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Alternative stents in ST-segment elevation myocardial infarction: improving the efficacy of primary percutaneous coronary intervention Tuncay Yetgin1, Shimpei Nakatani1, Yoshinobu Onuma1 & Robert-Jan M van Geuns*,1
Abstract Despite the efficacy of primary percutaneous coronary intervention in achieving epicardial reperfusion in ST-segment elevation myocardial infarction, it is often limited by impaired microvascular perfusion attributable to distal embolization of plaque and thrombus, and stent malappostion due to vessel constriction and thrombus apposition, attenuating the full benefits of myocardial reperfusion and resulting in unfavorable clinical outcomes. In the long run implantation of permanent metallic implants have negative effect the biological behavior of the target vessel with a continuous low device failure over the years. Recently, however, efforts have been realized to tackle these shortcomings and optimize mechanical reperfusion by improvements to stent design, as substantiated by the self-expanding stent, the mesh-covered stent and the bioresorbable vascular scaffold. In this article, we provide an overview of the role of these novel, innovatively designed, alternative devices in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Primary percutaneous coronary intervention (PPCI) remains the preferred reperfusion modality in patients presenting with ST-segment elevation myocardial infarction (STEMI) [1] . The recent ESC guidelines also prefers percutaneous coronary intervention (PCI) with stent implantation over balloon-angioplasty alone as it reduces the risk of abrupt closure, re-infarction and repeat revascularization [2] , and newer drug-eluting stent (DES) are apparently more effective and safer compared with bare-metal stent (BMS) [3] . While PPCI with stent implantation is highly effective in achieving epicardial coronary reperfusion, it fails to restore optimal myocardial tissue-level reperfusion in 10–20% of patients as assessed by thrombolysis in myocardial infarction (TIMI) flow analysis (TIMI 0 or 1 flow) or myocardial blush grading (MBG; less than grade 2). This is also represented by suboptimal ST-segment resolution (STR) in close to 20% of patients. All these parameters have been linked to an increased risk of stent thrombosis within 30 days and, an at least threefold increase of mortality at 1 year [4–8] . Suboptimal myocardial reperfusion during PPCI is an multifactorial phenomenon that includes inflammation, thrombus embolisation and complement system activation. The presence of visible coronary thrombus at the time of PPCI introduces special challenges for the interventional cardiologist but also offers opportunities for procedure optimalization. High thrombus burden is known to be associated with an increased incidence of distal embolization, a significant pathogenetic component of no-reflow and may limit reperfusion at the microcirculatory level as measured by myocardial blush grade (MBG) and STR. Moreover, large thrombus burden is associated with a
Keywords
• bioresorbable scaffold • mesh-covered stents • primary percutaneous
coronary intervention
• self-expanding stent • ST-segment elevation
myocardial infarction
1 Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, ‘s-Gravendijkwal 230, 3015 GE Rotterdam, The Netherlands *Author for correspondence: Tel.: +31 0104635260; Fax: +31 0104369154; [email protected]
10.2217/FCA.15.26 © 2015 Future Medicine Ltd
Future Cardiol. (2015) 11(3), 347–357
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Review Yetgin, Nakatani, Onuma & van Geuns the mesh-covered stent and the bioresorbable vascular scaffold (BVS). Stent apposition ●●The self-expanding stent
Figure 1. Stentys self-expanding Nitinol stent. The Stentys coronary stent (STENTYS S.A., Paris, France) is a self-expanding stent made of Nitinol, a titanium alloy with superelastic properties and Z-shaped struts (width of 68–77 μm and a thickness of 102–133 μm) linked by small interconnections. The stent is coated with a biostable, polysulphone polymer eluting Paclitaxel or Sirolimus. Three different diameters intended for small (2.5–3.0 mm), medium (3.0–3.5 mm) and large diameter vessels (3.5–4.5 mm). Image courtesy of STENTYS S.A., Paris, France.
higher frequency of major adverse cardiac events (MACE) and is a strong independent predictor of long-term mortality [9] . Another difficulty with the presence of thrombus is the potential underestimation of the vessel size, possibly resulting in implantation of an undersized stent and late stent malappostion, the latter representing an important predictor for stent thrombosis [10,11] . Embolized thrombi have different components like organized thrombus atherosclerotic plaque debris and fresh thrombus deriving from different origin. Accordingly, important shortcomings of current mechanical treatment strategies for STEMI remain. Postponing stent implantation by 4–16 h after primary restoring flow has been demonstrated to reduce no-reflow and increase myocardial salvage but is costly and less patient friendly [12] . Several therapeutic strategies have been studied that aim to reduce thrombus burden and encompass pharmacological (e.g., glycoprotein IIb/IIIa inhibitors) and mechanical (e.g., embolic protection devices, manual or mechanical thrombectomy) approaches. Recently, however, the armamentarium of the interventional cardiologist has been extended by novel stent-based platforms with innovations in stent design, potentially overcoming aforementioned challenges and improving the efficacy of PPCI still within a single procedure. This review comprises an overview of the role of novel alternative stents in the setting of STEMI (Table 1) , including the self-expanding stent,
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The Stentys coronary stent (STENTYS S.A., Paris, France) is a self-expanding stent made of Nitinol, a titanium alloy with super-elastic properties and Z-shaped struts linked by small interconnections (Figure 1) . These connections are located throughout the stent both in the length and circumference, apart from the first and last 2 mm and can be disconnected by inflation of an angioplasty balloon between the struts to provide side-branch access [13] . The short expandable segments and the unique, feature of this stent to gradually grow in volume in the first hours to days after the procedure allows gentle deployment with less trauma, potentially resulting not only in less intimal proliferation, but also less plaque disruption and/or thrombus dislodgement, which eventually may lead to less distal embolization [14,15] . Another potential benefit of this stent in the acute setting may be the facilitation of optimal stent apposition due to its capacity to self-appose, resulting in less malapposition, especially, when considering the fluctuating vessel diameters due to resolution of thrombus and vasoconstriction. The Stentys coronary stent is available as a BMS or a DES with a biostable, polysulphone polymer eluting Paclitaxel or Sirolimus, both with a nominal strut width of 68–77 μm and a thickness of 102–133 μm, with the Sirolimus-eluting variant currently being under investigation [16] . It is manufactured in diameters ranging from 2.5 to 4.5 mm and in lengths ranging from 17 to 27 mm. Both stents are compatible with 0.014inch guidewires and six-French guiding catheters [17] . The current version is deployed with a classical selfexpanding stent delivery system where an outer sleeve covers the stent during positioning and needs to be retracted to release the stent. The disadvantage of this system is the relative high crossing profile and the risk of forward motion of the stent when the stent cover is retracted. These limitations require a good training before actual start of device usage and a learning-curve has to be expected. ●●Self-expanding stent utilization in STEMI
The first-in-man study evaluating the safety and feasibility of the self-expandable Stentys
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Alternative stents in STEMI
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Table 1. Clinical trials investigating self-expanding stents, mesh-covered stents and bioresorbable vascular scaffolds in ST-segment elevation myocardial infarction. Study
Study type
N
Device
Primary efficacy end point and outcome
Clinical end point and outcome
Ref.
APPOSITION I (2011) Multicenter, single-arm
25
Stentys BMS
Multicenter, randomized Multicenter, single-arm
80
Stentys BMS
6-month ischemia-driven target lesion revascularization (12%), no further 6-month MACE (-) 6 m MACE
[20]
APPOSITION II (2012) APPOSITION III (2013)
High rates of technical, device and procedural success, complete 3-day/6-month IVUS/OCT-derived stent apposition (↑) OCT-derived stent apposition at 3 days
1-year mortality (2.0%), 1- year target vessel re-infarction (1.3%), 1-year overall MACE (9.3%)
[21]
APPOSITION IV† (2013)
Multicenter, doublerandomized
62
Stentys DES (sirolimus)
60
MGuard BMS
Self-expanding stent
1000 Stentys BMS/DES (paclitaxel)
(↑) OCT-derived stent apposition and coverage at 4 months
[17]
[16]
Mesh-covered stent MAGICAL (2010)
Multicenter, single-arm Piscione et al. (2010) Multicenter, single-arm MASTER (2012) Multicenter, randomized MICAMI-MGUARD Multicenter, (2013) randomized Romaguera et al. Single-center, (2013) single-arm Bioresorbable vascular scaffold BVS STEMI first Single-center, study (2014) single-arm Prague 19 (2014) Multicenter, single-arm
Final TIMI 3 flow (90%), MBG 3 (73%), complete STR (61%) MGuard BMS Final TIMI 3 flow (100%), MBG 3 (90%), complete STR (90%) MGuard BMS/ (↑) Complete STR, final TIMI 3 flow, MGuard Prime BMS (-) MBG 2/3 MGuard BMS (-) Final TIMI 3 flow, (↑) MBG 3, corrected TIMI frame count MGuard Prime BMS Final TIMI 3 flow (82%), MBG 3 (55%), complete STR (59%)
49
Absorb BVS
41
Absorb BVS 1.1
100 433 40 56
High rate of final TIMI-flow III and good scaffold apposition on OCT 98% of procedural success and good scaffold apposition on OCT
6-month MACE (1.7%)
[29]
1-month MACE (0%)
[30]
(-) 1-month mortality or MACE
[31]
(-) 6-month MACE
[37]
9-month MACE (3.6%)
[38]
6-month MACE (2.6%)
[41]
One scaffold thrombosis and one target-vessel re-infarction up to 9 months follow-up
[42]
4-month mid-term results. (↑): Significantly improved end point; (-): Neutral effect on end point; BMS: Bare-metal stent; BVS: Bioresorbable vascular scaffold; DES: Drug-eluting stent; IVUS: Intravascular ultrasound; MACE: Major adverse cardiovascular events; MBG: Myocardial blush grade; OCT: Optical coherence tomography; STR: ST-segment resolution; TIMI: Thrombolysis in myocardial infarction.
†
stent was published in 2009 [18] . In the prospective, multicenter, single-arm OPEN I study, 40 patients with stable or unstable angina based on de novo coronary bifurcation lesions were treated with the self-apposing Stentys BMS or DES. Procedural success was achieved in 95.5% of the cases with a MACE rate of 5.1% at 30 days due to a single case of peri-procedural nonSTEMI and one ischemia-driven target lesion revascularization (TLR) at day 6 [18] . Subsequent 6-month follow-up results of the full OPEN I study with an additional 23 included patients confirmed the initially observed safety and feasibility findings [19] .
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The first study investigating the use of the Stentys stent in the setting of STEMI was performed by Amoroso et al. in 2011 [20] . In this prospective, nonrandomized trial involving 25 STEMI patients, the expansive property of the Stentys stent indeed translated into less malapposition as shown by a significant 19% increase in lumen area distal to the culprit lesion and a concordant 18% expansion of implanted stents at 3 days post-PCI, measured by intravascular ultrasound, in the absence of malapposed stents at 6 months [20] . These findings suggest that this device follows the growth of the vessel lumen while vasoconstriction and
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Review Yetgin, Nakatani, Onuma & van Geuns thrombus are resolving. Furthermore, technical, device and procedural success rates were 100, 96 and 96%, respectively, with a 12% rate of ischemia-driven TLR at 6 months, confirming the safety and feasibility in this setting. The initially observed benefits of this stent in terms of optimal appositioning were corroborated by the results of the subsequent randomized APPOSITION II trial [17] . In this trial, 80 patients with STEMI undergoing PPCI were randomized to receive a self-expanding Stentys stent (n = 43) or a balloon-expandable stent (n = 37). Strut malapposition at 3 days, as measured by optical coherence tomography (OCT), was significantly lower in patients allocated to the self-expandable stent compared with the balloon-expandable stent (0.58 vs 5.46%; p 30 to 1 year) after stent implantation target vessel MI was significant higher compared with balloon angioplasty only suggesting more negative effects of permanent metallic implants beyond strut apposition after the first year [45] . For patients presenting with STEMI this is important as they present usually at a younger age compared with stable angina patients. With the current fast reperfusion treatment and secondary prevention life expectancy for young STEMI patients is very good.
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Alternative stents in STEMI The potential advantages of the BVS implantation in the setting of STEMI are therefore the following: ●● Malapposed struts could disappear completely
when the device is bioresorbed at long-term follow-up. In the other words, the risk of stent thrombosis could be disappearing after full bioresorption of BVS; ●● The relatively thick struts (approximately 150
μm) which generally result in a relative large strut/vessel wall area ratio of 0.23 potentially leads to better capturing of thrombotic material behind the struts and therefore reduction of distal embolization;
●● The thicker struts will create low shear stress
in the intrastrut spaces. This low shear stress initially might predispose to platelet activations, but at later phase creates neointimal tissues. After the loss of mechanical integrity (approximately at first year), the scaffold area starts to enlarge and therefore the lumen dimension remains stable, despite the formation of thick tissue layer on the top of the underlying plaques. This layer could seal the ruptured plaques [46] . The use of fully bioresorbable drug-eluting scaffolds may therefore provide a favorable arterial healing compared with the permanent metallic stents. On the other hand, there is a technical challenge to implant BVS in the setting of STEMI, especially for selecting the proper scaffold size. At PPCI, the presence of thrombus burden, catecholamine stimulation, inflammatory substances and general or localized vasoconstriction contributed by the impaired microcirculation in the ischemic or infarcted myocardium could lead to underestimation of the vessel size. In addition, it should be noted that platelet activity associated with low shear stress behind the thick BVS struts might necessitate potent inhibition of platelet at least in the early phase of scaffold implantation. ●●Bioresorbable vascular scaffold utilization
in STEMI
The early trials in stable patients treated with BVS showed excellent results, while very limited data are available in patients with STEMI. Kajiya et al. initially showed a feasibility of BVS implantation in the setting of STEMI in case series [47] . Subsequently, two prospective, nonrandomized trials investigating the feasibility
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and acute performance of the BVS for the treatment of patients presenting with STEMI were reported in 2014 [48,49] . In the BVS STEMI first study comprising 49 patients, the procedural success was 97.9%. OCT analysis performed in 31 patients showed that the mean percentage of postprocedural malapposed struts per patient was 2.80 + 3.90% and scaffolds with >5% malapposed struts were 22.6%, which was similar to that of DESs. At the 30-day follow-up, target-lesion failure rate was 0%. No target-vessel revascularization and target vessel myocardial infarction were reported, while one nontarget-vessel non-Q-wave MI occurred. No cases of cardiac death or scaffold thrombosis were observed. In the Prague 19 study enrolling 41 STEMI patients, the procedural success rate was 98%. OCT analysis performed in 21 patients demonstrated that the mean percentage of postprocedural malapposed struts per patient was 1.1% and scaffolds with >5% malapposed struts were 0%. A single case of scaffold thrombosis was reported, which occurred 3 days after discontinuation of all indicated medication, including aspirin and ticagrelor, and one nontarget vessel myocardial infarction [49] . These studies showed that implantation of BVS in STEMI is feasible with acceptable imaging results as well as acute clinical results. The other study investigating the feasibility and acute performance for the treatment of ACS patients with comparison between BVS and DES was reported by Gori et al. in 2014 [50] . In the BVS group, 44% (n = 60) of patients presented with STEMI, while in the DES group, 45% (n = 46) presented with STEMI. 30-day and 6-month MACE rates were similar between both groups (all p >0.5) and BVS utilization did not influence the incidence of MACE (p > 0.9) in multivariate analysis. Definite or probable stent/scaffold thrombosis occurred in three BVS patients and two DES patients during the first 30 days. This study showed that implantation of BVS in ACS is feasible with short-term clinical results [50] . There are several on-going studies to further evaluate the use of ABSORB BVS in STEMI; three studies specifically focused on STEMI population (e.g., TROFI-II [51] , BVS in STEMI [52] , ISAR-Absorb MI [53] , while three others (e.g., ABSORB-ACS [54] , AIDA [55] , GABI-R [56] include STEMI patients as a part of all-comers or ACS population. TROFI-II study is a prospective, randomized (1:1), active control,
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Review Yetgin, Nakatani, Onuma & van Geuns single-blind and European multicenter clinical trial. The primary end point is the neointimal healing score measured by using intra-coronary optical frequency domain imaging at 6 months follow-up in STEMI patients treated with ABSORB BVS compared with a metallic DES (XIENCE). These new studies will provide us more evidence on use of BVS in STEMI in the future. Conclusion & future perspective Conventional PCI while attempting to open the occlusion is more likely to dislodge the thrombus downstream potentially inducing distal embolization and microvascular obstruction. While aspiration is an acceptable intervention to remove thrombus from the artery as much as
possible, there remains a significant amount of thrombus covering the interior vessel wall, introducing the stent sizing dilemma, with underexpansion potentially leading to malapposition, restenosis or stent thrombosis and overexpansion potentially causing dissection or no-reflow. The self-expanding stent platform is well-suited in such scenarios because of the gentle, selfapposing nature of Nitinol that is coupled with a unique stent design. These properties enable the stent to tailor its size to the vessel diameter when the actual size of the vessel is obscured and to provide full apposition and sustained coverage as any remaining thrombus dissolves over time. Another suitable option in this setting is the use of the mesh-covered stent. The ultra-thin mesh sleeve is intended to block atherothrombotic
Executive summary ST-segment elevation myocardial infarction (STEMI) ●●
Primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) often limited by stent malappostion, due to vessel constriction with thrombus apposition, and impaired microvascular perfusion, attributable to distal atherothrombotic embolization.
●●
Recent improvements to stent design may optimize PPCI efficacy.
Stent apposition ●●
Self-expanding stents aim to overcome undersizing of balloon-expandable stents caused by vessel constriction and thrombus apposition.
●●
Consistent picture of this self-expanding stent-based strategy in STEMI with regard to feasibility, safety and efficacy in terms of improved stent apposition and coverage.
●●
Adequately powered randomized trials are needed to determine whether these benefits result in improved long-term clinical outcomes after STEMI.
Microcirculatory protection ●●
Mesh-covered stents are intended to mitigate distal embolization and associated no-reflow by thrombus and atherosclerotic plaque exclusion.
●●
Consistent picture of this embolization protection strategy in STEMI with regard to feasibility, safety and efficacy in terms of improved myocardial reperfusion indices.
●●
Adequately powered randomized trials are needed to determine whether these benefits result in improved long-term clinical outcomes after STEMI.
Vascular restoration ●●
Drug-eluting bioresorbable vascular scaffolds (BVS) provide temporary scaffolding but are fully resorbed by biochemical reactions.
●●
ABSORB BVS composed of poly l-lactide and poly d,l-lactide have unique potential in vascular repair, such as late lumen enlargement, restoration of vasomotion, sealing of plaques, adaptive shear stress and plaque media reduction
●●
The use of BVS in STEMI may provide a favorable arterial healing with sealing the ruptured plaque followed by resorption of malapposed struts and has the potential to reduce the risk of long-term thrombosis.
●●
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The ongoing studies will provide more evidence on use of BVS in STEMI in the future.
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Alternative stents in STEMI extrusion through the stent struts during its implantation by entrapping these underneath the micronet against the vessel wall, thereby preventing distal embolization and protecting the microcirculation. The use of fully bioresorbable drug-eluting scaffolds might provide a favorable arterial healing without permanent caging and lumen compression and address the issues associated with metallic DES such as late malapposition, delayed endothelialisation and late/very late stent thrombosis. The bioresorbable technology might be able to seal and stabilize the ruptured plaques after creation of stabilization layer and final resorption of strut polymers [46,57] . As such, we believe that these novel and innovative stentbased strategies will set the basis for further References
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clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. JACC Cardiovasc. Interv. 6(10), 999–1009 (2013). 41 Serruys PW, Onuma Y, Garcia-Garcia HM et al.
Dynamics of vessel wall changes following the implantation of the absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months. EuroIntervention 9(11), 1271–1284 (2013). 42 Bourantas CV, Papafaklis MI, Garcia–Garcia
HM et al. Short and long-term implications of a bioresorbable vascular scaffold implantation on the local endothelial shear stress patterns. JACC Cardiovasc. Interv. 7(1), 100–101 (2014). 43 Hong MK, Mintz GS, Lee CW et al. Incidence,
mechanism, predictors, and long-term prognosis of late stent malapposition after bare-metal stent implantation. Circulation 109(7), 881–886 (2004). 44 Hong MK, Mintz GS, Lee CW et al. Late stent
malapposition after drug-eluting stent implantation: an intravascular ultrasound analysis with long-term follow up. Circulation 113(3), 414–419 (2006). 45 Brodie BR, Pokharel Y, Garg A et al. Very late
hazard with stenting versus balloon angioplasty for ST-elevation myocardial infarction: a 16-year single-center experience. J. Interv. Cardiol. 27(1), 21–28 (2014). 46 Brugaletta S, Radu MD, Garcia-Garcia HM
et al. Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: can the scaffold cap the plaque? Atherosclerosis 221(1), 106–112 (2012). 47 Kajiya T, Liang M, Sharma RK et al. Everolimus-
eluting bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI). EuroIntervention 9(4), 501–504 (2013). 48 Diletti R, Karanasos A, Muramatsu T et al.
Everolimus-eluting bioresorbable vascular scaffolds for treatment of patients presenting with ST-segment elevation myocardial infarction: BVS STEMI first study. Eur. Heart J. 35(12 ), 777–786 (2014).
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Alternative stents in STEMI •• First study evaluating the safety and feasibility of the Absorb bioresorbable vascular scaffold in the setting of STEMI. 49 Kocka V, Maly M, Tousek P et al. Bioresorbable
vascular scaffolds in acute ST-segment elevation myocardial infarction: a prospective multicentre study ‘Prague 19’. Eur. Heart. J. 35(12), 787–794 (2014). 50 Gori T, Schulz E, Hink U et al. Early outcome
after implantation of absorb bioresorbable drug-eluting scaffolds in patients with acute coronary syndromes. EuroIntervention 9(9), 1036–1041 (2014).
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51 ABSORB STEMI: the TROFI II Study.
https://clinicaltrials.gov/ct2/show 52 Performance of Bioresorbable Scaffold in
Primary Percutaneous Intervention of ST Elevation Myocardial Infarct (BVS in STEMI). www.clinicaltrials.gov/ct2/show 53 A Prospective, Randomized Trial of BVS
Veruss EES in Patients Undergoing Coronary Stenting for Myocardial Infarction (ISARAbsorb MI). https://clinicaltrials.gov/ct2/show 54 Study of ABSORB Stent in Acute Myocardial
Review
55 Amsterdam Investigator-initiateD Absorb
Strategy All-comers Trial (AIDA). https://clinicaltrials.gov/ct2/show 56 Observational Study to Evaluate Short and
Long-term Safety of the ABSORB Scaffold (GABI-R). www.clinicaltrials.gov/ct2/show 57 Gori T, Schulz E, Munzel T. Anatomic
stabilization and functional normalization of a ruptured coronary plaque 12 months after implantation of a bioresorbable scaffold. JACC Cardiovasc. Interv. 7(5), e47–e48 (2014).
Infarction (ABSORB-ACS). https://clinicaltrials.gov/ct2/show
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Alternative stents in ST-segment elevation myocardial infarction: improving the efficacy of primary percutaneous coronary intervention Tuncay Yetgin1, Shimpei Nakatani1, Yoshinobu Onuma1 & Robert-Jan M van Geuns*,1
Abstract Despite the efficacy of primary percutaneous coronary intervention in achieving epicardial reperfusion in ST-segment elevation myocardial infarction, it is often limited by impaired microvascular perfusion attributable to distal embolization of plaque and thrombus, and stent malappostion due to vessel constriction and thrombus apposition, attenuating the full benefits of myocardial reperfusion and resulting in unfavorable clinical outcomes. In the long run implantation of permanent metallic implants have negative effect the biological behavior of the target vessel with a continuous low device failure over the years. Recently, however, efforts have been realized to tackle these shortcomings and optimize mechanical reperfusion by improvements to stent design, as substantiated by the self-expanding stent, the mesh-covered stent and the bioresorbable vascular scaffold. In this article, we provide an overview of the role of these novel, innovatively designed, alternative devices in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Primary percutaneous coronary intervention (PPCI) remains the preferred reperfusion modality in patients presenting with ST-segment elevation myocardial infarction (STEMI) [1] . The recent ESC guidelines also prefers percutaneous coronary intervention (PCI) with stent implantation over balloon-angioplasty alone as it reduces the risk of abrupt closure, re-infarction and repeat revascularization [2] , and newer drug-eluting stent (DES) are apparently more effective and safer compared with bare-metal stent (BMS) [3] . While PPCI with stent implantation is highly effective in achieving epicardial coronary reperfusion, it fails to restore optimal myocardial tissue-level reperfusion in 10–20% of patients as assessed by thrombolysis in myocardial infarction (TIMI) flow analysis (TIMI 0 or 1 flow) or myocardial blush grading (MBG; less than grade 2). This is also represented by suboptimal ST-segment resolution (STR) in close to 20% of patients. All these parameters have been linked to an increased risk of stent thrombosis within 30 days and, an at least threefold increase of mortality at 1 year [4–8] . Suboptimal myocardial reperfusion during PPCI is an multifactorial phenomenon that includes inflammation, thrombus embolisation and complement system activation. The presence of visible coronary thrombus at the time of PPCI introduces special challenges for the interventional cardiologist but also offers opportunities for procedure optimalization. High thrombus burden is known to be associated with an increased incidence of distal embolization, a significant pathogenetic component of no-reflow and may limit reperfusion at the microcirculatory level as measured by myocardial blush grade (MBG) and STR. Moreover, large thrombus burden is associated with a
Keywords
• bioresorbable scaffold • mesh-covered stents • primary percutaneous
coronary intervention
• self-expanding stent • ST-segment elevation
myocardial infarction
1 Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, ‘s-Gravendijkwal 230, 3015 GE Rotterdam, The Netherlands *Author for correspondence: Tel.: +31 0104635260; Fax: +31 0104369154; [email protected]
10.2217/FCA.15.26 © 2015 Future Medicine Ltd
Future Cardiol. (2015) 11(3), 347–357
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Review Yetgin, Nakatani, Onuma & van Geuns the mesh-covered stent and the bioresorbable vascular scaffold (BVS). Stent apposition ●●The self-expanding stent
Figure 1. Stentys self-expanding Nitinol stent. The Stentys coronary stent (STENTYS S.A., Paris, France) is a self-expanding stent made of Nitinol, a titanium alloy with superelastic properties and Z-shaped struts (width of 68–77 μm and a thickness of 102–133 μm) linked by small interconnections. The stent is coated with a biostable, polysulphone polymer eluting Paclitaxel or Sirolimus. Three different diameters intended for small (2.5–3.0 mm), medium (3.0–3.5 mm) and large diameter vessels (3.5–4.5 mm). Image courtesy of STENTYS S.A., Paris, France.
higher frequency of major adverse cardiac events (MACE) and is a strong independent predictor of long-term mortality [9] . Another difficulty with the presence of thrombus is the potential underestimation of the vessel size, possibly resulting in implantation of an undersized stent and late stent malappostion, the latter representing an important predictor for stent thrombosis [10,11] . Embolized thrombi have different components like organized thrombus atherosclerotic plaque debris and fresh thrombus deriving from different origin. Accordingly, important shortcomings of current mechanical treatment strategies for STEMI remain. Postponing stent implantation by 4–16 h after primary restoring flow has been demonstrated to reduce no-reflow and increase myocardial salvage but is costly and less patient friendly [12] . Several therapeutic strategies have been studied that aim to reduce thrombus burden and encompass pharmacological (e.g., glycoprotein IIb/IIIa inhibitors) and mechanical (e.g., embolic protection devices, manual or mechanical thrombectomy) approaches. Recently, however, the armamentarium of the interventional cardiologist has been extended by novel stent-based platforms with innovations in stent design, potentially overcoming aforementioned challenges and improving the efficacy of PPCI still within a single procedure. This review comprises an overview of the role of novel alternative stents in the setting of STEMI (Table 1) , including the self-expanding stent,
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The Stentys coronary stent (STENTYS S.A., Paris, France) is a self-expanding stent made of Nitinol, a titanium alloy with super-elastic properties and Z-shaped struts linked by small interconnections (Figure 1) . These connections are located throughout the stent both in the length and circumference, apart from the first and last 2 mm and can be disconnected by inflation of an angioplasty balloon between the struts to provide side-branch access [13] . The short expandable segments and the unique, feature of this stent to gradually grow in volume in the first hours to days after the procedure allows gentle deployment with less trauma, potentially resulting not only in less intimal proliferation, but also less plaque disruption and/or thrombus dislodgement, which eventually may lead to less distal embolization [14,15] . Another potential benefit of this stent in the acute setting may be the facilitation of optimal stent apposition due to its capacity to self-appose, resulting in less malapposition, especially, when considering the fluctuating vessel diameters due to resolution of thrombus and vasoconstriction. The Stentys coronary stent is available as a BMS or a DES with a biostable, polysulphone polymer eluting Paclitaxel or Sirolimus, both with a nominal strut width of 68–77 μm and a thickness of 102–133 μm, with the Sirolimus-eluting variant currently being under investigation [16] . It is manufactured in diameters ranging from 2.5 to 4.5 mm and in lengths ranging from 17 to 27 mm. Both stents are compatible with 0.014inch guidewires and six-French guiding catheters [17] . The current version is deployed with a classical selfexpanding stent delivery system where an outer sleeve covers the stent during positioning and needs to be retracted to release the stent. The disadvantage of this system is the relative high crossing profile and the risk of forward motion of the stent when the stent cover is retracted. These limitations require a good training before actual start of device usage and a learning-curve has to be expected. ●●Self-expanding stent utilization in STEMI
The first-in-man study evaluating the safety and feasibility of the self-expandable Stentys
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Alternative stents in STEMI
Review
Table 1. Clinical trials investigating self-expanding stents, mesh-covered stents and bioresorbable vascular scaffolds in ST-segment elevation myocardial infarction. Study
Study type
N
Device
Primary efficacy end point and outcome
Clinical end point and outcome
Ref.
APPOSITION I (2011) Multicenter, single-arm
25
Stentys BMS
Multicenter, randomized Multicenter, single-arm
80
Stentys BMS
6-month ischemia-driven target lesion revascularization (12%), no further 6-month MACE (-) 6 m MACE
[20]
APPOSITION II (2012) APPOSITION III (2013)
High rates of technical, device and procedural success, complete 3-day/6-month IVUS/OCT-derived stent apposition (↑) OCT-derived stent apposition at 3 days
1-year mortality (2.0%), 1- year target vessel re-infarction (1.3%), 1-year overall MACE (9.3%)
[21]
APPOSITION IV† (2013)
Multicenter, doublerandomized
62
Stentys DES (sirolimus)
60
MGuard BMS
Self-expanding stent
1000 Stentys BMS/DES (paclitaxel)
(↑) OCT-derived stent apposition and coverage at 4 months
[17]
[16]
Mesh-covered stent MAGICAL (2010)
Multicenter, single-arm Piscione et al. (2010) Multicenter, single-arm MASTER (2012) Multicenter, randomized MICAMI-MGUARD Multicenter, (2013) randomized Romaguera et al. Single-center, (2013) single-arm Bioresorbable vascular scaffold BVS STEMI first Single-center, study (2014) single-arm Prague 19 (2014) Multicenter, single-arm
Final TIMI 3 flow (90%), MBG 3 (73%), complete STR (61%) MGuard BMS Final TIMI 3 flow (100%), MBG 3 (90%), complete STR (90%) MGuard BMS/ (↑) Complete STR, final TIMI 3 flow, MGuard Prime BMS (-) MBG 2/3 MGuard BMS (-) Final TIMI 3 flow, (↑) MBG 3, corrected TIMI frame count MGuard Prime BMS Final TIMI 3 flow (82%), MBG 3 (55%), complete STR (59%)
49
Absorb BVS
41
Absorb BVS 1.1
100 433 40 56
High rate of final TIMI-flow III and good scaffold apposition on OCT 98% of procedural success and good scaffold apposition on OCT
6-month MACE (1.7%)
[29]
1-month MACE (0%)
[30]
(-) 1-month mortality or MACE
[31]
(-) 6-month MACE
[37]
9-month MACE (3.6%)
[38]
6-month MACE (2.6%)
[41]
One scaffold thrombosis and one target-vessel re-infarction up to 9 months follow-up
[42]
4-month mid-term results. (↑): Significantly improved end point; (-): Neutral effect on end point; BMS: Bare-metal stent; BVS: Bioresorbable vascular scaffold; DES: Drug-eluting stent; IVUS: Intravascular ultrasound; MACE: Major adverse cardiovascular events; MBG: Myocardial blush grade; OCT: Optical coherence tomography; STR: ST-segment resolution; TIMI: Thrombolysis in myocardial infarction.
†
stent was published in 2009 [18] . In the prospective, multicenter, single-arm OPEN I study, 40 patients with stable or unstable angina based on de novo coronary bifurcation lesions were treated with the self-apposing Stentys BMS or DES. Procedural success was achieved in 95.5% of the cases with a MACE rate of 5.1% at 30 days due to a single case of peri-procedural nonSTEMI and one ischemia-driven target lesion revascularization (TLR) at day 6 [18] . Subsequent 6-month follow-up results of the full OPEN I study with an additional 23 included patients confirmed the initially observed safety and feasibility findings [19] .
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The first study investigating the use of the Stentys stent in the setting of STEMI was performed by Amoroso et al. in 2011 [20] . In this prospective, nonrandomized trial involving 25 STEMI patients, the expansive property of the Stentys stent indeed translated into less malapposition as shown by a significant 19% increase in lumen area distal to the culprit lesion and a concordant 18% expansion of implanted stents at 3 days post-PCI, measured by intravascular ultrasound, in the absence of malapposed stents at 6 months [20] . These findings suggest that this device follows the growth of the vessel lumen while vasoconstriction and
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Review Yetgin, Nakatani, Onuma & van Geuns thrombus are resolving. Furthermore, technical, device and procedural success rates were 100, 96 and 96%, respectively, with a 12% rate of ischemia-driven TLR at 6 months, confirming the safety and feasibility in this setting. The initially observed benefits of this stent in terms of optimal appositioning were corroborated by the results of the subsequent randomized APPOSITION II trial [17] . In this trial, 80 patients with STEMI undergoing PPCI were randomized to receive a self-expanding Stentys stent (n = 43) or a balloon-expandable stent (n = 37). Strut malapposition at 3 days, as measured by optical coherence tomography (OCT), was significantly lower in patients allocated to the self-expandable stent compared with the balloon-expandable stent (0.58 vs 5.46%; p 30 to 1 year) after stent implantation target vessel MI was significant higher compared with balloon angioplasty only suggesting more negative effects of permanent metallic implants beyond strut apposition after the first year [45] . For patients presenting with STEMI this is important as they present usually at a younger age compared with stable angina patients. With the current fast reperfusion treatment and secondary prevention life expectancy for young STEMI patients is very good.
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Alternative stents in STEMI The potential advantages of the BVS implantation in the setting of STEMI are therefore the following: ●● Malapposed struts could disappear completely
when the device is bioresorbed at long-term follow-up. In the other words, the risk of stent thrombosis could be disappearing after full bioresorption of BVS; ●● The relatively thick struts (approximately 150
μm) which generally result in a relative large strut/vessel wall area ratio of 0.23 potentially leads to better capturing of thrombotic material behind the struts and therefore reduction of distal embolization;
●● The thicker struts will create low shear stress
in the intrastrut spaces. This low shear stress initially might predispose to platelet activations, but at later phase creates neointimal tissues. After the loss of mechanical integrity (approximately at first year), the scaffold area starts to enlarge and therefore the lumen dimension remains stable, despite the formation of thick tissue layer on the top of the underlying plaques. This layer could seal the ruptured plaques [46] . The use of fully bioresorbable drug-eluting scaffolds may therefore provide a favorable arterial healing compared with the permanent metallic stents. On the other hand, there is a technical challenge to implant BVS in the setting of STEMI, especially for selecting the proper scaffold size. At PPCI, the presence of thrombus burden, catecholamine stimulation, inflammatory substances and general or localized vasoconstriction contributed by the impaired microcirculation in the ischemic or infarcted myocardium could lead to underestimation of the vessel size. In addition, it should be noted that platelet activity associated with low shear stress behind the thick BVS struts might necessitate potent inhibition of platelet at least in the early phase of scaffold implantation. ●●Bioresorbable vascular scaffold utilization
in STEMI
The early trials in stable patients treated with BVS showed excellent results, while very limited data are available in patients with STEMI. Kajiya et al. initially showed a feasibility of BVS implantation in the setting of STEMI in case series [47] . Subsequently, two prospective, nonrandomized trials investigating the feasibility
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Review
and acute performance of the BVS for the treatment of patients presenting with STEMI were reported in 2014 [48,49] . In the BVS STEMI first study comprising 49 patients, the procedural success was 97.9%. OCT analysis performed in 31 patients showed that the mean percentage of postprocedural malapposed struts per patient was 2.80 + 3.90% and scaffolds with >5% malapposed struts were 22.6%, which was similar to that of DESs. At the 30-day follow-up, target-lesion failure rate was 0%. No target-vessel revascularization and target vessel myocardial infarction were reported, while one nontarget-vessel non-Q-wave MI occurred. No cases of cardiac death or scaffold thrombosis were observed. In the Prague 19 study enrolling 41 STEMI patients, the procedural success rate was 98%. OCT analysis performed in 21 patients demonstrated that the mean percentage of postprocedural malapposed struts per patient was 1.1% and scaffolds with >5% malapposed struts were 0%. A single case of scaffold thrombosis was reported, which occurred 3 days after discontinuation of all indicated medication, including aspirin and ticagrelor, and one nontarget vessel myocardial infarction [49] . These studies showed that implantation of BVS in STEMI is feasible with acceptable imaging results as well as acute clinical results. The other study investigating the feasibility and acute performance for the treatment of ACS patients with comparison between BVS and DES was reported by Gori et al. in 2014 [50] . In the BVS group, 44% (n = 60) of patients presented with STEMI, while in the DES group, 45% (n = 46) presented with STEMI. 30-day and 6-month MACE rates were similar between both groups (all p >0.5) and BVS utilization did not influence the incidence of MACE (p > 0.9) in multivariate analysis. Definite or probable stent/scaffold thrombosis occurred in three BVS patients and two DES patients during the first 30 days. This study showed that implantation of BVS in ACS is feasible with short-term clinical results [50] . There are several on-going studies to further evaluate the use of ABSORB BVS in STEMI; three studies specifically focused on STEMI population (e.g., TROFI-II [51] , BVS in STEMI [52] , ISAR-Absorb MI [53] , while three others (e.g., ABSORB-ACS [54] , AIDA [55] , GABI-R [56] include STEMI patients as a part of all-comers or ACS population. TROFI-II study is a prospective, randomized (1:1), active control,
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Review Yetgin, Nakatani, Onuma & van Geuns single-blind and European multicenter clinical trial. The primary end point is the neointimal healing score measured by using intra-coronary optical frequency domain imaging at 6 months follow-up in STEMI patients treated with ABSORB BVS compared with a metallic DES (XIENCE). These new studies will provide us more evidence on use of BVS in STEMI in the future. Conclusion & future perspective Conventional PCI while attempting to open the occlusion is more likely to dislodge the thrombus downstream potentially inducing distal embolization and microvascular obstruction. While aspiration is an acceptable intervention to remove thrombus from the artery as much as
possible, there remains a significant amount of thrombus covering the interior vessel wall, introducing the stent sizing dilemma, with underexpansion potentially leading to malapposition, restenosis or stent thrombosis and overexpansion potentially causing dissection or no-reflow. The self-expanding stent platform is well-suited in such scenarios because of the gentle, selfapposing nature of Nitinol that is coupled with a unique stent design. These properties enable the stent to tailor its size to the vessel diameter when the actual size of the vessel is obscured and to provide full apposition and sustained coverage as any remaining thrombus dissolves over time. Another suitable option in this setting is the use of the mesh-covered stent. The ultra-thin mesh sleeve is intended to block atherothrombotic
Executive summary ST-segment elevation myocardial infarction (STEMI) ●●
Primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) often limited by stent malappostion, due to vessel constriction with thrombus apposition, and impaired microvascular perfusion, attributable to distal atherothrombotic embolization.
●●
Recent improvements to stent design may optimize PPCI efficacy.
Stent apposition ●●
Self-expanding stents aim to overcome undersizing of balloon-expandable stents caused by vessel constriction and thrombus apposition.
●●
Consistent picture of this self-expanding stent-based strategy in STEMI with regard to feasibility, safety and efficacy in terms of improved stent apposition and coverage.
●●
Adequately powered randomized trials are needed to determine whether these benefits result in improved long-term clinical outcomes after STEMI.
Microcirculatory protection ●●
Mesh-covered stents are intended to mitigate distal embolization and associated no-reflow by thrombus and atherosclerotic plaque exclusion.
●●
Consistent picture of this embolization protection strategy in STEMI with regard to feasibility, safety and efficacy in terms of improved myocardial reperfusion indices.
●●
Adequately powered randomized trials are needed to determine whether these benefits result in improved long-term clinical outcomes after STEMI.
Vascular restoration ●●
Drug-eluting bioresorbable vascular scaffolds (BVS) provide temporary scaffolding but are fully resorbed by biochemical reactions.
●●
ABSORB BVS composed of poly l-lactide and poly d,l-lactide have unique potential in vascular repair, such as late lumen enlargement, restoration of vasomotion, sealing of plaques, adaptive shear stress and plaque media reduction
●●
The use of BVS in STEMI may provide a favorable arterial healing with sealing the ruptured plaque followed by resorption of malapposed struts and has the potential to reduce the risk of long-term thrombosis.
●●
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The ongoing studies will provide more evidence on use of BVS in STEMI in the future.
Future Cardiol. (2015) 11(3)
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Alternative stents in STEMI extrusion through the stent struts during its implantation by entrapping these underneath the micronet against the vessel wall, thereby preventing distal embolization and protecting the microcirculation. The use of fully bioresorbable drug-eluting scaffolds might provide a favorable arterial healing without permanent caging and lumen compression and address the issues associated with metallic DES such as late malapposition, delayed endothelialisation and late/very late stent thrombosis. The bioresorbable technology might be able to seal and stabilize the ruptured plaques after creation of stabilization layer and final resorption of strut polymers [46,57] . As such, we believe that these novel and innovative stentbased strategies will set the basis for further References
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