Summary
Background
Coronary stents have evolved over time, from bare-metal stents to drug-eluting stents, and now to bioactive stents.
Aims
We sought to explore the immediate outcome of the titanium-nitride-oxide-coated bioactive stent, Titan2 ® , in real-world practice, and the incidence of major cardiac events at follow-up.
Methods
Consecutive patients admitted for percutaneous intervention for at least one significant (≥ 50%) lesion in a native coronary artery were treated with Titan2 ® stent implantation. The primary endpoint was total major adverse cardiac events at 12-month follow-up. Secondary endpoints included target lesion revascularization at 12-month follow-up and the duration of dual antiplatelet therapy.
Results
Among 356 patients (mean age 67.4 ± 12.1 years), 77.2% were male and 39.3% were treated for myocardial infarction (MI). A total of 546 Titan2 ® stents were implanted in 420 lesions. Angiographic and clinical procedural success was achieved in all cases. No cases of in-hospital major adverse cardiac events or acute stent thrombosis were reported. Of 335 patients (94.1%) with 12-month clinical follow-up, four (1.2%) died, MI occurred in five (1.5%), target lesion revascularization was performed in 17 (5.1%) and major adverse cardiac events occurred in 24 (7.2%). One patient (0.3%) suffered late stent thrombosis during follow-up, but no cases of acute or subacute stent thrombosis occurred. Dual antiplatelet therapy continued beyond 6 months in 64.5% of patients.
Conclusions
In real-world practice, Titan2 ® stent implantation achieves an excellent immediate outcome, with a low incidence of major adverse cardiac events at 12-month follow-up.
Résumé
Contexte
La sécurité des stents bio-actifs recouverts d’oxynitrure de titane a été démontrée pour des populations non sélectionnées de type « vie réelle ».
Objectifs
Analyser d’une part les résultats immédiats obtenus après implantation de stents coronaires bio-actifs Titan2 ® dans une pratique de type « vie réelle » et d’autre part les résultats cliniques à savoir les Major Adverse Cardiac Events (MACE) à 12 mois de suivi.
Méthode
Trois cent cinquante-six patients consécutifs ont été enrôlés pour suivre un traitement par angioplastie percutanée pour au moins une lésion coronaire significative (50 %). Toutes les lésions ont été traitées par implantation d’un stent Titan2 ® . L’objectif principal de ce suivi de cohorte était le taux de MACE à 12 mois. Les objectifs secondaires comprenaient le taux de revascularisation de la lésion cible (TLR) à 12 mois et l’analyse de la durée du traitement antiplaquettaire.
Résultats
L’âge moyen était de 67,4 ± 12,1 ans, 77,2 % étaient des hommes. Un total de 546 Titan2 ® ont été implantés dans 420 lésions. Le succès angiographique et clinique a été atteint pour toutes les procédures. Aucun évènement cardiaque majeur intrahospitalier n’a été rapporté ni aucune thrombose aiguë. Le suivi clinique à 12 mois a été obtenu pour 335 (94,1 %) patients. Quatre patients sont décédés (1,2 %) et cinq patients ont subi un infarctus (1,5 %). Une revascularisation du vaisseau cible a été effectuée chez 17 (5,1 %) patients. Vingt-quatre (7,2 %) patients ont déploré un évènement cardiaque majeur. Un (0,3 %) patient a souffert d’une thrombose tardive, mais aucun cas de thrombose aiguë ou sub-aiguë n’est arrivé.
Conclusion
Dans une pratique de type « monde réel », l’implantation du stent Titan2 ® est associé à d’excellents résultats cliniques, avec un taux d’évènements cardiaques majeurs faible à 12 mois de suivi.
Abbreviations
BAS
bioactive stents
DES
drug-eluting stents
LAD
left anterior descending
LCx
left circumflex
MACE
major adverse cardiac event
MI
myocardial infarction
PCI
percutaneous coronary intervention
RCA
right coronary artery
TIMI
thrombolysis in myocardial infarction
TLR
target lesion revascularization
Background
Coronary stent implantation has become the standard-of-care percutaneous coronary intervention (PCI), providing a safer approach and a better outcome than balloon angioplasty . Nevertheless, since the introduction of coronary stents, in-stent restenosis has been the ‘stumbling block’ of this technology, resulting in repeat revascularization with increased total costs . The restenosis rate following bare-metal stent implantation may approach 30% in some patient subgroups, such as those with diabetes, small coronary vessels or long lesions .
The introduction of drug-eluting stents (DES) has revolutionized the field of interventional cardiology, as it has reduced the incidence of restenosis by 50–70% . However, recent worrisome data from registries and meta-analyses have raised concern about the long-term safety of DES, highlighting higher rates of late and very late stent thrombosis, a potentially life-threatening complication .
Stent technology has evolved recently, with the invention of bioactive stents (BAS). The safety of titanium-nitride-oxide-coated bioactive stents (Titan2 ® ) has been established in several reports from real-life unselected populations . Interestingly, some randomized trials have demonstrated a better outcome with BAS compared with paclitaxel-eluting stents in high-risk patients with complex (type B and C) coronary lesions and in those with myocardial infarction (MI) .
The current registry was a post-approval registry performed at the request of, and under the control of, the French High Authority of Health (Haute Autorité de santé, Saint-Denis La Plaine, France). The aims were to confirm the safety and efficacy of Titan2 ® BAS in ‘on-label’ indications in real-world practice (with no exclusion criteria) and estimate the duration and average cost per patient of dual antiplatelet therapy.
Methods
Study protocol
The registry protocol was designed under the control of the French High Authority of Health, and through collaboration between the main investigator, an independent contract research organization and the manufacturer, Hexacath. It was officially validated and accepted on 12 June 2007 by the French High Authority of Health. No financial compensation was given to any of the participating centres to conduct the registry, as dictated by the French High Authority of Health. The current registry was executed under complete data monitoring and surveillance by an independent contract research organization company (MAPI NAXIS, Lyon, France). The current registry was conducted according to the ‘Standard Medical Practice’ (les bonnes pratiques en épidémiologie 1998 version), and law No. 78-17 dated 06 January 1978 referring to private freedom, and following the article L.4113-6 of the French Public National Health Code.
Study design and population
The EVIDENCE Registry is a prospective multicentre non-randomized observational registry performed in 21 French medical centres, with the chief aim to confirm the safety and efficacy of the Titan2 ® BAS stent in real-world practice. Before the launch of the registry, a scientific main investigator was nominated (Prof. J.-M. Lablanche, Cardiology Department, University Hospital of Lille, France) and assigned the task of selecting the participating centres, as well as validating the process of data collection and statistical analysis. Participating centres were selected on the basis of their high annual volume of PCI performance and their capability to execute the procedures and undertake the necessary follow-up. Recruitment of the participating centres and attendant cardiologists started in June 2007. Participating centres were representative of the French national figures regarding the volume of angioplasties executed per year.
From October 2007 to March 2008, 356 consecutive patients with symptomatic coronary artery disease amenable for PCI were enrolled, provided that they were 18 years or over, with at least one significant coronary lesion (defined as ≥ 50% diameter stenosis by visual estimation) in a native coronary artery. Treatment of more than one vessel was permissible, but only the Titan2 ® stent was allowed, as dictated by the registry. Before inclusion, a written informed consent was obtained from each patient after full explanation of the study protocol, the type of data collected, the method of data processing and the scope of data collection. Collected data were given a code number for the centre and another for the patient, to ensure patient anonymity.
Device
A commercially available stainless steel tubular stent with the unique helicoidal design was used. The Titan2 ® (Hexacath, Paris, France) stent is a thin-strut (0.07–0.09 mm) balloon-expandable stent made of stainless steel and coated with titanium-nitride-oxide, which prevents discharge of nickel, chromium and molybdenum ions. The coating process is performed by plasma-enhanced vapour deposition of titanium in a pre-specified gas mixture of nitrogen and oxygen in a vacuum chamber. Stents were available in lengths of 7, 10, 13, 16, 19 and 22 mm and in diameters of 2.5, 2.75, 3.0, 3.5 and 4.0 mm.
Adjunctive pharmacological therapy
All included patients were pretreated with aspirin (100 mg daily). Oral clopidogrel was initiated at a loading dose of 300 mg before the procedure. The protocol gave no specific recommendations regarding the duration of clopidogrel maintenance therapy, since one of the objectives of this registry was to investigate the routine medical practice concerning the duration of dual antiplatelet therapy following PCI with BAS. During the procedure, intravenous heparin was given to maintain an activated clotting time of 200–300 seconds. Use of periprocedural glycoprotein IIb/IIIa inhibitors was left up to the operator’s discretion. The medical treatment of coronary artery disease was optimized according to the contemporary guidelines.
Quantitative coronary analysis
Coronary angiograms were obtained in multiple views after intracoronary injection of nitrates. Quantitative analysis of angiographic data before the procedure was performed in each participating centre according to the standards of care, using validated edge-detection techniques. Visual assessment included thrombolysis in myocardial infarction (TIMI) flow, calcification, thrombus, lesion length, lesion classification, dissection grade and aneurysm. A contrast-filled non-tapered catheter was used for calibration. Interpolated reference vessel diameter, lesion length and percent initial diameter stenosis were measured before the procedure as well as residual stenosis following stent implantation.
Angioplasty procedure
Lesions were treated according to contemporary interventional techniques. The investigators used similar materials and techniques throughout the study to maintain consistency and standardization of care. Predilatation was left to the operator’s discretion. The operator decided the appropriate diameter to be implanted, aiming at a stent: vessel ratio of 1.1:1 prior to stent placement (using nominal pressure). Stents were expanded by adjusting the balloon inflation pressure to achieve an angiographic appearance of the expanded stent slightly larger than the reference vessel segment. After stent deployment, post-dilatation was allowed. An additional Titan2 ® stent could be deployed in overlap with the first in case of edge dissection, incomplete lesion coverage or otherwise suboptimal result (at the operator’s discretion).
Follow-up protocol
The total follow-up period extended from June 2007 to March 2009. All patients were observed during hospital stay for the occurrence of the clinical endpoints prespecified by the study protocol (as described below). Patients were prospectively followed up for a period of 12 months by means of clinic visits or telephone contacts by the attendant cardiologists to obtain information concerning their clinical status, hospitalization, invasive procedures and medications. Follow-up contacts were performed at 3 and 12 months following stent implantation. Follow-up coronary angiography was performed for patients who developed recurrent symptoms during the follow-up period. The decision to perform further revascularization for the target lesion at follow-up coronary angiography was based on clinical justification (as described below). A specialized independent Contract Research Organization (MAPI NAXIS) performed additional telephone contacts with patients at 3 and 12 months following stent implantation. Beforehand, all attendant cardiologists had faxed a signed formal agreement of participation to MAPI NAXIS. All patient data available from hospital records or attendant cardiologists were collected in the EVIDENCE Registry case report forms in each of the participating centres, which were provided by MAPI NAXIS. At the end of follow-up, all case report forms were sent to MAPI NAXIS and carefully reviewed to ensure quality control of the registered data.
Study endpoints and definitions
The primary endpoint of the study was the occurrence of major adverse cardiac events (MACE) at 12-month follow-up. Secondary endpoints included target lesion revascularization (TLR) at 12-month follow-up and the duration and average cost per patient of dual antiplatelet therapy. MACE were defined as a composite of cardiac death, non-fatal MI (including Q-wave and non-Q-wave MI) and TLR. MI was diagnosed by persistent ischaemic-type chest pain with a rise in the creatine kinase-MB fraction of more than three times the upper limit of normal, according to the guidelines for PCI . Q-wave MI was distinguished by the development of new abnormal Q waves, while their absence identified non-Q-wave MI. TLR was defined as a repeat intervention (surgical or percutaneous) to treat significant luminal stenosis (defined as ≥ 50% diameter stenosis by visual estimation) within the stent or in the 5-mm distal or proximal segments adjacent to the stent. Revascularization was regarded as ‘clinically driven’ if it was motivated by angina symptoms and/or proven myocardial ischaemia in the target vessel territory by non-invasive testing. Angiographic success was defined as successful implantation of the assigned study stent into the target lesion with residual stenosis less than 20% and TIMI 3 flow at the conclusion of the procedure, in the absence of dissection or thrombosis. Clinical success was defined as angiographic success in the absence of in-hospital MACE. Stent thrombosis was diagnosed by the occurrence of acute coronary syndrome with angiographic evidence of either index vessel occlusion or thrombus within the study stent, according to the ‘definite category’ definition of the Academic Research Consortium . Stent thrombosis was classified into: acute (occurring within 24 hours of the index procedure), subacute (> 24 hours but < 30 days) and late (> 30 days).
Statistical analysis
To estimate the number of patients that would give an adequately powered sample size, we hypothesized a MACE toll of 11% at 12-month follow-up. This figure was based on prior studies employing the Titan2 ® stent in unselected populations, that reported 10.4% and 10.9% MACE at 9 and 12 months’ follow-up, respectively . Given the above assumption, the number of patients necessary to achieve such a proportion, with a 95% confidence interval, was calculated by means of the following formula:
n = p × 1 − p × 1,96 e 2
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