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 () 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.
The prevalence of chronic total occlusion (CTO) is reported to be around 18.4% among patients with significant coronary artery disease . Of these CTO patients, only 36% underwent percutaneous revascularization . The 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 [4–6].
Ultrathin strut polymer-free, sirolimus-probucol coated drug-eluting stents (PF-SES) are safe and effective in large scale all-comers population with low rate of target lesion revascularization (TLR) . The polymer-free matrix of these stents consists of sirolimus and its matrix builder probucol. Their safety and efficacy have been proven similar to the one reported with zotarolimus stents in ISAR-TEST 5 trial . The objective of this study was to assess the safety and efficacy of PF-SES in the treatment of “real-world” de-novo and restenotic CTO lesions.
2.1. Patient Population and Centers
The ISAR 2000 all-comers registry (http://ClinicalTrials.gov identifier 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.
2.2. 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  were recruited into the international ISAR 2000 all-comers registry. However, for this study, we only selected patients who were treated for CTO lesions (de novo or restenotic). The numbers of stents or treated vessels with reference vessel diameters from 2.0 mm to 4.0 mm were not limited.
2.3. Stents, Periprocedure Details, and Medications
PF-SES (Coroflex ISAR, B. Braun Melsungen, Melsungen AG, Germany) were implanted according to each institution’s guidelines and in accordance with proper indications for national reimbursement. The polymer-free stent platform consists of a premounted, thin strut (50/60 μm) cobalt-chromium 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/mm2 is available on the abluminal stent surface only. Sirolimus is the active antiproliferative drug whereas the anti-inflammatory 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. The 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.
The 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.
2.4. Data Collection
To handle the wealth of the data, an electronic data capture system was used. This database was previously used in prior large scale unselected patient cohorts [10, 11] and also used for this assessment . The national principal investigators in each country verified 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.
2.5. Endpoints and Definitions
The 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 defined in-hospital, whereas the all-cause death rate was used to define MACE at 9 months (MI, TLR, in-hospital cardiac death, and all deaths post discharge). The Academic Research Consortium (ARC) criteria were used to define acute/subacute stent thrombosis .
For simplicity reason and based on a previous protocol , a glomerular filtration rate (GFR) of <90 mL/min/1.73 m2 with a cut-off GFR rate for mandatory dialysis of <15 mL/min/1.73 m2 was used to define renal insufficiency. The angulation criterion of >45° was used to define severe vessel tortuosity.
2.6. Statistical Analysis
The statistical methods were also reported elsewhere . The two-sided Fisher’s exact and chi-squared 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-off value of 0.05 was considered statistically significant. Statistical analyses were conducted with SPSS V. 24.0 (IBM Munich, Germany). The biometric estimate in the original study  was calculated with nQuery/nTerim V.2.0 Advisor (Statistical Solutions Ltd, Cork, Ireland).
2.7. 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).
3.1. Patient Characteristics
A total of 111 patients with CTO (Table 1) were enrolled in the international ISAR 2000 all-comers registry which had an overall recruitment of 2877 patients . This amounted to 3.6% (111/2977) of the overall patient cohort. They were stratified 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). The 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 significantly different in terms of their baseline characteristics except for higher rate of hypertension in the ≥25 mm lesion length group (79.0% versus 61.2%, ).
3.2. Lesion Characteristics and Procedural Data
There 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 . Revascularizations in the right coronary artery (RCA) were most common as compared to the left anterior descending (LAD) and left circumflex artery (LCx), that is, 43.3% versus 29.1% versus 27.6% (). Of note were the significant differences in lesion characteristics between the short and the long lesion length groups. Diffuse disease (55.2% versus 73.9%, ), in-stent restenosis (1.7% versus 15.9%, ) and B2/C morphologies (89.7% versus 100.0%, ) were more frequent in lesions ≥ 25 mm in length. The average lesion lengths were 16.9 mm versus 35.2 mm, and the average DES lengths were 20.3 mm versus 36.9 mm. The overall technical success rate of PF-SES implantations in CTO lesions was high with 99.2% with no significant differences between groups ().
3.3. PeriProcedural Medications
Preprocedural antiplatelet therapy (Tables 3 and 4) did not differ between the two groups (Table 3). Clopidogrel remained the most preferred P2Y12 inhibitor to combine with aspirin as preprocedural dual antiplatelet therapy (DAPT) regime. The same DAPT distribution consisting of 55–60% clopidogrel, 15% prasugrel, and 10–15% ticagrelor was documented in both subgroups (Table 3). The average duration of DAPT duration was 9.7 months without differences between the groups (Table 4). Most of the patients were treated with DAPT for at least 6 months. There was only one patient exposed to oral anticoagulant in this cohort.
3.4. Clinical Outcomes
At 9 months, there were two patients (2%, 2/101) with TLR (primary endpoint). The rates of acute myocardial infarction (MI) and all-cause death at 9 months were 2% (2/101) and 3% (3/101), respectively. Hence, the composite MACE rate at 9 months was 5.9% (6/101). The in-hospital follow-up was event free except for one acute MI (1%, 1/111). There seems to be a higher 9-month MACE rate for the >25 mm lesion group, but the difference did not reach statistical significance (). There was no report of acute, subacute, or late stent thrombosis (Table 5).
Despite the conflicting data regarding the clinical benefit [3, 4], CTO revascularizations are associated with better clinical outcomes as those in patients with low ejection fraction or ischemic burden [13–15]. Data on long-term outcomes also show lower mortality in patients with successful CTO PCI [16–18].
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 identified to be absence of tapered stump structure, TIMI flow grade 0 pre-PCI, high serum creatinine concentrations, and lesion length . However, with the ever-improving PCI techniques and dedicated devices, CTO-PCI has seen significant improvement in terms of procedural success [4–6].
For patients to benefit 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% . This study demonstrated the importance of the choice of stents used in maintaining vessel patency. The use of DES in the registry dramatically reduced both reocclusion and nonocclusive angiographic restenosis compared to BMS . The overall restenosis rate of DES in CTO was 11% . 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 .
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 reflect the unrestricted, day-to-day practice from various European and Asian centers in the treatment of CTO.
The outcome of CTO lesions stented with PF-SES from this study is encouraging. The 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. The MACE rate at 9-month follow-up is also favorably low at 5.9% (4.3% for lesions < 25 mm and 7.3% for lesions > 25 mm, ). 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 .
The results support the use of PF-SES as an efficacious and safe therapeutic option in the treatment of CTO. The 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 long-term (>1 year).
5.1. Strengths and Limitations of This Study
The CTO cohort in this study was extracted from the largest all-comers registry under routine use of PF-SES, which can be safely and effectively implanted with favorable rates of TLR and MACE. The data suggest that the use of PF-SES in high-risk patients with complex lesions (diabetes mellitus, ACS, diffuse disease, and CTO) is feasible. However, since this is a subgroup analysis from a “real-world” observational study, data collection and monitoring may not have been as stringent as in randomized control trials with the possibility of some underreporting of events. Although the number of patients reported in this assessment was small, the results nevertheless described the potential of PF-SES performance in the specific cohort of CTO patients. It also would have been useful to provide more details on the chronic kidney disease stages relative to their glomerular filtration rates, which was not done in this assessment. Likewise, the use of the J-SCORE and/or the time course of the occlusion along with the lesion crossing (antegrade/retrograde) would have helped to provide additional details of the performed CTO recanalization.
Conflicts of Interest
Florian Krackhardt received lecturing fees, and Matthias W. Waliszewski and Michael Boxberger served full time employment at the Department of Medical Scientific Affairs, B. Braun Melsungen AG.
Ahmad Syadi Mahmood Zuhdi and Muhammad Dzafir Ismail drafted and prepared the manuscript. Florian Krackhardt, Matthias W. Waliszewski, and Michael Boxberger contributed to the conception, design, data analysis, and interpretation. Wan Azman Wan Ahmad critically revised the manuscript for submission. All authors gave final approval of the version to be published.
The authors would like to express gratitude to Denny Herberger (Germany) and Ms. Zoey Hooi (Malaysia) for their relentless efforts providing regulatory and logistic support to conduct this study.
P. Fefer, M. L. Knudtson, A. N. Cheema et al., “Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry,” Journal of the American College of Cardiology, vol. 59, no. 11, pp. 991–997, 2012.View at: Publisher Site | Google Scholar
V. Farooq, P. W. Serruys, H. M. Garcia-Garcia et al., “The negative impact of incomplete angiographic revascularization on clinical outcomes and its association with total occlusions: the SYNTAX (Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery) trial,” Journal of the American College of Cardiology, vol. 61, pp. 282–294, 2013.View at: Publisher Site | Google Scholar
J. A. Grantham, S. P. Marso, J. Spertus, J. House, D. R. Holmes, and B. D. Rutherford, “Chronic total occlusion angioplasty in the United States,” JACC: Cardiovascular Interventions, vol. 2, no. 6, pp. 479–486, 2009.View at: Publisher Site | Google Scholar
V. G. Patel, K. M. Brayton, A. Tamayo et al., “Incidence of angiographic success and procedural complications in patients undergoing percutaneous coronary chronic total occlusion interventions: a weighted meta-analysis of 18,061 patients from 65 studies,” JACC: Cardiovascular Interventions, vol. 6, no. 2, pp. 128–136, 2013.View at: Publisher Site | Google Scholar
D. Karmpaliotis, T. Michael, E. S. Brilakis et al., “Retrograde coronary chronic total occlusion revascularization: procedural and in-hospital procedural outcomes from a multicenter registry in the United States,” JACC: Cardiovascular Interventions, vol. 5, no. 12, pp. 1273–1279, 2012.View at: Publisher Site | Google Scholar
S. Rathore, H. Matsuo, M. Terashima et al., “Procedural and in-hospital outcomes after percutaneous coronary intervention for chronic total occlusions of coronary arteries 2002 to 2008: impact of novel guidewire techniques,” JACC: Cardiovascular Interventions, vol. 2, no. 6, pp. 489–497, 2009.View at: Publisher Site | Google Scholar
F. Krackhardt, V. Kocka, M. W. Waliszewski et al., “Polymer-free sirolimus-eluting stents in a large-scale all-comers population,” Open Heart, vol. 4, no. 2, p. e000592, 2017.View at: Publisher Site | Google Scholar
S. Massberg, R. A. Byrne, A. Kastrati et al., “Polymer-free sirolimus- and probucol-eluting versus new generation zotarolimus-eluting stents in coronary artery disease: the intracoronary stenting and angiographic results: test efficacy of sirolimus–and probucol-eluting versus zotarolimus-eluting stents (ISAR TEST 5) trial,” Circulation, vol. 124, no. 5, pp. 624–632, 2011.View at: Publisher Site | Google Scholar
S. Windecker, P. Kolh, F. Alfonso et al., “ESC/EACTS guidelines on myocardial revascularization: the task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI),” European Heart Journal, vol. 35, no. 37, pp. 2541–2619, 2014.View at: Publisher Site | Google Scholar
M. Leschke, M. Waliszewski, M. Pons et al., “Thin strut bare metal stents in patients with atrial fibrillation: is there still a need for BMS?” Catheterization and Cardiovascular Interventions, vol. 88, no. 3, pp. 358–366, 2016.View at: Publisher Site | Google Scholar
J. Wöhrle, M. Zadura, S. Möbius-Winkler et al., “SeQuentPlease World Wide Registry: clinical results of SeQuent please paclitaxel-coated balloon angioplasty in a large-scale, prospective registry study,” Journal of the American College of Cardiology, vol. 60, no. 18, pp. 1733–1738, 2012.View at: Publisher Site | Google Scholar
D. E. Cutlip, S. Windecker, R. Mehran et al., “Clinical end points in coronary stents trials: a case for standardized definitions,” Circulation, vol. 115, no. 17, pp. 2344–2351, 2007.View at: Publisher Site | Google Scholar
S. Pujadas, V. Martin, X. Rosselló et al., “Improvement of myocardial function and perfusion after successful percutaneous revascularization in patients with chronic total coronary occlusion,” International Journal of Cardiology, vol. 169, no. 2, pp. 147–152, 2013.View at: Publisher Site | Google Scholar
C. Bucciarelli-Ducci, D. Auger, C. Di Mario et al., “CMR guidance for recanalization of coronary chronic total occlusion,” JACC: Cardiovascular Imaging, vol. 9, no. 5, pp. 547–556, 2016.View at: Publisher Site | Google Scholar
G. E. Christakopoulos, G. Christopoulos, M. Carlino et al., “Meta-analysis of clinical outcomes of patients who underwent percutaneous coronary interventions for chronic total occlusions,” American Journal of Cardiology, vol. 115, no. 10, pp. 1367–1375, 2015.View at: Publisher Site | Google Scholar
E. L. Hannan, Y. Zhong, A. K. Jacobs et al., “Patients with chronic total occlusions undergoing percutaneous coronary interventions characteristics, success, and outcomes,” Circulation: Cardiovascular Interventions, vol. 9, no. 5, p. e003586, 2016.View at: Publisher Site | Google Scholar
D. Joyal, J. Afilalo, and S. Rinfret, “Effectiveness of recanalization of chronic total occlusions: a systematic review and meta-analysis,” American Heart Journal, vol. 160, no. 1, pp. 179–187, 2010.View at: Publisher Site | Google Scholar
S. George, J. Cockburn, T. C. Clayton et al., “Long-term follow-up of elective chronic total coronary occlusion angioplasty: analysis from the U.K. Central Cardiac Audit Database,” Journal of the American College of Cardiology, vol. 64, no. 3, pp. 235–243, 2014.View at: Publisher Site | Google Scholar
M. Salarifar, M. R. Mousavi, S. Saroukhani et al., “Percutaneous coronary intervention to treat chronic total occlusion: predictors of technical success and one-year clinical outcome,” Texas Heart Institute Journal, vol. 41, no. 1, pp. 40–47, 2014.View at: Publisher Site | Google Scholar
R. Valenti, R. Vergara, A. Migliorini et al., “Predictors of reocclusion after successful drug-eluting stent-supported percutaneous coronary intervention of chronic total occlusion,” Journal of the American College of Cardiology, vol. 61, no. 5, pp. 545–550, 2013.View at: Publisher Site | Google Scholar
H. J. Colmenarez, J. Escaned, C. Fernandez et al., “Efficacy and safety of drug-eluting stents in chronic total coronary occlusion recanalization: a systematic review and meta-analysis,” Journal of the American College of Cardiology, vol. 55, no. 17, pp. 1854–1866, 2010.View at: Publisher Site | Google Scholar
B. M. Rahel, G. J. Laarman, J. C. Kelder, J. M. Ten Berg, and M. J. Suttorp, “Three-year clinical outcome after primary stenting of totally occluded native coronary arteries: a randomized comparison of bare-metal stent implantation with sirolimus-eluting stent implantation for the treatment of total coronary occlusions (Primary Stenting of Totally Occluded Native Coronary Arteries [PRISON] II study),” American Heart Journal, vol. 157, no. 1, pp. 149–155, 2009.View at: Publisher Site | Google Scholar
D. E. Kandzari, A. S. Kini, D. Karmpaliotis et al., “Safety and effectiveness of everolimus-eluting stents in chronic total coronary occlusion revascularization: results from the EXPERT CTO multicenter trial (Evaluation of the XIENCE coronary stent, performance, and technique in chronic total occlusions),” JACC: Cardiovascular Interventions, vol. 8, no. 6, pp. 761–769, 2015.View at: Publisher Site | Google Scholar