Academic Editor: Federico Ronco
Coronary angioplasty was first introduced in 1977. From plain old balloon angioplasty to the introduction of bare metal stents in 1986 and dual antiplatelet therapy in 1992 to much more later on. Due to the unacceptable rate of stent restenosis, drug eluting stents (DES) were introduced in 2000. The first generation showed an increase in late stent thrombosis which led to the introduction of the second generation DES with biocompatible or biodegradable polymers and thinner platforms. However very late stent thrombosis and late restenosis might still pose problems in the latter. Furthermore, there has been major debate regarding the impact of long-term vessel caging on normal vasomotricity and long-term positive remodeling. To resolve these issues, the bioresorbable vascular scaffolds (BVS) were launched into the real world in 2011, showing promising initial results. Multiple randomized trials, meta-analyses, and registries were performed, mainly with the Absorb Bioresorbable Vascular Scaffold System (Abbott Vascular, Chicago, IL, USA). This new technology is hindered by certain features, such as the BVS radial strength, its strut thickness, and the inflammatory process related to scaffold degradation. Moreover, there is known data indicating higher thrombosis rate with the Absorb BVS compared with the new generation of DES, despite similar cardiovascular death. In this review, we discuss the clinical procedural and technical evidence on BVS, with emphasis on their clinical impact. We finally tackle the future directions on device and procedural improvement while asking: is the bioresorbable technology still the way to the future?
Drug-eluting stents (DES) caused a remarkable reduction in the restenosis rate [1], but led to a progressive increase in late stent thrombosis (ST) [2]. The latter was reduced with the development of second-generation DES which provided thinner struts with a biocompatible or biodegradable polymer. Despite that, there still remains cases where ST - especially very late ST (VLST) - and late restenosis occur [3]. ST remains an issue due to the permanent metallic struts, possible inflammation caused by polymer degeneration, and/or negative effects of antiproliferative drugs on endothelial regeneration. Furthermore, long-term vessel caging impairs arterial physiology impeding normal vasomotricity while promoting long-term positive remodeling. With all that, DES still conferred excellent outcomes with very low restenosis rates and even much lower VLST (occurring more than 1 year).
In 2000, the first in man use of the self-degrading Igaki-Tamai coronary stent [4] -the first bioresorbable vascular scaffold (BVS or BRS)- showed favorable outcomes. BVS necessarily had to be compared to DES which already conferred very low rates of adverse events. In 2011, BVS were finally introduced into clinical practice, showing good initial short term outcomes [5]. It was thought they conferred multiple advantages over metallic stents including: reduction in long-term adverse effects of permanent materials, restoration of vasoreactivity in the long term, maintaining the applicability of future treatment options for multivessel disease and long lesions, use in STEMI patients who might have less extensive disease, pediatric applications and the relevance to perform noninvasive imaging, such as computed tomographic angiography or magnetic resonance imaging [5, 6].
Several studies were conducted, mainly with the Absorb BVS System (Abbott
Vascular, USA), with nearly 200,000 devices implanted worldwide by June 2017 [7].
The Absorb BVS consists of a 150-
Intracoronary imaging (ICI) studies highlighted the potential advantage of BVS showing recovery of pulsatility at 12 months, and late lumen gain with plaque regression between 2 and 5 years [5, 6]. However, multiple studies showed that those scaffolds still had multiple limitations like low radial strength while having thick struts. This made BVS less ideal for complicated and calcified lesions where deliverability and stent expansion would be problematic. Furthermore, there was concern regarding higher episodes of stent thrombosis that was seen in the Absorb BVS as compared to DES. This was postulated to be due to scaffold degeneration causing local inflammation and consequently thrombosis.
In this review, current data regarding technical and clinical evidence on BVS will be discussed while considering future directions.
Several BVS with variable resorption from 1 to 3 years have been examined in clinical trials. All are impregnated with an antiproliferative limus family drug. The characteristics of the main promoted BVS are summarized in Table 1. The clinical/historical data are outlined as follows:
Scaffold | Manufacturer | Polymer | Eluted drug | Strut thickness (μm) |
Radial Strength (kPa) |
Resorption time (months) |
Development status |
Igaki-Tamai | Kyoto Medical | PLLA | None | 170 | 73 | 24-36 | CE mark |
Absorb 1.1 | Abbott Vascular | PLLA | Everolimus | 156 | 250 | 24-48 | CE mark - FDA |
DESolve | Elixir Medical | PLLA | Novolimus | 150 | 218 | 12-24 | CE mark |
Magmaris | Biotronik | BIOlute coating | Sirolimus | 150 | 313 | 12 | CE mark |
ART 18Z | Terumo | PDLLA | drug free | 170 | NA | 18-24 | CE Mark |
CE, Conformité Européenne; NA, not available; PDLLA, poly dl lactic acid; PLGA, poly lactic-co glycolic acid; PLLA, poly l lactic acid; PTD-PC, poly-tyrosine-derived polycarbonate. |
It’s made from non-drug-eluting, high-molecular-weight poly-l-lactic acid (PLLA)
monofilaments [4] with a helical coil pattern and a strut thickness of
170
Clinical trial (year) | Number of patients (BVS : DES) | Primary end point | Primary outcome | DOCE rate (%; BVS vs. DES) | Scaffold thrombosis rate (%; BVS vs. DES) |
ABSORB II (2015) | 501 (2 : 1) | Vasomotion/minimal lumen diameter (3 years) | Ongoing (3‑year follow‑up) | 5 vs. 3 (P = 0.35) | 0.9 vs. 0 (P = 0.55) |
ABSORB China (2015) | 480 (1 : 1) | In‑segment lumen loss (1 year) | 0.19 |
3.4 vs. 4.2 (P = 0.62) | 0.4 vs. 0 (P = 1.00) |
ABSORB Japan (2015) | 400 (2 : 1) | Target-lesion failure (1 year) | 4.2% vs. 3.8% (P |
NA* | 1.5 vs. 1.5 (P = 1.00) |
EVERBIO II (2015) | 240 (1 : 2)‡ | Late lumen loss (9 months) | 0.28 |
12 vs. 9 (P = 0.6) | 1.3 vs. 0 |
STEMI-TROFI II (2015) | 191 (1 : 1) | Healing score§ (6 months) | 1.74 vs. 2.80 (P |
1.1 vs. 0 | 1.1 vs. 0 |
ABSORB III (2015) | 2,008 (2 : 1) | Target-lesion failure (1 year) | 7.8% vs. 6.1% (P = 0.16, P |
10.9 vs. 7.8% (P = 0.03) | 1.5 vs. 0.7 (P = 0.13) |
AIDA-2015 | 1,845 | 24-month TVF | 11.7% vs. 10.7% (P = 0.43) | NA* | 3.5% vs. 0.9% (hazard ratio, 3.87; P |
BVS, bioresorbable vascular scaffold; DES, drug-eluting stent; DOCE, device-oriented composite end point; NA, not available; P |
Based on the above data, the Food and Drug Administration released a safety alert in March 2017 recommending the adherence to dual antiplatelet therapy (DAPT) during BVS use while avoiding their use in small vessels to help decrease MACE [15].Three-year data for the ABSORB III trial then came out with the BVS group having higher event rates than EES, particularly TVMI and DT. Finally, a recent 5-year Follow-Up of the ABSORB III Trial, showed a higher rate of cumulative adverse event after BVS compared with EES which mainly ended at 3 years, coincident with complete scaffold resorption [16].
Registries included a large number of patients with different plaque morphologies and clinical presentations allowing us to detect both common and uncommon features of using BVS. Stent thrombosis remained to raise a lot of concern which led to the design of randomized studies targeting that issue.
Initial registries were single centered and/or had 12 months’ short term follow up. For example, the ABSORB Extend study (first 512 patients enrolled; 12-month MACE 4.3) [18] showed that minor routine oversizing of the BVS followed by high pressure post-dilatation was safe with a low rate of MACE and no reported ScT. In the Polish National registry (591 patients) [19], in patients with acute coronary syndrome (ACS) and those with complex lesions, early in-hospital results showed no significant differences between BVS and EES in the primary composite MACE endpoint. More recently, in the RAI Registry, a total of 1,505 patients were enrolled with predilatation and post-dilatation performed in practically all the cases. At one-year follow-up, TLR and ScT rates were 3.3% and 1.3%, respectively. TLR was significantly higher in the off-label group (4.0% vs. 2.2%; P = 0.05) while a trend towards a higher ScT rate was observed in the off-label group (1.7% vs. 0.6%; P = 0.06). At multivariate analysis, treatment of in-stent restenosis, chronic total occlusion and BVS diameter were independent predictors of TLR [20].
In the large multicenter Ghost-EU registry, authors looked at 1189 patients who underwent angioplasty with the Absorb BVS [21]. The only independent predictor of TLF was diabetes (HR 2.41, P = 0.006) and TLF occurred at a rate of 4.4% at 6 months. The cumulative incidence for definite or probable ScT was concerning with 1.5% at 30 days and 2.1% at 6 months. Independent predictors in this registry included ostial lesions (P = 0.049) and impaired left ventricular ejection fraction (P = 0.019). In both this registry and the BVS registry Gottingen, the rates of device-related complications with BVS were not negligible and did not decline over time [22].
Finally, the ISAR-ABSORB registry included 419 patients (39% with ACS) undergoing PCI with BVS [23]. The incidence of TLR and definite ST at 12 months were 13.1% and 2.6% respectively. At 2 years, there was a 21.6% MACE rate and a 4.2% rate of proven or probable ST [23].
Lipinski et al. looked at 10510 patients treated with BVS where post-dilatation was performed in 52% of lesions. Compared to DES, there were higher rates of MI (OR 2.06, P = 0.002) and definite or probable ScT (OR 2.06, P = 0.03) in the BVS group [24]. No significant difference was found for all-cause and cardiovascular mortality.
Collet C. et al. looked at 16,830 patients treated with ABSORB. There was 1.8% overall rate of definite or probable ScT, and the residual diameter stenosis percentage was the only factor associated with ScT [25]. A similar meta-analysis of 1730 patients was conducted by the same authors with 24 months follow-up [26]. There was a higher incidence of DT in patients treated with Absorb BVS compared to those treated with EES, with 92% of the very late ScT occuring in the absence of DAPT. They also had a higher tendency for TLF (OR 1.48; P = 0.09) driven by a greater risk of TVMI and ischemia-driven TLR. No difference was found for cardiovascular mortality.
Polimeni et al. looked at 5219 patients and had similar findings for BVS with
higher rates of TLF (9.4% vs 7.2%; OR = 1.33; P = 0.008) and DT (2.3% vs
0.7%; OR = 3.22; P
Elias et al. looked at 3258 patients treated with BVS and 2319 with EES. The BVS
group had higher rates of TLF (OR 1.34; P = 0.003), definite/probable DT (OR
2.86; P
Sorrentino S et al. looked at 5,583 patients undergoing Absorb vs. metallic
EES with a mean follow-up of 2 years. There was a higher incidence of TLF (9.6%
vs. 7.2% with number needed to harm: 41; P
A meta-analysis by Cassese S et al. compared BVS vs. EES in 5583 patients for
mid-term clinical outcomes. BVS displayed a higher risk of TLF (odds ratio =
1.35; P = 0.0028) and ScT (OR 3.24; P
De Rosa et al. recent meta-analysis on 2,318 patients aimed to assess the safety and efficacy of everolimus eluting-BVS vs. EES in ACS patients undergoing PCI. There was a higher risk of definite ST/ScT in patients treated with BVS compared to EES (2.3% vs. 1.08%, P = 0.03) and an increased risk of TLR at mid-term (9.5 months) follow-up [31]. Finally, two recent meta-analyses done on 10 and 6 randomized controlled trials respectively with 3 years follow-up found that BVS was inferior to second-generation DES in both safety and efficacy [32, 33].
Mid-term outcome data for BVS and 2nd generation DES were compared in a recent systematic review and meta-analysis on a total of 1758 patients in the setting of ACS. BVS had higher risk of TLR and ScT at follow-up than the 2nd generation DES. ScT was the key factor determining the decreased safety and effectiveness of BVS relative to DES [34]. Other studies cited in this article (like AIDA and TROFI II trials) have also included patients with ACS and shown comparable results.
The prospective multicenter study RIBS VI included 141 patients treated with BVS for either BMS-ISR or DES-ISR. The study suggested that the use of BVS in patients with ISR was effective and safe. In this challenging anatomic scenario, BVS obtained late angiographic and clinical results similar to DEB but inferior to EES [35].
Like Absorb, the DESolve (Elixir Medical) BVS, has a PLLA backbone with a biodegradable polylactide-based polymer coating that elutes the antiproliferative drug novolimus. The unique features of the DESolve scaffold include (1) intrinsic self-correcting deployment that becomes operative in the event of minor strut malapposition, and (2) relative elasticity/ductility which provides a wide range of expansion without risk of stent fracture [36].
The first series of the DESolve showed a LLL at 6 months of 0.19
This BVS has a 170
It was developed in parallel to the PLLA polymeric scaffold [38]. However, RMS
has a good radial strength with minor early elastic recoil and a superior
compliance to vascular anatomy. They are electropolished which helps with
trackability. Their implantation is more practical because of single step
inflation. The safety and performance of the DREAMS 2G scaffold (i.e.
2
However, available evidence is currently limited to small observational studies. Positive outcomes have been reported for up to 3 years after second-generation drug-eluting RMS implantation in clinical trials. However, evidence is still lacking for this novel device, and more long-term clinical outcomes from the BIOSOLVE trials and further randomized trials involving other clinical and lesion subsets are needed in the future [39].
The main theoretical advantage for BVS was thought to be restoration of vasomotricity [6, 40]. Data from randomized trials showed that the restoration of vasoreactivity/vasomotion was directly proportional to the degree of BVS reabsorption -12 and 24 months after implantation- and was influenced by plaque composition and endothelial function [6, 40]. Furthermore, it was noted that the resorption process of the scaffold was variable depending on scaffold design and thickness along with certain patient characteristics [40]. For example, if the scaffold was overexpanded, it was associated with faster degradation and consequently high rates of restenosis [41]. With a similar restenosis rate as compared to everolimus-eluting stent (EES), the minimal lumen diameter (MLD) at 2 years was similar.
It was established that to obtain better outcomes with BVS and decrease the rates of ST [6], operators had to follow specific steps different from the routine steps for DES implantation. Oversizing Absorb BVS in small vessels was associated with a higher rate of (MACE) as compared to DES [42].
The key steps in BVS implantation, known as PSP (predilatation, sizing, postdilatation) are:
Step 1: Lesion preparation with predilatation
Operators are expected to use an appropriate size balloon to obtain a stent-like result before scaffolding with a theoretical benefit of decreasing ST.
Step 2: Sizing, stepwise deployment, and balloon inflation
Severe underexpansion was demonstrated in all reported cases of acute or
subacute BVS thrombosis [43], which underlines the importance of careful BVS
sizing. ICI might be used to accurately choose the right size BVS. Next,
deployment should be done gradually (2 atm every 5 seconds) up to 12 atm to avoid
proximal and distal injury [44]. Finally, balloon inflation should be maintained
for
Step 3: Postdilatation with a non-compliant balloon
It was shown that the lower the postdilatation rate the higher the rate of scaffold thrombosis (ScT). Deployment is completed with high pressure inflation of a non-compliant balloon with a nominal diameter up to 0.25-0.50 mm larger than the nominal scaffold diameter. The choice of balloon can also be guided by ICI that can detect insufficient expansion vs. scaffold undersizing. Differentiating between the two can help prevent rupture or stent fracture [6, 44].
The first issue is whether the clinical outcomes could be modified by improving the implantation technique. Studies have looked at the impact of device sizing and implantation techniques on acute device performance indices, including acute gain, expansion index, asymmetry index, eccentricity index, and strut embedment [45].
Optimal predilatation and postdilatation were expected to improve performance and reduce the rate of ScT from 3.3% to 1.0%, which still remained significant even after multivariate adjustment (hazard ratio, 0.19; P = 0.012) [43, 46]. However, this has not been proven by randomized studies.
The latest American guidelines advocate DAPT following DES for at least 6 months in patients with stable ischemic heart and for at least 12 months in patients with ACS [47]. However, the interruption of DAPT accounted for around 1/3 of BVS thromboses, and also VLScT. Stone G suggested that if intraluminal scaffold dismantling (ILSD) is visualized on OCT, prolonged DAPT has to be considered, especially in patients with low bleeding risk. Re-stenting with a metallic DES may also be appropriate in severe cases of ILSD [48].
Therefore, the increased risk of ScT up to 2 years provides a good rationale for continuation of DAPT for that period [47].
BVS differ from their metallic counterparts when it comes to their intrinsic mechanical properties [49]. They have sub-optimal ductility, which effects scaffold retention on balloon catheter and limits the range of scaffold expansion during deployment. Second, they have thick struts to offset their low radial strength and help prevent recoil during vessel remodeling. Finally, they have limited elongation-to-break, which defines the opening range of the BVS. This makes BVS less practical options for difficult lesions whether in tortuous vessels or calcified lesions, among others.
Imaging is crucial in assessing ScT, restenosis, and TVR in patients undergoing BVS implantation.
A systematic analysis of all reported ScT cases evaluated by ICI was conducted [49]. Malapposition (24%), incomplete lesion coverage (18%) and under-deployment (12%) were most frequently observed. In late/very late cases, malapposition (35%), late discontinuity (31%), and peri-strut low-intensity areas (indicating the presence of neointima [19%]) were the predominant features.
This provides evidence that optimizing stent sizing and deployment might help to decrease the potential risk of ScT [42, 49]. This, however, does not address late discontinuity and peri-strut low-intensity areas.
Late discontinuity is a benign change during the bioresorption process and doesn’t cause any complications if the scaffold struts are well covered by neointima. However, during bioresorption, struts might not be fully covered by neointima which brings thrombogenic proteoglycan into contact with blood; then, late discontinuity could be a malignant potential cause of VLScT [49].
That late discontinuity relative to ILSD was often observed by OCT imaging at the time of BVS VLST and was considered to be causally related to the thrombotic event [50].
Moreover, thick stent struts may lead to turbulence in flow and areas of oscillatory shear stress that could promote platelet activation or thrombogenicity especially when struts are left malapposed [51].
The first generation of BVS was limited by a high rate of scaffold restenosis and TVR, which was similar to that reported for BMS [52]. Such event could be related to either a suboptimal elution of antiproliferative drug or the complex implantation technique required and the subsequent injury. ICI including 3D OCT in symptomatic BVS restenosis showed extensive neointimal thickening [53].
Newer BVS with better characteristics were reported, with promising results (Table 3):
Scaffold | Manufacturer | Backbone | Coating | Eluted drug | Strut thickness (μm) | Resorption time (months) | Development status |
DESolve Cx | Elixir | PLLA | Biodegradable polymer | Novolimus | 120 | 2 years | CE mark |
Absorb BVS gen 2 | Abbott Vascular | PLLA | poly-lactic-co-glycolic acid | Everolimus | 36 months | CE mark | |
MeRes 100 | Meril life Sciences | PLLA | PDLLA | Sirolimus | 100 | 50% at 4-6 mo; complete resorption |
CE mark |
FORTITUDE | Amaranth Medical | Ultra-high molecular-weight PLLA | PDLLA | Sirolimus | 150 | 10 mo | CE mark |
Mirage | Manli Cardiology, Siingapore | PLLA | PLLA | Sirolimus | 125 | CE mark | |
Firesorb | Shanghai MicroPort Medical | PLLA | PDLLA | Sirolimus | 100-125 | 3 years | CE mark |
DOCE indicates device-oriented composite end point; MACE, major adverse cardiac event; NA, data not available; PLLA, poly-l-lactide; PDLLA, poly(l-lactide-co-d, llactide); POCE, patient-oriented composite end point; RCT, randomized controlled trial; ScT, scaffold thrombosis; and TVF, target vessel failure. |
• The DESolve Cx novolimus-eluting BVS, Elixir
• The Absorb BVS 2nd generation, Abbott Vascular
• The MeRes100 sirolimus-eluting BVS, Meril Life Sciences
• The Fortitude, Magnitude, and Aptitude sirolimus eluting BVSs, Amaranth Medical
• The MIRAGE sirolimus-eluting bioresorbable microfiber scaffold (Manli Cardiology, Singapore)
• The Firesorb sirolimus-eluting BVS, Shanghai MicroPort Medical
Therefore, thinner struts, lower crossing profile, and fast resorption characteristics could be the way to go. Also, obtaining strong radial force because of new post-processing of the polymer looks encouraging and might help improve outcomes.
The added value of this “vascular restoration therapy” is still waiting for a
proof of evidence, while safety concerns are already known, together with the
challenging device implantation, the worse trackability, the longer procedural
times, and the larger amounts of contrast used [52]. Furthermore, the PLLA based
BVS have lower tensile strength ranging from 45 to 70 MPa compared with 1449 MPa
for cobalt-chromium based stents. The elongation at break for polymers is 2% to
6% compared with 40% for metallic stents [52, 54]. These gaps in mechanical
properties are a challenge to overcome, and despite the progress in improving the
polymer composition, structure, and production process, the performance of the
currently available polymer-based BVS technology appears to remain inferior to
the second-generation metallic DES. Late dismantling of the polymer can also
occur at the final stages of resorption, with the risk of ScT [50]. To overcome
the tensile strength and stiffness deficiency, the first-generation BVS structure
consisted of thick struts (150
To address that issue, ABSORB IV was a prospective, randomized study, a
continuation of ABSORB III. However, two new criteria were implemented: all
treated vessels had to have a RVD of
The Resorbable Magnesium scaffold appears to have better mechanical properties compared with PLLA-based polymers, with tensile strength ranging from 220 to 330 MPa and elongation at break of 40%. The RMS may become the way to go especially that it combines the physical properties of the metallic stents while being the fastest-dissolving device currently available, over just a 12-month period [38, 54]. Up to 3 years post implantation, RMS had good outcomes with only 2 ScT reported so far having strut malapposition as their underlying cause [39]. More data are still needed to prove their non-inferiority as compared to DES.
In summary, and to date, BVS have failed to demonstrate a clinical benefit over the conventional metallic stent. Further development of the bioresorbable technology is needed to overcome the limitations of first-generation BVS [56].
To conclude, this review article aimed to be broad, comprehensive and updated concerning the actual knowledge on BVS. Thinner struts, newer design characteristics, appropriate patient selection, and standardized techniques of implantation may lead to better outcomes and improve the care of our patients. In EuroPCR 2018 [57], Gregg Stone said that “we’ve learned a tremendous amount”, and with the ongoing developments “we can get very close, if not equivalent, to metallic DES. And then the promise comes after 3 years”.
NA designed and drafted this work. WS critically revised this work. All authors gave final approval.
Included in the submission.
The authors declare no acknowledgments.
This research received no external funding.
The authors declare no conflict of interest to report.