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Bioresorbable coronary scaffold systems

Bioresorbable scaffolds have shown promising results when implanted in simple lesions. New generation platforms are eagerly expected to challenge the signals of increased scaffold thrombosis

Vasileios F Panoulas MD MSc MRCP PhD
National Heart and Lung Institute,
Imperial College London, UK
Alfonso Ielasi MD
Cardiology Department, Bolognini Hospital, Seriate (BG), Italy
The introduction of bioresorbable scaffolds (BRS) has changed the landscape of percutaneous coronary revascularisation and is considered the fourth revolution in interventional cardiology. To date, BRS have shown promising short and long-term results in the treatment of simple de novo lesions. Results from real-world registries have also reported acceptable short and intermediate-term outcomes with BRS, albeit with some signals for increased rates of early stent thrombosis. New generation scaffolds with thinner struts have emerged and are promising improved outcomes. In this review we discuss the currently available evidence behind the commercially available scaffolds and future perspectives of the BRS field. 
Despite improvements in the safety profile of drug-eluting stents (DES),1 late lumen loss (LLL), stent thrombosis (ST) and permanent vessel caging remain inherited limitations. BRS provide temporary support to the vessel wall with a scaffold that will subsequently disappear in approximately three years. Even though increases in the plaque size in the first couple of years post-implantation have been observed compared to their metallic counterparts, BRS compensate by facilitating plaque regression2 and by promoting expansive remodelling3 at long-term follow-up. 
Despite the positive experience with BRS in de novo simple lesions, the efficacy and long-term behaviour of this new technology implanted in complex lesions remains unknown. Recently several real-world registries have emerged, reporting their early experience with BRS. The BRS currently approved for clinical use in Europe include the everolimus-eluting Absorb v1.1 bioresorbable vascular scaffold (BVS, AbbottVascular, CA, USA) and the novolimus-eluting DESolve BRS (Elixir Medical Corporation, Sunnyvale, CA, USA), both made of poly-L-lactic acid (PLLA) which degrades gradually over time via hydrolysis.
The initial experience with BRS implantation in de novo simple lesions has been promising with excellent long-term outcomes (major adverse cardiovascular events, MACE 3.4%). In the ABSORB Cohort A, 30 patients with single de novo lesions were treated with Absorb v.1.0. At five years there was an increase in minimal luminal diameter and area which was primarily attributed to a persistent reduction in plaque area size.4 The ABSORB multi-imaging modality study (45 patients [cohort B1] and 56 patients [cohort B2]) revealed unchanged LLL after the first year of Absorb 1.1 implantation, whereas on intravascular ultrasound (IVUS), mean lumen, scaffold and vessel area showed enlargement up to two years.5 Between the second and third year there was a significant reduction in the plaque area behind the struts. 
In the three-year period, the MACE rate was 10%.6 In the ABSORB II randomised controlled trial,7 335 patients treated with Absorb v1.1 were compared to 166 patients treated with a permanent metallic everolimus-eluting stent (EES, Xience, Abbott Vascular, Santa Clara, CA, USA). The ABSORB II included patients with one or maximum two de novo relatively simple lesions (ostial, left main, bifurcation, chronic total occlusion, heavily calcified or in-stent restenosis lesions were all excluded). 
Despite the lower post-implantation acute lumen gain observed in lesions treated with BVS, one-year target lesion failure (TLF, composite of cardiac death, target vessel myocardial infarction or clinically indicated target lesion revascularisation [TLR]) was similar between the two groups (BVS versus EES; 5% versus 3%, p=0.35).  Early experience with other BRS platforms has also been favourable for simple de novo lesions. In its first clinical evalutation,8 the DESolve (Elixir Medical, Sunnyvale, CA) novolimus eluting BRS was implanted in 16 patients with de novo simple coronary artery lesions. At 12 months, no MACE directly attributable to the BRS occurred whereas LLL at six months was 0.19±0.19mm. In the DESolve NX study (120 patients), the DESolve, BRS demonstrated a TLR of 1.6% and MACE of 3.25% at six months.9
Simple de novo lesions however only reflect a very small portion of real-world practice. In the last year initial evidence from the use of Absorb v1.1 BVS in real-world registries has emerged. A small propensity matched study from Costopoulos et al.10 demonstrated similar 1-year MACE (3.3% versus 7.6%, p=0.19) in all-comer patients treated with Absorb v1.1 versus newer generation EES, respectively. The multicentre GHOST-EU registry11 consisting of 1189 patients is the largest “all-comers” BVS registry to date. 
The TLF rate was 3.5% at the median follow-up time of 109 days. Despite the acceptable 4.4% Kaplan Meier estimated TLF at six months, the GHOST-EU registry revealed some worrying signals of scaffold thrombosis (1.5% at 30 days, 2.1% at six months), which exceeds the incidences reported in newer generation DES all-comer registries. In the Dutch AMC (Academic Medical Center) registry,12 where 135 real-world patients (159 lesions) treated with the Absorb v1.1 were followed-up for six months, the cumulative TVR rate was 8.5% including a 6.3% TLR rate, a 3% rate of MI and a 3% rate of definite scaffold thrombosis (three subacute and one late), concurring with the GHOST-EU findings. 
In the BVS Expand13 single centre registry (200 patients), which excluded patients with STEMI and  previous CABG, the six-month MACE rate was 3.3%, TLR 2.2%, MI 1.7%, whereas four (2.2%) definite scaffold thrombosis occurred. The findings from all these studies (GHOST-EU, AMC, BVS Expand) suggest that the current BRS generation, which is characterised by significantly thicker and wider struts (~150×200μm), compared to new generation DES (80×80μm) may be more thrombogenic, particularly when under-expanded or malapposed. 
This highlights the importance of an optimal scaffold implantation technique using intracoronary imaging. In the German multicentre ASSURE (ABSORB: Postmarketing Surveillance Registry to Monitor the Everolimus-eluting Bioresorbable Vascular Scaffold in Patients With Coronary Artery Disease) registry,14 183 patients treated with Absorb v1.1 were followed up for one year. Of note, this study excluded long lesions (defined as >28mm) and lesions with a vessel diameter of >3.3mm. 
The one-year MACE rate was 5%, TLR 2.8%, MI 1.6%, whereas no scaffold thrombosis was observed. The ABSORB first registry15 is a multicentre (1200 patients), prospective global registry of real-world patients treated with the Absorb v1.1. In the first 30 days, total rate of MI was 0.8%, whereas no cardiac deaths were reported. Definite or probable scaffold thrombosis rates were 0.42%, almost a third of those reported in the GHOST-EU. 
A number of studies have emerged for the use of Absorb v1.1 BVS in particular lesion subjects. Naganuma et al.16 presented data on BVS treatment of bifurcation lesions (SB ≥2.25mm), in a cohort of 63 patients, 48 (68.5%) of whom had true bifurcation lesions. Out of 70 bifurcations treated, provisional stenting technique was selected for the majority (50/70, 71.4%) whereas systematic double stenting was reserved for 14 (20%) cases. At a median follow-up of 182 days, three (4.8%) MACE, no deaths, three (4.8%) TVR, two (2.9%) TLR and no scaffold thrombosis were observed. 
In vitro studies17,18 suggest that: (1) provisional stenting with proximal optimisation technique should be the preferred strategy where feasible; (2) final kissing balloon (FKB) should only be performed when deemed necessary rather than as routine practice (FKB-mini kissing at low pressure with minimal protrusion of the SB balloon does not appear to be associated with in vitro scaffold disruption18); (3) when a crossover to a two-stent technique is deemed necessary, T-stenting and small protrusion (TAP) in high angle bifurcations ≥75o and mini-crush with a DES in the SB for angles <75o are feasible options. 
When treating bifurcations with BRS, one should keep in mind the higher incidence of post-procedural SB occlusion compared to EES19, a complication more pronounced with small SB with a reference vessel diameter ≤0.5mm. The role of BVS in the treatment of in-stent restenosis (ISR) has been evaluated in a small study (25 patients) by Ielasi et al.21 At a mean follow up of nine months TLR was observed in two patients (8%) and was successfully treated with re-PCI, whereas non-target vessel MI was seen in one patient (4%). 
Another candidate subset of lesions to be treated with BVS are ostial lesions where suboptimal DES positioning can either lead to geographic miss or floating struts.20 Gori et al.21 were the first to put BVS to the test by reporting the first clinical data on angiographic and short-term clinical outcomes of BVS implanted in 37 patients for the treatment of ostial lesions. At six months follow-up there was one death of unknown cause and one definite scaffold thrombosis. 
Treatment of diffuse disease with BVS, offering a ‘cage-free’22 approach to intervention, appears most appealing for the treatment of this lesion subset. Kawamoto et al.23 in a study of 23 patients treated with ‘full plastic jacket’ (defined as a continuous segment of overlapping Absorb v1.1 measuring 60mm or more) report an estimated one-year MACE of 19.2% mainly driven by TLR (18%). These results are acceptable when comparing them to one-year outcomes of full metal jacket (MACE 18.2%).24
Treating chronic total occlusions (CTO) using BVS is also an appealing strategy. A case series of ten patients with CTOs treated with BVS by two expert CTO operators25 was reported by Garbo et al. In eight cases the CTO involved the RCA, total stent length was 85mm and on average 3.6 stents were used. At a mean follow-up time of six months no events were noted. Long-term results from large CTO BRS registries are eagerly awaited and expected to revolutionise the field.
BRS implantation for left main (LM) lesions is associated with particular challenges. These include the larger size of LM, which often exceeds the dilatation limit of 4.2mm of the Absorb v1.1 3.5 mm and even the 4.5mm limit of other platforms such as the DESolve. Furthermore LM bifurcation stenting can be challenging particularly when operators wish to perform kissing balloon inflation in a SB with a reference vessel diameter of >2.5–3.0mm. In a case series of three patients treated with Absorb v1.1, Miyazaki et al.26 described LM lesions ‘suitable’ for BRS stenting; these include ostial LAD lesions (Medina 0.1.0) requiring crossover stenting and distal bifurcation lesions not involving the LCx ostium. 
BRS implantation is not recommended for cases where the LCx ostium is larger than 3.0mm and requires intervention due to large plaque burden. BRS implantation could be feasible even for vessel sizes of more than 4.2mm as long as the lesion characteristics do not allow expansion of lumen diameter to more than 4.0mm. These recommendations, however, should be viewed with caution and large studies with long-term follow-up are eagerly awaited to establish the role of BVS stenting in LM disease.
The role of BVS in the treatment of STEMI has also been a matter of interest. In the ‘Prague 19’ study,27 142 consecutive patients presenting with ST elevation were treated with Absorb BRS or DES. BRS were not implanted in long (where more than one scaffold was needed), calcific or tortuous lesions, in cases with RVD lower than 2.3mm or higher than 3.7mm, in the presence of ST, poor antiplatelet compliance, anticoagulation or comorbidity with limited survival expectancy. 
As such, patients treated with BRS (about 30% of the total STEMI population) were lower risk patients with very low diabetes (2.5% versus 24.6%, p=0.003) and prior MI prevalence (2.5% versus 12.3%, p=0.137) compared to the controlled group treated with metallic stents.  Authors report a case of sub-acute thrombosis after cessation of the dual antiplatelet therapy. During the short-term follow-up (less than half of the patients followed-up at six months), a total of two patients suffered a MACE in the BRS compared to four in the metallic stent group. 
No statistical significance was observed in outcomes between the two groups, however caution is recommended due to the small sample sizes and the unadjusted baseline confounders (for example, diabetes). In another relatively small registry, Diletti et al.28 described their experience in BRS implantation in 49 STEMI patients. Of the total 267 consecutive STEMI patients in the study period, 49 (18%) were included in the study (exclusion criteria included previous metallic stent, left main disease, previous CABG, age >75 years). 
Device success was 97.9% whereas at OCT analysis 7/31 patients (22.6%) had >5% malapposed struts. This could be attributed to the low rate of post-dilatation (20.4%) in the STEMI setting. With regards to outcomes, only one NSTEMI case occurred in a non-target vessel whereas no cases of scaffold thrombosis were recorded, suggesting that BVS implantation in STEMI patients is feasible. 
In the largest multicentre registry of BVS to date use in STEMI (the Italian RAI registry),29 74 (out of a total of 1232) consecutive STEMI patients were treated with Absorb v1.1 with procedural success of 97.3% (one patient experienced a reinfarction due to subacute BRS thrombosis whereas another had slow flow phenomenon). At six-month follow-up, two non-fatal MI (2.7%), three target lesion revascularisations (4.1%), and one subacute BVS thrombosis were reported.
BRS are a promising new technology still in its early stages. Questions remain on the efficacy and performance of BRS in the long run, the optimal duration of dual antiplatelet therapy, the short and long-term outcomes in the treatment of complex lesions and their head-to-head comparison with new generation DES. 
In May 2014, Elixir Medical Corporation (Sunnyvale, CA, United States), received CE (Conformité Européenne) Mark approval for its DESolve® 100μm Novolimus-Eluting Bioresorbable Coronary Scaffold System, whereas other manufacturers (Absorb, REVA, ART, Xinsorb, IDEAL, Acute etc.) are also working on reducing strut thickness, increasing radial strength, increasing size range, reducing absorption time to approximately one year and improving BRS deliverability. 
These improved technical characteristics will enable BRS to tackle the majority of complex lesions, whilst minimising procedure times and optimising future outcomes.
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