Author + information
- Received February 19, 2013
- Revision received March 24, 2013
- Accepted April 16, 2013
- Published online July 16, 2013.
- Masahiro Natsuaki, MD∗,
- Ken Kozuma, MD†,
- Takeshi Morimoto, MD‡,
- Kazushige Kadota, MD§,
- Toshiya Muramatsu, MD⋮,
- Yoshihisa Nakagawa, MD¶,
- Takashi Akasaka, MD#,
- Keiichi Igarashi, MD∗∗,
- Kengo Tanabe, MD††,
- Yoshihiro Morino, MD‡‡,
- Tetsuya Ishikawa, MD§§,
- Hideo Nishikawa, MD⋮⋮,
- Masaki Awata, MD¶¶,
- Mitsuru Abe, MD##,
- Hisayuki Okada, MD∗∗∗,
- Yoshiki Takatsu, MD†††,
- Nobuhiko Ogata, MD‡‡‡,
- Kazuo Kimura, MD§§§,
- Kazushi Urasawa, MD⋮⋮⋮,
- Yasuhiro Tarutani, MD¶¶¶,
- Nobuo Shiode, MD###,
- Takeshi Kimura, MD∗∗ (, )
- on behalf of the NEXT Investigators
- ∗Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
- †Division of Cardiology, Teikyo University Hospital, Tokyo, Japan
- ‡Center for General Internal Medicine and Emergency Care, Kinki University School of Medicine, Osaka-Sayama, Japan
- §Department of Cardiology, Kurashiki Central Hospital, Kurashiki, Japan
- ⋮Division of Cardiology, Saiseikai Yokohama-City Eastern Hospital, Yokohama, Japan
- ¶Division of Cardiology, Tenri Hospital, Tenri, Japan
- #Department of Cardiovascular Medicine, Wakayama Medical University Hospital, Wakayama, Japan
- ∗∗Division of Cardiology, Hokkaido Social Insurance Hospital, Sapporo, Japan
- ††Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan
- ‡‡Division of Cardiology, Iwate Medical University Hospital, Morioka, Japan
- §§Division of Cardiology, Saitama Cardiovascular and Respiratory Center, Kumagaya, Japan
- ⋮⋮Division of Cardiology, Mie Heart Center, Mie, Japan
- ¶¶Division of Cardiology, Kansai Rosai Hospital, Amagasaki, Japan
- ##Division of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
- ∗∗∗Division of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
- †††Division of Cardiology, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan
- ‡‡‡Division of Cardiology, Tokai University Hospital, Isehara, Japan
- §§§Division of Cardiology, Yokohama City University Medical Center, Yokohama, Japan
- ⋮⋮⋮Division of Cardiology, Caress Sapporo Tokeidai Memorial Hospital, Sapporo, Japan
- ¶¶¶Division of Cardiology, Okamura Memorial Hospital, Shizuoka, Japan
- ###Division of Cardiology, Tsuchiya General Hospital, Hiroshima, Japan
- ↵∗Reprint requests and correspondence:
Dr. Takeshi Kimura, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto, Japan, 606-8507.
Objectives NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) was designed for evaluating the noninferiority of a biolimus-eluting stent (BES) relative to an everolimus-eluting stent (EES) in terms of target lesion revascularization (TLR) at 1 year.
Background Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited.
Methods The NEXT trial is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BES with EES. Between May and October 2011, 3,235 patients were randomly assigned to receive either BES (n = 1,617) or EES (n = 1,618).
Results At 1 year, the primary efficacy endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group, demonstrating noninferiority of BES relative to EES (p for noninferiority <0.0001, and p for superiority = 0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% vs. 0.06%, p = 0.18). An angiographic substudy enrolling 528 patients (BES: n = 263, and EES: n = 265) demonstrated noninferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03 ± 0.39 mm vs. 0.06 ± 0.45 mm, p for noninferiority <0.0001, and p for superiority = 0.52) at 266 ± 43 days after stent implantation.
Conclusions One-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and extremely low rate of stent thrombosis.
(NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial [NEXT]; NCT01303640)
Drug-eluting stents (DES) using biodegradable polymers have been designed to overcome the long-term adverse vascular reactions related to the durable polymer. The NOBORI biolimus-eluting stent (BES) (Terumo, Tokyo, Japan) is a stainless steel alloy stent with relatively thick strut (120 μm) using an abluminally coated biodegradable polymer (polylactic acid) eluting biolimus A9, a highly lipophilic analogue of sirolimus. An alternative direction in developing DES with fewer long-term adverse vascular reactions was the use of a more biocompatible durable polymer. A recent network meta-analysis demonstrated that a second-generation cobalt-chromium everolimus-eluting stent (EES) using a biocompatible durable polymer (fluorinated copolymer) with thin strut (81 μm) was associated with a markedly lower risk for 1-year stent thrombosis (ST) as compared with both bare-metal stents and the first-generation DES, indicating that cobalt-chromium EES should be regarded as the current standard for the DES-versus-DES trials (1). Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited (2).
Therefore, we designed a large-scale randomized trial comparing BES with EES powered to evaluate noninferiority in terms of efficacy outcomes.
NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) is a prospective, multicenter, randomized, assessor-blind, noninferiority trial comparing BES with EES in Japan. Patients scheduled for percutaneous coronary intervention (PCI) using DES among 98 participating centers (List A in the Online Appendix) were to be enrolled without any exclusion criteria.
Patients were randomly assigned to undergo PCI with either BES or EES. Randomization was performed by a web-based allocation system and was stratified by center, diabetic status, and participation in the imaging substudies (angiography, intravascular ultrasound, optical coherence tomography, and coronary endothelial function). The study-group assignments were blinded to the statistician, members of the independent clinical events committee, steering committee, clinical research organization (Research Institute for Production Development, Kyoto, Japan), angiographic core laboratory (Cardiocore, Tokyo, Japan), and the sponsor (Terumo Japan) (List B in the Online Appendix).
The study protocol was approved by the institutional review board at each participating center. Written informed consent was obtained from all the study patients.
Details of the study procedures and follow-up are described in the Online Methods. Recommended antiplatelet regimen was aspirin (≥81 mg daily) indefinitely and thienopyridine (75-mg clopidogrel daily or 200-mg ticlopidine) for at least 3 months. Duration of dual antiplatelet therapy was left to the discretion of each attending physician. Status of antiplatelet therapy was evaluated throughout the follow-up period as previously described (3). Persistent discontinuation of thienopyridine was defined as withdrawal lasting at least 2 months.
The primary efficacy endpoint was any target lesion revascularization (TLR) at 1 year, whereas the primary safety endpoint was a composite of death or myocardial infarction (MI) at 3 years. All the angiograms of patients with target vessel revascularization (TVR) were to be analyzed by the angiographic core laboratory in an attempt to adjudicate TLR accurately. Primary endpoint events were adjudicated by the independent and blinded clinical event committee. Other endpoints and the definitions of the endpoints are described in the Online Methods.
Angiographic substudy and quantitative coronary angiography
Qualitative and quantitative coronary angiography was centrally evaluated at 1 angiographic core laboratory with use of CAAS version 5.9 (Pie Medical Imaging, Maastricht, the Netherlands). In patients enrolled in the angiographic substudy, follow-up angiography was to be performed between 240 days and 365 days after the index PCI procedure. Follow-up angiography based on local site protocol was also allowed. The primary endpoint for the angiographic substudy was in-segment late loss. Details of the angiographic analysis are described in the Online Methods.
Categorical variables are presented as number and percentage and were compared with the chi-square test or Fisher exact test. Continuous variables were expressed as mean ± SD or medians with interquartile ranges. Continuous variables were compared using the Student t test or Wilcoxon rank sum test based on their distributions.
The trial was a noninferiority trial, which was powered for evaluating noninferiority of BES to EES on the primary efficacy endpoint at 1 year. Details on sample size calculation are described in the Online Methods.
Clinical outcomes were analyzed according to the intention-to-treat principle. Each endpoint was assessed by the Kaplan-Meier method and compared by log-rank test. Effect of treatment was compared by Cox proportional hazard model, and was expressed as hazard ratios with 95% confidence intervals.
All statistical analyses were performed by a physician (M.N.) and a statistician (T. Morimoto) with the use of JMP version 10.0 (SAS Institute, Cary, North Carolina) and SAS version 9.2 (SAS Institute). All reported p values were 2-sided, and p values <0.05 were regarded as statistically significant except for the noninferiority testing. One-sided p values <0.025 were considered statistically significant to attest noninferiority.
Characteristics of patients and revascularization procedures
Between May and October 2011, a total of 3,241 patients (35%) were enrolled in the trial among 9,342 patients who underwent PCI using DES in the participating centers during the enrollment period. Excluding 6 patients who withdrew consent, 3,235 patients were randomly assigned to receive either BES (n = 1,617) or EES (n = 1,618) (Fig. 1).
The study population included large numbers of patients with advanced age, diabetes, multivessel coronary artery disease, and prior PCI, and significant numbers of patients with heart failure, hemodialysis, left main coronary artery disease, small-vessel disease, chronic total occlusion, and bifurcation lesions, whereas the prevalence of patients with acute MI and high SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) scores was low. The 2 groups of patients were generally well balanced in terms of baseline clinical and lesion characteristics (Tables 1 and 2⇓⇓).
The acute device success and patient success rates were very high and comparable between the BES and EES groups (Table 2).
Complete 1-year follow-up was achieved in 3,209 patients (99.2%) (Fig. 1). A large proportion of patients continued dual antiplatelet therapy at 1 year (Fig. 2). Follow-up angiography was performed in 2,103 patients (65%) within the first year.
The primary endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group (p = 0.93). The difference in the rate of TLR between the BES and EES groups was 0.07% (95% CI: −2.0% to 1.5%), demonstrating noninferiority of BES to EES in terms of TLR with a noninferiority margin of 3.4% (p for noninferiority <0.0001). Cumulative incidences of clinically driven TLR and TVR were also not significantly different between the 2 groups (Table 3, Fig. 3). The angiographic core laboratory evaluated the angiograms at the time of events in 170 patients (83%) of 204 patients with reported TVR events.
For the subgroup analysis for TLR, the interaction between the treatment group and the subgroup factor was not significant for any of the pre-specified subgroup factors, and the treatment effect of BES compared with EES was not significant in any subgroups (Fig. 4).
Cumulative incidence of definite ST at 1 year was extremely low and not significantly different between the BES and EES groups (0.25% and 0.06%, p = 0.18).
We enrolled 528 patients in the angiographic substudy (Fig. 1, Online Tables 1 and 2). Follow-up angiograms were available for analysis in the angiographic core laboratory in 457 patients at 266 ± 43 days after index PCI. In-segment late loss was 0.03 ± 0.39 mm in the BES group, and 0.06 ± 0.45 mm in the EES group (p = 0.52). The difference in in-segment late loss between the 2 groups was −0.03 mm (95% CI: −0.09 to 0.05 mm), demonstrating noninferiority of BES to EES with a noninferiority margin of 0.195 mm (p for noninferiority <0.0001). In-stent late loss, binary angiographic restenosis rate, and rate of peri-stent contrast staining were also not different between the 2 groups. However, the rate of stent fracture was significantly higher in the BES group than in the EES group (Table 4, Fig. 5). Among 9 lesions with stent fracture, 4 lesions (44%) underwent TLR due to restenosis.
The main findings of the current study were the following: 1) 1-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population; and 2) 1-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and an extremely low rate of definite ST.
Although biodegradable polymer DES have been developed mainly to overcome late adverse events, it is crucially important for biodegradable polymer DES to have efficacy in preventing early restenosis at least equivalent to that of current standard DES using biocompatible durable polymer. NOBORI was designed with minimal modification of BioMatrix stent leaving ultra-thin biocompatible Parylene primer layer on top of the stent platform. NOBORI was recently evaluated in 2 randomized trials powered for clinical outcomes. The COMPARE II (Comparison of the Everolimus Eluting With the Biolimus A9 Eluting Stent) trial demonstrated noninferiority of BES relative to EES, although procedural failure of the assigned stent was significantly more frequent in the BES group (2). On the other hand, noninferiority of BES relative to a sirolimus-eluting stent was not demonstrated in the SORT-OUT V (Randomised Clinical Comparative Study of the Nobori and the Cypher Stent) (4). The current largest randomized trial comparing BES with EES powered for evaluating TLR, which could be regarded as the most appropriate efficacy measure of DES, demonstrated that BES and EES were equally effective in preventing restenosis within 1 year after PCI. Furthermore, the acute device success rate was also comparable, negating the concern on the deliverability of BES suggested in the COMPARE II trial (2). However, careful follow-up should be mandatory to investigate whether the BES group, with its higher rate of stent fracture, might be prone to late adverse events such as very late ST and late TLR.
The rate of definite ST at 1 year after BES implantation was not significantly different from that after EES implantation, although the current trial was not powered for evaluating this low-frequency event. Reported antithrombotic efficacy of fluorinated copolymer coated on EES (1,5) might not have become apparent due to very low ST rates in the current trial, which could be related to predominant inclusion of a stable coronary artery disease population and less propensity of Japanese patients for ST (3,6).
Regarding late adverse events, use of BioMatrix was clearly associated with fewer cardiac events related to very late ST in the LEADERS (Limus Eluted From A Durable Versus ERodable Stent Coating) trial, suggesting that the potential benefit of BES would only emerge at very long-term follow-up (7). Continued follow-up of the current and the COMPARE II trials (2) would shed light on the long-term outcome of biodegradable polymer BES as compared with durable polymer EES, providing crucial information for the future development of improved metallic DES.
First, patients participating in the current trial were not fully monitored, and therefore, underreporting of the adverse events, ST in particular, was possible. However, angiograms in patients with TVR were rigorously evaluated for the presence of thrombus in the angiographic core laboratory, and adjudication of death and MI events was conducted very carefully to exclude the possibility of ST. Second, despite the “all-comers” trial design, the current study patients seemed not to represent the real clinical practice as reported in other “all-comers” trials (8). Third, the actual 1-year rate of TLR was lower than expected, leading to a relatively large noninferiority margin. Finally, the high prevalence of follow-up angiography based either on the current study protocol or on the local site protocols certainly inflated the rates of TLR.
The 1-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and an extremely low rate of definite ST.
Terumo Japan is a study sponsor of the NEXT trial. Dr. Kozuma has served on the advisory boards of Abbott Vascular and Terumo; and has received lecture fees from Abott Vascular and Terumo. Dr. Kadota has received honoraria from Abott Vascular and Terumo; and has served on the advisory boards of Vascular. Dr. Tanabe served on the advisory board of Terumo Japan and Abbott Vascular. Dr. Morino has served on the advisory board of Abbott Vascular and Terumo. Dr. T. Kimura has served on the advisory board of Terumo Japan and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Natsuaki and Kozuma contributed equally to this work.
- Abbreviations and Acronyms
- biolimus-eluting stent(s)
- drug-eluting stent(s)
- everolimus-eluting stent(s)
- myocardial infarction
- percutaneous coronary intervention
- stent thrombosis
- target lesion revascularization
- target vessel revascularization
- Received February 19, 2013.
- Revision received March 24, 2013.
- Accepted April 16, 2013.
- 2013 American College of Cardiology Foundation
- Christiansen E.H.,
- Jensen L.O.,
- Thayssen P.,
- et al.
- Kolandaivelu K.,
- Swaminathan R.,
- Gibson W.J.,
- et al.
- Kimura T.,
- Morimoto T.,
- Nakagawa Y.,
- et al.,
- for the j-Cypher Registry Investigators
- Stefanini G.G.,
- Kalesan B.,
- Serruys P.W.,
- et al.