Efficacy and Safety of Polymer-Free Ultrathin Strut Sirolimus-Probucol Coated Drug-Eluting Stents for Chronic Total Occlusions: Insights from the Coroflex ISAR 2000 Worldwide Registry

Objective Coronary revascularization in chronic total occlusion (CTO) is associated with improved clinical outcomes. The choice of the coronary stent is crucial in maintaining long-term vessel patency after CTO revascularization. We investigated the efficacy and safety of polymer-free ultrathin strut sirolimus-probucol coated drug-eluting stents (PF-SES) for CTO lesions. Methods Patients with CTO lesions treated with PF-SES were identified from the prospective multicenter international ISAR 2000 registry. The primary endpoint was clinically driven target lesion revascularization (TLR) at 9 months. Secondary endpoints were 9-month major adverse cardiac events (death, myocardial infarction, or TLR) (MACE) and the occurrence of stent thrombosis. Results A total of 111 patients with CTO lesions (n=127) were available for analysis. The 9-month clinical follow-up rate was 91%. The mean reference vessel diameter and lesion length were 2.76 mm ± 0.40 and 26.8 mm ± 13.1, respectively. The overall DAPT duration was 9.7 ± 2.8 months. Only one (1%) in-hospital MI was reported. The TLR and MACE rates at 9 months were 2% (2/101) and 5.9% (6/101), respectively. The 9-month accumulated rates of definite or probable stent thrombosis was 0% (0/101). Conclusion Revascularizations for CTO with PF-SES are associated with low rates of TLR and MACE at 9 months with no stent thrombosis. These initial findings need to be compared with results of other new generation DES of larger studies.


Introduction
e prevalence of chronic total occlusion (CTO) is reported to be around 18.4% among patients with signi cant coronary artery disease [1]. Of these CTO patients, only 36% underwent percutaneous revascularization [1]. e lack of predictability in terms of procedural success and vessel patency post percutaneous coronary interventions (PCI) have made CTO revascularization not as attractive as non-total occlusive lesions. Furthermore, the failure rate of CTO revascularization is reported to be around 40% [2,3]. However, the development of new CTO guidewires and techniques together with the use of new generation DES in CTO revascularization has increased the procedural success and safety to the level similar to non-CTO revascularization [4][5][6].
Ultrathin strut polymer-free, sirolimus-probucol coated drug-eluting stents (PF-SES) are safe and e ective in large scale all-comers population with low rate of target lesion revascularization (TLR) [7]. e polymer-free matrix of these stents consists of sirolimus and its matrix builder probucol. eir safety and e cacy have been proven similar to the one reported with zotarolimus stents in ISAR-TEST 5 trial [8]. e objective of this study was to assess the safety and e cacy of PF-SES in the treatment of "real-world" denovo and restenotic CTO lesions.

Patient Population and Centers.
e ISAR 2000 all-comers registry (http://ClinicalTrials.gov identi er NCT02629575) is a prospective data collection of patients in 26 Asian (South Korea and Malaysia) and 36 European (Czech Republic, France, Germany, Slovakia, and Spain) cardiac centers.

Inclusion and Exclusion
Criteria. Patients 18 years or older with stable angina, objective evidence of myocardial ischemia, and acute coronary syndrome (ACS) who met the requirement for PCI [9] were recruited into the international ISAR 2000 allcomers registry. However, for this study, we only selected patients who were treated for CTO lesions (de novo or restenotic). e numbers of stents or treated vessels with reference vessel diameters from 2.0 mm to 4.0 mm were not limited. e polymer-free stent platform consists of a premounted, thin strut (50/60 μm) cobaltchromium stent whose abluminal surface only is sandblasted to permit a microporous surface for the polymer-free matrix consisting of sirolimus and probucol. Sirolimus with a concentration of 1.2 μg/mm 2 is available on the abluminal stent surface only. Sirolimus is the active antiproliferative drug whereas the anti-in ammatory probucol is an excipient which controls the release of sirolimus. Probucol mimics the function of a polymer by retarding the sirolimus release.
Vascular accesses via the femoral or radial artery were both permitted with a recommended introducer sheath of at least 5 Fr in diameter. e technique of stent implantation was up to the operators' discretion. Intravenous heparin (70 IU/kg) was given to all patients and supplemented on an as-needed basis. Platelet aggregation inhibitor loading was not mandatory but recommended if possible prior to PCI according to institutional preferences of the cardiac center. e use of various antiplatelet inhibition agents (6 months or more) such as clopidogrel (75 mg/day), prasugrel (10 mg/day), or ticagrelor (90 mg twice daily) was permissible (as recommended by the treating physician) while acetylsalicylic acid 100-325 mg daily was prescribed life-long.

Data Collection.
To handle the wealth of the data, an electronic data capture system was used. is database was previously used in prior large scale unselected patient cohorts [10,11] and also used for this assessment [7]. e national principal investigators in each country veri ed the accuracy of the data when routinely performed web-based plausibility checks indicated any discrepancies. To assure the data quality, automatic queries were sent directly to the investigators.

Endpoints and De nitions.
e primary endpoint was the 9-month clinically driven target lesion revascularization (TLR) rate, whereas secondary endpoints were the 9-month major adverse cardiac events (MACE) rate, the in-hospital MACE rate, and the corresponding rates of myocardial infarction (MI) and TLR (coronary artery bypass grafting and percutaneous coronary intervention). Cardiac death was only de ned in-hospital, whereas the all-cause death rate was used to de ne MACE at 9 months (MI, TLR, in-hospital cardiac death, and all deaths post discharge). e Academic Research Consortium (ARC) criteria were used to de ne acute/subacute stent thrombosis [12].
For simplicity reason and based on a previous protocol [10], a glomerular ltration rate (GFR) of <90 mL/min/1.73 m 2 with a cut-o GFR rate for mandatory dialysis of <15 mL/ min/1.73 m 2 was used to de ne renal insu ciency. e angulation criterion of >45°was used to de ne severe vessel tortuosity.

Statistical Analysis.
e statistical methods were also reported elsewhere [7]. e two-sided Fisher's exact and chisquared tests were used for categorical variables. In case the Shapiro-Wilk test revealed a strong deviation from a normal distribution, the Mann-Whitney test was used instead of the unpaired t-test. A cut-o p value of 0.05 was considered statistically signi cant. Statistical analyses were conducted with SPSS V. 24.0 (IBM Munich, Germany). e biometric estimate in the original study [7] was calculated with nQuery/nTerim V.2.0 Advisor (Statistical Solutions Ltd, Cork, Ireland).

Ethical Approval.
Ethics committees of all participating centers approved the study protocol prior to patient recruitment. In France, this noninterventional study was nationally approved by Comité Consultative sur le Traitement de I'Information en matière de Recherche dans le domaine de la Santé (CTIRS dossier number 14.613) and the Commission Nationale de I'informatique et des Libertés (CNIL, demande d'autorisation number 915019). (Table 1) were enrolled in the international ISAR 2000 allcomers registry which had an overall recruitment of 2877 patients [7]. is amounted to 3.6% (111/2977) of the overall patient cohort. ey were strati ed into two groups: patients with lesions < 25 mm and ≥25 mm in length. Patient baseline characteristics are described in Table 1. Mean age for the cohort with CTO was 64.9 years. Diabetes mellitus was present in 45.0% (50/111) of patients who were predominantly male (73.9%, 82/111). e rate of acute coronary syndrome (ACS) in CTO cohort; STEMI and NSTEMI were 8.1% (9/111) and 12.6% (14/111), respectively. In general, the two groups were not signi cantly di erent in terms of their baseline characteristics except for higher rate of hypertension in the ≥25 mm lesion length group (79.0% versus 61.2%, p � 0.040).

Lesion Characteristics and Procedural Data.
ere were 127 CTO lesions (Table 2) which were treated with PF-SES which constituted 3.9% (127/3254) of the total number of lesions in ISAR 2000 all-comers registry [7]. Revascularizations in the right coronary artery (RCA) were most common as compared to the left anterior descending (LAD) and left circum ex artery (LCx), that is, 43.3% versus 29.1% versus 27.6% (p � 0.005). Of note were the signi cant di erences in lesion characteristics between the short and the long lesion length groups. Di (Tables 3 and 4) did not di er between the two groups (Table 3). Clopidogrel remained the most preferred P2Y12 inhibitor to combine with aspirin as preprocedural dual antiplatelet therapy (DAPT) regime. e same DAPT distribution consisting of 55-60% clopidogrel, 15% prasugrel, and 10-15% ticagrelor was documented in both subgroups (Table 3). e average duration of DAPT duration was 9.7 months without di erences between the groups ( Table 4). Most of the patients were treated with DAPT for at least 6 months. ere was only one patient exposed to oral anticoagulant in this cohort.

Discussions
Despite the con icting data regarding the clinical bene t [3,4], CTO revascularizations are associated with better clinical outcomes as those in patients with low ejection fraction or ischemic burden [13][14][15]. Data on long-term outcomes also show lower mortality in patients with successful CTO PCI [16][17][18]. Unfortunately, due to the technical complexity, relatively lower procedure success rates, and higher periprocedural complications [2,3], CTO-PCI from the outset is not as appealing as PCI in less complex coronary lesions. Predictors of unsuccessful PCI are identi ed to be absence of tapered stump structure, TIMI ow grade 0 pre-PCI, high serum creatinine concentrations, and lesion length [19]. However, with the ever-improving PCI techniques and dedicated devices, CTO-PCI has seen signi cant improvement in terms of procedural success [4][5][6].
For patients to bene t long term and to justify the risk of CTO-PCI, to maintain the target vessel patency is important. A large CTO registry of 800 patients with 6-to 9-month angiographic follow-up reported a reocclusion rate of 7.5% [20]. is study demonstrated the importance of the choice of stents used in maintaining vessel patency. e use of DES  in the registry dramatically reduced both reocclusion and nonocclusive angiographic restenosis compared to BMS [21]. e overall restenosis rate of DES in CTO was 11% [21]. A randomized controlled trial also reported that there is a 55% relative risk reduction (RRR) in MACE with the use of DES compared to BMS in CTO PCI [22]. Our study described the outcomes of CTO-PCI from "real-world" data using polymer-free ultrathin strut sirolimus-probucol coated drug-eluting stents (PF-SES). CTO-PCIs in this study were conducted in various centers with a broad spectrum of operator experience and revascularization techniques. Overall, the results of this study re ect the unrestricted, day-to-day practice from various European and Asian centers in the treatment of CTO. e outcome of CTO lesions stented with PF-SES from this study is encouraging. e overall 9-month TLR rate of both <25 mm and >25 mm CTO lesions is low at around 2%. We did not observe any acute, subacute, or late stent thrombosis in this study. e MACE rate at 9-month followup is also favorably low at 5.9% (4.3% for lesions < 25 mm and 7.3% for lesions > 25 mm, p � 0.358). By crude comparison, the EXPERT-CTO trial of XIENCE reported a clinically driven TLR rate of 6.3% and 0.9% subacute stent thrombosis and 0.5% late probable stent thrombosis at one year [23].

Conclusion
e results support the use of PF-SES as an e cacious and safe therapeutic option in the treatment of CTO. e result at least for short term (9 months) is promising, and a longer follow-up would be of interest to determine if PF-SES angioplasty is able to maintain vessel patency in the longterm (>1 year).