Stent Passivation with Silicon Carbide as a Possible Alternative to Drug-eluting Stents - A Comprehensive Review of Pre-clinical and Clinical Results

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Abstract

Metallic stenting has significantly improved short-term procedural outcomes and substantially reduced the rate of restenosis in patients undergoing percutaneous coronary interventions (PCI). Drug-eluting stents (DES) are often used in PCI procedures as they have been associated with a significant reduction in the rate of restenosis compared with PCI alone or PCI with bare-metal stents (BMS). However, there have been reports of stent thrombosis (ST) with DES, especially in patients at high risk of death, thrombosis or restenosis. Surface passivation of stents by amorphous silicon carbide (aSiC:H) coating has been shown in pre-clinical studies to reduce the thrombogenecity and possibly improve the biocompatibility of the stent surfaces. Clinical trials have generally shown low rates of ST, major adverse cardiac events (MACE) and target lesion revascularisation (TLR) in patients with stenotic lesions, with these rates also being low in high-risk patients. Based on indirect comparisons of aSiC:H-coated stents with DES, the former may be alternatives to DES, especially in high-risk patients.

Disclosure
The author has no conflicts of interest to declare.
Correspondence
Christoph Hehrlein, Department of Cardiology, University of Heidelberg, Bergheimerstr. 58, 69115 Heidelberg, Germany. E: christoph.hehrlein@uniklinik-Frelburg.de
Received date
18 August 2009
Accepted date
04 September 2009
Citation
ICR - Volume 4 Issue 1;2009:4(1):60-63
Correspondence
Christoph Hehrlein, Department of Cardiology, University of Heidelberg, Bergheimerstr. 58, 69115 Heidelberg, Germany. E: christoph.hehrlein@uniklinik-Frelburg.de
DOI
http://dx.doi.org/10.15420/icr.2009.4.1.60

Percutaneous coronary interventions (PCI) for the treatment of coronary artery obstructions are associated with a high rate of restenosis (20–57%) in the first six months after the procedure.1,2 Metallic stenting has significantly improved short-term procedural outcomes and reduced restenosis rates in patients undergoing PCI.3,4 The surgical stent deployment procedure initially involves the advancement of a coronary guidewire to the stenotic target lesion. The stents used are usually balloon-expandable; they are mounted on a balloon in a compressed configuration. The balloon, with the mounted stent, is then passed along a coronary guidewire to the lesion site. The balloon is inflated to expand the stents, resulting in the stent pressing against the vessel wall, giving support to the vessel wall and preventing immediate early and late recoil (negative remodelling) of the artery in response to injury, thereby acting to prevent restenosis. The stents are then incorporated into the vessel wall by endothelial cell coverage of the stent struts.
Coronary artery stents were first introduced as bare-metal stents (BMS), produced from 316L surgical stainless steel containing iron (60–65%), nickel (12–14%) and chromium (17–18%). While BMS can significantly reduce the rate of restenosis to around 20–30%, drug-eluting stents (DES) were developed to further reduce the restenosis rate. Since neointima formation and immune response to injury or to a foreign body (stent) can result in restenosis, DES are coated with and elute antineoplastic and antithrombotic drugs to prevent neointima formation and thrombosis, respectively. Randomised controlled trials have shown a significant reduction in restenosis, late lumen loss and target lesion revascularisation (TLR) to levels under 10%, compared with BMS, albeit with a delayed in endothelialisation.5–8 DES are now widely used during PCI procedures and have even been used for PCI procedures in patients with high risk of death, thrombosis or restenosis, such as those with diabetes or acute coronary lesions.9–11 However, stent registries and meta-analyses of randomised controlled trials have suggested that DES may be associated with an increased incidence (0.4–2.8%) of stent thrombosis (ST), particularly late or even very late (one to three years of follow-up) ST,9–17 and this rate is even greater in high-risk patient populations.18–22 ST is a major issue as it is associated with an increase in the risk of myocardial infarction (MI) and death.

The occurrence of ST, especially late ST (later than one year), with DES has been attributed to: discontinuation of dual antiplatelet therapy with clopidogrel and aspirin, leading to increased platelet adherence;23,24 delayed endothelialisation due to the use of antineoplastic drugs as this delay can result in incomplete coverage of the stent struts and a prolonged time to formation of a functional vessel endothelial layer;25–27 and erosion of the stent polymer coating over time as it releases the drug and the erosion creates irregular surfaces that attract platelets and inflammatory cells.
Several strategies have been explored to develop alternative stents that have similar or lower restenosis rates than the DES but with a reduced rate of ST. One strategy is to passivate the surface of the metallic stents, by coating them with either amorphous silicon carbide (aSiC:H), carbon, heparin or phosphorylcholine, etc. The interaction of blood constituents with poorly compatibile materials can lead to unwanted effects such as immune response, neointima formation, thrombosis and restenosis.28,29 Surface passivation aims to improve the biocompatibility of the material, thereby reducing these interactions and, in turn, reducing thrombogenecity. Passivation is also intended to decrease the rate of restenosis and prevent the delay in endothelialisation.25,30–32 Surface passivation aims to achieve reduction in the interaction of blood constituents with the stent surface by using semi-conducting materials to inhibit electron transfer between the blood constituents and metallic surfaces.33–35 This inhibition can prevent the unwanted effects of protein/cell–stent interaction, as electron transfer from the protein solution to the metallic surface induces neointima formation and activation of the clotting cascade. This article will review the results of pre-clinical and clinical studies to evaluate the potential of aSiC:H-coated metallic stents as alternatives to DES.

Pre-clinical Studies to Evaluate the Use of Silicon Carbide Passivation

The aSiC:H coating is an amorphous, hydrogen-rich, phosphorous-doped modification and metallic stents are coated with it by a chemical vapour deposition process. An in vitro study showed that silicon carbide prevents electron transfer to adhering cells and proteins much better than BMS.36 In this study, the aSiC:H-coated stents increased the critical electron gap to >0.9eV, leading to lower electron transfer into the stent material. These findings indicate that aSiC:H coating can indeed act to passivate the surface of the stent, and may thereby improve stent biocompatibility.

The biocompatibility and thrombogenecity of aSiC:H-coated stents have been evaluated by in vitro and in vivo studies. In vitro and in vivo tests by Amon et al. investigated the suitability of aSiC:H for stainless steel stents.37In vitro tests showed aSiC:H to have no cytotoxic reaction to L929 mice fibroblasts, to induce no damage to red blood cells and to exhibit no mutagenic potential. To assess the biocompatibility and haemocompatibility of the stents, an in vitro test was carried out in which the stented vessels underwent blood perfusion for three days. It was observed that these vessels remained open at the end of this perfusion period, with aSiC:H-stented vessels showing no signs of thrombus formation. These in vitro and in vivo results show that the aSiC:H coat has no cytotoxicity, haemotoxicity or mutagenicity, that it reduces the thrombogenecity of the stent surface, and may also improve its biocompatibility.
The results of a recent in vitro study support the results of the study by Amon et al.,37 in suggesting reduced thrombogenecity and high biocompatibility of aSiC:H-coated stents. This in vitro study observed a significantly lower rate of platelet adhesion and activation on aSiC:H-coated stainless steel stents than on uncoated 316L stainless steel or L605 cobalt–chromium (CoCr) stent surfaces.36 There was also an absence of fibrin formation on aSiC:H-coated CoCr stent surfaces compared with uncoated CoCr stents, which were completely covered with fibrin thrombus. These lower rates of platelet adhesion and activation, and of fibrin activation, with the passivated stents have been attributed to the inhibitory action of aSiC:H on electron transfer. These results show that the aSiC:H coating can reduce thrombogenecity and may improve the biocompatibility of stents.36 Results of other in vitro studies also show the low thrombogenecity and high biocompatibility of aSiC:H-coated stents.38–40
The use of aSiC:H-coated self-expanding nitinol stents has been evaluated in vitro. Nitinol, a nickel (55%) and titanium (45%) alloy, is fast becoming the material of choice for peripheral stents as it may produce less damage and platelet activation than stainless steel.41 In an in vitro study, self-expanding nitinol stents with and without the aSiC:H coating were examined in a chandler loop model of a superficial femoral artery.42 The short-term results of the study showed markedly lower levels of β-thromboglobulin (β-TG) and of the formation of the thrombin-antithrombin (TAT) III complex with the coated stents versus the uncoated stents.

Platelet activation by mechanical stress and by platelet aggregation is represented by β-thromboglobulin while the amount of coagulation induced by the foreign material (of the loop and the stents) is represented by the level of the formed TAT III complex. There was also an absence of thrombus formation on the aSiC:H coating. Therefore, aSiC:H-coated self-expanding nitinol stents have been shown to have reduced thrombogenecity compared with uncoated self-expanding stents.
Apart from the relatively high thrombogenecity potential of DES, a delay in endothelialisation with DES can also cause problems as it can lead to stent thrombosis and possibly restenosis. Even with BMS, there is still some delay in endothelialisation. For instance, in an in vitro study, no continuous endothelial layers could be observed after 24 hours of contact between the calf pulmonary artery endothelial cells and the 316L stainless steel. This is in contrast to the results of in vitro studies that have evaluated aSiC:H-coated stents under the same time and experimental conditions as the stainless steel. In these studies, a continuous endothelial cell layer, with cell–cell contacts, was noted to be covering the whole aSiC:H-coated stent sample. The results suggest more rapid endothelialisation and a short time to functional endothelial layer formation with the silicon carbide-coated stents,35 and are consistent with the findings of a previous in vitro study.40

Clinical Studies Evaluating the Use of Silicon Carbide Passivation

A preliminary study in 44 patients with threatened or abrupt vessel closure showed a low rate (9%) of combined in-hospital complications (including death, emergency revascularisation, stent-related MI and ST) and of major bleeding after PCI using aSiC:H-coated stainless steel stents.43 The study also showed a restenosis advantage over stainless steel BMS, as the observed restenosis rate of 21% at six-month follow-up is lower than the restenosis rates observed in studies using the latter type of stents. The findings of this study are supported by a clinical trial by Carrie et al. in which 241 patients at a moderate risk of stent thrombosis underwent PCI using aSiC:H-coated stainless steel stents.44 The patients had either unstable angina and/or recent MI, with most lesions having complex characteristics. The results showed a high rate of successful stent deployment (97.4%) and clinical success (95.4%), defined as successful deployment without procedural or clinical event. The restenosis and adverse event rates were quite low at one-year follow-up, as indicated by a major adverse cardiac events (MACE) rate of 15.8% and TLR rate of 7.1%.

In a combined patient population of 446 patients from two series of studies, including the study by Carrie et al.,44 the frequency of subacute ST in patients treated with PCI using the aSiC:H-coated stainless steel stents was as low as 0.5%.44,45 Additionally, in another study deployment of aSiC:H-coated stainless steel stents, when compared with different stents, was associated with a univariate reduction in risk of restenosis.46 Further to these studies, a randomised study in 485 patients with Braunwald IIB or IIIB unstable angina also evaluated the use of aSiC:H-coated stainless steel stents.47 Patients were randomly assigned to undergo PCI using either aSiC:H-coated stainless steel stents or uncoated stents. The treatment protocol included an antiplatelet regimen. While there was no difference in TLR rates in the Braunwald IIB (moderate-risk) patient groups, there was a lower incidence of death/MI/ischaemia-driven TLR at six-month follow-up in the coated stent group compared with the uncoated stent group (4.7 versus 15.3%; p=0.02) in the patient subgroup with Braunwald IIIB symptoms (high-risk group).
In contrast to the largely positive results of the aforementioned clinical studies, two other clinical studies suggest that aSiC:H-coated stents may not have a restenosis advantage over BMS, and thereby a greater and worse restenosis rate than DES. In an open, non-randomised study in 165 patients with normal or high risk of ST, six-month follow-up after implantation with aSiC:H-coated tantalum stents also showed an absence of in-hospital mortality.48 Follow-up data at six months also showed a low rate of ST, with rates of 1.4 and 0.5% reported for acute and subacute ST, respectively. The subacute ST rate was not significantly different between the normal and high-risk groups. However, a 26.8% restenosis rate was reported, and this does not represent an advantage over BMS, at least not at mid-term follow-up (six months).
A prospective randomised study conducted in two study centres evaluated the long-term clinical outcomes of aSiC:H-coated stents.49 In this study, 497 patients with stenotic lesions received either aSiC:H-coated stainless stents or uncoated 316L stainless steel stents. There was a low and non-significant difference in the rate of MACE between the coated and uncoated stent groups (12 versus 14.3%; p=0.50), although acute MIs were less frequent in the coated stent group after ≥60 weeks of stent deployment. This study showed that even in the long term there was a similar binary restenosis rate between the two groups (coated versus uncoated stent 30 versus 26.7%; p=0.56). Nevertheless, these two studies confirm that aSiC:H-coated stents are associated with low rates of mortality, ST and MACE.

Recently, an aSiC:H-coated CoCr stent has been evaluated in two single-arm studies (see Figure 1). It should be noted that the CoCr alloy used for these stents allows thin struts, as opposed to the relatively thick strut with stainless steel. The use of thin struts may have significant implications as they have been associated with favourable reductions in rates of restenosis compared with thicker struts.50
A recent single-arm stent registry investigated the use of aSiC:H-coated CoCr stents for PCI for the treatment of 161 lesions in 145 consecutive patients with extended coronary artery disease.51 The procedural success rate was again shown to be quite high (97.2%). The rate of late lumen observed loss (0.75±0.71mm [in-stent]) was similar to that noticed after deployment of DES.52 The rates of TLR (4.9%) and MACE (5.6%) were quite low. There was also an absence of risk of acute or late ST (0% ST), which supports the antiplatelet effects of aSiC:H-coated stents. This indication of an antiplatelet effect has significant economic and clinical implications as dual antiplatelet therapy would be much shorter after aSiC:H-coated stent implantation than with DES. Interestingly, the low restenosis and MACE rates occurred in high-risk patients with complex lesions (59% of all lesions were moderate- to high-risk lesions). These results suggest that the aSiC:H-coated stents may be of particular importance in high-risk patients, as studies have shown a lower incidence of stent thrombosis with aSiC:H than with DES. The results observed in the current stent registry may be attributed to the improved biocompatibility of coated stents and its consequent effects.
Another stent registry also evaluated the outcomes of using aSiC:Hcoated CoCr stents in consecutive ‘real-world’ patients with stable or unstable angina, MI or acute/recent MI who required PCI.20 This was a single-centre, single-treatment-arm, non-randomised registry that enrolled 515 consecutive patients who were treated for 540 lesions using PCI. The results were obtained at six-month follow-up. Consistent with other studies evaluating aSiC:H-coated carbide stents, the angiographic success rate was quite high (99.8%). The rate of late lumen loss was quite low and the value was similar to that of DES known from other trials. The rates of ST, MACE and total mortality were low (0.4, 8.7 and 3.5%, respectively). TLR and total vessel revascularisation (TVR) rates were also low (5.2 and 6.4% per patient, respectively), and were similar to those seen with DES.

MACE, TLR and TVR rates were also low in the group of high-risk patients with diabetes (10.7, 7.6 and 7.1%, respectively). Although this study was of a single-arm design, the mid-term follow-up (six months) results of this registry, compared with DES results from other trials, suggest that the aSiC:H-coated CoCr stents may be alternatives to DES, especially in high-risk patients.

Conclusions and Future Research

DES have significantly reduced the rate of restenosis in PCI procedures. However, there have been reports of a high rate of stent thrombosis, especially after one year of stent deployment, and the rates are even greater in patients at high risk of death, thrombosis or restenosis. aSiC:H-coating of metal stents has been evaluated as a method of passivating the stent surfaces, and pre-clinical studies have shown this coating to reduce thrombogenecity and possibly improve the biocompatibility of the stent surfaces. Clinical data for the aSiC:H-coated metal stents, largely from single-arm studies, non-randomised trials and stent registries, have generally shown low rates of ST, MACE, TLR and restenosis. Based on mainly indirect comparisons, it seems that these rates are either similar to or better (lower) than for DES, and better than BMS, at least at intermediate-stage follow-up (six months). There also seems to be a better safety and clinical outcome profile of the aSiC:H-coated stents compared with other stents in high-risk patients. aSiC:H-coated stents, especially those utilising the CoCr alloy, therefore, may be alternatives to DES, particularly in the high-risk patient subpopulation. Despite the promising data regarding the aSiC:H surface passivation of stents, it should be noted that few randomised trials have investigated their use and none have directly compared aSiC:H-coated stents with DES. The data available are largely from non-randomised studies and stent registries, and although they indicate a good safety and efficacy profile with the surface passivated stents, they can be considered to be only suggestive due to the study designs. Future research should include large long-term randomised trials sufficiently powered to compare aSiC:H stents with DES, and should also focus on the high-risk patient subpopulation. Ôûá

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