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Current and future perspectives on drug-eluting bioresorbable coronary scaffolds Alfonso Ielasi*,1 & Maurizio Tespili1
ABSTRACT: Despite improvements in stent platform, polymer and drug elution, the permanent metallic stents have significant limitations as they distort vessel physiology, predispose to late thrombosis and may preclude surgical revascularization. Bioresorbable scaffold (BRS) technology has evolved over the last few years to overcome these drawbacks. Actually, different BRS are either available or under clinical and preclinical investigation. However, the use of BRS has largely been restricted to patients recruited into clinical trials with a relatively small number of ‘real world’ patients treated with these devices. Here, we highlight the potentialities of these devices, describe the evidence from the recent clinical trials and discuss the potential advantages, as well as challenges, that this novel technology may face in routine clinical practice. Background The landscape of percutaneous coronary intervention (PCI) has evolved dramatically over the last 35 years. At the beginning, plain old balloon angioplasty (POBA) revolutionized the treatment of coronary artery disease. However, the outcomes following POBA were compromised by re-narrowing due to elastic recoil, abrupt coronary occlusion secondary to severe dissection and neointimal hyperplasia [1–3] . The advent of bare-metal stents (BMS) reduced both the re-narrowing rate and the risk of acute vessel occlusion compared with POBA [2,4] . However, new problems such as restenosis emerged [5] . The introduction of drug-eluting stents (DES), which were developed by coating BMS with antiproliferative drugs (i.e., sirolimus or paclitaxel), significantly reduced restenosis and target lesion revascularization (TLR) rates compared with BMS [6,7] . DES, which were considered the third revolution in interventional cardiology, broadened the applications of PCI particularly in complex subset of lesions and high-risk patients [8,9] . However, first-generation DES were associated with an increased risk of very late stent thrombosis (ST) [10–12] , but newer-generation DES, with thinner struts and biocompatible or biodegradable polymers, have a considerably improved safety profile [13–15] . Although DES technology seems to cover the needs of the interventional cardiologists, they cannot be considered the optimal solution as they permanently trap the coronary into a metallic cage. The presence of a foreign body within the artery wall can be a source of chronic inflammation and may interfere with the endothelial function, delaying the vessel wall healing that is associated with a higher risk of ST [16–18] . In addition, it has been demonstrated that stent implantation has an unfavorable effect on the geometry of curved arteries; however, it is unknown if this alteration may be associated with increasing risk for neointima hyperplasia. Other important drawbacks of the metallic stents is the risk of precluding surgical revascularization when implanted in potential ‘anastomotic’ segments of the coronary tree. Thus, the ideal solution would be a transient bioresorbable
KEYWORDS
• bioresorbable scaffolds • coronary angioplasty • drug-eluting stents
Division of Cardiology, ‘Bolognini’ Hospital, Via Paderno 21, 24068, Seriate (BG), Italy *Author for correspondence: Fax: +39 035 3063635; [email protected] 1
10.2217/FCA.14.14 © 2014 Future Medicine Ltd
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Review Ielasi & Tespili scaffold (BRS) that would accomplish the same goals as metallic DES within the first year after implantation (seal dissections, prevent abrupt vessel closure and suppress neointimal hyperplasia) and would then disappear, allowing the vessel to return to its natural state whilst maintaining access for future surgical revascularization, if required. The absence of a rigid permanent cage may result in restoration of endothelial function and shear stress, reducing the risk of late events and favoring positive remodeling of the vessel. These benefits may also result in reduced need for long-term dual antiplatelet therapy (DAT). Today, several BRS are available but only two devices have acquired Conformité Européenne (CE) mark approval and only one is currently used in clinical practice. Here, we provide a brief overview of the available (under development or under preclinical validation or undergoing clinical trials) drug-eluting BRS and discuss the potential additional advantages and limitations that these devices may have in everyday clinical practice. Drug-eluting BRS ●●ABSORB bioresorbable vascular scaffold
The ABSORB bioresorbable vascular scaffold (BVS; Abbott Vascular, Santa Clara, CA, USA) constitutes semicrystalline poly-l-lactic acid (PLLA) coated with amorphous poly-d,l-lactide polymer eluting everolimus. Degradation of the bioresorbable components (PLLA and polyd,l-lactide) of the scaffold is mainly through hydrolysis, followed by macrophage phagocytosis of the resulting degradation products, a process that is completed within 3 years [19] . Two versions of the BVS have been assessed in clinical trials. The safety and feasibility of the BVS 1.0 was tested in the open-label prospective ABSORB Cohort A’ trial [20] . At 6 months, the angiographic in-stent late lumen loss (LLL) was 0.44 mm with evidence of scaffold shrinkage (-11.8%) as measured by intravascular ultrasound (IVUS). However, vasomotion appeared to be restored with induced vasoconstriction and vasodilatation possible in the treated segment [21] . To prolong the mechanical BVS strength and reduce late recoil, a second generation BVS (1.1) has been introduced. Of note, BVS 1.1 has a smaller maximum circular unsupported surface area [22] , a more uniform strut distribution and improved stent retention. Importantly, these changes have not resulted in an increased amount of polymeric material or an increase in
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strut thickness. Proprietary process changes have been implemented to increase radial strength. In addition, these changes have reduced polymer degradation rates at early time points and thus prolonged mechanical integrity of the scaffold throughout the first few months following implantation [23] . The efficacy of the BVS 1.1 was assessed in the ABSORB Cohort B trial which recruited 101 patients with single or two-vessel de novo disease all receiving a 3.0 × 18 mm BVS. At 6-month follow-up, there was only 1 TLR and LLL was 0.19 ± 0.18 mm. At 2 years, LLL was 0.27 ± 0.20 mm. Scaffold area progressively increased during follow-up although at 6 months there was significant reduction in minimal lumen area on IVUS as compared with baseline (6.60 ± 1.22 to 6.37 ± 1.12 mm 2 ; p 2.0 mm), as well as those with long lesions thus giving the opportunity to evaluate the BVS performance in both these groups. An interim report on the 24-month clinical outcomes from the first 250 patients enrolled showed MACE and target vessel failure rates of 4.4 and 4.8%, respectively [29] . Recently, the first 450 patients enrolled in this trial have completed 12 months follow-up and an interim report presented seven cases (1.5%) of device failure [30] . In particular, scaffold dislodgement occurred in 3 (0.67%) cases, while subacute or late scaffold thrombosis occurred in four (0.89%) cases. All scaffold dislodgements occurred in the left circumflex, and in two cases dislodgement was observed after reinsertion of the same device. The friction between the thick (156 μn) polymeric
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BVS struts with large crossing profiled and a tortuous/calcified vessel or a daughter catheter (i.e., Guideliner), may result in device dislodgement when forcefully pushing the scaffold. Among the scaffold thrombosis, two out of four cases seemed to be related to either premature DAT discontinuation (less than 30 days) or resistance to clopidogrel, while one case occurred at the site of overlapping scaffold [30] . Even if in the ABSORB trials DAT was mandatory for at least 6 months, its optimal duration is, however, unknown and in particular cases such as overlapping scaffolds, a relatively longer duration with more potent agents (i.e., ticagrelor or prasugrel) could be considered [30] . The prospective, randomized ABSORB II study will compare BVS 1.1 to the Xience Prime everolimus-eluting stent (Abbott Vascular) in patients with stable angina and single- or twovessel disease. The trial is expected to complete in 2015. The multicenter, randomized ABSORB III trial aiming to recruit over 2000 patients with up to two de novo lesions in different epicardial vessels (vessel diameter 2.5–3.75 mm, length ≤24 mm) and randomize these to BVS 1.1 or Xience Prime. Finally, the ABSORB IV study will aim to add another 4000 patients to ABSORB III in order to assess for BVS 1.1 superiority over Xience Prime with regards to TLF between 1 and 5 years. The Amsterdam Investigator initiated Absorb strategy all-comers trial is a prospective, randomized (1:1), active-control, single-blinded, all-comer, noninferiority study. About 2690 all-comer subjects will be enrolled in order to evaluate the efficacy and performance of the ABSORB BVS versus the Xience family in the treatment of coronary lesions. The study population includes both simple and complex lesions, in patients with stable and acute coronary syndromes. The follow-up continues for 5 years and the primary end point of the trial is target vessel failure, defined as the composite of cardiac death, MI and TVR at 2 years [31] . DESolve BRS The DESolve BRS (Elixir Medical, Sunnyvale, CA, USA) is made from a PLLA-based polymer eluting novolimus, a major metabolite of sirolimus. The DESolve is designed to be fully resorbed within 2 years. In the first-in-man (FIM) study, 15 patients with lesion length 6
On preclinical studies On preclinical studies
AMS: Absorbable metallic stent; CE: Conformité Européenne; NA: Not available.
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Review Ielasi & Tespili Table 2. Main bioresorbable vascular scaffold clinical trial. Scaffold
Clinical study
Number of patients
End points
Late loss (mm)
Target lesion revascularization (%)
Major adverse cardiovascular event (%)
ABSORB 1.0 ABSORB Cohort A ABSORB 1.1 ABSORB Cohort B
30
0.44 at 6 months
0 at 5 years
3.4 at 5 years
AMS-3 DREAMS
BIOSOLVE-I
46
DESolve
DESolve 1 DESolve Nx
15 120
REVA REVA ReZolve
RESORB RESTORE
27 50
Procedural success, 5-year MACE LLL, TLR and MACE at 6 months, and 1, 2 and 3 years Target lesion failure at 6 and 12 months LLL at 6 months Procedural success, LLL at 6 months and 5-year MACE MACE TLR at 6 months, LLL at 12 months
101
0.27 at 12 months 3.6 at 12 months
10 at 3 years
0.64 at 6 month, 4.3 at 6 months, 6.5 at 0.52 at 12 months 12 months
4.3 at 6 months, 6.5 at 12 months
0.19 at 6 months 0.21 at months
20 at 12 months 3.25 at 6 months
6.7 at 12 months 1.6 at 6 months
1.81 at 6 months 66.7 at 6 months 0.20 at 12 months 2 of 12 at 6 months
NA 2 of 12 at 6 months
AMS: Absorbable metallic stent; LLL: Late lumen loss; MACE: Major adverse cardiac events; TLR: Target lesion revascularization.
bioresorption. Furthermore, serial IVUS-virtual histology analysis demonstrated a reduction in dense calcium of 15.4 and 12.9% at 6 and 12 months, respectively, compared with postprocedure. This phenomenon was interpreted as a surrogate marker for the bioabsorption of the scaffold [40] . Minimal changes in arterial geometry The permanent metallic stents may modify arterial geometry and local hemodynamics contributing to neointimal proliferation and adverse events at follow-up [53,54] . BRS offer the potential advantage to avoid permanent vascular alterations. ABSORB BVS produces less alteration in vessel angulation and curvature than metallic stents [55] . Furthermore, ABSORB BVS has been shown to restore the coronary configuration to pre-implant level between 6- and 12-month follow-up [56] . Restoration of vascular physiology Different studies have reported an abnormal vasomotion in the coronary segment distal to the segment where a permanent DES was implanted [57] . This may restrict the distal flow and predispose to late thrombotic events at the stent site. BRS technology, which has been described as a vascular reparative therapy, promises the return to normal vessel biomechanics after complete scaffold bioresorption [58] . In the ABSORB Cohort A, an evaluation of the ‘scaffolded’ segment following intracoronary administration of acetylcholine suggested that the scaffolding
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function of the polymeric struts had completely disappeared and the ‘scaffolded’ segment could exhibit vasomotion at 2 years [59] . Magnesium BRS have also demonstrated the recovery of the responsiveness of the treated vessel to vasoactive agents [39] . Ability to cover vulnerable plaques Metallic stents do not seem to protect the vessel from neoatherosclerosis or plaque progression. Brugaletta et al. showed that the developed neointima after a BRS implantation covers the superficial plaques [60] . This is of great importance in case of vulnerable plaques (i.e., a thin cap fibroatheroma), which after the BRS deployment is likely to be transformed to a more stable one, namely thick cap fibro-atheroma. In this way, BRS may intervene in the atherosclerotic process providing a symmetrical uniform fibrous neointimal layer, which along with late lumen enlargement and lack of any permanent metallic vascular cage may help to stabilize and transform high-risk vulnerable plaques to be more stable [61] . This appealing idea is indirectly supported by studies on the concept of plaque passivation by stents [62] , and BRS providing a symmetrical and circumferential thick fibrous cap with functional endothelium, late lumen enlargement and normal shear stress distribution [61] . From clinical trials to clinical practice BRS may theoretically improve clinical outcomes in patients requiring revascularization as the absence of a permanent metallic cage
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Current & future perspectives on drug-eluting bioresorbable coronary scaffolds in the vessel wall may reduce chronic injury, predisposing to restenosis and ST. Currently available data has shown the complete biodegradation of the device at follow-up [40,63] , vessel remodeling with lumen gain over time [63] , and signs of physiological vasomotion of the ‘scaffolded’ coronary segment [21,40] . Furthermore, promising results have been shown in patients with simple lesions at different follow-up periods up to 5 years (Table 2) [32,40,63,64] . To date, the ABSORB is the only scaffold commercially available and the only one that has been used in everyday clinical practice. However, the experience with ABSORB was initially limited to younger patients with AHA/ACC Type A or B lesions in moderate-sized vessels [65] . Thus, there has been limited data about the ABSORB performance in
complex lesions such as thrombotic lesions, bifurcations, chronic total occlusions, calcified lesions, diffuse disease requiring overlapping scaffolds, restenosis, as well as in complex patients such as diabetics with or without multivessel disease. (Figures 1 & 2) Early, preliminary ‘real world’ experience with ABSORB [66] may allow drawing of suggestions on which patients/lesions are best suited for these devices. Aside from simple lesions, patients with long diffuse left anterior descending disease and those requiring multivessel revascularization are interesting candidates for ABSORB as the eventual resorption of the BVS within the following years may avoid a ‘full metal jacket’ that can predispose to ST and restenosis [67] . This is particularly important for younger patients since such an approach does not only
Long lesion involving the distal LAD
B
A Baseline
STEMI
E After BVS implantation
F Baseline
G
D Baseline
After BVS implantation NSTEMI
Recurrent in-stent restenosis
C
Review
After BVS implantation
H Baseline
After BVS implantation
Figure 1. ABSORB bioresorbable vascular scaffold use in every day clinical practice. (A) Long lesion involving the distal and mid left anterior descending artery (B) treated with multiple (2.5 × 18 mm, 2.5 × 28 mm, 3.0 × 28 mm and 3.0 × 18 mm) BVS implantion in overlap. (C) Recurrent in-stent restenosis in the first obtuse marginal (D) treated with 3.0 × 18 mm and 3.5 × 28 mm BVS implantation in overlap. (E) Acute thrombotic right coronary artery occlusion in the ST-elevation myocardial infarction setting (F) treated with a 3.5 × 28 mm BVS implantation. (G) Patient presented with NSTEMI due to subocclusive thrombotic lesion (H) treated with a 3.0 × 18 mm BVS in the proximal LAD. BVS: Bioresorbable vascular scaffold; LAD: Left anterior descending artery; NSTEMI: Non-ST-elevation myocardial infarction; STEMI: ST-elevation myocardial infarction.
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Chronic total occlusion
A
B Baseline
After BVS implantation Bifurcation lesion
D
C Baseline
After BVS implantation
Figure 2. ABSORB bioresorbable vascular scaffold use in chronic total occlusion and bifurcation lesions. (A) Long chronic total occlusion of the proximal left anterior descending artery, (B) treated with multiple (3.0 × 18 mm, 3.0 × 28 mm, 3.5 × 28 mm and 3.5 × 18 mm) BVS implantation from distal to proximal left anterior descending artery. (C) Left anterior descending artery bifurcation lesion at the first diagonal branch (D) treated with provisional strategy and 3.0 × 18 mm BVS implantation. BVS: Bioresorbable vascular scaffold.
maintain access for future bypass graft surgery if required, but also offers the possibility of further PCI treatment without the additional permanent metallic layers. However, it is important not to forget that there is no published data regarding clinical outcomes in complex lesions treated with BVS [66] . The importance of intravascular imaging, pre- and post-dilatation in optimizing scaffold implantation and expansion should not be underestimated, particularly in the case of complex lesions (i.e., long lesions, small vessels,
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calcified plaques) where the scaffold underexpansion may be associated with subacute or late thrombotic events. However, the importance of meticulous procedural technique cannot be overemphasized – it should take longer to implant a BVS as compared with a conventional DES. Conclusion BRS have been heralded as the fourth revolution in interventional cardiology. This novel technology not only provides transient scaffolding and
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Current & future perspectives on drug-eluting bioresorbable coronary scaffolds restores flow in the diseased segment, but also restores vascular integrity and function. Over recent years, huge improvements have been made in the field of BRS with encouraging data emerging from their use in clinical practice. The current results have provided promise for the future, although data regarding their use in complex lesions and long-term clinical outcomes in the ‘real world’ are lacking. The message that arises from their first applications is that BRS should not be considered as another type of stent, but as a totally different device that has special strengths, weaknesses and limitations, but also introduces a novel therapeutic potential. The BRS field is an exciting area where further improvements will advance PCI practice.
safety in complex subset of patients and lesions, allowing a concrete comparison versus the currently available new-generation ‘permanent’ metallic stents. BRS will hopefully improve on the already excellent results obtained with PCI, especially with regards to in-stent restenosis, ST and clinical outcomes in high-risk patients such as those with diabetes and long lesions. Undoubtedly, further technological refinements to overcome current challenges (i.e., reduce strut thickness without compromising radial strength and improving device deliverability, DAT duration and so on), and long-term safety and efficacy data from adequately powered clinical trials, are required to allow BRS to become mainstream for coronary intervention of the future.
Future perspective To date, most of the data for BRS use are derived from small, nonrandomized studies with short- or mid-term follow-up. Furthermore, very few data are currently available on the BRS performance in ‘real world’ patients. As further evidence emerges regarding their use, interventionalists will increase the use of these novel devices, for also the treatment of more complex lesions. This will shed more light regarding their efficacy and
Financial & competing interests disclosure
Review
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t-estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY Bioresorbable vascular scaffold technology & the beginning of the fourth revolution in interventional cardiology ●●
Although drug-eluting stent technology seems to cover the needs of the interventional cardiologists, they cannot be
considered the optimal solution as they permanently trap the coronary into a metallic cage. The presence of a foreign body within the artery wall can be a source of chronic vessel inflammation and may interfere with the endothelial function delaying the vessel wall healing that is associated with a higher risk of stent thrombosis. Thus, the ideal solution would be a transient bioresorbable scaffold (BRS) that would initially keep the vessel open as well as metal stents and would then disappear, allowing the vessel to return to its natural state. Different BRS are currently either being assessed in randomized clinical trials or are under development ●●
Today, several BRS are available: some of them are under development, some others are under preclinical validation, a
few are undergoing clinical trials and only two devices have acquired Conformité Européenne mark approval, but only one (ABSORB, biovascular scaffold; Abbott Vascular, CA, USA) is currently used in clinical practice. Promising emerging clinical evidences ●●
Data actually available suggest that the use of BRS in the context of clinical trials is associated with low rates of cardiac
adverse events in patients with simple lesions and at mid-term clinical follow-up, with the added advantage of not leaving a permanent ‘metallic’ trail behind, remodeling the vessel with lumen gain over time and restoring the normal vessel physiology after resorption. Future challenges ●●
Very few data are currently available on the BRS performance in ‘real world’, complex patients (acute coronary
syndrome, diabetics, multivessel diseases) and lesions (long lesions, bifurcation, restenosis, chronic total occlusions). Further data are needed in order to allow a concrete comparison versus the currently available new-generation ‘permanent’ metallic stents.
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Analyzes the vasoreactivity of a coronary segment, previously scaffolded by the ABSORB device, in relationship to its intravascular ultrasound-virtual histology composition.
60 Brugaletta S, Radu MD, Garcia-Garcia HM
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et al. Vascular compliance changes of the coronary vessel wall after bioresorbable vascular scaffold implantation in the treated
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JL et al. Plaque sealing and passivation with a mechanical self-expanding low outward force nitinol vShield device for the treatment of IVUS and OCT-derived thin cap fibroatheromas (TCFAs) in native coronary arteries: report of the pilot study vShield Evaluated at Cardiac hospital in Rotterdam for Investigation and Treatment of TCFA (SECRITT). EuroIntervention 8(8), 945–954 (2012). 63 Ormiston JA, Serruys PW, Onuma Y et al.
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Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting
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scaffold in patients with de novo coronary artery disease: the ABSORB Cohort A trial. JACC Cardiovasc. Interv. 6(10), 999–1009 (2013). •• Reports the longest follow-up currently available with a drug-eluting bioresorbable scaffold. 65 Liang M, Kajiya T, Lee CH et al. Initial
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Current and future perspectives on drug-eluting bioresorbable coronary scaffolds Alfonso Ielasi*,1 & Maurizio Tespili1
ABSTRACT: Despite improvements in stent platform, polymer and drug elution, the permanent metallic stents have significant limitations as they distort vessel physiology, predispose to late thrombosis and may preclude surgical revascularization. Bioresorbable scaffold (BRS) technology has evolved over the last few years to overcome these drawbacks. Actually, different BRS are either available or under clinical and preclinical investigation. However, the use of BRS has largely been restricted to patients recruited into clinical trials with a relatively small number of ‘real world’ patients treated with these devices. Here, we highlight the potentialities of these devices, describe the evidence from the recent clinical trials and discuss the potential advantages, as well as challenges, that this novel technology may face in routine clinical practice. Background The landscape of percutaneous coronary intervention (PCI) has evolved dramatically over the last 35 years. At the beginning, plain old balloon angioplasty (POBA) revolutionized the treatment of coronary artery disease. However, the outcomes following POBA were compromised by re-narrowing due to elastic recoil, abrupt coronary occlusion secondary to severe dissection and neointimal hyperplasia [1–3] . The advent of bare-metal stents (BMS) reduced both the re-narrowing rate and the risk of acute vessel occlusion compared with POBA [2,4] . However, new problems such as restenosis emerged [5] . The introduction of drug-eluting stents (DES), which were developed by coating BMS with antiproliferative drugs (i.e., sirolimus or paclitaxel), significantly reduced restenosis and target lesion revascularization (TLR) rates compared with BMS [6,7] . DES, which were considered the third revolution in interventional cardiology, broadened the applications of PCI particularly in complex subset of lesions and high-risk patients [8,9] . However, first-generation DES were associated with an increased risk of very late stent thrombosis (ST) [10–12] , but newer-generation DES, with thinner struts and biocompatible or biodegradable polymers, have a considerably improved safety profile [13–15] . Although DES technology seems to cover the needs of the interventional cardiologists, they cannot be considered the optimal solution as they permanently trap the coronary into a metallic cage. The presence of a foreign body within the artery wall can be a source of chronic inflammation and may interfere with the endothelial function, delaying the vessel wall healing that is associated with a higher risk of ST [16–18] . In addition, it has been demonstrated that stent implantation has an unfavorable effect on the geometry of curved arteries; however, it is unknown if this alteration may be associated with increasing risk for neointima hyperplasia. Other important drawbacks of the metallic stents is the risk of precluding surgical revascularization when implanted in potential ‘anastomotic’ segments of the coronary tree. Thus, the ideal solution would be a transient bioresorbable
KEYWORDS
• bioresorbable scaffolds • coronary angioplasty • drug-eluting stents
Division of Cardiology, ‘Bolognini’ Hospital, Via Paderno 21, 24068, Seriate (BG), Italy *Author for correspondence: Fax: +39 035 3063635; [email protected] 1
10.2217/FCA.14.14 © 2014 Future Medicine Ltd
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Review Ielasi & Tespili scaffold (BRS) that would accomplish the same goals as metallic DES within the first year after implantation (seal dissections, prevent abrupt vessel closure and suppress neointimal hyperplasia) and would then disappear, allowing the vessel to return to its natural state whilst maintaining access for future surgical revascularization, if required. The absence of a rigid permanent cage may result in restoration of endothelial function and shear stress, reducing the risk of late events and favoring positive remodeling of the vessel. These benefits may also result in reduced need for long-term dual antiplatelet therapy (DAT). Today, several BRS are available but only two devices have acquired Conformité Européenne (CE) mark approval and only one is currently used in clinical practice. Here, we provide a brief overview of the available (under development or under preclinical validation or undergoing clinical trials) drug-eluting BRS and discuss the potential additional advantages and limitations that these devices may have in everyday clinical practice. Drug-eluting BRS ●●ABSORB bioresorbable vascular scaffold
The ABSORB bioresorbable vascular scaffold (BVS; Abbott Vascular, Santa Clara, CA, USA) constitutes semicrystalline poly-l-lactic acid (PLLA) coated with amorphous poly-d,l-lactide polymer eluting everolimus. Degradation of the bioresorbable components (PLLA and polyd,l-lactide) of the scaffold is mainly through hydrolysis, followed by macrophage phagocytosis of the resulting degradation products, a process that is completed within 3 years [19] . Two versions of the BVS have been assessed in clinical trials. The safety and feasibility of the BVS 1.0 was tested in the open-label prospective ABSORB Cohort A’ trial [20] . At 6 months, the angiographic in-stent late lumen loss (LLL) was 0.44 mm with evidence of scaffold shrinkage (-11.8%) as measured by intravascular ultrasound (IVUS). However, vasomotion appeared to be restored with induced vasoconstriction and vasodilatation possible in the treated segment [21] . To prolong the mechanical BVS strength and reduce late recoil, a second generation BVS (1.1) has been introduced. Of note, BVS 1.1 has a smaller maximum circular unsupported surface area [22] , a more uniform strut distribution and improved stent retention. Importantly, these changes have not resulted in an increased amount of polymeric material or an increase in
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strut thickness. Proprietary process changes have been implemented to increase radial strength. In addition, these changes have reduced polymer degradation rates at early time points and thus prolonged mechanical integrity of the scaffold throughout the first few months following implantation [23] . The efficacy of the BVS 1.1 was assessed in the ABSORB Cohort B trial which recruited 101 patients with single or two-vessel de novo disease all receiving a 3.0 × 18 mm BVS. At 6-month follow-up, there was only 1 TLR and LLL was 0.19 ± 0.18 mm. At 2 years, LLL was 0.27 ± 0.20 mm. Scaffold area progressively increased during follow-up although at 6 months there was significant reduction in minimal lumen area on IVUS as compared with baseline (6.60 ± 1.22 to 6.37 ± 1.12 mm 2 ; p 2.0 mm), as well as those with long lesions thus giving the opportunity to evaluate the BVS performance in both these groups. An interim report on the 24-month clinical outcomes from the first 250 patients enrolled showed MACE and target vessel failure rates of 4.4 and 4.8%, respectively [29] . Recently, the first 450 patients enrolled in this trial have completed 12 months follow-up and an interim report presented seven cases (1.5%) of device failure [30] . In particular, scaffold dislodgement occurred in 3 (0.67%) cases, while subacute or late scaffold thrombosis occurred in four (0.89%) cases. All scaffold dislodgements occurred in the left circumflex, and in two cases dislodgement was observed after reinsertion of the same device. The friction between the thick (156 μn) polymeric
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Review
BVS struts with large crossing profiled and a tortuous/calcified vessel or a daughter catheter (i.e., Guideliner), may result in device dislodgement when forcefully pushing the scaffold. Among the scaffold thrombosis, two out of four cases seemed to be related to either premature DAT discontinuation (less than 30 days) or resistance to clopidogrel, while one case occurred at the site of overlapping scaffold [30] . Even if in the ABSORB trials DAT was mandatory for at least 6 months, its optimal duration is, however, unknown and in particular cases such as overlapping scaffolds, a relatively longer duration with more potent agents (i.e., ticagrelor or prasugrel) could be considered [30] . The prospective, randomized ABSORB II study will compare BVS 1.1 to the Xience Prime everolimus-eluting stent (Abbott Vascular) in patients with stable angina and single- or twovessel disease. The trial is expected to complete in 2015. The multicenter, randomized ABSORB III trial aiming to recruit over 2000 patients with up to two de novo lesions in different epicardial vessels (vessel diameter 2.5–3.75 mm, length ≤24 mm) and randomize these to BVS 1.1 or Xience Prime. Finally, the ABSORB IV study will aim to add another 4000 patients to ABSORB III in order to assess for BVS 1.1 superiority over Xience Prime with regards to TLF between 1 and 5 years. The Amsterdam Investigator initiated Absorb strategy all-comers trial is a prospective, randomized (1:1), active-control, single-blinded, all-comer, noninferiority study. About 2690 all-comer subjects will be enrolled in order to evaluate the efficacy and performance of the ABSORB BVS versus the Xience family in the treatment of coronary lesions. The study population includes both simple and complex lesions, in patients with stable and acute coronary syndromes. The follow-up continues for 5 years and the primary end point of the trial is target vessel failure, defined as the composite of cardiac death, MI and TVR at 2 years [31] . DESolve BRS The DESolve BRS (Elixir Medical, Sunnyvale, CA, USA) is made from a PLLA-based polymer eluting novolimus, a major metabolite of sirolimus. The DESolve is designed to be fully resorbed within 2 years. In the first-in-man (FIM) study, 15 patients with lesion length 6
On preclinical studies On preclinical studies
AMS: Absorbable metallic stent; CE: Conformité Européenne; NA: Not available.
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Review Ielasi & Tespili Table 2. Main bioresorbable vascular scaffold clinical trial. Scaffold
Clinical study
Number of patients
End points
Late loss (mm)
Target lesion revascularization (%)
Major adverse cardiovascular event (%)
ABSORB 1.0 ABSORB Cohort A ABSORB 1.1 ABSORB Cohort B
30
0.44 at 6 months
0 at 5 years
3.4 at 5 years
AMS-3 DREAMS
BIOSOLVE-I
46
DESolve
DESolve 1 DESolve Nx
15 120
REVA REVA ReZolve
RESORB RESTORE
27 50
Procedural success, 5-year MACE LLL, TLR and MACE at 6 months, and 1, 2 and 3 years Target lesion failure at 6 and 12 months LLL at 6 months Procedural success, LLL at 6 months and 5-year MACE MACE TLR at 6 months, LLL at 12 months
101
0.27 at 12 months 3.6 at 12 months
10 at 3 years
0.64 at 6 month, 4.3 at 6 months, 6.5 at 0.52 at 12 months 12 months
4.3 at 6 months, 6.5 at 12 months
0.19 at 6 months 0.21 at months
20 at 12 months 3.25 at 6 months
6.7 at 12 months 1.6 at 6 months
1.81 at 6 months 66.7 at 6 months 0.20 at 12 months 2 of 12 at 6 months
NA 2 of 12 at 6 months
AMS: Absorbable metallic stent; LLL: Late lumen loss; MACE: Major adverse cardiac events; TLR: Target lesion revascularization.
bioresorption. Furthermore, serial IVUS-virtual histology analysis demonstrated a reduction in dense calcium of 15.4 and 12.9% at 6 and 12 months, respectively, compared with postprocedure. This phenomenon was interpreted as a surrogate marker for the bioabsorption of the scaffold [40] . Minimal changes in arterial geometry The permanent metallic stents may modify arterial geometry and local hemodynamics contributing to neointimal proliferation and adverse events at follow-up [53,54] . BRS offer the potential advantage to avoid permanent vascular alterations. ABSORB BVS produces less alteration in vessel angulation and curvature than metallic stents [55] . Furthermore, ABSORB BVS has been shown to restore the coronary configuration to pre-implant level between 6- and 12-month follow-up [56] . Restoration of vascular physiology Different studies have reported an abnormal vasomotion in the coronary segment distal to the segment where a permanent DES was implanted [57] . This may restrict the distal flow and predispose to late thrombotic events at the stent site. BRS technology, which has been described as a vascular reparative therapy, promises the return to normal vessel biomechanics after complete scaffold bioresorption [58] . In the ABSORB Cohort A, an evaluation of the ‘scaffolded’ segment following intracoronary administration of acetylcholine suggested that the scaffolding
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function of the polymeric struts had completely disappeared and the ‘scaffolded’ segment could exhibit vasomotion at 2 years [59] . Magnesium BRS have also demonstrated the recovery of the responsiveness of the treated vessel to vasoactive agents [39] . Ability to cover vulnerable plaques Metallic stents do not seem to protect the vessel from neoatherosclerosis or plaque progression. Brugaletta et al. showed that the developed neointima after a BRS implantation covers the superficial plaques [60] . This is of great importance in case of vulnerable plaques (i.e., a thin cap fibroatheroma), which after the BRS deployment is likely to be transformed to a more stable one, namely thick cap fibro-atheroma. In this way, BRS may intervene in the atherosclerotic process providing a symmetrical uniform fibrous neointimal layer, which along with late lumen enlargement and lack of any permanent metallic vascular cage may help to stabilize and transform high-risk vulnerable plaques to be more stable [61] . This appealing idea is indirectly supported by studies on the concept of plaque passivation by stents [62] , and BRS providing a symmetrical and circumferential thick fibrous cap with functional endothelium, late lumen enlargement and normal shear stress distribution [61] . From clinical trials to clinical practice BRS may theoretically improve clinical outcomes in patients requiring revascularization as the absence of a permanent metallic cage
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Current & future perspectives on drug-eluting bioresorbable coronary scaffolds in the vessel wall may reduce chronic injury, predisposing to restenosis and ST. Currently available data has shown the complete biodegradation of the device at follow-up [40,63] , vessel remodeling with lumen gain over time [63] , and signs of physiological vasomotion of the ‘scaffolded’ coronary segment [21,40] . Furthermore, promising results have been shown in patients with simple lesions at different follow-up periods up to 5 years (Table 2) [32,40,63,64] . To date, the ABSORB is the only scaffold commercially available and the only one that has been used in everyday clinical practice. However, the experience with ABSORB was initially limited to younger patients with AHA/ACC Type A or B lesions in moderate-sized vessels [65] . Thus, there has been limited data about the ABSORB performance in
complex lesions such as thrombotic lesions, bifurcations, chronic total occlusions, calcified lesions, diffuse disease requiring overlapping scaffolds, restenosis, as well as in complex patients such as diabetics with or without multivessel disease. (Figures 1 & 2) Early, preliminary ‘real world’ experience with ABSORB [66] may allow drawing of suggestions on which patients/lesions are best suited for these devices. Aside from simple lesions, patients with long diffuse left anterior descending disease and those requiring multivessel revascularization are interesting candidates for ABSORB as the eventual resorption of the BVS within the following years may avoid a ‘full metal jacket’ that can predispose to ST and restenosis [67] . This is particularly important for younger patients since such an approach does not only
Long lesion involving the distal LAD
B
A Baseline
STEMI
E After BVS implantation
F Baseline
G
D Baseline
After BVS implantation NSTEMI
Recurrent in-stent restenosis
C
Review
After BVS implantation
H Baseline
After BVS implantation
Figure 1. ABSORB bioresorbable vascular scaffold use in every day clinical practice. (A) Long lesion involving the distal and mid left anterior descending artery (B) treated with multiple (2.5 × 18 mm, 2.5 × 28 mm, 3.0 × 28 mm and 3.0 × 18 mm) BVS implantion in overlap. (C) Recurrent in-stent restenosis in the first obtuse marginal (D) treated with 3.0 × 18 mm and 3.5 × 28 mm BVS implantation in overlap. (E) Acute thrombotic right coronary artery occlusion in the ST-elevation myocardial infarction setting (F) treated with a 3.5 × 28 mm BVS implantation. (G) Patient presented with NSTEMI due to subocclusive thrombotic lesion (H) treated with a 3.0 × 18 mm BVS in the proximal LAD. BVS: Bioresorbable vascular scaffold; LAD: Left anterior descending artery; NSTEMI: Non-ST-elevation myocardial infarction; STEMI: ST-elevation myocardial infarction.
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Chronic total occlusion
A
B Baseline
After BVS implantation Bifurcation lesion
D
C Baseline
After BVS implantation
Figure 2. ABSORB bioresorbable vascular scaffold use in chronic total occlusion and bifurcation lesions. (A) Long chronic total occlusion of the proximal left anterior descending artery, (B) treated with multiple (3.0 × 18 mm, 3.0 × 28 mm, 3.5 × 28 mm and 3.5 × 18 mm) BVS implantation from distal to proximal left anterior descending artery. (C) Left anterior descending artery bifurcation lesion at the first diagonal branch (D) treated with provisional strategy and 3.0 × 18 mm BVS implantation. BVS: Bioresorbable vascular scaffold.
maintain access for future bypass graft surgery if required, but also offers the possibility of further PCI treatment without the additional permanent metallic layers. However, it is important not to forget that there is no published data regarding clinical outcomes in complex lesions treated with BVS [66] . The importance of intravascular imaging, pre- and post-dilatation in optimizing scaffold implantation and expansion should not be underestimated, particularly in the case of complex lesions (i.e., long lesions, small vessels,
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calcified plaques) where the scaffold underexpansion may be associated with subacute or late thrombotic events. However, the importance of meticulous procedural technique cannot be overemphasized – it should take longer to implant a BVS as compared with a conventional DES. Conclusion BRS have been heralded as the fourth revolution in interventional cardiology. This novel technology not only provides transient scaffolding and
future science group
Current & future perspectives on drug-eluting bioresorbable coronary scaffolds restores flow in the diseased segment, but also restores vascular integrity and function. Over recent years, huge improvements have been made in the field of BRS with encouraging data emerging from their use in clinical practice. The current results have provided promise for the future, although data regarding their use in complex lesions and long-term clinical outcomes in the ‘real world’ are lacking. The message that arises from their first applications is that BRS should not be considered as another type of stent, but as a totally different device that has special strengths, weaknesses and limitations, but also introduces a novel therapeutic potential. The BRS field is an exciting area where further improvements will advance PCI practice.
safety in complex subset of patients and lesions, allowing a concrete comparison versus the currently available new-generation ‘permanent’ metallic stents. BRS will hopefully improve on the already excellent results obtained with PCI, especially with regards to in-stent restenosis, ST and clinical outcomes in high-risk patients such as those with diabetes and long lesions. Undoubtedly, further technological refinements to overcome current challenges (i.e., reduce strut thickness without compromising radial strength and improving device deliverability, DAT duration and so on), and long-term safety and efficacy data from adequately powered clinical trials, are required to allow BRS to become mainstream for coronary intervention of the future.
Future perspective To date, most of the data for BRS use are derived from small, nonrandomized studies with short- or mid-term follow-up. Furthermore, very few data are currently available on the BRS performance in ‘real world’ patients. As further evidence emerges regarding their use, interventionalists will increase the use of these novel devices, for also the treatment of more complex lesions. This will shed more light regarding their efficacy and
Financial & competing interests disclosure
Review
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t-estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
EXECUTIVE SUMMARY Bioresorbable vascular scaffold technology & the beginning of the fourth revolution in interventional cardiology ●●
Although drug-eluting stent technology seems to cover the needs of the interventional cardiologists, they cannot be
considered the optimal solution as they permanently trap the coronary into a metallic cage. The presence of a foreign body within the artery wall can be a source of chronic vessel inflammation and may interfere with the endothelial function delaying the vessel wall healing that is associated with a higher risk of stent thrombosis. Thus, the ideal solution would be a transient bioresorbable scaffold (BRS) that would initially keep the vessel open as well as metal stents and would then disappear, allowing the vessel to return to its natural state. Different BRS are currently either being assessed in randomized clinical trials or are under development ●●
Today, several BRS are available: some of them are under development, some others are under preclinical validation, a
few are undergoing clinical trials and only two devices have acquired Conformité Européenne mark approval, but only one (ABSORB, biovascular scaffold; Abbott Vascular, CA, USA) is currently used in clinical practice. Promising emerging clinical evidences ●●
Data actually available suggest that the use of BRS in the context of clinical trials is associated with low rates of cardiac
adverse events in patients with simple lesions and at mid-term clinical follow-up, with the added advantage of not leaving a permanent ‘metallic’ trail behind, remodeling the vessel with lumen gain over time and restoring the normal vessel physiology after resorption. Future challenges ●●
Very few data are currently available on the BRS performance in ‘real world’, complex patients (acute coronary
syndrome, diabetics, multivessel diseases) and lesions (long lesions, bifurcation, restenosis, chronic total occlusions). Further data are needed in order to allow a concrete comparison versus the currently available new-generation ‘permanent’ metallic stents.
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Review Ielasi & Tespili 12 Stettler C, Wandel S, Allemann S et al.
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