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Self-Apposing Stent Technology and the Future of PCI for STEMI
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Primary PCI is considered the gold standard for the treatment of patients experiencing STEMI. Despite improvement in outcomes compared with thrombolysis, MACE after primary PCI is still higher than in patients treated for stable CAD, particularly in the first 30 days. This is not surprising, as the environment surrounding an MI is different from that of stable atherosclerotic plaque.
In STEMI, vessels are often totally occluded due to a plaque rupture and large thrombus burden. Coronary thrombus and its disintegration during the procedure increases the risk for distal microembolization (roughly 15% after primary PCI), leading to the no-reflow phenomenon, with the associated risk for microvascular obstruction entailing increased infarct size and systolic dysfunction. Thrombus debris is amenable to reduced mechanical trauma at the time of stent expansion. In addition, the sudden ischemic milieu in ACS often causes hypo-perfused coronary vessels due to endothelial dysfunction with decreased vasomotor capacity resulting in vasoconstriction. The consequently hypo-perfused culprit artery hinders correct angiographic visual estimation of the true vessel lumen diameter, which in turn renders the identification of the appropriate stent size difficult.
Mikkel M. Schoos
Roxana Mehran
In addition, it has been reported that as the vessel recovers after a successful procedure, clot material from the acute thrombus may be entrapped between the vessel wall and the stent, which eventually dissolves by bio-absorption facilitated by antiplatelet and anticoagulant treatment, along with re-establishment of vasomotor functions and vasodilation. These processes have been shown to increase the vessel reference area within days and are very likely the dominant factors in the high prevalence of stent malapposition after primary PCI of up to 40%.
Stent malapposition is well known as a driver for in-stent restenosis and has consistently been reported as a main risk factor for stent thrombosis, as well as stent placement in an ACS patient. Correct sizing of a coronary stent ideally involves vessel size estimation by IVUS or optical coherence tomography. These techniques, however, are time consuming and are not utilized in the acute setting of STEMI reperfusion. Considering these challenges of treating STEMI patients, an alternative stent design and technology may improve outcomes by reducing distal embolization and addressing the problems associated with stent sizing and malapposition, both during the index procedure and when positive remodeling occurs in the vessel over time.
Self-Apposing Stent Technology
Stentys is currently the only self-apposing stent available for use in the coronaries, which has the same underlying nitinol stent platform that is compatible with a 6F guiding-catheter and a 0.014-inch guidewire. The stent is deployed by withdrawing a retractable sheath that releases the stent, deploying it from distal to proximal. Three markers on the delivery system are used to position and deploy the stent. The self-apposing BMS and paclitaxel-eluting stent (PES) are commercially available in Europe, the Middle East and South America. The self-apposing BMS is an investigational device in the United States. The self-apposing sirolimus-eluting stent (SES) is currently being investigated in Europe, with approval expected in late 2014.
Clinical Evidence
The evidence on self-apposing stents originates from Stentys, particularly from the APPOSITION program in the STEMI indication, in which the self-apposing stent has been studied since 2009.
The self-apposing stent technology was first tested in the APPOSITION I trial, which was a prospective, single-arm, multicenter, international feasibility trial of the bare-metal stent version in 25 STEMI patients. Stent expansion and apposition were estimated at 3 days post-procedure with IVUS. The trial showed that post-STEMI, a vessel’s mean reference area increases 19% within 3 days, and that the self-apposing stent follows this expansion with a mean stent area increase of 18%. Six-month results showed a similar in-stent late lumen loss for the self-apposing BMS (0.71 mm) as compared with conventional BMS technology. Thus APPOSITION I indicated the ability of the stent to accommodate post-procedure changes in vessel size while limiting late loss.
In the subsequent prospective, randomized, multicenter, international APPOSITION II trial, the Stentys BMS was compared with the Abbott Vision or Medtronic Driver stent in 80 STEMI patients; stent strut malapposition at 3 days post-procedure was investigated under OCT. The self-apposing BMS was superior to standard BMS in stent strut apposition (malapposed struts: 0.58% vs. 5.46%; P<.001), with 0% of patients treated with self-apposing BMS having a malapposed stent at 3 days vs. 28% for standard BMS technology (stent malapposition defined as >5% of the stent struts malapposed). This trial also showed an in-stent late loss of 0.7 mm, which is comparable to conventional BMS, but high in comparison to DES; however, the trial was not powered to address differences in clinical metrics.
Unlike conventional balloon-expandable stents, a self-expanding stent does not require a deployment balloon to be placed in a vessel. The stent is usually made of nitinol — a nickel-titanium alloy — and is constructed with a memory-shape. When an outer sheath constraining the stent is withdrawn, the stent naturally expands itself until inhibited by the vessel wall from expanding further. This characteristic enables the stent to be deployed with minimal vessel trauma by reducing the need for high-pressure ballooning.
Figure 1. Top panel: A Stentys self-apposing stent apposes well to the aneurysmal portion as well as the proximal and distal segments of the tapered glass tube. Bottom panel: A self-expanding stent adapts to the proximal and distal segments of the tapered tube, but does not appose to the aneurysmal portion.
Photos courtesy of Stentys SA
However, in current generation self-expanding stents, the outward force of expansion (chronic outward force) is reduced as the stent expands to avoid excessive continual force against the vessel wall. This addresses the issue of high levels of restenosis, which was reported with self-expanding stents like the Wallstent (Boston Scientific). As a result, and because a balloon is not used during deployment, additional dilation is often necessary to adequately treat the lesion and enable sufficient stent expansion and luminal gain, which can be done with low-pressure post-dilation. Once expanded, the stent is designed to have sufficient radial resistive force (crush-resistant force) to keep the stent open and avoid vessel recoil.
Self-apposition is not the same as self-expansion, as not all self-expanding stents are self-apposing. In theory, self-apposition is the ability of the stent to appose itself to the vessel wall without requiring additional manipulation of the stent with ballooning. This property indicates the flexibility of the stent to take the shape and form of the vessel and prevent malapposition. An example of this would be in a situation where there are abrupt irregular diameters along the length of the stent, such as in an ectatic vessel or in the presence of an aneurysm. This ability to appose is enabled by a combination of the property of self-expansion and a specific stent design. Stent struts need to be sufficiently short to enable the stent to abruptly change shape and fit the contours of the vessel. Figure 1 compares the deployment of a self-expanding stent with the self-apposing stent in aneurysmal, tapered tubes and further demonstrates the property of self-apposition.
Figure 2. Top and middle panels: Disconnection of deployed Stentys stents in two tapered silicon tubes showing good apposition without the need for kissing balloon inflations. Bottom panel: A look through the sidebranch of a silicon tube in which a Stentys stent has been disconnected. No struts are visible jailing the sidebranch, only the stent struts against the opposing vessel wall can be seen.
However, in real-life clinical practice, additional manipulation of the self-apposing stent with ballooning still appears to be required. Additional manipulation of the stent is not necessary for proper vessel apposition per se, but rather to generate the outward force to treat the underlying plaque and enable the stent to expand sufficiently. This was seen in the APPOSITION III trial, which was a prospective, multicenter, international study of 1,000 STEMI patients in 51 centers across Europe. The study aimed to evaluate the safety and efficacy of self-apposing BMS and a PES in a large population and looked at MACE at 1 year after the procedure. The results were presented at EuroPCR 2013 and showed a 1-year MACE rate of 9.3%, with cardiac death of 2% and definite stent thrombosis of 2.8% in the overall APPOSITION III cohort. An interesting lesson learned from APPOSITION III was the importance of post-dilation, which became apparent after an interim analysis of in-hospital outcomes was conducted after including the first 400 patients. Post-dilatation significantly reduced rates of cardiac death/target vessel MI (2.4% vs. 5%) and stent thrombosis (definite, 1.9% vs. 5%) at 1 year compared with patients treated without post-dilatation. The MACE rate of the post-dilation subgroup was 8.4% at 1 year, and cardiac death was 1.7%.
Additional evidence from the OPEN I trial demonstrated a late lumen loss of 0.39 mm for the self-apposing PES at 6 months, in line with other PES. Two-year IVUS follow-up of a subset of patients in OPEN I (in comparison with baseline and 6-month IVUS) showed that the self-apposing stent diameter stabilizes between 0 and 6 months.
Another advantage of the self-apposing stent could lie in the scaffold construction. Due to the nature of the nitinol material, self-expanding stents deployed at a bifurcation would jail a sidebranch. The nitinol material cannot be deformed to create an opening to a sidebranch (as is possible with balloon-expandable stents), due to the memory-shape property that causes a nitinol stent to conform back to its original stent design. The self-apposing stent, however, has the additional ability to enable the bridges between stent struts to be disconnected. With a regular percutaneous transluminal coronary angioplasty balloon inserted in between the stent struts at the carina, the bridges can be disconnected by inflating the balloon at low pressure (8 atmospheres). Due to the self-expanding properties of the stent, this then releases part of the stent that opens up toward the sidebranch, providing additional ostial coverage (Figure 2). This feature is available all along the length of the stent, except the first and last 2 mm. Although the bifurcation indication is still off-label in the United States, 220 patients have been enrolled in European centers in the single-arm OPEN II trial, and results were presented at Transcatheter Cardiovascular Therapeutics 2013. At 6 months, the composite endpoint of cardiac death, emergent CABG, target vessel MI and clinically driven target lesion revascularization occurred in 10.1% of patients, which compares well to previous data provided by the BBC, NORDIC and CACTUS trials.
Ongoing Research
Studies in progress for the STEMI indication include the APPOSITION IV randomized DES trial and the APPOSITION V randomized BMS trial. The APPOSITION IV trial randomly assigned 150 STEMI patients to the self-apposing SES or the Resolute zotarolimus-eluting stent (ZES; Medtronic) in 11 centers throughout Europe. The primary endpoint is late stent strut malapposition at 9 months post-procedure, with secondary endpoints of strut coverage at 4 and 9 months, and stent strut malapposition at 4 months. Results at 4 months for a subgroup of 60 patients who were scheduled for 4-month follow-up were presented at TCT 2013. The self-apposing SES had significantly better apposition and a higher number of stents that were fully covered compared with the control (32% vs. 4%). Late lumen loss at 4 months was 0.16 mm for the self-apposing SES, which was equivalent to the ZES. Presentation of the 9-month results is expected at EuroPCR 2014. However, this study is not powered to identify possible differences in clinical endpoints.
Investigators of the APPOSITION V trial are randomly assigning 880 STEMI patients to the Stentys BMS or the Abbott Multi-Link BMS in up to 80 sites worldwide. This trial is an approved investigational device exemption (IDE) trial in the United States, which upon completion will support a pre-market approval application for the self-apposing BMS in the United States. The primary endpoint of the study is target vessel failure at 12 months post-procedure. Secondary endpoints include acute and late stent malapposition measured in an IVUS/OCT substudy.
Conclusion
Continuous efforts are being undertaken for further improvement in patient outcome in the area of primary PCI, where MACE is typically higher than after treatment for stable CAD. A self-apposing stent system, which deploys without the need for high-pressure post-dilatation and adapts to the vessel size both during the procedure and over time, could be a possible tool to improve outcomes, especially in relation to reducing stent malapposition.