Author + information
- Received September 30, 2014
- Revision received December 5, 2014
- Accepted December 18, 2014
- Published online May 1, 2015.
- Tommaso Gori, MD, PhD∗∗ (, )
- Eberhard Schulz, MD∗,
- Ulrich Hink, MD∗,
- Madeleine Kress∗,
- Nadja Weiers∗,
- Melissa Weissner∗,
- Alexander Jabs, MD∗,
- Philip Wenzel, MD∗,
- Davide Capodanno, MD, PhD† and
- Thomas Münzel, MD∗
- ∗2 Medizinische Klinik und Poliklinik–Kardiologie, Angiologie und Internistische Intensivmedizin, University Medical Center, Mainz, Germany
- †Ferrarotto Hospital, University of Catania, Catania, Italy
- ↵∗Reprint requests and correspondence:
Dr. Tommaso Gori, 2 Medizinische Klinik, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.
Objectives The purpose of this study was to describe the multimodal outcome 12 months after implantation of coronary bioresorbable scaffolds (BVS) for the treatment of patients with acute coronary syndromes (ACS).
Background Functional and imaging data on the use of BVS are limited to simple, stable lesions; in the setting of ACS, only short-term clinical follow-up data are available, and no information from intracoronary imaging and vasomotion tests has been reported.
Methods A total of 133 patients (age 62 ± 12 years, 74% males, 15% diabetic) underwent BVS (n = 166) implantation for the treatment of thrombotic lesions in the setting of ACS (43% non–ST-segment elevation myocardial infarction, 38% ST-segment elevation myocardial infarction, 20% unstable angina). Clinical, angiographic, intracoronary imaging, and vasomotor endpoints were evaluated at 12 months.
Results During the 374 days (interquartile range: 359 to 411 days) of follow-up, there were 4 deaths; 3 definite and 1 probable in-BVS thromboses (all in the first 6 months). At 12-month angiography (75 patients, 83 BVS), in-segment late lumen loss was 0.19 ± 0.45 mm, and 3 (4%) patients showed binary restenosis. Optical coherence tomography (80 BVS, n = 70) showed a mean lumen area of 6.3 ± 2.3 mm2. Malapposition was evidenced in 21 (26%) BVS. Endothelium-dependent and -independent vasodilation were observed in 48% and 49% of the BVS.
Conclusions Twelve months after BVS implantation, clinical, intracoronary imaging, and vasomotion data appear to provide a rationale for the use of BVS in the setting of ACS and the basis for a randomized study.
Everolimus-eluting bioresorbable vascular scaffolds (BVS) have been recently introduced in more than 60 countries worldwide for the treatment of de novo coronary lesions, independently of patient and lesion characteristics. Analogue to metal stents, BVS initially provide mechanical scaffolding, preventing acute occlusion and early recoil, and release everolimus for the inhibition of neointima proliferation. Thereafter, the resorption of the scaffold struts has been hypothesized to protect vascular geometry/biomechanics and, in the long-term, allow positive remodeling (1). The latter concepts extend beyond the traditional treatment with metal stents, and phenomena such as the restoration of vasomotion, late luminal gain (in contrast to late luminal loss), and expansive remodeling have been advocated as potential advantages of BVS over traditional metal stents (1). These phenomena strongly rely on modifications in plaque/vessel biology, but to date they have been tested only in stable, type A lesions (2,3). Unstable plaques differ regarding many basic aspects (e.g., inflammation, endothelial dysfunction/damage, histopathological characteristics) from stable ones, and the previously-mentioned processes require confirmation in this setting. To date, only short-term clinical outcomes after BVS implantation are available for patients with acute coronary syndrome (ACS). Although these data appear to be comparable to second-generation drug-eluting stents (4–9), important information is still missing, including longer-term outcome data, as well as angiographic, functional, and imaging outcomes.
Absorb everolimus-eluting BVS (Abbott Vascular, Abbott Park, Illinois) are balloon-expandable scaffolds consisting of a polymer backbone of poly-L-lactic acid coated with an amorphous matrix of poly-D and -L-lactic acid polymer.
Since May 2012, BVS have been commercially available in the European Union for the treatment of de novo coronary lesions independently of the patient’s clinical presentation. The present report includes all consecutive patients who received a BVS for the treatment of culprit plaques in the setting of unstable angina with high thrombotic burden, non–ST-segment elevation myocardial infarction (STEMI) or STEMI between May 2012 and May 2013. Clinical data were collected in an anonymized way with the approval of the local ethics committee. Patients who underwent an invasive follow-up gave written informed consent for the collection of data within the framework of the prospective MICAT Registry (Ethical committee reference number 837.123.13 8808-F, NCT02180178).
Implantation was performed without specific inclusion/exclusion criteria but respecting the CE certification and manufacturer’s indications. BVS were not used to treat lesions in the left main coronary, in-stent restenoses, lesions in bypass, and bifurcation lesions in which a 2-stent strategy was chosen. No patients were on chronic therapy with anticoagulant agents. Pre-dilation was performed in all cases; thrombus aspiration and post-dilation were left to the operator’s discretion. Aspirin (loading dose 250 to 500 mg) was administered periprocedurally to patients not on chronic antiplatelet treatment and was protracted indefinitely. Dual antiplatelet therapy with prasugrel, ticagrelor, or clopidogrel was started periprocedurally with an oral loading dose and prescribed for 12 months after the event.
The 12-month clinical follow-up data were collected from all patients during clinical visits or per telephone using standardized questionnaires. A composite of cardiovascular death, any myocardial infarction, and target lesion revascularization (TLR) was taken as the definition of a major adverse event (10). For data quality purposes, all outcome data were acquired by 1 investigator and adjudicated by another investigator.
An invasive 12-month follow-up was recommended to the first 100 patients given the novelty and complexity of the procedure. These patients also underwent the following measurements:
Quantitative coronary angiography analysis
Quantitative coronary angiography (QCA) analysis was performed using Xcelera (Philips, Eindhoven, the Netherlands). Definitions are described in Online Table 1.
Assessment of endothelium-dependent and -independent function
QCA analysis was performed in the scaffolded segment in random order by staff not aware of the temporal sequence of the images. Endothelium-dependent and -independent vasomotion were studied as described in the Online Appendix and as previously published (11).
Optical coherence tomography
Methods and definitions are described in the Online Appendix.
Continuous variables are presented as mean ± SD; categorical variables as counts and percentages. Responses to vasomotor stimuli are described as group average and as cumulative frequencies of individual changes in response to each dose. The changes in minimum lumen diameter (MLD) among time periods (before implantation, after implantation, and at follow-up) were compared with 1-way repeated measures analysis of variance. All analyses were exploratory. All statistical tests were performed with SPSS version 22 (IBM, Armonk, New York).
Between May 2012 and May 2013, 260 BVS were implanted in 210 patients for all indications. In the same period, 133 patients received 164 scaffolds for the treatment of culprit plaques in the setting of ACS.
Clinical characteristics and outcome
Follow-up was available in 100% of the patients at median 374 days (interquartile range: 359 to 411 days) (Tables 1 and 2⇓). Events have been partially reported in our previous publication (9). During follow-up, a total of 18 composite events (13.5%), including 4 deaths (1 sudden death, probable in-BVS thrombosis), 4 STEMIs (all within the first 6 months, 3 caused by in-BVS thromboses treated with DES implantation), and 5 non-STEMIs (1 due to in-BVS restenosis, also treated with DES implantation) were observed. There were another 2 TLRs within the first 6 months. In 1 case, the patient presented with unstable angina 3 weeks after the index PCI due to a de novo lesion >5 mm distal to the BVS. Optical coherence tomography (OCT) showed incomplete expansion of the BVS, which was post-dilated with a good result. Balloon-only post-dilation of a BVS was performed in another patient in the setting of a staged procedure 2 weeks after BVS implantation for OCT evidence of malapposition. The result was controlled with OCT to exclude recoil in both cases. OCT and post-dilation had not been performed at the time of BVS implantation in either case. A third patient showed ∼50% BVS restenosis, which was left untreated in the absence of symptoms and evidence of ischemia 6 months after implantation. Three other patients showed binary restenoses in the absence of signs of ischemia at the scheduled 12-month follow-up; all were treated with PTCA and implantation of a DES. Representative images of the events are presented in Figure 1.
Quantitative coronary angiography
Control angiography was performed in 75 patients (83 BVS) at 372 days (interquartile range: 359 to 398 days). Follow-up was not carried out in 25 of the initially planned 100 patients who preferred, due to the absence of symptoms, to undergo exercise tests only (negative in all cases). Baseline and follow-up angiographic parameters are shown in Table 3 and Online Table 2. The changes in MLD between index procedure and follow-up and the distribution of late lumen loss are also shown in Figure 2. In-segment late lumen loss was 0.19 ± 0.45 mm (range −0.72 to 1.74 mm). The 3 binary restenoses (3.6% of the BVS, 4% of the patients) were all observed in-scaffold.
Optical coherence tomography
OCT was performed in 70 patients (80 scaffolds); data are shown in Table 4. A total of 14,498 struts were identified. The mean length of the scaffold was 19.6 ± 4.8 mm. A maximum scaffold eccentricity >1.5 was present in 17 (21%) BVS; the maximum value observed was 1.9. At least 1 malapposed strut was present in 21 (26%) scaffolds; the mean malapposition area in these patients was 4.1 ± 3.7 mm2. At least 1 uncovered strut was present in 24 (30%) scaffolds. At follow-up, the remnant of the culprit plaque could be identified in 70 cases. The minimum thickness of its cap was 260 ± 137 μm (range 0 to 620 μm) (Figure 2C).
Endothelium-dependent and -independent responses
Acetylcholine and nitroglycerin responses were studied in 52 (65%) and 63 (79%) scaffolds, corresponding to 49 (70%) and 60 (86%) patients. All 3 doses of acetylcholine were administered in 38 (73%) cases (only the highest dose was not applied in the right coronary artery and, in case of vasospasm, at 1 of the lower doses). When analyzed as the average of all subjects, no significant change in the mean lumen diameter were observed in response to the infusions (baseline: 2.6 ± 0.51 mm; during saline infusion: 2.5 ± 0.45 mm; acetylcholine dose 1: 2.5 ± 0.45 mm; acetylcholine 2: 2.5 ± 0.43 mm; acetylcholine 3: 2.3 ± 0.63 mm; nitroglycerin: 2.6 ± 0.44 mm, p = 0.32). The individual responses to each dose of acetylcholine and nitroglycerin were, however, heterogeneous and are presented in Figure 3. A total of 31%, 33%, and 33% of the in-BVS segments responded with a dilation to the low-, mid-, and high-acetylcholine dose, respectively; 21%, 22%, and 37% responded with a constriction to the low-, mid-, and high-acetylcholine dose, respectively. Forty-eight percent of the segments responded with a vasodilation during administration of at least 1 dose of acetylcholine. Forty-nine percent responded with vasodilation after nitroglycerin. The mean response to nitroglycerin was 4 ± 7% (p < 0.001). There were no complications during follow-up examinations.
BVS are currently approved for use independently of the lesion and clinical presentation. Data in patients with ACS remain, however, limited to clinical outcomes and to the periprocedural period or short-term (1-month) follow-up (4,5,8,9). We report on the 12-month clinical, angiographic, intracoronary imaging, and functional outcomes of a single-center cohort of unselected, consecutive patients treated with BVS in the setting of ACS.
Summary of the data
The composite endpoint rate of 13.5% was expectedly higher than those previously observed in stable patients (10), but comparable with those of previous randomized controlled studies or all-comer registries enrolling ACS patients treated with DES (12–16) (incidence variable between 4.9% and 26.3% on the basis of definitions used, clinical presentation, and extent of disease). The large majority of events occurred in the first 6 months. The incidence of restenosis was quite low and was comparable to that of DES (12–16). The incidence of definite in-BVS thrombosis, in line with our recently reported figures from a larger dataset of patients (17), was relatively high and will require further attention.
Late lumen loss was very modest and comparable to previous BVS papers in stable settings (3,10). For comparison, the value observed in the SPIRIT trial with second-generation drug-eluting stents was 0.23 ± 0.29 mm at 12 months, that is, slightly larger than that observed here (18). A total of 3 (4%) BVS showed binary restenosis at the 12-month follow-up, and were asymptomatic in all cases. Taken together, these data support the use of BVS with respect to the prevention of acute occlusion and recoil at implantation and the inhibition of neointima proliferation in the subsequent period.
Neointima thickness, area, and % restenosis in our cohort were comparable to that observed in metal stents in similar settings (19). The incidence of malapposition was also very similar to that observed after DES implantation in the setting of STEMI (20). The malapposition area was, however, larger as compared with that reported immediately after BVS implantation (21). The rate of uncovered struts was low and was comparable to previous data in metal stent and BVS (19).
Finally, the remnants of the culprit plaque were covered in the majority of cases (95.7%) by a homogeneous, signal-rich tissue that was thicker than 65 μm (the threshold commonly used for discriminating thin- from thick-cap fibroatheroma in de novo lesions ). Findings of a layer presenting OCT characteristics possibly compatible with those of a fibrous cap have been previously hypothesized to witness the transformation of vulnerable lesions to stable plaques (1). This hypothesis (and the existence of a threshold for a “stable” cap) remains speculative and will need prospective validation.
Acetylcholine responses are an accepted diagnostic and risk stratification tool (23), but data on the functional restoration of lesions responsible for an acute event have not been reported before. In our population, endothelium-dependent and -independent vasodilation were observed in about one-half of the lesions, a figure that might improve after further withdrawal of the scaffolding function of the BVS (and the effects of everolimus). Evidence of vasoconstriction in 37% of the lesions at the highest acetylcholine dose, however, points to the long-term persistence of vascular spasm phenomena in a subgroup of patients.
Study limitations and strengths
The fact that this was not a randomized, controlled trial does not allow us to exclude the existence of an inclusion bias even though patients were consecutively enrolled without inclusion/exclusion criteria. To guarantee data quality, all data were entered by 1 researcher and were monitored against original clinical documents by another one. Control coronary angiography was not performed in some of the patients in the absence of symptoms or other evidence of ischemia. This obviously represents a negative bias against the device; since the outcomes reported are in line with those of other studies in stable settings, however, we do not believe that this bias played a significant role. No control group was included in this report; however, we previously showed that the clinical characteristics and short-term outcome of these patients, consecutively included in the present report, do not differ from those of patients who received metal stents during the same period in our institution (9), and the vast majority of the clinical events occurred early after implantation. As well, the vasomotion properties of BVS are obviously unique, and a control group would have added no information with regard to this endpoint. Because OCT was not systematically performed at implantation, we cannot conclude whether this was present directly after implantation of whether it was acquired at later timepoints (e.g., as the effect of the dissolution of thrombi jailed between scaffold struts and vessel wall). Whatever the mechanism, the implications of the resulting flow disturbances will have to be further investigated. Despite the high resolution of OCT, the identification of uncovered struts is challenging and to a certain extent arbitrary, and the incidence of uncovered struts, in this like in other reports, should be interpreted cautiously. The maximum percent restenosis measured by OCT was larger than theoretically expected on the basis of late lumen loss measures. Differences in the resolution of the methods, the nonuniform distribution of neointima, and the fact that scaffold struts are invisible at x-ray might concur to explain this discrepancy.
Long-term outcome data after BVS implantation are limited to chronic stable settings, type A lesions, and patients selected using stringent inclusion/exclusion criteria (24). In the current report, we provide the first clinical, functional, and imaging outcome data at 12 months in an unselected cohort of high-risk patients who received 1 or more BVS for the treatment of a thrombotic culprit lesion. Collectively, the incidence of events was high but comparable to that of previous series with metal stents; the implications of malapposed struts and the episodes of in-BVS thrombosis will require further assessments. Finally, the evidence that the majority of the lesions was covered by a high-intensity, low-attenuation layer suggestive of fibrotic neointima as well as the normalization of endothelial responses in about 50% of the lesions provide a biological background for the use of BVS in the treatment of culprit lesions and provide the rationale for a large-scale, long-term follow-up trial.
WHAT IS KNOWN? Outcome data on the use of BVS are to date limited to simple, stable lesions; these studies report a normalization of vascular function as early as 1 year after scaffold implantation. The physiology and pathology of thrombotic lesions is however radically different, and these data cannot be directly extrapolated to the setting of acute coronary syndromes. In this setting, only short-term clinical follow-up data are available, and no information from intracoronary imaging and vasomotion tests has been reported.
WHAT IS NEW? We report clinical, intracoronary imaging and vasomotion data 12 months after BVS implantation in patients with thrombotic lesions: our data support the concept of vascular and lesion regeneration after scaffold implantation.
WHAT IS NEXT? Further data, with a longer follow-up, are now necessary.
The authors wish to thank Mrs. Julia Weber, Mrs. Clara Steffen, and Mr. Jonas Obitz for their dedication and work.
Drs. Gori, Hink, and Münzel have received speaker fees from Abbott Vascular and/or St. Jude Medical. Dr. Schulz has held presentations for Abbott Vascular. Abbott Vascular had no role in any phase of this research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- bioresorbable scaffolds
- minimum lumen diameter
- optical coherence tomography
- quantitative coronary angiography
- ST-segment elevation myocardial infarction
- Received September 30, 2014.
- Revision received December 5, 2014.
- Accepted December 18, 2014.
- American College of Cardiology Foundation
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