Passive Stent Coatings in the Drug-Eluting Era

Potential risk factors involved in the pathophyisology of stent thrombosis. Reproduced with permission from Honda and Fitzgerald.<SUP>13</SUP>
Scanning electron micrographs from flow loop model studying (A) an uncoated BX VELOCITY™ stent (Cordis Corp., Miami, Florida) showing fibrin and platelet deposition on the stent struts and (B) a heparin-coated BX Velocity stent showing minimal fibrin and
Explants from stented porcine coronary arteries (A) Bare metal stent at 1 hour showing sparse coverage of fibrin strands and red blood cells (B) Endothelial progenitor cell (EPC) antibody coated stent at 1 hour showing > 70% coverage of the stent surfa

Ian Menown, MD, Rob Lowe, MD, Ian Penn, MD

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 < 3.0 mm). Single-vessel stenting was performed in 88% of patients. Patients received 10,000 U of heparin, but no GP IIb/IIIa inhibitors or post-procedural heparin. At one-month follow-up there was no stent thrombosis, and only a 1.8% incidence of non-Q-wave MI. At six-month follow-up (89/110 patients), overall binary restenosis was 12.1%, with no further incidence of MI and no late occlusions.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 < 0.02) in subsequent neointimal hyperplasia at six weeks was also reported.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

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