Up to two million percutaneous coronary intervention (PCI) procedures are performed worldwide each year.1 Coronary stents are typically implanted in over 90% of these procedures following two landmark studies demonstrating significant reduction in restenosis rates compared to balloon angioplasty alone.2,3 Recent advances in stent technology have yielded further marked reductions in restenosis rates.4–10 However, as the use of PCI, enabled by these advances, is increasingly stretched into more complex anatomical and clinical scenarios, so the potential risk of subacute thrombosis may be increased. In a review of eight clinical series of 22,763 patients undergoing bare metal stent deployment, subacute thrombosis was reported in a mean of 1.2% of cases, but varied from 0.4% with intravascular ultrasound (IVUS) guided stenting to 2.8% after multivessel stenting.11 This is of clinical relevance because, in contrast to restenosis which is not usually associated with increased mortality, subacute thrombosis may have an associated six-month mortality of over 20%.12 Multiple risk factors11,13 may be involved in the pathophysiology of stent thrombosis (Figure 1). These include device-related factors (stent material/alloy, design, surface coating, associated pharmacotherapeutic agents, multiple or long stents) in addition to patient/lesion-related factors (smaller vessels, longer lesions, plaque characteristics, coronary blood flow, platelet/coagulation activity, acute coronary syndrome, impaired left ventricular function) and procedure-related factors (suboptimal stent deployment, adjunctive peri-procedural antithrombotic therapy). Thus, focus has been brought onto the structure and composition of stents, with particular interest in how the vessel responds to the foreign device and in methods to improve biocompatibility. In this paper we evaluate developments in passive thromboresistant stent coatings and address whether such coatings still have a role in the contemporary era of antiproliferative drug-eluting stents. Metallic Characteristics Before discussing stent coatings, it is useful to review the metallic characteristics of, and host response to, the bare metal. Stent implantation is associated with early thrombus deposition on the strut surfaces (Figure 2), acute inflammation, granulation tissue development, giant cell infiltration, and ultimately smooth muscle cell proliferation and extracellular proteoglycan matrix synthesis.14 The severity of arterial injury during stent deployment correlates with increased inflammation and late neointimal growth. Corrosion of the stent surface could theoretically induce an inflammatory response, leading to thrombosis and/or restenosis. However, in vivo, formation of a surface metal oxide film retards corrosion and long-term follow-up does not suggest evidence of local or distant toxicity secondary to migration of corrosion particles.15 The majority of current stents are manufactured in 316 L stainless steel alloy, composed primarily of iron (60–65%), nickel (12–14%) and chromium (17–18%), the latter providing excellent anticorrosion properties in addition to radial strength.16 Tantalum may have theoretical advantages over stainless steel in terms of radiopacity and lack of ferromagnetism, as well as forming a stable, resistant surface metal oxide film,17,18 but has not been found to decrease stent thrombosis compared with stainless steel.19 Nitinol alloy (nickel ~55%, titanium ~45%) appears to have satisfactory in vivo biocompatibility,20 although it is no better tolerated than stainless steel, its main utility being for stents/devices requiring its superelastic and thermal shape memory properties. Newer alloys include niobium alloy, a heavy metal-free, corrosion-retardant material with similar mechanical properties to steel,21 and cobalt-based alloys which may enable thinner strut size while preserving radiopacity and radial strength. This may be clinically relevant since use of thinner (50 µm) compared to thicker (140 µm) stent struts has been associated with favorable reductions in rates of clinical and angiographic restenosis,22 and may lead to a reduction in profile and enhanced flexibility which can be particularly advantageous in the design of small-vessel stents. In addition to stent composition, stent design, geometry, configuration and surface refinement may influence biocompatibility.23–25 Passive Stent Coatings In order to provide a biologically inert barrier between the stent surface, circulating blood and endothelial wall, a variety of different stent coatings have been evaluated in multiple study registries, non-randomized and randomized trials. Results of the principal clinical trials are summarized in Table 1. Gold. One of the first coatings to be tested, gold, provides excellent fluoroscopic visibility and in preclinical studies, was associated with reduced thrombogenicity, decreased neointimal formation, and even antibacterial properties.26,27 However, recent trials have not demonstrated clinical benefit over conventional stents,28,29 some even suggesting an increased tendancy to stent restenosis.30–32 In a prospective, multi-center trial, vom Dahl et al. randomized 204 patients to otherwise identical uncoated (n = 101) or gold-coated (n = 103) stents.31 At six months, those with gold-coated stents had significantly greater neointimal proliferation (neointimal volume 47 versus 41 mm3; p = 0.04) as assessed by IVUS, and a smaller angiographic minimal luminal diameter (1.47 versus 1.69 mm, p = 0.04). Similarly, Kastrati et al. randomized patients to uncoated (n = 367) or gold-coated (n = 364) Inflow stents and found increased angiographic binary restenosis in those with gold-coated stents (49.7% versus 38.1%; p = 0.003) at six months.30 It has been suggested that post-plating thermal processing by smoothing the surface coating, may negate the adverse tissue response to gold, although this remains to be confirmed in clinical studies.33 Heparin. Heparin has been evaluated predominately as a fixed (passive) stent coating, although it may also be actively released from a drug-eluting platform (as described under active stent coatings). Multiple non-randomized studies have shown that fixed heparin-coated stents are well-tolerated and may reduce thrombotic complications.34–35 The incidence of stent thrombosis with the Hepacoat™ stent (Cordis Corporation, Miami, Florida) in clinical trials has ranged from 0.1% in elective cases, to 0.7% in acute myocardial infarction,11 with similar rates reported from “real world” registry data.36,37 Haude et al., in the heparin-COAted STents in small coronary arteries (COAST) trial,38 randomized patients undergoing small-vessel PCI (2.0–2.6 mm) to a bare stent (JoStent® Flex Stent, Abbot Vascular Devices, Redwood City, California) (n = 196), a Flex Stent with a fixed heparin-coated stenting (n = 197), or a third arm treated by balloon-only angioplasty (n = 195). No differences were noted in subacute thrombosis, although event rates were low (0.5% after bare or heparin-coated stenting and 1.0% after angioplasty; p = ns). Carbon. Pre-clinical evaluation of a diamond-like carbon nanocomposite film coating has suggested reduced thrombogenicity following stent implantation and possibly reduced neointimal hyperplasia.39 A turbastratic carbon film-coated stent (CarboStent,™ Sorin, S.p.A., Milan, Italy) also appears to be well-tolerated. In a series of 112 patients at relatively high risk of thrombosis, late restenosis or target vessel failure, Antoniucci et al. reported 0% incidence of stent thrombosis or myocardial infarction (MI) and a six-month angiographic restenosis rate of 25% (late loss 0.81 ± 0.88 mm).40 In view of these possible antithrombotic properties, the ANTARES (Aspirin alone antiplatelet regimen after intracoronary placement of the CarboStent) study41 evaluated the use of aspirin monotherapy (without thienopyridines) after CarboStent implantation in 110 patients (76% with stable angina, 30% with complex lesion characteristics, 32% with lesions > 15 mm and 28% with vessel diameter 42 However in a recent randomized trial comparing CarboStent with stainless steel stent implantation in 329 patients undergoing single-lesion PCI, no differences in major adverse events or binary restenosis were reported.43 Silicon carbide. Hydrogen-rich amorphous silicon carbide (a-SiC:H) coating may also improve thromboresistance. Carrie et al. studied the a-SiC:H coated stainless steel (Tenax) stent in 241 moderate-risk patients, achieving successful deployment without procedural or clinical event in 95.4% of patients, with a 7.1% one-year target lesion revascularization rate and 15.8% one year incidence of major adverse cardiac events.44 Fournier et al. implanted Tenax™ stents (Biotronik, Berlin, Germany) in 206 moderate to high risk patients and reported 1 acute thrombosis, 1 non-Q wave MI and a 1.9% incidence of clinically driven repeat PCI at six months.45 The TRUST study (Tenax for the Prevention of Restenosis and Acute Thrombotic Complications, a Useful Stent Trial in Patients with ACS) randomly assigned 485 patients with Braunwald IIB or IIIB unstable angina to PCI with a Tenax stent or non-coated stent.46 Patients were given clopidogrel for 30 days but use of GP IIb/IIIa antagonists was discouraged (only ~2% of patients) so as not to obscure the potential benefit of the stent coating. In the patient subgroup with Braunwald IIIB symptoms, those receiving a Tenax stent compared to those receiving a non coated stent had a lower incidence of death/MI/or ischaemia driven target vessel revascularisation at six months (4.7% versus 15.3%; p = 0.02) with a trend to reduced events at 9- and 18-month follow-up. Titanium-nitride-oxide. A Titanium-nitride-oxide (TiNOX) coating has been found useful in an initial preclinical evaluation which noted significant reductions in platelet and fibrinogen binding with TiNOX-coated stents compared with uncoated stainless steel stents. Interestingly a significant 44–47% reduction (p 47 Phosphorylcholine. The naturally occurring zwitterionic (i.e. neutrally charged) phospholipid polymer phosphorylcholine (PC) coating mimics the outside surface of red blood cells, where PC head groups are found in 90% of the lipid components in the form of glycerophospholipids or sphingomyelin. This biological mimicry may confer potentially thromboresistant properties. Several registries and a randomised trial have found PC-coated stents to be well tolerated with favourable event rates even in acute patients. Galli et al. studied 100 consecutive patients within 24 hours of acute MI, undergoing PCI with a PC-coated stent (mean stent diameter 3.5 ± 0.4 mm; mean stent length, 17 ± 4.5 mm).48 No acute or subacute thrombosis was reported. At six-month follow-up there was a low incidence of major adverse events (13%) and an angiographic restenosis rate of 12%. The Italian BiodivYsio open registry,49 reported results of 218 consecutive patients, two-thirds with an acute coronary syndrome, in which 90% of stents were PC-coated. One death and 3 (1.4%) MIs were reported during in-hospital follow-up, but 189 (87%) patients remained asymptomatic at six months. The multicentre SOPHOS (Study Of PHosphorylcholine coating On Stents) trial50 in 425 patients with angina undergoing PCI with PC-coated stents reported a six-month death/MI rate of 16/425 (3.8%) and a binary restenosis rate (at pre-specified angiographic follow-up; n = 200) of 17.7%. Grenadier et al.,51 in a study of 97 moderate- to high-risk patients undergoing 2.0 mm vessel stenting, reported 1 acute stent thrombosis, 10.3% major adverse cardiac events at six months, and target lesion revascularization in 8/18 patients who clinically required angiography. DISTINCT (bioDIvysio STent IN Controlled Trial)52 was a prospective, multi-center trial which randomized 622 patients with de novo lesions (length = 25 mm, diameter 3.0–4.0 mm) to the PC-coated, BiodivYsio-added support stent (n = 313), or the MULTI-LINK DUET stent (Guidant Corporation, Indianapolis, Indiana) (n = 309). Of note, patients in the PC arm had a higher incidence of LAD lesions (p = 0.03) and a longer mean stent length (19.5 versus 17.9; p = 0.01). Nevertheless, despite these disadvantageous baseline characteristics, the PC-coated stent was found to be equivalent to the DUET stent with respect to the primary endpoint of six-month target vessel failure (8.3 versus 7.4%; p = ns) and secondary endpoint of six-month angiographic binary restenosis (19.7 versus 20.1; p = ns). No patient in the PC arm had subacute thrombosis compared to a 0.65% incidence in the DUET arm (p = ns). Active (Drug-Eluting) Stent Coatings Full discussions of individual active stent coatings are covered elsewhere. However, to place passive coatings in context, active coatings should be considered and fall under one or more of the following headings. Antithrombotic. Several antithrombotic agents have been or are undergoing clinical evaluation. Heparin, while mainly evaluated as a passive fixed coating (described earlier), has also been studied as an active coating using a drug-eluting platform. Worhle et al.53 assigned 277 moderate- to high-risk patients to an active heparin-coated stent (with heparin elution from a polyamine platform) or control stent, and did not note any difference in subacute stent thrombosis (1.9% versus 1.3%; p = ns), major adverse events (25.2% versus 25.7%; p = ns), or rates of restenosis at six-month angiographic follow-up (33.1% versus 30.3%; p = ns). Pre-clinical evaluation of stent-based delivery of alternative antithrombotic agents, hirudin or prostaglandin I2, for example, has been encouraging54 and further studies are planned. Anti-inflammatory. Reduction of local inflammation post-PCI is desirable, given its potential association with thrombosis and restenosis. Following encouraging pre-clinical work with dexamethasone,55 the non-randomized prospective STRIDE (Study of Anti-Restenosis with the BiodivYsio Dexamethasone-Eluting Stent) trial,56 reported no cardiac deaths, MI, or CABG, 2 (3.3%) target lesion revascularizations, and a six-month binary restenosis rate of 13.3%. There was a suggestion of greater benefit in patients with unstable compared with stable angina (loss index 0.22 versus 0.46; p = ns) in keeping with a higher degree of inflammation in unstable patients. In contrast to promising pre-clinical results, coating with the “anti-migratory” matrix metalloproteinase inhibitor batimastat was not found to be superior to a non-coated stent in the randomized BRILLIANT 1 (Batimastat (BB–94) antiRestenosis trIaL utiLizIng the BiodivYsio locAl drug delivery PC steNT) clinical study. Clinical studies of drug elution with other steroid anti-inflammatory agents are underway, including methylprednisolone57 and 17–B estradiol58 which may have roles as pro-healing agents. In the first-in-man estrogen and stents to eliminate restenosis (EASTER) trial, only 2 of 30 patients undergoing stenting with the 17–B estradiol-eluting biodivYsio stent had > 50% restenosis at six-month angiography.58 Use of bisphosphonates such as clodronate or alendronate as anti-inflammatory agents to inhibit macrophage activity (thereby potentially modulating smooth muscle cell response to injury and reducing neointimal formation following stenting) also appears to be a promising strategy.59 Antiproliferative. While not all delivery platform/drug combinations have been successful, multiple randomized clinical trials with sirolimus-eluting4–7 and non-polymer or polymer-coated paclitaxel stents8–10 have led to marked and durable reduction in restenosis, leading to optimism that such stent coatings may represent a cure for this Achilles heel of PCI. Numerous other agents, including sirolimus or paclitaxel analogues, angiopeptin, and tyrosine kinase inhibitors are under intensive evaluation. Angiographic and clinical endpoints of 14 randomized clinical trials involving 5,747 patients, comparing drug-eluting with non-drug-eluting stents, have been well summarized by Hill et al. in a recent extensive systematic review.60 With any new drug or device, overall benefit is a function of safety versus efficacy, with safety being of primary concern. While reduction of restenosis is clearly valuable, restenosis is rarely complicated by myocardial infarction or death. Thus it is not surprising that even in the larger sirolimus or paclitaxel trials,6,7,10 or in the Hill et al. meta-analysis,60 no reduction in death or non-fatal MI was found. Early concerns regarding a theoretical increase in subacute thrombosis risk due to delayed or incomplete re-endothelialization of stent struts, stent malapposition or positive vessel remodeling ± aneurysm formation, have not been borne out from longer-term follow-up of randomized trial data.61–64 The importance of suitable polymer selection was highlighted by a histopathological study of atherectomy specimens from patients undergoing stenting with the QUAds-QP2 stent, which suggested that the drug-eluting, non-biodegradable polyacrylate sleeves may have been proinflammatory, leading to delayed healing65 and potentially, an excessive proliferative response once drug elution had worn off.61 Innovative drug delivery platforms include the Conor MedStent (Conor Medsystems, Inc., Palo Alto, California) with multiple laser-cut holes enabling the housing and releasing of multiple drugs at varying times, bioabsorbable polymers, resorbable drug-polymer conjugates, and bioabsorbable stents. However, while drug-eluting stents themselves may not be associated with increased subacute thrombotic risk compared to bare metal stents, the increasingly challenging lesions and clinical scenarios in which drug-eluting stents are being used (due to a lessening of restenosis concerns) means that ongoing registries, large enough to adequately evaluate the incidence of thrombotic complications are required. Careful angioplasty technique may help reduce the risk of stent thrombosis such as full lesion coverage, ensuring the balloon injury zone is within the stent treatment zone and use of post-dilatation where required. In some cases, IVUS guidance may help avoid undesirable under- or oversizing and improve assessment of malapposition post-deployment. A lower threshold for the use of GP IIb/IIIa receptor blockers and prolonged dual antiplatelet therapy would appear prudent.11 Thromboresistant Stent Coating in the Drug-Eluting Era In higher-risk patients such as those with complex anatomy, acute coronary syndromes, following brachytherapy procedures or prior to non-cardiac surgery, drug-eluting coatings with enhanced thromboresistance may be desirable. Changes to stent design may facilitate this. The Janus CarboStent™ (Sorin S.p.A., Milan, Italy), for example, consists of an integral Carbofilm coating combined with the capability to load the drug into and release it from deep sculptures made on the external surface of the stent. Pre-clinical studies using tacrolimus showed only mild inflammation scores and a significant reduction of intimal proliferation compared with a control stent.66 Alternatively, modifications to the stent coating may be useful. The PC coating only needs to be ~0.1 µm thick to impart biocompatibility, but increasing the thickness of the coating on the outer stent surface allows absorption of low-molecular weight drugs for delivery into the vessel wall. Higher molecular weight drugs can be adsorbed by an adaptation of the PC coating, enabling interaction with negatively charged groups found in many large biological molecules such as anti-sense DNA fragments and antibodies. Pre-clinical studies of the rapamycin analogue ABT–578 eluted from a PC-coated BiodiVsio stent have been promising, and evaluation is ongoing of ABT–578 elution from a PC-coated Medtronic S8 Driver cobalt chromium alloy stent.67 An innovative approach to improve thrombo-resistance has been reported using a coating of CD34 antibodies to enable the capture of naturally occurring, circulating endothelial progenitor cells, leading in pre-clinical studies to rapid healing with smooth endothelization over and between stent struts, and a reduction in neointimal hyperplasia (Figure 3).68 Conclusion While percutaneous stent implantation has overtaken bypass graft surgery as the most frequently performed method of coronary revascularisation and technological developments have enabled its increasing use in multivessel disease, complex anatomy and smaller vessels,69 stent-associated thrombosis and restenosis have remained important concerns. As modifications to stent composition, design, geometry, configuration and surface refinement have yielded only modest improvements in biocompatibility, a variety of different stent coatings to provide a biologically inert barrier between the stent surface, circulating blood and endothelial wall have been tested. Several passive stent coatings, including carbon, silicon carbide and phosphorylcholine appear to be well-tolerated in clinical trials and may reduce subacute stent thrombosis, particularly in higher-risk patients, although they have not led to any clear reduction in restenosis. Active stent-based drug delivery represents a significant advance, in particular, the use of antiproliferative drugs to reduce restenosis. However, as PCI is stretched into increasingly challenging scenarios, methods to optimize safety (whether using drug-eluting or bare metal stents), particularly in more complex settings such as saphenous vein graft PCI, thrombus-containing lesions or chronic total occlusion need to be clearly defined. Thrombo-resistant coatings capable of acting as drug delivery platforms may be desirable to improve safety, especially in higher-risk lesions. In summary, while the transition from bare metal, to coated, to drug-eluting stents is mechanistically promising, the potential for ongoing structural, functional and pharmacological development remains.
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