Author + information
- Received December 12, 2016
- Revision received February 10, 2017
- Accepted March 9, 2017
- Published online June 5, 2017.
- Erhan Tenekecioglu, MDa,
- Patrick W. Serruys, MD, PhDa,b,∗ (, )
- Yoshinobu Onuma, MD, PhDa,
- Ricardo Costa, MDc,
- Daniel Chamié, MDc,
- Yohei Sotomi, MDd,
- Ting-Bin Yu, PhDe,
- Alexander Abizaid, MD, PhDc,
- Houng-Bang Liew, MDf and
- Teguh Santoso, MD, PhDg
- aDepartment of Interventional Cardiology, Erasmus University Medical Center, Thoraxcenter, Rotterdam, the Netherlands
- bDepartment of Cardiology, Imperial College, London, United Kingdom
- cDepartment of Invasive Cardiology, Institute Dante Pazzanese of Cardiology, São Paulo, Brazil
- dDepartment of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
- eDuning, Tustin, California
- fDepartment of Cardiology, Queen Elizabeth Hospital II, Sabah, Malaysia
- gDepartment of Internal Medicine, Faculty of Medicine, Dr. Cipto Mangunkusumo and Medistra Hospitals, University of Indonesia, Jakarta, Indonesia
- ↵∗Address for correspondence:
Dr. Patrick W. Serruys, Erasmus University, Westblaak 98, 3012KM Rotterdam, the Netherlands.
Objectives The primary objective of this study was to evaluate the safety and effectiveness of the Mirage (Manli Cardiology, Singapore) bioresorbable microfiber sirolimus-eluting scaffold compared with the Absorb (Abbott Vascular, Santa Clara, California) bioresorbable vascular scaffold in the treatment of stenotic target lesions located in native coronary arteries, ranging from ≥2.25 to ≤4.0 mm in diameter. Secondary objectives were to establish the medium-term safety, effectiveness, and performance of the Mirage device.
Background The current generation of bioresorbable scaffolds has several limitations, such as thick square struts with large footprints that preclude their deep embedment into the vessel wall, resulting in protrusion into the lumen with microdisturbance of flow. The Mirage sirolimus-eluting bioresorbable microfiber scaffold is designed to address these concerns.
Methods In this prospective, single-blind trial, 60 patients were randomly allocated in a 1:1 ratio to treatment with a Mirage sirolimus-eluting bioresorbable microfiber scaffold or an Absorb bioresorbable vascular scaffold. The clinical endpoints were assessed at 30 days and at 6 and 12 months. In-device angiographic late loss at 12 months was quantified. Secondary optical coherence tomographic endpoints were assessed post–scaffold implantation at 6 and 12 months.
Results Median angiographic post-procedural in-scaffold minimal luminal diameters of the Mirage and Absorb devices were 2.38 mm (interquartile range [IQR]: 2.06 to 2.62 mm) and 2.55 mm (IQR: 2.26 to 2.71 mm), respectively; the effect size (d) was −0.29. At 12 months, median angiographic in-scaffold minimal luminal diameters of the Mirage and Absorb devices were not statistically different (1.90 mm [IQR: 1.57 to 2.31 mm] vs. 2.29 mm [IQR: 1.74 to 2.51 mm], d = −0.36). At 12-month follow-up, median in-scaffold late luminal loss with the Mirage and Absorb devices was 0.37 mm (IQR: 0.08 to 0.72 mm) and 0.23 mm (IQR: 0.15 to 0.37 mm), respectively (d = 0.20). On optical coherence tomography, post-procedural diameter stenosis with the Mirage was 11.2 ± 7.1%, which increased to 27.4 ± 12.4% at 6 months and remained stable (31.8 ± 12.9%) at 1 year, whereas the post-procedural optical coherence tomographic diameter stenosis with the Absorb was 8.4 ± 6.6%, which increased to 16.6 ± 8.9% and remained stable (21.2 ± 9.9%) at 1-year follow-up (Mirage vs. Absorb: dpost-procedure = 0.41, d6 months = 1.00, d12 months = 0.92). Angiographic median in-scaffold diameter stenosis was significantly different between study groups at 12 months (28.6% [IQR: 21.0% to 40.7%] for the Mirage, 18.2% [IQR: 13.1% to 31.6%] for the Absorb, d = 0.39). Device- and patient-oriented composite endpoints were comparable between the 2 study groups.
Conclusions At 12 months, angiographic in-scaffold late loss was not statistically different between the Mirage and Absorb devices, although diameter stenosis on angiography and on optical coherence tomography was significantly higher with the Mirage than with the Absorb. The technique of implantation was suboptimal for both devices, and future trials should incorporate optical coherence tomographic guidance to allow optimal implantation and appropriate assessment of the new technology, considering the novel mechanical properties of the Mirage.
Bioresorbable scaffolds (BRS) may potentially overcome many pitfalls related to metallic drug-eluting stents. If BRS are ultimately expected to have the same range of applicability as durable metal stents, the gap in the mechanical properties between the 2 devices should be minimal.
Currently the existing limitations are: 1) low tensile and radial strength, necessitating thick struts to prevent acute recoil; 2) insufficient ductility, which affects scaffold crimping and retention on the delivery balloon and limits the range of scaffold expansion during deployment; and 3) early mechanical disruption or late structural discontinuity of the struts inherent to the polymer used and its elongation at break and resorption decay. In other words, the optimal performance goal and the mechanical dilemma with BRS is to obtain high tensile strength combined with ductility and high elongation at break (1).
Polylactide and poly(d,l-lactide) have tensile strengths ranging between 45 and 70 MPa, with an elongation at break of 2% to 6%, whereas cobalt chromium has a tensile strength of 1,449 MPa and an elongation at break of 40% (2). Currently, polymer experts test the complex composition of polymers, mixing polylactide, polyglycolide, and polycaprolactone to alter mechanical properties and to achieve radial strength and ductility that could be comparable at least with stainless steel stents. Another way to modify the mechanical properties of the polylactide is to intervene on the molecular orientation of the polymer by using proprietary manufacturing processes that involve stretching (melt extrusion, drawing) and temperature alteration (annealing). Manli Cardiology’s (Singapore) microfiber technology has explored the concept of molecular orientation of polylactide to create a circular single monofilament (diameter 125/150 μm) with specific mechanical properties. The scaffold design consists of a helicoid coil structure in which the monofilament maintains its directional mechanical properties as well as its circular geometry (Figure 1). In the final assembly of the scaffold, 3 longitudinal spines are attached at ambient temperature to guarantee the mechanical stability of the helicoid structures. The Mirage sirolimus-eluting bioresorbable microfiber scaffold (BRMS) (Manli Cardiology), with strut thickness of 125 μm, has a tensile strength of 300 MPa with an elongation at break of 35% and a radial strength of 120 kPa, very comparable with the radial strength of the XIENCE V (Abbott Vascular, Santa Clara, California) with a strut thickness of 81 μm. In addition, in vitro and in vivo degradation profiles have confirmed that the Mirage polylactide is basically fully biodegraded after 14 months (Figures 1 and 2).
The primary objective of this study was to evaluate the safety and effectiveness of the Mirage BRMS compared with the Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular) in the treatment of stenotic target lesions located in native coronary arteries, ranging from ≥2.25 to ≤4.0 mm in diameter. The secondary objectives of this study were to establish the medium-term safety, effectiveness, and performance of the Mirage BRMS, assessed at multiple time points, through assessment of clinical, angiographic, and optical coherence tomographic (OCT) data.
Description of the device
The Mirage is a poly-l-lactic acid–based scaffold with <5% of dextrorotary isomer of polylactic acid. As described in the introduction, the device has a helicoid structure, which provides high flexibility. The strut thickness for a scaffold with a diameter ≤3 mm is 125 μm, whereas scaffolds with diameters >3 mm have a strut thickness of 150 μm. The aim of this new technology is not only to reduce strut thickness but also to increase the embedment of the struts. Because of the round shape of the struts, it will be more easy to embed the struts into the vessel wall, thereby reducing disturbance of flow (3). The vessel coverage ratio is high, about 40% to 47%, compared with 27% for the Absorb BVS. The device is available with diameters of 2.5, 2.75, 3.0, 3.5, and 4.0 mm and lengths of 18, 28, and 38 mm. The crossing profile of the smallest device (2.5 mm) is as low as 1.12 mm, whereas the 4.0-mm scaffold has a profile of 1.47 mm. Three radiopaque markers are incorporated in the device and allow fluoroscopic assessment. Of note, the helicoid structure contributes to the flexibility of the device and facilitates side-branch access through the fenestration between the helicoid rings. The internal scaffold dimensions for the various nominal sizes available as a function of inflation pressure are reported in Online Table 1. The limit of scaffold expansion of the Mirage is approximately 10% (Solomon Su, polymer engineer from Manli Company, personal communication, January 2017). With the Mirage, molecular weight decreases by more than 90% in approximately 1 year, whereas with the Absorb, the depolymerization process is complete within approximately 3.5 years (4).
Clinical trial, imaging modalities, and study population
The Mirage clinical trial is a randomized trial with a 1:1 allocation between the Mirage BRMS and the Absorb BVS. Before the start of the randomization trial, 8 patients were included as a run-in phase at 2 sites, 1 in Indonesia and 1 in Malaysia. Patients were recruited between August 25 and October 23, 2014. Enrollment was completed in October 2014. Patients underwent angiography and OCT imaging pre- and post-procedure, at 6 and 12 months.
The angiographic endpoint is in-scaffold late luminal loss at 12 months. Secondary OCT endpoints include multiple parameters, whereas the secondary clinical endpoints are a composite of cardiac death, target vessel myocardial infarction (MI), and clinically indicated target lesion revascularization (CI-TLR) (5).
Inclusion and exclusion criteria for the present study are identical to the criteria used for the ABSORB Cohort B trial (2). Patients with known hypersensitivity or contraindications to aspirin, heparin, bivalirudin, ticlopidine and clopidogrel, poly(l-lactide), poly(d,l-lactide), sirolimus, everolimus, or platinum or sensitivity to contrast media that could not be adequately pre-medicated, acute MI (ST-segment elevation MI or non–ST-segment elevation MI), left ventricular ejection fractions ≤30%, renal insufficiency (e.g., serum creatinine level more than 2.0 mg/dl or dialysis), planned elective surgery within the first 6 months after the coronary procedure that would require discontinuing either aspirin or clopidogrel, concurrent medical conditions with life expectancy <18 months, restenotic lesions, lesions located in the left main coronary artery, lesions involving an epicardial side branch ≥2 mm in diameter by visual assessment and/or ostial lesion >40% stenosis by visual estimation or side branch requiring pre-dilatation, thrombus or another clinically significant stenosis (including side branch) in the target vessel, total occlusion (TIMI [Thrombolysis In Myocardial Infarction] flow grade 0) before wire passing, moderate to severe calcification, and tortuosity of the target vessel were excluded. The ethics committee at each participating institution approved the protocol, and each patient gave written informed consent before inclusion.
The target lesion was pre-dilated in both groups. A pre-dilatation ratio of 1:1 between the pre-dilatation balloon and the reference vessel with a balloon shorter than the Mirage and Absorb devices was mandated. After intracoronary nitrate injection, quantitative coronary angiography (QCA) was used for proper vessel sizing before scaffold implantation. Following scaffold implantation, post-dilatation was left to the discretion of the operator, but when performed it was applied to the entire length of the scaffolded segment using a balloon with a similar matched length. After the scaffold implantation procedure, intravascular imaging was performed for documentary purposes (Online Table 2).
Minimal luminal diameter, interpolated reference diameter, diameter stenosis (DS), and late loss in the device and in the 5 mm proximal and distal to the device were determined by QCA (Pie Medical Imaging, Leiden, the Netherlands) (6). The balloon artery ratio was evaluated by measuring the average pre-procedural reference diameter of the mean proximal (5 mm) and mean distal (5 mm) edge diameter versus the fully expanded balloon (maximal balloon diameter according to chart of the manufacturer, during delivery or at the time of post-dilatation) (7). Acute recoil was quantified by measuring the fully expanded balloon during implantation in comparison with the diameter of the vessel post-scaffolding (8). Reference diameter and percentage DS were calculated using the interpolation method (9,10).
All procedures were done under angiographic guidance. OCT imaging was performed only for documentary purposes. Post-procedural luminal areas (minimal, mean, and reference), luminal asymmetry and eccentricity, and strut coverage and apposition were assessed using OCT imaging. The scaffold expansion index was specifically defined as the ratio of minimal scaffold area divided by maximum reference luminal area (2).
The population included patients with de novo lesions 48 mm in length in 2 different epicardial vessels allowing scaffold implantation with overlapping of a maximum of 2 scaffolds per lesion. The device was available in 2 lengths, 18 and 28 mm, and the device diameters in the inventory were 2.5, 3.0, 3.5, and 4.0 mm.
Clinical device success was defined as successful delivery of the device and attainment of <50% residual stenosis by QCA of the target lesion using the Mirage scaffold and delivery system. Clinical procedural success was defined as attainment of 50% residual stenosis of the target lesion and no in-hospital major cardiac events up to 7 days after the index procedure. Major adverse cardiac events were categorized either as patient-oriented composite endpoints (all-cause death, any MI, any revascularization) or device-oriented composite endpoints (cardiac death, target vessel MI, target lesion revascularization [TLR]). Periprocedural MI was defined according to the definition of the Society for Cardiovascular Angiography and Interventions (5). Spontaneous MI was defined according to the third universal definition (11).
Target lesion failure was a composite of cardiac death that could not be clearly attributed to a noncardiac event or non-target-vessel-related, target-vessel-related MI, or CI-TLR. Clinically indicated revascularizations imply positive results on a functional study, ischemic electrocardiographic changes at rest in a myocardial distribution consistent with the target vessel, or ischemic symptoms. Revascularization of a target lesion with an in-lesion DS ≥70% (by QCA) in the absence of the aforementioned ischemic signs or symptoms was also considered clinically indicated.
This feasibility study was designed to provide preliminary observations and generate hypotheses for future studies. The sample size was not defined on the basis of an endpoint hypothesis but rather to provide some information about device efficacy and safety. The sample size requirement was established by assessment of the minimum number of patients needed to provide reliable and nontrivial results. The sample size is in the range of the test group in the ABSORB Cohort A trial (n = 30) and the ABSORB Cohort B1 (n = 45) and Cohort B2 (n = 56) trials (12,13). The current clinical investigation is essentially a first-in-human study whose aim was to provide information on safety and effectiveness with a limited number of subjects exposed to the Mirage BRMS, compared with the Absorb BVS. The angiographic endpoint was in-device late luminal loss assessed by QCA at 12-month follow-up.
Continuous variables were tested for normality using the Kolmogorov-Smirnov test and are expressed as mean ± SD or median (interquartile range [IQR]) as appropriate. Most angiographic data had a non-Gaussian distribution, whereas the OCT data had a Gaussian distribution. Categorical variables are presented as counts and percentages. Continuous variables were compared using the Kruskal-Wallis test or the Mann-Whitney U test. Categorical variables were compared using the Fisher exact test. Because the trial was designed as a feasibility study, instead of p values, effect sizes (d values) were used in the statistical analysis.
Baseline patient demographics and lesion characteristics
Table 1 shows the baseline patient demographics and lesion characteristics and tabulates either the mean difference (age) or the relative rate of baseline characteristics with their 95% confidence intervals. The majority of the patients had stable angina and silent ischemia. Two patients (with ST-segment elevation myocardial infarction or non–ST-segment elevation myocardial infarction) were protocol violations but were included in the intention-to-treat analysis.
The majority of the treated lesions were located in the left anterior descending coronary artery. Lesions were characterized by moderate or severe calcification in 46% and 35% in the Mirage and Absorb groups, respectively. Small vessels, according to interpolated reference vessel diameter <2.5 mm on QCA, were found in 7 of 35 patients (20%) in the Mirage group and 9 of 34 patients (27%) in the Absorb group. Bifurcations with side branches visually ≥2 mm and/or protected by guidewires were involved in the treated lesions in 49% and 41% of the Mirage and Absorb groups, respectively. In terms of American College of Cardiology/American Heart Association classification, the majority of lesions were classified as type B2 lesions. The core laboratory adjudicated the lesions as type C in 29% and 38% of patients treated with the Mirage and Absorb devices. With regard to the technique of implantation, pre-dilatation was the rule, with only 2 exceptions in the Absorb group; device success was 100% in both groups, and 6 patients needed an additional scaffold or stent. Noticeably, balloon post-dilatation was performed in only 57% and 59% of the Mirage and Absorb patients (Table 2).
Study course and rates of follow-up
Sixty patients were randomized, 31 to the Mirage BRMS and 29 to the Absorb BVS, including 35 and 34 lesions, respectively. One patient in the Mirage group had a scaffold thrombosis on day 3. The angiographic residual DS of this severely calcified lesion, even after post-dilatation, was 33%. OCT imaging showed an expansion and eccentricity index of 80.5% and 0.47, respectively. Intrascaffold dissection and malapposition were also diagnosed on OCT imaging. The patient showed antiplatelet resistance to both clopidogrel and aspirin (576 aspirin reaction units), and genotype analysis indicated decreased CYP2C19 activity and a poor metabolizer phenotype. The patient received 2 metallic drug-eluting stents and was further treated with ticagrelor. The quantitative coronary angiographic data from this lesion were not included in the 6- or 12-month angiographic follow-up. Figure 3 is a flowchart that provides the rate of OCT, angiographic, and clinical follow-up at 6 and 12 months. In addition, the flowchart reports all TLR at 6 and 12 months. In each group, 2 patients were lost to follow-up. At 1 year, the cumulative rate of all TLR was 20.7% (n = 6 patients) in the Mirage group and 18.5% (n = 4 patients; 1 patient underwent 2 TLRs) in the Absorb group. The values of QCA pre-TLR for these patients were carried forward to 6 months and/or 1 year in the statistical analysis. In the Mirage group, 3 patients had non-ischemia-driven TLR at angiographic follow-up.
QCA at baseline showed an obstruction lesion length of about 14 mm with a reference interpolated diameter of 2.85 mm and a minimal luminal diameter of 1.25 mm, resulting in DS of 56% in both groups. The median DS was 16.3% in the Mirage BRMS group and 12.3% in the Absorb BVS group (d = 0.48). Acute recoil was numerically slightly higher in the Absorb group, 7.11% versus 5.97% in the Mirage group, but that difference failed to reach statistical significance (p = 0.285, d = −0.40). Absolute acute recoil was 0.20 mm (IQR: 0.14 to 0.28 mm) in the Mirage group and 0.24 mm (IQR: 0.17 to 0.36 mm) in the Absorb group (d = −0.23). Post-procedure, there was no significant difference between the Mirage and Absorb groups, but there was borderline significance (p = 0.058, d = 0.48) for median DS (16.3% vs. 12.3%). The latter difference in DS became significant at 6 months (28% vs. 16.9%, p = 0.026, d = 0.36) and was confirmed at 12 months (28.6% vs. 18.2%, p = 0.046, d = 0.39). However, all differences in mean DS were nonsignificant, and it must be emphasized that there was no statistical difference in median angiographic late loss at 6 months (0.18 mm vs. 0.13 mm) and 12 months (0.36 mm vs. 0.22 mm) (Table 3).
Figure 4 shows the cumulative distribution frequency curves for in-device late luminal loss (median) in the Mirage and Absorb study groups at 6 and 12 months. The binary restenosis rates at 6 months were 12.1% in the Mirage group (4 of 33 lesions) and 11.8% in the Absorb group (4 of 34 lesions), whereas the rates at 12 months were 19.4% (6 of 31 lesions) in the Mirage group and 16.7% (5 of 30 lesions) in the Absorb group.
In the scaffolded segments, side branches visually ≥2 mm and/or protected by guidewires were documented at the core laboratory in 49% (17 of 34) of Mirage lesions and 41% (14 of 34) of Absorb lesions. However, the rates of side-branch occlusion were only 1 case in the Mirage group and no cases in the Absorb group.
OCT substudy at 6 months and 1 year
Table 4 shows the quantitative OCT results post-procedure at 6- and 12-month follow-up. Post-procedure, all quantitative measurements for the Mirage and Absorb devices did not differ, with the exception of the scaffold eccentricity index. Post-procedure scaffold expansion percentages at baseline were 75.6 ± 23.4% for the Mirage and 84.6 ± 9.7% for the Absorb (d = −0.50). The frequency of post-dilatation with a balloon different from the delivery balloon was similar in both scaffold groups (48.6% in the Mirage group, 40% in the Absorb group, d = 0.77). The ratio of the nominal diameter of the post-dilatation balloon to the nominal diameter of the scaffold was comparable (1.02 ± 0.04 in the Mirage group, 1.04 ± 0.06 in the Absorb group, d = −0.40). The post-dilatation balloon nominal diameters were large enough to expand the device in both study groups (ratio of post-dilatation balloon nominal diameter to mean reference diameter on OCT imaging 1.13 ± 0.14 for the Mirage and 1.09 ± 0.10 for the Absorb; d = 0.34). The difference in the ratio of nominal scaffold diameter to mean reference diameter on OCT imaging between the Mirage and Absorb groups and in the ratio of expected scaffold diameter according to dilatation pressure to mean reference diameter on OCT imaging in the Mirage and Absorb groups were not statistically different (p = 0.070, d = 0.74 and p = 0.430, d = 0.19) (Table 5).
In particular, the in-scaffold minimal luminal area (MLA) post-procedure was identical in both groups. At 6-month follow-up, the percentage of luminal area stenosis and DS calculated according to 2 different methods were significantly higher in the Mirage group compared with the Absorb group. In particular, MLA was significantly lower in the Mirage group than the Absorb group (2.91 ± 1.57 mm2 vs. 3.98 ± 1.73 mm2, p = 0.011, d = −0.66). These statistically significant differences were maintained at 12 months. The MLA in the Mirage was then 2.85 ± 1.50 mm2 versus 3.95 ± 1.91 mm2 (p = 0.036, d = −0.65). Of note, no malapposition was documented in both groups. Strict serial assessments by OCT imaging in the Mirage group showed for all quantitative measurements, significant change between post-procedure and 6 months with decreases in the absolute parameters (mean in-scaffold luminal area, MLA) and increases in relative changes (luminal and percentage DS). Between 6 and 12 months, there was an additional significant decrease in MLA (difference −0.36; 95% confidence interval: −0.57 to −1.59; p = 0.003, d = 0.25). The other relative measurements (luminal area and percentage DS) also indicated an additional increase in stenosis, albeit of borderline significance (Table 6). Serial OCT measurements in the Absorb group showed a similar pattern of change, although the quantitative differences were numerically lower (Table 7). In patients without TLR, serial OCT measurements demonstrated comparable luminal DS in the Absorb and Mirage groups (Figure 5).
Clinical events in the study groups are listed in Table 8. At 6- and 12-month follow-up, there was no statistical difference for MI, target lesion failure, or CI-TLR between the scaffold groups.
Figure 6A shows the device-oriented composite endpoint. In the Mirage group, 1 patient experienced a periprocedural MI according to the definition of the Society for Cardiovascular Angiography and Interventions, and another experienced a definite scaffold thrombosis on day 3, resulting in ST-segment elevation myocardial infarction and TLR. Subsequently, 3 patients underwent CI-TLR, so that the cumulative incidence of events was 16.9% at 360 days. In the Absorb group, 4 CI-TLRs were observed up to 360 days, resulting in a composite endpoint of 11.0%.
Figure 6B shows the patient-oriented composite endpoints, including all death, MI, or revascularization. The cumulative event up to 540 days amounted to 31.7% with the Absorb BVS and 25.8% with the Mirage BRMS.
The findings of the present study can be summarized as follows: First, at 12-month follow-up, median angiographic in-scaffold late luminal loss with the Mirage and Absorb were not statistically different, although, in the absence of a prospective and proper statistical hypothesis, no formal conclusion can be stated regarding the equivalence and/or noninferiority of the new Mirage device compared with the Absorb. Second, the secondary angiographic and OCT endpoint indicated less satisfactory performance of the Mirage compared with the Absorb, although the technique of implantation was suboptimal considering the novel mechanical properties of the Mirage, which were not fully exploited in this trial.
The Manli technology originated from research conducted in Singapore, and the first-in-human trial was conducted in the same geographic area, namely, Indonesia and Malaysia. Considering the complexity of the patients and lesions in this region, it was decided to conduct up front a randomized trial comparing the new technology with the Absorb technology, which was granted Conformité Européene mark and U.S. Food and Drug Administration approval, so that the performance of the new technology could be better assessed with its comparator among patients recruited exclusively in Indonesia and Malaysia. The study population and the morphological types of lesions treated are characterized by a high incidence of silent ischemia, frequent involvement of bifurcations, and type B and C lesions.
In this small randomized trial comparing the Mirage BRMS and Absorb BVS, there were no major difference in acute mechanical behavior between the 2 devices in terms of recoil, balloon/artery ratio, expansion index, and resulting minimal luminal diameter.
At 12 months, binary restenosis rates were comparable. These binary restenosis rates were somewhat higher than previously reported for the BVS device and presumably attributed to the more complex morphology of the lesions attempted (type B2 and C lesions in 90%) (14). At the time of patient enrollment, the technique of implantation did not incorporate current knowledge derived from more contemporary studies of BRS, such as oversized pre-dilatation, mandatory post-dilatation, systematic use of noncompliant balloons, and use of intravascular imaging for guidance (7). In the present trial, only one-half of the lesions were post-dilated, and scaffold expansion was 75.6 ± 23.4% for the Mirage and 84.6 ± 9.7% for the Absorb. The technical criteria for appropriate implantation (ratio of post-dilatation balloon nominal diameter to nominal scaffold diameter, and so on) were fulfilled in both arms. The scaffolds used were adequately sized and precluded “small-size device problems” immediately post-implantation at follow-up (9).
In the ABSORB Cohort B trial, in-scaffold late luminal loss was 0.19 ± 0.18 mm at 6 months and 0.27 ± 0.32 mm at 12 months (15). In the first-in-human trial of the Elixir DESolve coronary scaffold system, angiographic late luminal loss at 180 days was 0.19 ± 0.19 mm (16). In absence of QCA at 12 months in the DESolve trial, 12-month multislice computed tomographic findings can be interpreted as a surrogate for conventional angiography and documented luminal DS of 15.9 ± 10.0%. The results for the Absorb and DESolve devices have demonstrated comparable follow-up patterns in terms of late luminal loss. In the Absorb arm of the present trial, the median in-scaffold late luminal loss at 6-months was 0.17 mm (IQR: 0.05 to 0.23 mm) and 0.23 mm (IQR: 0.15 to 0.37 mm) at 12 months and seems comparable with the performance in the ABSORB Cohort B trial. In the Mirage arm, the median late luminal loss at 6-month follow-up was 0.23 mm (IQR: 0.04 to 0.44 mm) and 0.37 mm (IQR: 0.08 to 0.72 mm) at 12 months, values higher than the late losses in the ABSORB Cohort B and DESolve trials.
The scaffold manufacturing process of wrapping a circular monofilament around a metallic rod allows a large variety of nominal device sizes (2.5 mm, 2.75 mm, 3.0 mm, and so on). Therefore, selection of precisely sized device should be made to treat vessels whose dimensions have been thoroughly investigated and sized using OCT imaging.
OCT imaging, which provides a more sensitive and accurate measurement of luminal dimension, clearly indicated some significantly larger reduction of luminal area at follow-up in the Mirage group than in the Absorb group. The fact that the Mirage strut is not translucent on OCT renders assessment of the scaffold area at baseline difficult and makes the evaluation of the scaffold expansion or shrinking at follow-up problematic. It is therefore difficult to attribute the luminal area reduction at 6 or 12 months to either early shrinking (too rapid bioresorption of the scaffold), an excess of neointimal growth (insufficient cytostatic cell inhibition), or a combination of both phenomena.
In other words, future trials should incorporate OCT guidance to allow optimal implantation, taking advantage of quarter-sized devices and noncompliant balloons. It remains unclear what would be the optimal condition of implantation. Because the ductility of this device (in other words, its capability of expansion) is rather limited, sizing is of paramount importance if the operator wants to adequately use the tensile strength of the device and its ability to resist elongation at break. In other words, the operator should be aware of the unique mechanical feature of this novel technology and accordingly should adjust the sizing technique to take the advantage of the mechanical features of the Mirage BRMS.
First, in the absence of formal statistical hypothesis, the sample size was not based on statistical power. The numbers of lesions and patients tested were insufficient to draw statistically sound conclusions.
Second, although this was a first-in-human trial, relatively complex lesions were included in both arms, and the complexity of the lesions may have affected angiographic late loss. Strict inclusion and exclusion criteria were not respected in 45% of the patients, and more complex lesions were included in the study compared with the protocol-mandated inclusion and exclusion criteria. In a first-in-human study, investigators should follow exactly the inclusion and exclusion criteria, and extremely complex lesions should not be included in this kind of feasibility and safety trial.
The present first-in-human study comparing 2 BRS demonstrated that at 12 months, angiographic in-device late luminal loss was similar between the Mirage BRMS and Absorb BVS. The other angiographic or OCT parameters (DS) suggested a slightly but significantly higher degree of percentage luminal obstruction with the Mirage compared with the Absorb, although this did not translate into either angiographic binary restenosis or clinical outcomes. The relatively high degree of late loss in both arms could be due to the inclusion of complex lesions and suboptimal technique of implantation. Because the technology is new, with struts having different mechanical and optical properties compared with other BRS, OCT guidance is of paramount importance to establish the optimal implantation technique with this particular device.
WHAT IS KNOWN? Pre-dilatation, sizing, and post-dilatation are of paramount importance during the implantation of BRS. Smooth lesions provide acceptable results with the Absorb BVS, which has wide clinical experience.
WHAT IS NEW? Different technologies for BRS are under development. With its high tensile strength, the Mirage BRMS promises treatment of complex lesions. With the present trial, the indispensable role of post-dilatation of the scaffold and OCT imaging during implantation has been recognized.
WHAT IS NEXT? Introducing the new technologies into the field will shed light on the treatment opportunities for more complex lesions. Adequate lesion preparation with OCT imaging during the implantation process appears to fill the “gap” in the treatment of complex diseases with BRS.
For supplemental tables, please see the online version of this article.
Drs. Serruys and Onuma are members of the International Advisory Board of Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- sirolimus-eluting bioresorbable microfiber scaffold(s)
- bioresorbable scaffold(s)
- bioresorbable vascular scaffold(s)
- clinically indicated target lesion revascularization
- diameter stenosis
- interquartile range
- myocardial infarction
- minimal luminal area
- optical coherence tomographic
- quantitative coronary angiography
- target lesion revascularization
- Received December 12, 2016.
- Revision received February 10, 2017.
- Accepted March 9, 2017.
- 2017 American College of Cardiology Foundation
- ↵Serruys PW. Effects of polymer manufacturing processes on the mechanical properties of BRS. Presented at: TCT 2015—Transcatheter Cardiovascular Therapeutics 2015 Congress; October 14, 2015; San Francisco, CA.
- Serruys P.W.,
- Onuma Y.,
- Ormiston J.A.,
- et al.
- Otsuka F.,
- Pacheco E.,
- Perkins L.E.,
- et al.
- Cutlip D.E.,
- Windecker S.,
- Mehran R.,
- et al.
- Ishibashi Y.,
- Nakatani S.,
- Sotomi Y.,
- et al.
- Mattesini A.,
- Secco G.G.,
- Dall’Ara G.,
- et al.
- Tateishi H.,
- Suwannasom P.,
- Sotomi Y.,
- et al.
- Serruys P.W.,
- Chevalier B.,
- Sotomi Y.,
- et al.
- Thygesen K.,
- Alpert J.S.,
- Jaffe A.S.,
- et al.
- Onuma Y.,
- Dudek D.,
- Thuesen L.,
- et al.
- Onuma Y.,
- Serruys P.W.,
- Muramatsu T.,
- et al.
- Serruys P.W.,
- Onuma Y.,
- Dudek D.,
- et al.
- Verheye S.,
- Ormiston J.A.,
- Stewart J.,
- et al.