Author + information
- Received November 4, 2016
- Accepted November 17, 2016
- Published online March 6, 2017.
- Jens Wiebe, MDa,b,
- Oliver Dörr, MDa,
- Hanna Ilstada,
- Oliver Husser, MD, PhDb,
- Christoph Liebetrau, MDc,
- Niklas Boeder, MDa,
- Timm Bauer, MDa,
- Helge Möllmann, MDc,
- Adnan Kastrati, MDb,
- Christian W. Hamm, MDa,c and
- Holger M. Nef, MDa,∗ ()
- aUniversity of Giessen, Medizinische Klinik I, Department of Cardiology, Giessen, Germany
- bDeutsches Herzzentrum München, Munich, Germany
- cKerckhoff Heart and Thorax Center, Department of Cardiology, Bad Nauheim, Germany
- ↵∗Address for correspondence:
Dr. Holger M. Nef, University of Giessen, Medizinische Klinik I, Department of Cardiology, Klinikstraße 33, 35392 Giessen, Germany.
Objectives The purpose of this study was to compare the 1-year outcome of everolimus-eluting bioresorbable scaffolds (eBRS) and Novolimus-eluting bioresorbable scaffolds (nBRS) in patients undergoing percutaneous coronary intervention in a real-life clinical practice scenario.
Background eBRS and nBRS are available and have been proved safe for coronary artery stenting in well-selected patients.
Methods Consecutive patients who underwent bioresorbable scaffold implantation were evaluated retrospectively via 2:1 propensity matching. Target lesion failure comprising cardiac death, target vessel myocardial infarction, and target lesion revascularization was examined after 12 months, along with its individual components as well as scaffold thrombosis.
Results A total 506 patients were available for matching. Of these, 212 eBRS patients (mean age = 62.9 years) and 106 nBRS patients (mean age = 63.1 years) were analyzed after matching. Baseline characteristics and clinical presentation were comparable in both groups. Acute coronary syndromes were present in 53.3% of the eBRS group and in 48.1% of the nBRS group (p = 0.383). Lesion characteristics were also similar. Pre-dilation (99.5% vs. 98.1%; p = 0.218) and post-dilation (84.4% vs. 86.8%; p = 0.576) were performed in the same proportion of matched eBRS and nBRS patients, respectively. The 1-year rates of target lesion failure (4.7% vs. 4.5%; p = 0.851), target lesion revascularization (2.6% vs. 3.5%; p = 0.768), cardiac death (1.5% vs. 2.0%; p = 0.752), and definite scaffold thrombosis (2.0% vs. 1.0%; p = 0.529) did not differ significantly between the eBRS and nBRS groups.
Conclusions The present study reveals comparable clinical results for the 2 types of bioresorbable scaffolds when used during routine practice, but further evidence from randomized controlled trials is needed.
Bioresorbable scaffolds (BRS) have entered routine clinical practice with good reason, as they have demonstrated similar clinical outcomes compared with drug-eluting metal stents (DES) and noninferiority regarding antirestenotic efficiency (1–4). In addition, several positive effects related to their dissolving character have been observed, including late luminal enlargement and the restoration of vessel vasomotion (5,6). Several different materials and types of BRS are currently under investigation, with poly-L-lactic acid (PLLA) providing the most common basis. At present, 2 PLLA-based BRS are commercially available in Europe: an everolimus-eluting BRS (eBRS) (Absorb Bioresorbable Vascular Scaffold, Abbott Vascular, Santa Clara, California) and a Novolimus-eluting BRS (nBRS) (DESolve scaffold, Elixir Medical, Sunnyvale, California) (7). Both are degraded via hydrolysis and the Krebs cycle into carbon dioxide and water. The 2 BRS share several mechanical characteristics, including a strut thickness of approximately 150 μm. In addition to the eluted drug, however, there are slight differences in design and mechanical properties that could potentially have an impact on procedural and clinical outcomes.
The most widely investigated BRS is the eBRS, and several studies that were carried out mostly with selected patients have been reported. A recent meta-analysis demonstrated that target lesion revascularization (TLR) occurs in 2.7% of patients after 1 year, which is comparable with the incidence with DES (8). nBRS were evaluated in a prospective, single-arm study that showed a TLR rate of 3.3% after 1 year (9). A direct comparison of the 2 BRS types is presently not available, however, and there is also a lack of data on the use of these devices in everyday clinical practice. Therefore, the aim of the present analysis was to make a direct comparison of the procedural performance and clinical results of eBRS and nBRS during routine clinical practice.
All consecutive patients treated with either the eBRS or nBRS at the University Hospital of Giessen, Germany, between October 2012 and December 2015 were evaluated. The nBRS has been available for implantation since March 2014. Patients were included in a local registry, the German-Austrian ABSORB Registry or the DESolve post-market registry. All of these studies were approved by the ethics board of Justus Liebig University of Giessen, Germany. General criteria for BRS implantation were any evidence of myocardial ischemia, including electrocardiographic findings, cardiac enzymes, and symptoms; reference vessel diameter between 2.3 and 4.0 mm; age ≥18 years; and the absence of contraindications to dual-antiplatelet therapy (DAPT) or scaffold components. Because of evidence of a learning curve, which has been previously described, the first 100 patients treated with the eBRS were excluded from this investigation (10). A learning curve was not observed for the patients treated with the nBRS (Online Table 1). Furthermore, only patients undergoing single-vessel intervention during the index procedure were considered for propensity matching. The study flowchart is displayed in Figure 1.
The eBRS consists of a backbone with zigzag hoops and bridges and is composed of PLLA. It has an elution containing poly-D-L-lactic acid and 100 μg/cm2 anti-inflammatory everolimus in a 1:1 ratio. The struts are approximately 150 μm thick, leading to a crossing profile of 1.4 mm. Radiopaque markers are located at both ends. Full dissolution is achieved within 2 to 3 years (11). Three different diameters (2.5, 3.0, and 3.5 mm) and 5 different lengths (8, 12, 18, 23, and 28 mm) are available.
The nBRS scaffold has a PLLA backbone of tubular hoops connected by bridges, and its elution is the anti-inflammatory drug Novolimus at 5 μg/mm scaffold length. Strut thickness is approximately 150 μm, and the crossing profile is 1.4 mm. Both ends have radiopaque markers for visualization. The degradation process takes approximately 1 to 2 years. Presently, 4 different diameters (2.5, 3.0, 3.25, and 3.5 mm) and 3 different lengths (14, 18, and 28 mm) are available. The nBRS has 2 unique features: overexpansion up to 0.5 mm above nominal is possible without an inherent risk for strut fracture, leading to a wider safety margin. The nBRS is also able to self-correct for minor malapposition, because it can expand to the nominal diameter in cases of underdeployment.
Implantation of BRS was performed primarily via radial access, if feasible. Periprocedural unfractionated heparin (5,000 IU) and 500 mg aspirin were administered. Pre-dilation was mandatory and post-dilation was highly recommended, but the decision to use the latter was ultimately left to the implanting physician’s discretion.
The type of post-procedural DAPT was prescribed according to the patient’s clinical presentation and current guidelines (12). Because of limited evidence regarding DAPT duration and BRS, DAPT was prescribed for 12 months in all patients.
Baseline examination and follow-up
Baseline testing included documentation of medical history and medications, physical examination, 12-lead electrocardiography, and laboratory testing. Patients were followed-up via telephone and standardized questionnaires or office visits.
Endpoints of interest were a patient-oriented endpoint (major adverse cardiac events [MACE]), which included TLR, myocardial infarction, or cardiac death, and a device-oriented composite endpoint (target lesion failure [TLF]), which included target vessel myocardial infarction, clinically driven surgical or percutaneous TLR, or death of cardiac cause. Further parameters of interest were target vessel failure, comprising target vessel revascularization, target vessel myocardial infarction, and cardiac death, all components of the composite endpoints, and definite scaffold thrombosis according to Academic Research Consortium criteria (13).
Categorical variables are presented as numbers and percentages and were compared using the chi-square test, whereas continuous variables are displayed as mean ± SD and were compared using the Student t test. All tests were 2- tailed, and a p value <0.05 was considered to indicate statistical significance. Event rates are presented as Kaplan-Meier estimates with 95% confidence intervals. Both groups were analyzed separately and by propensity matching. Propensity matching was performed with R version 2.3 (R Foundation for Statistical Computing, Vienna, Austria) and the MatchIt package in a 2-to-1 nearest neighbor method. Thus, 2 control subjects (eBRS) for each treatment subject (nBRS) were identified. Baseline characteristics (age, sex, history of myocardial infarction, percutaneous coronary intervention, bypass surgery, hypertension, diabetes, insulin-dependent diabetes, hypercholesterolemia, smoking, family history, clinical presentation) as well as angiographic characteristics (lesion type, lesion classification according to the American College of Cardiology and American Heart Association, mean reference vessel diameter, mean lesion length) and procedure-related factors (pre-dilation, post-dilation) were used as matching criteria. To identify predictors of TLF, a univariate analysis of baseline clinical characteristics, lesion characteristics, and procedural findings was performed first. Then a multivariate logistic regression model considering age, sex, diabetes, acute coronary syndrome, complex lesion morphology, post-dilation, and predictors of TLF in the univariate analysis was applied to identify independent predictors of TLF and to calculate the hazard ratio and the 95% confidence interval.
A total of 400 eBRS and 106 nBRS patients were found to be eligible for matching. There was a significantly higher incidence of acute coronary syndromes (64.3% vs. 48.1%; p = 0.002) in the eBRS group at hospital admission. Accordingly, more eBRS patients underwent catheterization for ST-segment elevation myocardial infarction (29.0% vs. 17.0%; p = 0.013) and fewer for stable coronary artery disease (33.3% vs. 48.1%; p = 0.005) than patients in the nBRS group. Ostial lesions were less common (1.8% vs. 7.5%; p = 0.002) in the eBRS group, and post-dilation was performed less often (78.0% vs. 86.8%; p = 0.045). An overview of the unmatched baseline characteristics is shown in Table 1.
After propensity matching, a total of 212 eBRS patients with a mean age of 62.9 years and 106 nBRS patients with a mean age of 63.1 years were used for further analysis. There were no relevant differences found in the baseline characteristics following matching. The proportions of patients with acute coronary syndromes (53.3% vs. 48.1%), ST-segment elevation myocardial infarctions (19.3% vs. 17.0%), non–ST-segment elevation myocardial infarctions (18.9% vs. 18.9%), and stable angina (43.4% vs. 48.1%) were comparable in the 2 matched groups. Complex lesions occurred in 47.6% of the eBRS group and in 44.3% in the nBRS group. The visually estimated reference vessel diameter and lesion length were 2.67 ± 0.53 mm and 12.9 ± 0.4 mm in the eBRS group and 2.73 ± 0.49 mm and 12.4 ± 8.8 mm in the nBRS group, respectively. A summary of the baseline characteristics can be found in Table 1.
General procedural parameters (duration of the procedure, amount of contrast agent, radiation time) did not differ between the 2 groups. Pre- and post-dilation were performed in almost every case. Furthermore, the applied pressures for pre-dilation (14.4 ± 3.6 atm vs. 14.1 ± 3.8 atm; p = 0.567) and post-dilation (14.0 ± 7.2 atm vs. 14.0 ± 6.9 atm; p = 0.982) were comparable, as were the implanted total device lengths (26.7 ± 14.1 mm vs. 28.7 ± 17.6 mm; p = 0.310). Intravascular imaging (intravascular ultrasound or optical coherence tomography), however, was used less often in the eBRS group (35.9% vs. 51.9%; p < 0.001). There was no statistically relevant difference in the post-procedural antiplatelet and anticoagulant medication. Further procedural details are listed in Table 2.
Clinical outcomes after 1 year
Follow-up data were available for nearly every patient in the eBRS and nBRS groups (95.8% vs. 94.3%; p = 0.575). In general, there were no relevant differences found in the clinical outcomes after 1 year. The rates of MACE and TLF were 5.8% versus 4.5% (p = 0.602) and 4.7% versus 4.5% (p = 0.861) for the eBRS versus nBRS groups, respectively (Figure 2). After 1 year, the scaffold thrombosis rates were 2.0% and 1.0% (p = 0.529), and 1.5% or 2.0% of the patients with implanted eBRS or nBRS, respectively, died of cardiac causes. All reported cases of scaffold thrombosis were definite. There were 2 subacute scaffold thromboses noted in the eBRS group (after 4 and 17 days) and 1 in the nBRS group (after 7 days). Two further late scaffold thromboses were noted in the eBRS group (after 38 and 77 days). Further details of the follow-up results are presented in Table 3. In addition, no differences regarding clinical outcomes were found between the unmatched groups, as well as when comparing the results of the last 106 eBRS patients versus the 106 nBRS patients (Online Tables 2 to 4). In a univariate analysis, previous percutaneous coronary intervention (77.8% [7 of 9] vs. 34.0% [118 of 203]; p < 0.05) and the maximal balloon diameter used for post-dilation (5.25 mm vs. 2.95 mm; p < 0.01) were found to be more frequent and larger in patients who experienced TLF in the eBRS group. However, in the multivariate analysis, no predictor of TLF was found. In the nBRS group, the presence of non–ST-segment elevation myocardial infarction (75.0% [3 of 4] vs. 16.7% [17 of 102]; p < 0.05) at hospital submission and complex lesion morphology (100.0% [4 of 4] vs. 42.2% [43 of 102]; p < 0.05) were associated with TLF, but in the multivariate analysis, no predictor of TLF was identified. Taking all patients into account, previous age (68.2 years vs. 62.8 years; p < 0.05) and the maximal balloon diameter used for post-dilation (4.7 mm vs. 3.0 mm; p < 0.01) were predictors of TLF in the univariate analysis, and both age (hazard ratio: 1.1; 95% confidence interval: 1.0 to 1.2; p < 0.05) and maximal balloon diameter (hazard ratio: 1.3; 95% confidence interval: 1.0 to 1.6; p < 0.05) were predictors of TLF in the multivariate analysis.
Subgroup analysis of patients with small BRS
In a subgroup analysis, patients with at least 1 implanted BRS of 2.5 mm were compared with those with only larger size BRS. In the small eBRS group (reference vessel diameter 2.34 ± 0.38 mm), a trend toward higher rates of MACE (7.4% vs. 5.0%), TLF (7.4% vs. 3.2%), and scaffold thrombosis (2.9% vs. 1.5%) in comparison with larger eBRS was observed, which was not statistically significant. Cardiac death was found significantly more often in the small eBRS group (4.5% vs. 0.0%; p < 0.05). No event was noted in the small nBRS group (reference vessel diameter 2.38 ± 0.32 mm), and no relevant differences were found in comparison with larger size nBRS. There were also no differences found between eBRS and nBRS (Table 4).
The present analysis is the first to describe a direct comparison of the procedural and clinical outcomes of 2 different types of BRS. The major findings of this investigation are as follows: 1) in a well-balanced cohort of patients undergoing BRS implantation during routine clinical practice, no relevant differences were found regarding the procedural parameters despite small differences in the BRS design; and 2) 1-year follow-up data revealed comparable clinical outcomes for the 2 types of BRS with reasonable event rates, demonstrating similar efficacy of the devices in a real-world setting.
BRS represent a major breakthrough in technology for the treatment of coronary artery disease. A variety of different types are under development, with PLLA-based BRS being the most widely investigated (7). Only 2 PLLA-based BRS, however, have obtained the Conformité Européenne mark, which allows unrestricted use for coronary applications in Europe: eBRS and nBRS. It should be noted that there are some slight differences in the design of the 2 types of BRS: the eBRS has fewer peaks per hoop (6 vs. 9), slightly smaller vessel coverage (“footprint”; 27% vs. 30%), and higher radial strength than the nBRS (1.3 atm vs. 1.1 atm). Strut thickness and crossing profiles, however, are comparable (14). During bench testing, the fracturing threshold was lower for the eBRS regarding main branch and side branch post-dilation as well as for the mini-kissing maneuver (14). In comparing acute recoil, no differences were found within the first minute, with only small changes in the diameters of the 2 BRS; however, within 1 h the nBRS showed an increase in diameter (“self-correction”) such that the diameter after 1 h was significantly larger than that of the Absorb eBRS (14). When evaluating the acute mechanical performance of the eBRS and nBRS by optical coherence tomography in vivo, comparable minimal luminal area (5.8 ± 1.9 mm2 vs. 6.1 ± 2.6 mm2; p = 0.43) and mean luminal area (7.1 ± 2.2 mm2 vs. 7.2 ± 1.9 mm2; p = 0.77) were found. However, the residual area stenosis was smaller with the nBRS (20.1% vs. 14.9%; p < 0.01), whereas the minimal (2.7 mm vs. 2.9 mm; p < 0.01) and maximal (3.2 mm vs. 3.5 mm; p = 0.01) BRS diameters were larger in nBRS patients (15). These differences were possibly influenced by the expansion of the nBRS immediately after implantation. Nevertheless, the present study did not demonstrate that different mechanical properties had an impact on clinical outcomes.
Presently, there is only 1 prospective study available that evaluated the clinical performance of nBRS, which was carried out in well-selected patients with stable coronary artery disease (9). A total of 126 patients were included in this prospective, multicenter, single-arm study. In-scaffold late luminal loss at 6 months was 0.20 ± 0.32 mm and was thus comparable with established DES (9). The composite of cardiac death, target vessel myocardial infarction, and clinically indicated TLR occurred in 5.7% of patients after 1 year and in 7.4% after 2 years, whereas the TLR rate was 3.3% after 1 year and 4.1% after 2 years. Within the follow-up period, 1 scaffold thrombosis was noted (9). The results for nBRS in the real-world scenario presented here are in line with these findings, because the observed 1-year rates of MACE and TLR were 4.5% and 3.5%, respectively.
In contrast, several randomized controlled trials have compared eBRS with the current generation of DES (16). As observed angiographically, in-scaffold late lumen loss after 6 months was between 0.17 and 0.28 mm in different randomized controlled trials (16). In the largest trial available to date, the ABSORB III study, almost 2,000 patients with stable coronary artery disease were randomized in a 2:1 ratio to receive either the eBRS or an everolimus-eluting DES (4). After 12 months, no statistically relevant differences were observed in the clinical outcome. A recent meta-analysis showed similar results of eBRS and DES, with a TLR rate of 2.7% and a scaffold thrombosis rate of 1.3% in the eBRS group (8). These results are also comparable with those of the present study, as the rates for TLR and scaffold thrombosis in the eBRS group were 2.6% and 2.0%. It should be noted, however, that studies included in this meta-analysis and the previously mentioned study on nBRS share strict inclusion criteria that do not reflect routine clinical practice.
The GHOST-EU registry is a retrospective data repository that to date represents the largest database on patients treated with eBRS during routine clinical practice. Characteristics of the population are comparable with the study population presented here (1). After 6 months, the observed event rates of TLR and scaffold thrombosis were 2.5% and 2.1%, nearly as high as in the present study after 1 year. The impact of a learning curve, however, as well as a more thorough implantation technique with a higher rate of post-dilation (only 49% in GHOST-EU) must be taken into account (1).
Patients included in this study were not enrolled in a randomized fashion. Although there were only small differences in the baseline characteristics of the unmatched cohort, a number of eBRS patients were excluded, which may influence results of the analysis. In addition pre- and post-dilation were included as matching criteria, although they are procedure related. The reason was to compare the results of patients undergoing comparable and the most optimal implantation technique, because it is known that both parameters have an influence on outcomes and are highly recommended. Furthermore, no criteria were pre-defined as to whether to implant either an eBRS or an nBRS, and the decision was ultimately left to the implanting physician; thus, selection bias cannot be ruled out. In addition, there may be some degree of historical bias, because the nBRS device was available later, which might be a reflected by a higher degree of acute coronary syndromes in the unmatched eBRS population. Intravascular imaging was also performed significantly less often in the the eBRS group, and it may not be possible to ignore its influence on clinical outcomes. However, because recommendations for implantation changed during the enrollment period, more frequent use of intravascular imaging was observed. No routine angiographic surveillance was scheduled, and thus no conclusions regarding potential restenosis can be made. Long-term follow-up will be required, because there may be differences in outcome due to different time frames until full resorption is achieved. Finally, the number of patients included in the study was relatively small, and thus the study was possibly underpowered to detect differences regarding clinical events between the groups. Thus the results of this study must be taken in this context as hypothesis generating.
The present study reveals that implantation of eBRS or nBRS in routine clinical practice is effective in general and is associated with reasonable clinical outcomes in a large variety of patients and anatomic settings. Event rates with the 2 BRS were similar, demonstrating that differences in the BRS design and elution do not affect general procedural parameters such as procedure and radiation time or amount of contrast agent or, most important, the 1-year clinical results. Nevertheless, future randomized controlled trials will be required to confirm the results of this study.
WHAT IS KNOWN? eBRS and nBRS are available and in clinical use. In studies investigating each BRS separately, both have shown similar clinical results and thus may be considered as treatment options for patients with coronary artery disease.
WHAT IS NEW? To date, this is the first direct clinical comparison of 2 different BRS. After 1 year, both groups showed similar clinical outcomes. Thus, differences regarding the mechanical properties and elution between both BRS did not affect clinical outcomes in this cohort.
WHAT IS NEXT? Long-term clinical follow-up after complete dissolution of both types of BRS might be able to reveal differences regarding patient outcomes. Further subgroup analysis will be required to evaluate whether a specific patient population or anatomic setting will benefit from the unique mechanical properties of each type of BRS. In addition, comparisons with BRS made from other materials and DES will be required.
The authors thank Elizabeth Martinson, PhD, for editorial assistance.
For supplemental tables, please see the online version of this article.
Dr. Hamm has received speaking honoraria from Abbott Vascular. Dr. Kastrati has patent applications related to drug-eluting stent coatings. Dr. Möllmann has received speaking honoraria from Abbott Vascular. Dr. Nef has received research grants (institutional) and speaking honoraria from Abbott Vascular and Elixir Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bioresorbable scaffold(s)
- dual-antiplatelet therapy
- drug-eluting metal stent(s)
- everolimus-eluting bioresorbable scaffold(s)
- major adverse cardiac event(s)
- Novolimus-eluting bioresorbable scaffold(s)
- poly-L-lactic acid
- target lesion failure
- target lesion revascularization
- Received November 4, 2016.
- Accepted November 17, 2016.
- American College of Cardiology Foundation
- Puricel S.,
- Arroyo D.,
- Corpataux N.,
- et al.
- Ormiston J.A.,
- Serruys P.W.,
- Onuma Y.,
- et al.
- Serruys P.W.,
- Onuma Y.,
- Dudek D.,
- et al.
- Wiebe J.,
- Nef H.M.,
- Hamm C.W.
- Abizaid A.,
- Costa R.A.,
- Schofer J.,
- et al.
- Wiebe J.,
- Liebetrau C.,
- Dorr O.,
- et al.
- Onuma Y.,
- Serruys P.W.,
- Perkins L.E.,
- et al.
- Windecker S.,
- Kolh P.,
- Alfonso F.,
- et al.
- Cutlip D.E.,
- Windecker S.,
- Mehran R.,
- et al.
- Mattesini A.,
- Boeder N.,
- Valente S.,
- et al.