Abstract
Background
To investigate clinical outcomes of percutaneous coronary intervention using a sirolimus-eluting stent with bioresorbable polymer, Ultimaster (BP-SES) compared with a permanent polymer everolimus-eluting stent, Xience (PP-EES) in patients with high risk (ST-segment elevation and non-ST-segment elevation myocardial infarction) acute coronary syndromes (ACS) enrolled in the CENTURY II trial.
Methods
CENTURY II is a prospective, multicenter, randomized, single blind, controlled trial comparing BP-SES and PP-EES, with primary endpoint of target lesion failure (TLF) at 9 month post-stent implantation. Out of 1123 patients enrolled in CENTURY II trial, 264 high risk ACS patients were included in this subgroup analysis, and the clinical outcomes including target lesion failure (TLF), target vessel failure (TVF), cardiac death, myocardial infarction, and stent thrombosis were evaluated at 24 months.
Results
The baseline clinical, angiographic and procedural characteristics were similar between two groups. At 24 months, TLF occurred in 6.3% of patients receiving a BP-SES and 6.5% of patients receiving a PP-EES (P = 0.95); TVF was 6.3% in patients receiving a BP-SES and 9.4% in patients receiving a PP-EES (P = 0.36). There were no significant differences in cardiac death, myocardial infarction and stent thrombosis rate.
Conclusions
BP-SES achieved similar safety and efficacy outcomes as PP-EES in this ACS subgroup of CENTURY II study, at 24-month follow-up. This finding is hypothesis-generating and needs to be confirmed in larger trials with longer follow-up.
Highlights
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This study reported the 24-month clinical outcomes of new-generation BP-SES compared with PP-EES in ACS subgroup from CENTURY II study.
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This is a pre-specified subgroup analysis of a large randomized, prospective, multicenter clinical trial.
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The BP-SES showed good and comparable clinical performance as PP-EES at 24 months.
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This substudy has a relatively small sample size and does not have sufficient power to draw definite conclusions, therefore should be considered as hypothesis generating.
1
Introduction
Late stent thrombosis (ST) and late stent restenosis have been associated with a chronic inflammatory vessel response induced by components of the permanent polymer matrix . This inflammatory process results in delayed arterial healing and hypersensitivity reactions, and has been demonstrated in histopathological studies of first-generation drug-eluting stents (DES) . The availability and use of DES with a bioresorbable polymer (BP) could overcome these drawbacks, providing safety and benefits in different clinical settings, including stable coronary artery disease (CAD) and acute coronary syndromes (ACS).
The safety and effectiveness of BP-based DES over bare metal stents (BMS) and first-generation DES has been proven previously in reducing the risk of very late ST and restenosis . Patients with ACS constitute a challenging subset with poorer outcomes after percutaneous coronary interventions (PCI) as compared to stable CAD, with an increased risk of ST and reinfarction. Therefore, the potential benefits of a BP-based DES in patients with ACS are important, but its efficacy and safety remains to be confirmed.
In the CENTURY II (Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease) trial, a sirolimus-eluting stent with BP, Ultimaster (BP-SES) showed safety and efficacy profiles similar to permanent polymer everolimus-eluting stent (PP-EES) at 9-month follow-up .
To date, there are few data regarding the comparison of the current gold-standard generation DES with the BP-SES in patients with high-risk ACS, including ST-segment elevation myocardial infarction (STEMI) and non-STEMI patients (NSTEMI). We present the analysis of a subgroup of patients with high risk ACS treated with BP-SES or PP-EES in the CENTURY II trial.
2
Methods
2.1
Study design
The CENTURY II study design and study devices have been described in detail in a previous publication . In brief, CENTURY II is a prospective, multicenter, randomized (1:1), single blind, controlled, non-inferiority, two-arm trial of BP-SES (Ultimaster DES, Terumo Corporation, Tokyo, Japan) and PP-EES (Xience DES, Abbott Vascular, Santa Clara, California, USA). Patients aged ≥ 18 years, with clinical evidence of ischemic heart disease and/or a positive functional study, good candidates for PCI using DES and acceptable candidates for CABG with reference vessel diameter between ≥ 2.5 mm and ≤ 4.0 mm were included in the study. A complete description of exclusion criteria is listed in Supplementary Appendix.
The global study included 1123 patients in 58 participating centers from Europe, Japan, and Korea, from February 2012 to January 2013. The current study included all patients with high-risk ACS (STEMI and NSTEMI). This ACS subgroup was prespecified in the protocol. Except for Japan (15 sites), and South Korea (1 site), all European centers (42 sites in 11 European countries) enrolled patients with high risk ACS (complete list in supplementary appendix). The study was approved by the institutional review committee at each participating center and all patients provided written informed consent.
2.2
Procedures
PCI were performed according to standard hospital practice. Patients were randomly assigned (1:1) to receive either BP-SES or PP-EES. Randomization of patients was stratified by general inclusion and exclusion criteria and balanced for diabetes mellitus, ACS (STEMI and NSTEMI) and multivessel disease. All further procedures (lesion pre-dilation, stenting or post-stenting dilation, usage of imaging modalities for result optimization or glycoprotein (GP) IIb/IIIa inhibitors) were left at operator’s discretion. Dual antiplatelet therapy (DAPT) prescription was according to hospital practice in all patients, with a duration for at least 6 months as per protocol recommendation. DAPT beyond 6 months was at the discretion of the treating physician considering prevailing guidelines . All patients were to be followed up at 1, 4, and 9 months and yearly up to 5 years.
2.3
Endpoints and definitions
The primary endpoint of CENTURY II study was target lesion failure (TLF), a device-oriented composite endpoint (cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization [TLR]) at 9 months post-stent implantation. Secondary endpoints were: (i) rate of target vessel failure (TVF) defined as composite of cardiac death and MI not clearly attributable to a non-target vessel, and clinically driven target vessel revascularization (TVR); (ii) patient-oriented composite endpoint (POCE) composed of all deaths, all MI and all coronary revascularizations; (iii) rate of TLR, TVR, ST, cardiac death, and MI; (iv) composite of cardiac death and MI; and (v) rate of bleeding and vascular complications according to Bleeding Academic Research Consortium (BARC) definitions . The endpoints were defined as per Academic Research Consortium (ARC) recommendations .
2.4
Angiographic analysis
All angiograms were assessed by an independent core laboratory (K.I.C. Co. Ltd, Kanagawa, Japan) using dedicated software (qAngio XA ver. 7.1, Medis, the Netherlands). Main angiographic parameters at baseline were minimum lumen diameter (MLD) before and after procedure, percentage diameter stenosis (DS%), and acute gain (defined as the change in MLD from baseline to the final procedural angiogram).
2.5
Statistical analysis
The statistical analysis plan has previously been published . The CENTURY II randomized trial was powered for non-inferiority of BP-SES compared with PP-EES for the primary endpoint of 9-month TLF. The Kaplan–Meier method was used to estimate event rates for time-to event outcomes, and data were compared with the log-rank test. All analyses were carried out using the SAS software, version 9.1 (SAS Institute, Inc., Cary, NC, USA).
2
Methods
2.1
Study design
The CENTURY II study design and study devices have been described in detail in a previous publication . In brief, CENTURY II is a prospective, multicenter, randomized (1:1), single blind, controlled, non-inferiority, two-arm trial of BP-SES (Ultimaster DES, Terumo Corporation, Tokyo, Japan) and PP-EES (Xience DES, Abbott Vascular, Santa Clara, California, USA). Patients aged ≥ 18 years, with clinical evidence of ischemic heart disease and/or a positive functional study, good candidates for PCI using DES and acceptable candidates for CABG with reference vessel diameter between ≥ 2.5 mm and ≤ 4.0 mm were included in the study. A complete description of exclusion criteria is listed in Supplementary Appendix.
The global study included 1123 patients in 58 participating centers from Europe, Japan, and Korea, from February 2012 to January 2013. The current study included all patients with high-risk ACS (STEMI and NSTEMI). This ACS subgroup was prespecified in the protocol. Except for Japan (15 sites), and South Korea (1 site), all European centers (42 sites in 11 European countries) enrolled patients with high risk ACS (complete list in supplementary appendix). The study was approved by the institutional review committee at each participating center and all patients provided written informed consent.
2.2
Procedures
PCI were performed according to standard hospital practice. Patients were randomly assigned (1:1) to receive either BP-SES or PP-EES. Randomization of patients was stratified by general inclusion and exclusion criteria and balanced for diabetes mellitus, ACS (STEMI and NSTEMI) and multivessel disease. All further procedures (lesion pre-dilation, stenting or post-stenting dilation, usage of imaging modalities for result optimization or glycoprotein (GP) IIb/IIIa inhibitors) were left at operator’s discretion. Dual antiplatelet therapy (DAPT) prescription was according to hospital practice in all patients, with a duration for at least 6 months as per protocol recommendation. DAPT beyond 6 months was at the discretion of the treating physician considering prevailing guidelines . All patients were to be followed up at 1, 4, and 9 months and yearly up to 5 years.
2.3
Endpoints and definitions
The primary endpoint of CENTURY II study was target lesion failure (TLF), a device-oriented composite endpoint (cardiac death, MI not clearly attributable to a non-target vessel, and clinically driven target lesion revascularization [TLR]) at 9 months post-stent implantation. Secondary endpoints were: (i) rate of target vessel failure (TVF) defined as composite of cardiac death and MI not clearly attributable to a non-target vessel, and clinically driven target vessel revascularization (TVR); (ii) patient-oriented composite endpoint (POCE) composed of all deaths, all MI and all coronary revascularizations; (iii) rate of TLR, TVR, ST, cardiac death, and MI; (iv) composite of cardiac death and MI; and (v) rate of bleeding and vascular complications according to Bleeding Academic Research Consortium (BARC) definitions . The endpoints were defined as per Academic Research Consortium (ARC) recommendations .
2.4
Angiographic analysis
All angiograms were assessed by an independent core laboratory (K.I.C. Co. Ltd, Kanagawa, Japan) using dedicated software (qAngio XA ver. 7.1, Medis, the Netherlands). Main angiographic parameters at baseline were minimum lumen diameter (MLD) before and after procedure, percentage diameter stenosis (DS%), and acute gain (defined as the change in MLD from baseline to the final procedural angiogram).
2.5
Statistical analysis
The statistical analysis plan has previously been published . The CENTURY II randomized trial was powered for non-inferiority of BP-SES compared with PP-EES for the primary endpoint of 9-month TLF. The Kaplan–Meier method was used to estimate event rates for time-to event outcomes, and data were compared with the log-rank test. All analyses were carried out using the SAS software, version 9.1 (SAS Institute, Inc., Cary, NC, USA).
3
Results
3.1
Patient characteristics
Out of 1123 patients enrolled in CENTURY II, 264 were high risk ACS patients which were randomly assigned to receive BP-SES (n = 126) or PP-EES (n = 138). Mean age was 63.7 years, 82.2% were male, and 23.4% were diabetic patients. In this subgroup, 23.1% were STEMI patients while 76.9% were NSTEMI patients ( Fig. 1 ). Baseline demographic and clinical characteristics did not significantly differ between two study groups ( Tables 1 and 2 ).
| Total HR-ACS n = 264 | BP-SES n = 126 | PP-EES n = 138 | P value | |
|---|---|---|---|---|
| Age, (years) | 63.7 ± 11.3 | 63.1 ± 11.3 | 64.3 ± 11.4 | 0.45 |
| Male gender, % (n) | 82.2% (217) | 79.3% (100) | 84.7% (117) | 0.25 |
| Clinical presentation | ||||
| STEMI, % (n) | 23.1% (61) | 23.0% (29) | 23.1% (32) | 0.97 |
| NSTEMI, % (n) | 76.8% (203) | 76.9% (97) | 76.8% (106) | 0.97 |
| Diabetes mellitus | 23.4% (62) | 25.4% (32) | 21.7% (30) | 0.48 |
| Insulin-treated, % (n) | 4.1% (11) | 5.5% (7) | 2.8% (4) | 0.38 |
| Hypertension, % (n) | 58.0% (152) | 58.8% (73) | 57.2% (79) | 0.79 |
| Dyslipidemia, % (n) | 51.9% (133) | 48.3% (59) | 55.2% (74) | 0.27 |
| Current smoking, % (n) | 36.5% (95) | 39.0% (48) | 34.3% (47) | 0.43 |
| Previous MI, % (n) | 33.3% (88) | 31.7% (40) | 34.7% (48) | 0.60 |
| Previous PCI, % (n) | 21.5% (57) | 21.4% (27) | 21.7% (30) | 0.95 |
| Multivessel disease | 50.3% (133) | 47.6% (60) | 52.9% (73) | 0.39 |
| LVEF, % | 56.3 ± 11.3 | 55.7 ± 11.5 | 56.9 ± 11.1 | 0.63 |
| Killip classification | 0.44 | |||
| Class 1, % (n) | 85.2% (52) | 82.7% (24) | 87.5% (28) | |
| Class 2, % (n) | 13.1% (8) | 13.7% (4) | 12.5% (4) | |
| Class 3–4, % (n) | 1.6% (1) | 3.4% (1) | 0.0% (0) | |
| Complexity of CAD | ||||
| ≥ 1 lesion > 20mm, % (n) | 46.7% (123) | 50.0% (63) | 43.8% (60) | 0.31 |
| ≥ 1 bifurcation, % (n) | 12.5% (33) | 11.9% (15) | 13.0% (18) | 0.78 |
| Left main, % (n) | 1.5% (4) | 0.7% (1) | 2.1% (3) | 0.36 |
| Total occlusion, % (n) | 14.3% (38) | 11.9% (15) | 16.6% (23) | 0.27 |
| Syntax score | 9.7 ± 6.5 | 9.2 ± 6.0 | 10.3 ± 6.9 | 0.25 |
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