In-Hospital and 1-Year Clinical Results from the French Registry Using Polymer-Free Sirolimus-Eluting Stents in Acute Coronary Syndrome and Stable Coronary Artery Disease

Objectives The aim of this postmarket clinical study was to assess the safety and efficacy of the latest generation polymer-free sirolimus-eluting stents (PF-SES) in an all-comers population comparing outcomes in stable coronary artery disease (CAD) versus acute coronary syndrome (ACS) in France. Background The efficacy and safety of the first-generation PF-SES have already been demonstrated by randomized controlled trials and “all-comers” observational studies. Methods For this all-comers observational, prospective, multicenter study, 1456 patients were recruited in 22 French centers. The primary endpoint was target lesion revascularization (TLR) rate at 12 months and secondary endpoints included major adverse cardiac events (MACE) and bleeding. Results 895 patients had stable CAD and 561 had ACS. At 12 months, 2% of patients had a TLR, with similar rates between stable CAD and ACS (1.9% vs 2.2%, p = 0.7). The overall MACE rate was 5.2% with an expected higher rate in patients with ACS as compared to those with stable CAD (7.3% vs 3.9%, p = 0.007). The overall bleeding event rate was 4.5%, with similar rates in stable CAD as compared to ACS patients (3.8% vs 5.6%, p = 0.3). Dual antiplatelet therapy (DAPT) interruptions prior to the recommended duration occurred in 41.7% of patients with no increase in MACE rates as compared to patients who did not prematurely interrupt DAPT (3.9% vs 6.1%, p = 0.073). Conclusions The latest generation PF-SES is associated with low clinical event rates in these all-comers patients. There was a high rate of prematurely terminated DAPT, without any effect on MACE at 12 months. This trial is registered with NCT03809715.


Introduction
Most commercially available coronary drug-eluting stents (DES) have polymer coatings, whether durable or resorbable, to fx the drug and slow down its elution.Some DES, such as the latest generation PF-SES Corofex ® ISAR NEO (B.Braun) device, an improved version of its predecessor the frst-generation PF-SES Corofex ® ISAR DES which was extensively studied in the ISAR 2000 registry, do not have polymers.
Te objective of this postmarket clinical study was to assess the safety and efectiveness endpoints of the latest generation PF-SES in an unselected large patient population comparing outcomes in stable coronary artery disease (CAD) and acute coronary syndrome (ACS) in a French cohort.

Study Design and Patient
Population.Tis study is an allcomers observational, nonrandomized, prospective, multicenter, postmarket registry (ClinicalTrials.govIdentifer: NCT03809715).A total of 1456 nonconsecutive patients of which 895 patients had stable CAD and 561 patients had ACS including 205 with ST-elevation myocardial infarction (STEMI) were recruited in 22 French centers.
Te inclusion criteria were as follows: patients who were at least 18 years of age with signifcant coronary lesions (>50% diameter stenosis) and patients fulflling the standard recommendations for percutaneous coronary intervention (PCI) based on the last European Society of Cardiology (ESC) recommendations.Exclusion criteria were as follows: intolerance to sirolimus and/or probucol, allergy to the coating's components, pregnancy and lactation, complete occlusion of the treated vessel due to a failed recanalization, cardiogenic shock, hemorrhagic diathesis or another disorder such as gastrointestinal ulceration or cerebral circulatory disorders which restrict the use of platelet aggregation inhibitor therapy and anticoagulation therapy, emergency cardiac surgery decision after myocardial infarction, patients with an ejection fraction of <30%, culprit coronary artery reference diameter <2.00 mm, and treatment of the left coronary stem.
Te primary endpoint was the accumulated target lesion revascularization (TLR) rate at 12 months.Patients needed to be symptomatic with proof of ischemia for TLR.In addition, onsite quantitative coronary angiography (QCA) or "angiographic eyeballing" was used to determine at least a 70% diameter stenosis at the initial angioplasty site.Te secondary endpoints during hospitalization were as follows: major adverse cardiac events (MACE) including target lesion revascularization (TLR), myocardial infarction (MI) (defned by a new event documented with elevated cardiac enzymes during the follow-up; elevated enzyme levels during the hospital stay are not considered as a new event), and cardiac death (defned by a proven cardiac death), and those at 12 months were as follows: MACE including TLR, MI, allcause death, and defnite and probable stent thrombosis.
Clinical and angiographic patient data were collected prospectively and recorded in a pseudonymized fashion (only the hospital could identify the patient), to meet all requirements regarding the updated general data protection regulation.Written informed consent was obtained from all patients before the procedure.Te study will be presented to at least one ethics committee.National requirements for obtaining several ethics committees' opinions or to oblige the physician to obtain ethical counseling from the responsible ethics committee will be considered appropriate.In France, for our registry, the study complies with the Helsinki Declaration, in its most recent version, and was approved by the French National Agency for the Safety of Medicines and Health Products.

Stent
Design, Procedure, and Follow-Up.Te latest generation PF-SES Corofex ® ISAR NEO (B.Braun), without polymer, was therefore the device used in our study.Instead of using a polymer, a nonpolymer coating technology is employed: the excipient probucol to gradually release the drug and the active drug sirolimus on the abluminal side only, which is a macrolide and potent cytostatic inhibitor of smooth muscle proliferation.Its antiproliferative efects have been proven in a plethora of studies [7].In addition, the stent backbone has ultrathin struts (55-65 µm), one of the thinnest struts thickness in the market.Te diferences between these two devices are mainly the modifed stent architecture, i.e., ring and slightly widened connectors, increasing radioopacity and subsequent visualization of the secondgeneration PF-SES as well as radial strength (50% increase) with less late recoil [8] (Figure 1).PCI was performed according to current clinical practice standards.Stent implantation procedures were carried out in compliance with approved indications as part of the manufacturer's CE certifcation.Te implantation of the study device was recommended in an unselected patient population with stable CAD or ACS in France.
Dual antiplatelet therapy (DAPT) of 6 months for stable CAD and 12 months for ACS was recommended, but the fnal decisions concerning DAPT duration, type of P2Y 12 receptor inhibitor, and the use of glycoprotein IIb/IIIa inhibitors were left to the physician's discretion [9].

Study Supervision, Data Management, and Defnitions.
Te study was initiated by B. Braun.Te scientifc study committee was responsible for the development of the protocol and the writing of the manuscript.Te committee had unrestricted access to all study data.
An independent clinical events committee, provided with all necessary and available data, adjudicated all major cardiovascular events and protocol endpoints.Procedural success was defned as a visually assessed <30% diameter stenosis without coronary dissection.

Statistical Analysis. Statistical analyses were conducted using SPSS version 23 (IBM, Munich, Germany).
Deviations from the study plan were assessed as protocol violations if at least one of the inclusion or exclusion criteria was not fulflled.All patients who received at least one device were included in the intention-to-treat analysis.All patients who received at least one device without any protocol violation were included in the per-protocol analysis.
Patient data were identifed by the patient number assigned during data entry, the study center, the time of treatment, and the time of recording.
Te standard procedures for the comparison of variables and outcomes between groups (e.g., study center, country, and age) were planned as follows: Fisher's exact test for binary variables, χ 2 test for categorical variables in k × 2 tables with k > 2, and Wilcoxon-Mann-Whitney U test or Student's t-test or ANOVA (analysis of variance) for continuous variables.In the case of small cell expectations occurring in the majority of the test situations, data of ordinal scale were to be analyzed by means of the U test instead of the χ 2 test.
All statistical tests were two-tailed with the prespecifed signifcance level of α � 5%.
Te statistical evaluation of the study data was organized by B. Braun Vascular Systems, Berlin organization.

Patient Demographic Data, Lesion Morphologies, and
Procedural Details.From November 2018 to December 2020, 1456 patients were treated for 2079 coronary lesions with 2110 DES in 22 centers in France.Te mean age of patients was 66.2 ± 11.3 years, and 74.2% of patients were men.Diabetes mellitus was found in 22.1% of patients in the ACS subgroup versus 28.9% of those in the stable CAD subgroup (p � 0.003).ACS accounted for 38.5% of PCI indications including STEMI for 14.1% and stable CAD for 61.5% (Table 1).
Treated lesions were complex (B2 or C, according to the American Heart Association/American College of Cardiology classifcation) in 39.3% of patients in the ACS subgroup versus 31.4% of those in the stable CAD subgroup (p < 0.001).Te mean number of DES per patient was 1.40 ± 0.66 (Table 2).
Most procedures were carried out using radial approach (92.7%).No data concerning the use of intracoronary imaging are available.Angiographic procedural success for all lesions treated was achieved in 99.2% of patients (Table 2).
Te remaining baseline data are summarized in Tables 1  and 2.

Medical Terapy.
All patients were treated with acetylsalicylic acid.Tere was no preloading in 50.7% of patients.Prior to angioplasty, patients were treated with clopidogrel in 26.4% of cases, ticagrelor in 21.3% of cases, and prasugrel in 1.6% of cases.After angioplasty, patients were treated with clopidogrel in 59.2% of cases, ticagrelor in 37.9% of cases, and prasugrel in 2.9% of cases.DAPT duration was inferior to 6 months in 5.8% of patients in the stable CAD population and 6-12 months in 87.7% of those in the stable CAD population.DAPT duration was superior to 12 months in 7.9% of those in the ACS population.Time to discharge was 2.5 ± 4.9 days.DAPT interruption occurred in 42.2% of patients.Te reasons for DAPT interruption were on physician's advice (38.5%), due to complications (1.5%), patient's own decision (0.4%), and unknown causes (1.3%) (Table 3).
Table 3 summarizes the remaining data.

Clinical Outcomes at 12
Months.Follow-up was obtained in 92% of the patients at 12.4 ± 0.7 months (Table 4).With the exception of expected higher rates of MI in the ACS subgroup (0.9% vs 0.1%, p � 0.024), no signifcant diference was found between the ACS and the stable CAD subgroups at hospital discharge regarding the rates of MACE, TLR, and cardiac death (Table 4).
Te rates of accumulated overall TLR and defnite and probable stent thrombosis were low: 2% and 0.6%, respectively.As expected, rates of overall MACE (7.3% vs 3.9%, p � 0.007) and all-cause death (3.8% vs 1.7%, p � 0.017) were higher in patients in the ACS subgroup than  those in the stable CAD subgroup.However, rates of overall TLR, defnite and probable stent thrombosis, and overall bleeding were similar in both stable CAD and ACS settings (Table 4).

Journal of Interventional Cardiology
Tere was a DAPT interruption prior to the recommended time in 42.2% of cases, without a signifcant increase in the rate of MACE in all patients: 3.9% in the case of DAPT interruption versus 6.1% in the case of no DAPT interruption (p � 0.073).Tere was no bleeding in 96.4% of patients in the DAPT interruption" group and 93.2% of patients in the "DAPT interruption" group, BARC 1 in 1.2% and 3.2%, BARC 2 in 0.7% and 2.4%, BARC 3 in 0.9% and 0.6%, BARC 5 in 0.1% and 0.6% (unknown in 0.6% and 0%) (p � 0.001) (Tables 3 and 4).
Te remaining baseline data are summarized in Table 4.

Discussion
Our data showed that the latest generation PF-SES with ultrathin struts is associated with high procedural success rates and low clinical event rates during hospitalization and at 12 months in all-comers patients, with moderate to highly complex lesions.Tere was a high rate of premature interruption of DAPT, without any efect on MACE or bleeding at 12 months, in this population with mostly low to intermediate complex lesions, highlighting the safety profle of this latest generation PF-SES.At 12 months, our study confrmed previous large-scale studies demonstrating the safety and efectiveness endpoints of the latest generation PF-SES with low rates of TLR (2.0%), MACE (5.2%), MI (1.1%), and all-cause death (2.5%).

Journal of Interventional Cardiology
Defnite and probable stent thrombosis occurred in 0.6% of cases at 1 year.In the ISAR 2000 registry, studying the safety and efectiveness endpoints of frst-and latest generation PF-SES, including in special cases such as left main angioplasty (which was an exclusion criterion in our study), 7000 patients had a 9-month low TLR and MACE rate (2.2% and 4.4%).MACE was signifcantly increased in the ACS population (6.3%) and left main lesions (6.7%).Probable or possible stent thrombosis occurred in 0.7% of cases [10].
Te strut thickness of PF-SES, investigated in our study (55-65 µm), corresponds to one of the thinnest struts currently in stent design technology.It is well known that the thickness of the struts increases the stent's thrombogenicity and restenosis.Reducing struts' thickness could reduce thrombogenicity and vascular infammation and improve the clinical impact of the devices.Tis could explain the good results found in our study.Tese results are confrmed at 1 year by a recent meta-analysis which showed that second-generation DES with ultrathin struts (<70 µm) had better outcomes than thicker second-generation DES in terms of target lesion failure (TLF) [6].Te long-term benefts of ultrathin struts DES have been confrmed by two recent large meta-analyses [7,8].Te frst meta-analysis, pooled data from 18 publications from 10 randomized trials, showed a reduction of 12% in TLF at 2 years and 19% at 3 years after ultrathin strut stent implantation [7].Te second meta-analysis showed the same data with the use of ultrathin struts DES after an average follow-up of 2.5 years with a 15% reduction in the rate of TLF essentially linked to the 25% reduction of TLR, without any diference in terms of MACE [8].
Te pathogenesis of delayed re-endothelialization after DES implantation is not fully elucidated.It appears that the presence of some polymers may induce an infammatory response that delays vascular healing [15].Te development of polymer-free DES was therefore motivated by the intention to obtain healing comparable to that of bare metal stent (BMS), leading to both low restenosis and low late thrombosis rates.No data concerning the use of intracoronary imaging in our registry are available, as interventional cardiologists were not asked to fll in this index in Using clopidogrel rather than ticagrelor had no efect on MACE, bleeding, and thrombotic events in stable CAD or ACS patients [16,17].As observed in our study, compared with 6 months of DAPT, 3-6 months of DAPT did not increase the risk of cardiovascular death, myocardial infarction, target vessel revascularization (TVR), defnite and probable stent thrombosis, and Bleeding Academic Research Consortium (BARC) 1 year after PF-SES implantation [18,19].In contrast to our study, DAPT interruption prior to the recommended time could lead to an increase in clinical event rates (MACE, TLR, MI, accumulated mortality) [20].
Tis large French multicenter (22 centers) observational study has some limitations: it is a registry, not a randomized trial, since the PF-SES was not compared to another DES in a control group.Te overall low event rate could be due in part to the population included with mostly low to intermediate complex lesions (e.g., A and B1 lesion types in more than two-thirds of cases).Tere was no learning curve for the latest generation PF-SES implantation, as it was similar to other contemporary DES.Te duration of DAPT was left to the operator's judgment at that time; however, it did not afect TLR, MACE, and bleeding at 12 months.

Conclusion
Te latest generation PF-SES with ultrathin struts is associated with high procedural success rates and low ischemic or bleeding events during the hospital stay and at 12-month follow-up.Tis all-comers patient population with stable CAD or ACS was also partly treated in moderate to highly complex lesions.Tere was a high rate of prematurely terminated DAPT, with no efect on MACE or bleeding at 12 months, in this population with mostly low to intermediate complex lesions, highlighting the highly favorable security profle of the DES.

Table 2 :
Lesion and procedural characteristics.

Table 4 :
[5]nical outcomes.Te randomized FRIENDLY OCT study showed that strut re-endothelialization was signifcantly higher for the latest generation PF-SES as compared to a sirolimus-eluting stent with biodegradable polymer.Tere was no signifcant diference in terms of cardiovascular events at 12 months[5].Tese results suggest faster vascular healing with the latest generation PF-SES associated with potential clinical benefts.