Abstract
Objective
To evaluate the clinical performance of the Cre8™ polymer-free drug-eluting-stent in unselected real-life population.
Background
Inflammation plays a key role in the multi-factorial process eventually leading to target vessel failure (TVF) after drug-eluting-stent (DES) implantation. The local chronic inflammatory reaction in the vessel wall at the site of stent implantation is, at least in part, attributed to interaction between the polymer coating of DES and vessel wall components. The belief that elimination of the polymer will reduce the occurrence of short and long-term TVF has led to the field of polymer-free DES development.
Methods and results
In this prospective, open-labeled, single-center, uncontrolled trial we enrolled consecutive patients undergoing PCI to receive the Cre8™ stent. The only exclusion criteria were instent restenosis and target vessel diameter < 2.5 mm. Primary end points were cardiac death and target vessel failure (TVF) at 1-year.
Overall, 215 patients were enrolled, in which 318 Cre8 stents were implanted. Study population was characterized by a high prevalence of comorbidities including 38% of diabetics. More than 50% presented with acute coronary syndromes. During 1-year of follow-up there were 1 case of sudden death and 1 case of non-cardiac death, as well as 2 cases of TVF.
Conclusion
In this small single-center trial of unselected real-life population, the polymer-free Cre8™ DES appears to be effective, as it was associated with very low rates of target-vessel-failure up to 1-year follow-up.
Highlights
- •
We evaluated the performance of a polymer free DES in consecutive all-comer population.
- •
Overall, 215 patients were enrolled, in which 318 Cre8 stents were implanted.
- •
During 1-year of follow-up there were 1 case of sudden death and 1 case of non-cardiac death.
- •
There were two cases of TVF.
1
Introduction
Although first and second-generation drug eluting stents (DESs) have significantly reduced the risk of target vessel revascularization compared with bare metal stents (BMSs) , in-stent restenosis still occurs, especially in diabetics, and stent thrombosis (ST) emerged as a major safety concern . Human autopsy studies have identified the polymer coating of the stent’s metal struts as a possible trigger for chronic local inflammatory response within the vessel wall . Moreover, ex-vivo scanning electron microscopy examinations of DESs before and after balloon expansion, demonstrated inhomogeneous distribution and poor integrity of the polymer coating, in all commercially available DESs examined .These irregularities, cracks and fractures of the polymer’s surface are thought to trigger local inflammatory reaction in the vessel wall, leading to increased risk of late stent thrombosis and in-stent restenosis.
In an effort to enhance safety and efficacy, DES focus has been shifted to developing strategies to eliminate the potential harm associated with the durable polymer coating. The following generation of DESs tried to deal with this challenge using more biocompatible and biodegradable polymers , however, several in vivo investigations still reported a significant local inflammatory response with these stents . A further attempt to improve the clinical performance of DESs by reducing polymer–vessel wall interaction was to completely devoid the polymeric substances as a carrier for drug elution . These new polymer-free DESs require alternative methods to load, keep and release adequate quantities of drug from the metallic platform into the vessel wall.
The Cre8™ stent is characterized by a permanent biocompatible i-Carbofilm struts coating and abluminal reservoirs loaded with a polymer-free sirolimus formulation (Amphilimus), to obtain a more efficient targeted elution towards the vessel wall . This stent has been pre-clinically and clinically tested with promising results, suggesting a safe and effective profile, with a possible advantage in diabetic patients in terms of reduced in-stent late lumen loss (LLL) .
In this single-center study we prospectively investigated the clinical performance of the polymer-free Cre8™ DES in a real-life, unselected patient population undergoing percutaneous coronary intervention (PCI).
2
Methods
2.1
Study design and population
It is a prospective, non-randomized, open-labeled, single-center study, enrolling all-comer consecutive patients. Eligible were patients ≥ 18 years old undergoing PCI due to any clinical condition the attending interventional cardiologist deemed amenable for PCI (ST elevation myocardial infarction [STEMI], non STEMI, unstable angina and stable angina). All patients signed an informed consent prior to the procedure as approved by the hospital ethical comity.
2.2
Study device
The Cre8™ stent is a CE-marked cobalt–chromium (80-μm) polymer-free DES which is in wide routine clinical use in Europe as well as in many other countries outside the USA. The stent’s struts are integrally coated by an ultra-thin (0.3-μm) passive carbon coating (i-Carbofilm, CID, Saluggia, Italy). The amphilimus formulation, constituted by sirolimus (0.9 μg/mm 2 ) formulated with an excipient composed of long-chain fatty acids mixture, to modulate the drug release, is loaded into abluminal reservoirs to obtain a targeted elution toward the vessel wall. About 70% of the drug is eluted within 30 days of implantation, while a complete elution of the drug is achieved within 90 days .
2.3
Study procedure and follow up
After signing the informed consent form, all patients underwent diagnostic coronary angiography. Patients enrolled to the study were those who had coronary lesions requiring angioplasty and stent implantation. The only angiographic exclusion criteria were in-stent restenosis (ISR), and target vessel diameter < 2.5 mm. All other types of lesions including long and complicated lesions, bifurcations and unprotected left main lesions were eligible. The only stent used in this study was the Cre8™ polymer-free DES. Available stent sizes were 2.5, 2.75, 3.0, 3.5 and 4 mm, whereas stent lengths ranged from 12 to 31 mm.
Periprocedural anticoagulation with heparin or bivalirudin and administration of glycoprotein IIb/IIIa inhibitors was according to the local practice. Post-procedure dual antiplatelet therapy was mandated for at least 6-months, with indefinite continuation of aspirin.
Follow-up included contacting patients by telephone at 1-month, 6-months and 1-year. All clinical events including death, myocardial infarction, stent thrombosis, any revascularization procedures, and cerebrovascular events were recorded.
2.4
Study end points
Primary end points included cardiac death and clinically driven target vessel failure (TVF) which was defined as repeated PCI or coronary artery bypass graft of the target vessel, or myocardial infarction, stent thrombosis (according to the Academic Research Consortium criteria ) or restenosis requiring revascularization, if the culprit lesion is located within the target vessel.
Secondary end points included 1-year all-cause mortality, target lesion revascularization (TLR), stent thrombosis, MI, unplanned PCI and stroke.
Major adverse cardiac and cerebrovascular events (MACCE) were defined as any combination of the following: total mortality, TVF, MI and stroke.
All endpoints were reviewed by 2 independent interventional cardiologists from the same institute who were not involved in this study.
2.5
Statistical analysis
All data are displayed as mean (± standard deviation) for continuous variables, and as the number (percentage) of patients in each group for categorical variables. The SPSS statistical package was used to perform all statistical evaluation (SSPS, Chicago, IL).
2
Methods
2.1
Study design and population
It is a prospective, non-randomized, open-labeled, single-center study, enrolling all-comer consecutive patients. Eligible were patients ≥ 18 years old undergoing PCI due to any clinical condition the attending interventional cardiologist deemed amenable for PCI (ST elevation myocardial infarction [STEMI], non STEMI, unstable angina and stable angina). All patients signed an informed consent prior to the procedure as approved by the hospital ethical comity.
2.2
Study device
The Cre8™ stent is a CE-marked cobalt–chromium (80-μm) polymer-free DES which is in wide routine clinical use in Europe as well as in many other countries outside the USA. The stent’s struts are integrally coated by an ultra-thin (0.3-μm) passive carbon coating (i-Carbofilm, CID, Saluggia, Italy). The amphilimus formulation, constituted by sirolimus (0.9 μg/mm 2 ) formulated with an excipient composed of long-chain fatty acids mixture, to modulate the drug release, is loaded into abluminal reservoirs to obtain a targeted elution toward the vessel wall. About 70% of the drug is eluted within 30 days of implantation, while a complete elution of the drug is achieved within 90 days .
2.3
Study procedure and follow up
After signing the informed consent form, all patients underwent diagnostic coronary angiography. Patients enrolled to the study were those who had coronary lesions requiring angioplasty and stent implantation. The only angiographic exclusion criteria were in-stent restenosis (ISR), and target vessel diameter < 2.5 mm. All other types of lesions including long and complicated lesions, bifurcations and unprotected left main lesions were eligible. The only stent used in this study was the Cre8™ polymer-free DES. Available stent sizes were 2.5, 2.75, 3.0, 3.5 and 4 mm, whereas stent lengths ranged from 12 to 31 mm.
Periprocedural anticoagulation with heparin or bivalirudin and administration of glycoprotein IIb/IIIa inhibitors was according to the local practice. Post-procedure dual antiplatelet therapy was mandated for at least 6-months, with indefinite continuation of aspirin.
Follow-up included contacting patients by telephone at 1-month, 6-months and 1-year. All clinical events including death, myocardial infarction, stent thrombosis, any revascularization procedures, and cerebrovascular events were recorded.
2.4
Study end points
Primary end points included cardiac death and clinically driven target vessel failure (TVF) which was defined as repeated PCI or coronary artery bypass graft of the target vessel, or myocardial infarction, stent thrombosis (according to the Academic Research Consortium criteria ) or restenosis requiring revascularization, if the culprit lesion is located within the target vessel.
Secondary end points included 1-year all-cause mortality, target lesion revascularization (TLR), stent thrombosis, MI, unplanned PCI and stroke.
Major adverse cardiac and cerebrovascular events (MACCE) were defined as any combination of the following: total mortality, TVF, MI and stroke.
All endpoints were reviewed by 2 independent interventional cardiologists from the same institute who were not involved in this study.
2.5
Statistical analysis
All data are displayed as mean (± standard deviation) for continuous variables, and as the number (percentage) of patients in each group for categorical variables. The SPSS statistical package was used to perform all statistical evaluation (SSPS, Chicago, IL).
3
Results
3.1
Study population
Overall, 215 patients were enrolled to the study between November 2012 and June 2013, requiring the implantation of 319 Cre8™ stents. Baseline clinical characteristics of the study cohort are provided in Table 1 . Mean age was 64.6 ± 10 years, with 87% of patients of male gender. A high prevalence of cardiovascular risk factors and previous vascular disease was observed, including diabetes mellitus in 38% of the patients, previous MI and PCI in 63 (29%) and 114 (53%) patients, respectively. Slightly more than half of the patients enrolled presented with acute MI or unstable angina. The rest were patients with stable disease who were referred for an elective intervention.
| Variable | |
|---|---|
| Gender, male n (%) | 188 (87) |
| Age, years mean ± SD | 64.6 ± 10 |
| Hypertension n (%) | 54 (25) |
| Dyslipidemia n (%) | 182 (84) |
| DM type II n (%) | 83 (38) |
| Current Smoking n (%) | 57 (26) |
| PVD n (%) | 18 (8) |
| s/p MI n (%) | 63 (29) |
| s/p PCI n (%) | 114 (53) |
| s/p CABG n (%) | 25 (12) |
| s/p TIA/CVA n (%) | 24 (11) |
| eGFR ≤ 30 mL/min n (%) | 5 (2) |
| Presenting diagnosis | |
| STEMI | 10 (5) |
| ACS (NSTEMI, unstable angina) | 102 (47) |
| Stable/Elective | 103 (48) |
| Anti platelet therapy at discharge | |
| Aspirin + clopidogrel n (%) | 182 (85) |
| Aspirin + ticagrelor n (%) | 10 (5) |
| Aspirin + prasogrel n (%) | 23 (10) |
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