Abstract
Coating of stent surface with a biocompatible material is suggested to improve stent safety profile. A proprietary process was developed to coat titanium-nitride-oxide on the stent surface, based on plasma technology that uses the nano-synthesis of gas and metal. Preclinical in vitro and in vivo investigation confirmed blood compatibility of titanium (nitride-) oxide films. Titanium-nitride-oxide-coated stents demonstrated a better angiographic outcome, compared with bare-metal stents at mid-term follow-up; however, they failed to achieve non-inferiority for angiographic outcome versus second-generation drug-eluting stents. Observational studies showed adequate clinical outcome at mid-term follow-up. Non-randomized studies showed an outcome of titanium-nitride-oxide-coated stents comparable to – or better than – first-generation drug-eluting stents at long-term follow-up. Two randomized controlled trials demonstrated comparable efficacy outcome, and a better safety outcome of titanium-nitride-oxide-coated stents versus drug-eluting stents at long-term follow-up. Evaluation by optical coherence tomography at mid-term follow-up revealed better neointimal strut coverage associated with titanium-nitride-oxide-coated stents versus drug-eluting stents; yet, neointimal hyperplasia thickness was greater.
Stents coated with titanium-nitride-oxide demonstrated biocompatibility in preclinical studies: they inhibit platelet and fibrin deposition, and reduce neointimal growth.
In observational and non-randomized studies, titanium-nitride-oxide-coated stents were associated with adequate safety and efficacy outcome.
In randomized trials of patients with acute coronary syndrome, titanium-nitride-oxide-coated stents were associated with a better safety outcome, compared with drug-eluting stents; efficacy outcome was comparable.
Key messages
Introduction
Stent implantation has become the standard-of-care of percutaneous coronary intervention. A major drawback of bare-metal stents (BMS) is in-stent restenosis resulting from neointimal hyperplasia (Citation1). Drug-eluting stents (DES) reduced in-stent restenosis; thereby, decreasing target-lesion revascularization (TLR) rates (Citation2). Yet, evidence suggested higher rates of (very) late stent thrombosis (ST) associated with first-generation DES, versus BMS (Citation3–5). Therefore, continuous development of stent platforms for improvement of their safety profile has become the focus of attention of stent industry. Coating of the stent surface with a biocompatible material was one of the techniques suggested to improve stent safety profile. The current review highlights the available evidence for the safety and efficacy of stents coated with titanium-nitride-oxide biocompatible surface coating, in preclinical, observational, and comparative non-randomized and randomized clinical studies.
Titanium-nitride-oxide-coated stents
The titanium-nitride-oxide-coated Titan2® (Hexacath, Paris, France) stent is a laser-cut slotted-tube stent made of medical-grade 316L stainless-steel coated with a thin layer of titanium-nitride-oxide (strut thickness 91 μm). The stent platform is the bare-metal Helistent™ (Hexacath, Paris, France) which has a helicoidal design that provides flexibility and conformability. Such design provides ultra-low recoil, while maintaining a collapse pressure of 1.2 bars – 50% higher than other stent designs known for excellent radial force. A proprietary process was developed to coat titanium-nitride-oxide on the surface of the stent, based on plasma technology that uses the nano-synthesis of gas and metal. Titanium-nitride-oxide is coated on all stent surfaces through a patented process which deposits nitride-oxide particles on the stent surface. Such coating is hard making it possible to use thinner struts. Fatigue tests simulating 10 years of stent implantation confirmed the integrity of coating as demonstrated by scanning electron microscopy (Citation6,Citation7). Titan2 stents are available in lengths of 7, 10, 13, 16, 19, 22 and 28 mm, and in diameters of 2.5, 2.75, 3.0, 3.5, 4.0 and 4.5 mm. The titanium-nitride-oxide-coated OPTIMAX™ (Hexacath, Paris, France) is a thiner-strut (81 μm) stent, based on a cobalt-chromium platform with a twin helicoidal design. The stent is available in lengths of 7, 10, 13, 16, 19, 22, and 28 mm, and in diameters of 2.25, 2.50, 2.75, 3.0, 3.5, and 4.0 mm. Both stents are mounted over a 140-cm-long rapid-exchange balloon catheter compatible with 0.014" guidewires.
Proof-of-concept and preclinical studies
Titanium has a better biocompatibility compared with stainless-steel, gold, or other surface coating materials, since it is highly resistant to corrosion; and therefore, prevents toxic ion release, an effect that reduces tissue reaction and inflammation (Citation8). In vitro and in vivo investigation showed a better blood compatibility for titanium oxide films, compared with low-temperature isotropic pyrolytic carbon (LTI-carbon), which is widely used for synthesis of artificial heart valves (Citation9). Measurement of blood clotting time and platelet adhesion confirmed the antithrombotic properties of titanium oxide films, and showed that blood compatibility of other materials (titanium, cobalt alloy, and LTI-carbon) can be improved by coating with such films (Citation10–12); as the thickness of the titanium oxide layer increased, blood compatibility further improved (Citation13). The mechanism underlying blood compatibility of titanium oxide is unclear; it might be attributed to physical properties, such as surface energy and semiconductivity. The optical bandgap of titanium oxide films (3.2 eV) is wider than that of fibrin (1.8 eV); this results in thinner protein layers on the film surface, less protein denaturation, and overall excellent antithrombotic properties (Citation14). Moreover, the lower interface tension between titanium oxide films and plasma proteins and the semiconducting nature of titanium oxide improve blood compatibility (Citation15). In vivo investigation of titanium oxide films was performed by implanting titanium-oxide-coated and uncoated LTI-carbon cylinders in the ventral aorta of dogs. Fourteen days later, examination by scanning electron microscopy revealed no platelet aggregation and almost no fibrin deposition on the surface of the titanium-oxide-coated LTI-carbon, in contrast to much platelet aggregation and fibrin deposition on the surface of the uncoated LTI-carbon (Citation16). Moreover, endothelial cells from human umbilical vein were seeded on various metallic sheets: 316L stainless-steel, nitinol, and 316L stainless-steel coated with either titanium nitride or titanium oxide; these cells were compared with cells seeded onto tissue culture, as control. Examination by scanning electron microscopy 48 h later revealed that the levels of cellularity on the metallic sheets coated with titanium oxide and titanium nitride were comparable or higher, whereas those on 316L stainless-steel and nitinol were lower, than controls, suggesting that use of stents coated with such materials might enhance better endothelial strut coverage (Citation17). The blood compatibility of titanium oxide can be improved by the addition of nitrogen. Platelet adhesion and fibrinogen deposition are lower for titanium-nitride-oxide than for titanium oxide (Citation18,Citation19). Chemical elementary analysis showed the presence of nitride-oxide particles on the surface of the titanium coating; the presence of nitride-oxide on the surface might contribute to biocompatibility (Citation20). A preclinical study in a porcine restenosis model (12 pigs) showed 47% reduction of neointimal hyperplasia with titanium-nitride-oxide-coated stents (TiNOX 2, metallic), versus 316L stainless-steel stents of identical design, at 6-week follow-up (p <.05). Furthermore, the titanium-nitride-oxide-coated stents were associated with less platelet adhesion and fibrinogen binding (p <.05) (Citation21). Such anti-proliferative effect associated with titanium-nitride-oxide-coated stents was comparable with that reported for sirolimus-eluting stents in pigs (Citation22).
Clinical studies
Studies of angiographic outcome
Although titanium-nitride-oxide-coated stent implantation was associated with a better angiographic outcome compared with BMS (Citation23,Citation24), late lumen loss and binary restenosis were higher with titanium-nitride-oxide-coated stents versus zotarolimus-eluting stents (ZES) in unselected patients (Citation25), and late lumen loss was greater with titanium-nitride-oxide-coated stents versus everolimus-eluting stents (EES) in diabetic patients (Citation26), at mid-term follow-up (). In an observational study, late lumen loss was 0.5 mm 9 months after titanium-nitride-oxide-coated stent implantation in diabetic patients (Citation27).
Table 1. Studies of surrogate angiographic endpoints following titanium-nitride-oxide-coated stent implantation.
Observational studies
In observational studies, implantation of the Titan stent (Stainless-Steel platform) in unselected patients was associated with acceptable efficacy (nearly 5% TLR rate), and a low incidence of ST at mid-term follow-up (Citation28–31) (). Similar results were obtained in diabetic patients, and in patients with small vessel disease (Citation27,Citation32). Likewise, in 2 reports, the OPTIMAX™ stent (Cobalt-Chromium platform) was associated with adequate efficacy and safety at mid-term follow-up (Citation33,Citation34). Yet, most of the available studies are single-center; many of them are small-sized (Citation28–30,Citation33,Citation34). Evidence derived from observational studies is often limited by selection bias.
Table 2. Observational studies of clinical outcome following titanium-nitride-oxide-coated stent implantation.
Non-randomized studies
In non-randomized studies, titanium-nitride-oxide-coated stent implantation in unselected patients was associated with better safety versus first-generation DES at mid- and long-term follow-up; efficacy was comparable (Citation35–37) (). In matched-pair comparison versus first-generation DES in registry data, overall major adverse cardiac events (MACE) rates were comparable at long-term follow-up (Citation38). In 2 small reports, titanium-nitride-oxide-coated stent implantation in selected cohorts was associated with comparable safety and efficacy, versus DES, at mid-term follow-up (Citation39,Citation40). Yet, comparison of outcome between alternative devices in non-randomized studies could also be limited by selection bias, even in studies reporting propensity score-matched analysis that accounts for possible “measurable” confounders; no adjustment could account for “immeasurable” confounders, such as operator’s discretion, operator’s experience, patient’s preference, and others.
Table 3. Non-randomized studies of clinical outcome following titanium-nitride-oxide-coated stent implantation.
Randomized studies
In small randomized studies, titanium-nitride-oxide-coated stent, versus BMS, implantation in unselected cohorts was associated with reduction of overall MACE, and a trend toward reduction of TLR, at mid- and long-term follow-up () (Citation23,Citation41,Citation42). In the TITAX AMI trial of patients presenting with acute myocardial infarction (MI), implantation of titanium-nitride-oxide-coated stents, versus paclitaxel-eluting stents (PES), was associated with reduction of overall MACE and recurrent MI, at long-term, but not at mid-term follow-up; definite ST was reduced all through; TLR rates were comparable all through (Citation43–45). In a gender-based analysis of the TITAX AMI trial, implantation of titanium-nitride-oxide-coated stents in men was associated with reduction of MACE, cardiac death, recurrent MI, and ST, compared with PES, at 3-year follow-up (p < .05 for all); TLR rates were comparable (p = .22). In women, MACE and the individual endpoints were comparable (p > .05 for all) (Citation46). In the adequately powered BASE ACS non-inferiority trial, Karjalainen et al., randomized 827 patients with acute coronary syndrome to receive either titanium-nitride-oxide-coated stents or EES: at 12-month follow-up, titanium-nitride-oxide-coated stents were non-inferior to EES for the primary endpoint of MACE (cardiac death, non-fatal MI, and ischemia-driven TLR): 9.6% versus 9.0%, respectively, pnon-inferiority = .001, psuperiority = .5. Patients who received titanium-nitride-oxide-coated stents had less frequent non-fatal MI, and a trend towards less frequent definite ST; the rates of cardiac death, and ischemia-driven TLR were comparable (Citation47). Similar results were observed at 2- and 4-year follow-up (Citation48,Citation49). In the final report of the trial at 5 years, titanium-nitride-oxide-coated stents were non-inferior to EES for MACE (14.4% versus 17.8%, respectively, pnon-inferiority < .001, psuperiority = .26). Non-fatal MI occurred less often with the titanium-nitride-oxide-coated stents, and so did definite ST; cardiac death and ischemia-driven TLR were comparable (Citation50). In a post-hoc analysis of the BASE ACS trial at 12 months, implantation of titanium-nitride-oxide-coated stents in patients with ST-elevation MI was associated with a trend toward less frequent MI and definite ST (p = .09, and p = .053, respectively), whereas in patients with non-ST-elevation acute coronary syndrome, those assigned to titanium-nitride-oxide-coated stents had less frequent MI (2.7% versus 6.8% respectively, p = .03) (Citation51). In a gender-based matched analysis of the trial at 2 years, implantation of titanium-nitride-oxide-coated stents in men was associated with reduction of MI (2.2% versus 5.4% respectively, p = .027); whereas in women, those assigned to titanium-nitride-oxide-coated stents had a trend toward less frequent MI (5% versus 12.2% respectively, p = .058) (Citation52). In another post-hoc matched analysis at a median of 5-year follow-up, diabetic patients assigned to titanium-nitride-oxide-coated stents had event rates comparable with those assigned to EES; in non-diabetic patients, implantation of titanium-nitride-oxide-coated stents was associated with reduction of MI (4.3% versus 8.1% respectively, p = .038) (Citation53). In a similar matched analysis, elderly patients assigned to titanium-nitride-oxide-coated stents had lower ST rates (0.6% versus 5.6% respectively, p = .006) (Citation54). Similarly, in a post-hoc matched analysis, patients with preexisting vascular disease assigned to titanium-nitride-oxide-coated stents had lower ST rates (0% versus 7.5%, respectively, p = .01) (Citation55). In pooled analysis of patient-level data from the BASE ACS and TITAX AMI trials to evaluate the 2-year outcome of titanium-nitride-oxide-coated stents versus the pooled group of DES (EES and PES) in patients presenting with ST-elevation MI, the propensity score-adjusted MACE rates were comparable between the 2 pooled groups (11.4% versus 13.7% respectively, p = .5); recurrent MI occurred less often in patients who received titanium-nitride-oxide-coated stents (3.3% versus 7.4% respectively, p = .032), and so did definite ST (0.8% versus 5.1% respectively, p = .007); yet, cardiac death and ischemia-driven TLR were comparable (p > .05 both) (Citation56). In one small randomized trial, the event rates following titanium-nitride-oxide-coated stent implantation in unselected patients were comparable with ZES at 1-year follow-up (Citation25). Similar results were reported at 5-year follow-up (Citation57). Yet, in another small randomized trial, overall MACE rate (a composite of death, non-fatal MI, stroke, and target vessel revascularization) was higher in diabetic patients who received titanium-nitride-oxide-coated stents, versus EES, at 1-year follow-up (14.5% versus 4.4% respectively, p = .02); interestingly, MACE rates were comparable in patients with non-insulin dependent diabetes mellitus (9.7% versus 3.2% respectively, p = .14). MI and TLR rates were comparable (Citation26). Finally, in a pooled analysis (n = 1774) of 3 studies (PORI registry, BERN registry, and TITAX AMI trial) comparing the outcome of titanium-nitride-oxide-coated stents versus PES at 12-month follow-up, fewer recurrent MI (2.7% versus 5.6%, respectively, p = .004) and total MACE events (8.9% versus 12.6%, respectively, p = .02) occurred with titanium-nitride-oxide-coated stents; the rates of death, TLR, and ST were comparable (p > .05 all) (Citation58).
Table 4. Randomized studies of clinical outcome following titanium-nitride-oxide-coated stent implantation.
Studies with optical coherence tomography
Very early evaluation by optical coherence tomography (OCT) 2 weeks after titanium-nitride-oxide-coated stent implantation showed adequate healing: 96.3% binary stent strut coverage, 1.8% malapposed struts; neointimal hyperplasia thickness was 71.5 ± 53.7 μm (Citation59) (). In another cohort, OCT performed at 30-day follow-up revealed 97.2% binary stent strut coverage, 3.2% malapposed struts; neointimal hyperplasia thickness was 109.7 ± 83.6 μm (Citation60). In a subgroup of the TITAX AMI trial, OCT revealed a lower percentage of uncovered struts, fewer malapposed struts, but greater neointimal hyperplasia thickness following titanium-nitride-oxide-coated stent implantation, versus PES, at long-term follow-up (Citation61). Similar results were demonstrated in patients with acute coronary syndrome (BASE ACS trial), versus EES, at mid-term (Citation62), and long-term follow-up (Karjalainen PP, personal communication, 2016). Likewise, parallel results were observed with the cobalt-chromium-based titanium-nitride-oxide-coated stents versus platinum-chromium-based EES in patients with acute coronary syndrome, at 2-month follow-up (Citation63).
Table 5. Studies of optical coherence tomography following titanium-nitride-oxide-coated stent implantation.
Future studies
The ongoing multi-center TIDES ACS trial is intended to randomize 1800 patients with acute coronary syndrome to either titanium-nitride-oxide-coated stents (OPTIMAX™) or EES with biodegradable polymer (Synergy™, Boston Scientific, MA); the primary endpoint is MACE at 12-month follow-up (ClinicalTrials.gov: NCT02049229) (Citation64). Furthermore, the ongoing OPTIMAX OCT study, explores the 1- and 6-month neointimal healing response to the OPTIMAX stent versus the Synergy stent evaluated by OCT, in patients with acute coronary syndrome (Karjalainen PP, personal communication, 2016).
Summary of the available evidence
Compelling indications for the use of the titanium-nitride-oxide-coated stents are summarized in . Currently, new-generation DES are the standard devices for stenting in stable and unstable coronary artery disease. The current European Society of Cardiology guidelines on myocardial revascularization recommend new-generation DES over BMS for revascularization of patients presenting with acute coronary syndrome (Class I, Level of Evidence A) (Citation65). However, the need for extended dual antiplatelet therapy following DES implantation can sometimes be challenging. The adequately powered DAPT trial demonstrated that dual antiplatelet therapy extended beyond 12 months following DES implantation significantly reduced ST and MACE, compared with aspirin alone continued after 12 months (Citation66). Extended duration of dual antiplatelet therapy increases the incidence of bleeding complications, compared with aspirin alone (Citation66). This might be especially pertinent in particular patient subsets that have elevated baseline risk of bleeding (for example, those maintained on long-term oral anticoagulation), in patients who need elective surgery in the near prospect, or in those in whom compliance with extended dual antiplatelet therapy is an issue (). The fact that dual antiplatelet therapy is needed for no more than 1 month following implantation of titanium-nitride-oxide-coated stents makes a case for the choice of such device in these particular patient subsets.
Table 6. Compelling indications for the use of the titanium-nitride-oxide-coated stents.
Substantial evidence supports the recommendation of titanium-nitride-oxide-coated stents as an alternative to second-generation DES during early percutaneous coronary intervention for patients with acute coronary syndrome, based on the results of a single adequately powered randomized trial (BASE ACS) that demonstrated non-inferiority of titanium-nitride-oxide-coated stents to EES for the clinical outcome at long-term follow-up (level of evidence B) (Citation47–50). In patients presenting with acute MI, evidence – although less robust – supports the implantation of titanium-nitride-oxide-coated stents as an alternative to DES, based on a single randomized trial (TITAX AMI) which demonstrated a better clinical outcome of titanium-nitride-oxide-coated stents versus PES in patients with acute MI at long-term follow-up (Citation43–45), and a pooled analysis of 2 randomized trials (TITAX AMI and BASE ACS) in patients with ST-elevation MI which showed a better clinical outcome of titanium-nitride-oxide-coated stents versus pooled DES (PES and EES) at long-term follow-up (Citation56), (level of evidence C). In unselected patients, again less robust evidence supports the implantation of titanium-nitride-oxide-coated stents as a better alternative to BMS, based on data from small randomized trials with adequate follow-up (Citation41,Citation42), and as an alternative to first-generation DES, based on data from a retrospective (propensity-score matched) study that showed a clinical outcome of titanium-nitride-oxide-coated stents comparable to that of sirolimus-eluting stents and PES at long-term follow-up (Citation38), and a non-randomized study that showed a better clinical outcome of titanium-nitride-oxide-coated stents versus PES at long-term follow-up (Citation35–37), (level of evidence C). In diabetic patients, little evidence discourages the use of titanium-nitride-oxide-coated stents as an alternative to second-generation DES, based on data from a small randomized trial which demonstrated worse outcome of titanium-nitride-oxide-coated stents versus EES (results were not consistent in patients with non-insulin dependent diabetes mellitus) (Citation26); yet, a small observational study demonstrated adequate clinical outcome at mid-term follow-up (Citation27). Again, little evidence suggests the usefulness of titanium-nitride-oxide-coated stents as an alternative to second-generation DES in patients with multi-vessel disease, based on data from a small randomized trial that showed a clinical outcome of titanium-nitride-oxide-coated stents comparable to that of second-generation DES at long-term follow-up (Citation39). Similarly, little evidence suggests the usefulness of titanium-nitride-oxide-coated stents in patients with small coronary arteries, based on a small observational study with mid-term follow-up (Citation32). No evidence exists on the use of titanium-nitride-oxide-coated stents in patients with in-stent restenosis, chronic total occlusion, unprotected left main coronary artery, or in percutaneous coronary intervention for saphenous vein grafts.
Disclosure statement
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Funding
The current research article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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