.com] 113 trials (90,584 patients), comparing the clinical performance of conclusion that both have comparable safety and efficacy profiles.17 bare metal, bioresorbable-polymer, and permanent-polymer stent Consistently, a recent 5-year follow-up reports of the COMPARE II and systems, Kang et al. concluded that not only the features of a particu- NEXT trials, in which bioresorbable polymer, biolimus-eluting Nobori lar polymeric carrier itself, but also specific stent alloy and design stent was compared to the second-generation everolimus-eluting PP- aspects, as well as the strut thickness and the used drug, all combined, DES, found no significant differences in relevant safety and efficacy may determine the safety of a particular DES system.16 endpoints, neither at short nor at mid- to long-term follow-up.18,19 A short bio-resorption time of the drug-eluting polymer, following While these findings raise questions, whether expected long-term stent implantation, should theoretically provide benefits in terms of late safety benefits of the BP-DES over PP-DES devices are indeed achiev- adverse safety events. Nevertheless, a recent meta-analysis of 16 ran- able, further independent trials are needed to evaluate their perfor- domized clinical trials (19,886 patients), comparing safety and efficacy mance, not only in general, but also in specific, more demanding patient of BP-DES and the second-generation PP-DES systems, reached a populations. F I G U R E 3 Kaplan–Meier curves of cumulative event rates of cardiac deaths and myocardial infarction (MI) composite endpoint, up until 5-year follow-up. BP-SES, bioresorbable polymer sirolimus- eluting stent; PP-EES, permanent polymer everolimus-eluting stent [Color figure can be viewed at wileyonlinelibrary.com] 182 IÑIGUEZ ET AL. F I G U R E 4 Kaplan–Meier curves of cumulative event rates of patient- oriented composite endpoint (POCE), up until 5-year follow-up. BP-SES, bioresorbable polymer sirolimus-eluting stent; PP-EES, permanent polymer everolimus-eluting stent [Color figure can be viewed at wileyonlinelibrary.com] To this end, it is known that treatment of MVD patients poses a sig- warrant further investigation through dedicated, sufficiently powered nificant challenge for the contemporary PCI practice, as they associate trials. Overall, the present study adds to the numerous published with worse clinical prognosis. Findings of the present study demon- evidence from recent years on excellent performance of Ultimaster strate excellent mid- to long-term safety and efficacy of the studied (BP-SES) system. This includes reports of favorable outcomes in general8,9 Ultimaster DES in terms of several key clinical outcomes. This data and specific subpopulations, like STEMI patients,21 bifurcations,22 complements earlier findings of the DISCOVERY 1TO3 trial, where long lesions,23 and small vessels.24 60 MVD patients were treated with the same DES and nearly complete Our analysis of TLF predictors implies that patient, lesion, and pro- strut coverage was noted very early after the initial stent implantation cedural complexity exert little impact on TLF in the studied context (within 1–3 months).20 This positive biological response implied a (Figure 5). Particularly interesting is that relative risk of TLF does not possibility that Ultimaster BP-SES system could provide beneficial seem to be impacted by the decision to perform complete over clinical outcomes in this high-risk patient population. Coupled with the incomplete coronary tree revascularization. This finding is at odds hypothesis-generating findings of the present study, these observations with current trends, favoring the complete approach as the more FIGURE 5 Predictors of target lesion failure (TLF): relative risk with 95% confidence interval (CI) of TLF at 5 years. Int. p-value: p-value for interaction IÑIGUEZ ET AL. 183 optimal modus operandi. Potential explanation could be that physiolog- OR CID ical assessment of stenosis in untreated vessels was determining fac- Andrés Iñiguez https://orcid.org/0000-0002-7758-6252 tor for deferring revascularization, leading as such to similar Bernard Chevalier https://orcid.org/0000-0002-8516-8317 outcomes. Caution, however, needs to be taken with interpretation of Ran Kornowski https://orcid.org/0000-0002-7708-8253 these findings, as they derive from a relatively small study subset of Shigeru Saito https://orcid.org/0000-0001-9560-1228 patients and as such warrant further analysis. Finally, bleeding rates were comparable at 1 year follow up while a higher cumulative bleeding incidence was noted in BP-SES treated RE FE RE NCE S MVD patients at 5 years. Considering no difference in DAPT use over the 5-year follow-up period, a possible explanation can be that higher 1. Casey C, Faxon DP. Multi-vessel coronary disease and percutaneous proportion of patients with high-risk for bleeding, including prevalence coronary intervention. Heart. 2004;90:341-346. 2. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. ESC/EACTS Guidelines of oral anticoagulant users, patients with traumas, and/or comorbidities on myocardial revascularization. Eur Heart J. 2018;2019;40:87–165. was acquired through 5 years follow-up in the BP-SES group. 3. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascu- larization. N Engl J Med. 2002;346:1773-1780. 5 | LIMITATIONS 4. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315-1323. Although MVD patients did constitute a balanced, predefined sub- 5. Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implanta- group of the CENTURY II trial, this substudy was not powered to tion of first-generation drug-eluting stents: a cause for concern. Cir- demonstrate non-inferiority of BP-SES to PP-EES. Therefore, herein culation. 2007;115:1440-1455. presented results are only hypothesis-generating and future studies, 6. Luscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circula- with sufficient power, are needed to corroborate these interesting tion. 2007;115:1051-1058. findings. Also notable is that the angiographic complexity of MVD 7. Abizaid A, Costa JR Jr. New drug-eluting stents: an overview on bio- patient in this CENTURY II substudy was relatively low (with baseline degradable and polymer-free next-generation stent systems. Circ SYNTAX score between 12 and 13 for both groups). Therefore, our Cardiovasc Interv. 2010;3:384-393. 8. Saito S, Valdes-Chavarri M, Richardt G, Moreno R, et al. A random- results cannot be extrapolated to all MVD patients seen in everyday ized, prospective, intercontinental evaluation of a bioresorbable poly- practice, that are treated by either PCI or CABG. Moreover, even mer sirolimus-eluting coronary stent system: the century ii (clinical though DMC and CEC members were blinded for patients' assign- evaluation of new terumo drug-eluting coronary stent system in the ment, logistical factors prevented blinding of study personnel. While treatment of patients with coronary artery disease) trial. Eur Heart J. this factor certainly warrants caution, we believe that its impact on 2014;35:2021-2031. 9. Wijns W, Valdes-Chavarri M, Richardt G, et al. Long-term clinical out- reported findings should not be significant, as to cast doubt on the comes after bioresorbable and permanent polymer drug-eluting stent overall conclusions of the study. implantation: final five-year results of the century ii randomised clini- cal trial. EuroIntervention. 2018;14:e343-e351. 10. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions 6 | CO NC LUSIO N for cardiovascular clinical trials: a consensus report from the bleeding academic research consortium. Circulation. 2011;123:2736-2747. 11. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coro- Our study reveals, that throughout the 5-year follow-up period, nary stent trials: a case for standardized definitions. Circulation. sirolimus-eluting bioresorbable polymer Ultimaster stent (BP-SES), dis- 2007;115:2344-2351. plays similarly good long-term safety and efficacy profile as the 12. Serruys PW, Farooq V, Kalesan B, et al. Improved safety and reduc- tion in stent thrombosis associated with biodegradable polymer-based everolimus-eluting permanent polymer Xience stent (PP-EES), in the biolimus-eluting stents versus durable polymer-based sirolimus-eluting treatment of MVD patients. stents in patients with coronary artery disease: final 5-year report of the leaders (limus eluted from a durable versus erodable stent coat- ing) randomized, noninferiority trial. JACC Cardiovasc Interv. 2013;6: ACKNOWLEDGMENTS 777-789. 13. Gada H, Kirtane AJ, Newman W, et al. 5-year results of a randomized The authors would like to express their utmost gratitude to all comparison of xience v everolimus-eluting and taxus paclitaxel- CENTURY II study investigators who actively contributed in meticu- eluting stents: final results from the spirit iii trial (clinical evaluation of the xience v everolimus eluting coronary stent system in the treat- lous data collection process for this trial. ment of patients with de novo native coronary artery lesions). JACC Cardiovasc Interv. 2013;6:1263-1266. 14. Zhang YJ, Pan DR, Pang S, Wu W, Xu B. Biodegradable or biocompat- CONF LICT OF IN TE RE ST ible polymer drug-eluting stent: a gordian knot. EuroIntervention. 2015;11:250-252. Except for the research grant received within the framework of the 15. Pilgrim T, Piccolo R, Heg D, et al. Biodegradable polymer sirolimus- CENTURY II study, the authors have no conflict of interest to declare. eluting stents versus durable polymer everolimus-eluting stents for 184 IÑIGUEZ ET AL. primary percutaneous coronary revascularisation of acute myocardial 21. Valdes-Chavarri M, Kedev S, Neskovic AN, et al. Randomized evalua- infarction. EuroIntervention. 2016;12:e1343-e1354. tion of a novel biodegradable polymer-based sirolimus-eluting stent 16. Kang SH, Park KW, Kang DY, et al. Biodegradable-polymer drug- in st-segment elevation myocardial infarction: the master study. eluting stents vs. bare metal stents vs. durable-polymer drug-eluting EuroIntervention. 2018;EIJ-D-17–01087. stents: a systematic review and bayesian approach network meta- 22. Orvin K, Carrie D, Richardt G, et al. Comparison of sirolimus eluting analysis. Eur Heart J. 2014;35:1147-1158. stent with bioresorbable polymer to everolimus eluting stent with 17. El-Hayek G, Bangalore S, Casso Dominguez A, et al. Meta-analysis of permanent polymer in bifurcation lesions: results from century ii trial. randomized clinical trials comparing biodegradable polymer drug- Catheter Cardiovasc Interv. 2016;87:1092-1100. eluting stent to second-generation durable polymer drug-eluting 23. Lesiak M, Araszkiewicz A, Grajek S, et al. Long coronary lesions stents. JACC Cardiovasc Interv. 2017;10:462-473. treated with thin strut bioresorbable polymer drug eluting stent: 18. Vlachojannis GJ, Smits PC, Hofma SH, et al. Biodegradable polymer experience from multicentre randomized century ii study. J Interv biolimus-eluting stents versus durable polymer everolimus-eluting Cardiol. 2016;29:47-56. stents in patients with coronary artery disease: final 5-year report 24. Wohrle J, Markovic S, Rottbauer W, et al. Bioresorbable polymer from the compare ii trial (abluminal biodegradable polymer biolimus- sirolimus-eluting coronary stent compared with permanent polymer eluting stent versus durable polymer everolimus-eluting stent). JACC everolimus-eluting coronary stent implantation for treatment of small Cardiovasc Interv. 2017;10:1215-1221. vessel coronary artery disease: century ii trial. EuroIntervention. 19. Natsuaki M, Kozuma K, Morimoto T, et al. Five-year outcome of a 2016;12:e167-e174. randomized trial comparing second generation drug-eluting stents using either biodegradable polymer or durable polymer: The nobori biolimus-eluting versus xience/promus everolimus-eluting stent trial How to cite this article: Iñiguez A, Chevalier B, Richardt G, (next). EuroIntervention. 2018;14(7):815–818. doi: 10.4244/EIJ-D- et al. Comparison of long-term clinical outcomes in multivessel 17-01050. 20. Chevalier B, Smits PC, Carrie D, et al. Serial assessment of strut cov- coronary artery disease patients treated either with erage of biodegradable polymer drug-eluting stent at 1, 2, and bioresoarbable polymer sirolimus-eluting stent or permanent 3 months after stent implantation by optical frequency domain imag- polymer everolimus-eluting stent: 5-year results of the ing: the discovery 1to3 study (evaluation with ofdi of strut coverage CENTURY II randomized clinical trial. Catheter Cardiovasc of terumo new drug eluting stent with biodegradable polymer at 1, 2, and 3 months). Circ Cardiovasc Interv. 2017;10(12):e004801. doi: 10. Interv. 2020;95:175–184. https://doi.org/10.1002/ccd.28224 1161/CIRCINTERVENTIONS.116.004801.