Self-expandable sirolimus-eluting stents compared to
second-generation drug-eluting stents for the treatment of the left main: a
propensity score analysis from the SPARTA and the FAILS-2 registries
Antonio Montefusco MD1, Fabrizio D’Ascenzo MD1, Sebastiano Gili MD1, Grzegorz Smolka MD PhD2, Alaide Chieffo MD3; Andreas Baumbach MD4, Javier Escaned MD PhD5, Paolo Sganzerla MD6, Francesco Tomassini MD7, Gioel Gabrio Secco MD PhD8, Fabrizio Ugo MD9, Corrado Tamburino MD PhD10, Annamaria Nicolino MD11, Massimo Mancone MD PhD12, Arnaldo Poli MD13, Kuan-Leong Yew MD14, Plinio Cirillo MD PhD15, Wojciech Wanha MD PhD2, Luigi Emilio Pastormerlo MD17, Roberto di Summa MD1, Antonio Colombo MD3, Fiorenzo Gaita MD1, Bernardo Cortese MD16,17
1 Department of Medical Sciences, Division of Cardiology, AOU Città della Salute e della Scienza, University of Turin, Turin, Italy
2 Division of Cardiology, Medical University of Silesia, Katowice, Poland 3 Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy 4 Queen Mary University, London, United Kingdom
5 Cardiovascular Institute, Hospital Clínico San Carlos, Madrid, Spain; Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
6 Division of Cardiology, AO Ospedale Treviglio-Caravaggio, Treviglio, Italy
7 Interventional Cardiology Unit, Infermi Hospital, Rivoli and San Luigi Gonzaga Hospital, Orbassano, Italy 8 Interventional Cardiology, Santi Antonio, Biagio e Cesare Arrigo Hospital, Alessandria, Italy
9 Division of Cardiology, San Giovanni Bosco Hospital, Turin, Italy
10 Division of Cardiology , Ferrarotto Hospital, University of Catania , Catania , Italy 11 Divison of Cardiology, Santa Corona Hospital, Pietra Ligure, Italy
12 Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiological and Geriatric Sciences, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
13 Division of Cardiology, Ospedale Civile di Legnano - ASST Ovest Mi, Legnano, Italy 14 Cardiology Department, Manipal Hospital, Klang, Selangor, Malaysia
15 Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy
16 Interventional Cardiology, ASST Fatebenefratelli-Sacco, Milano, Italy 17 Fondazione Monasterio CNR-Regione Toscana, Italy
Conflicts of interest: the authors have no conflicts of interest to declare
Word count: 3721 words, 3 tables, 5 figures
Corresponding author:
Sebastiano Gili
Department of Medical Sciences, AOU Città della Salute e della Scienza, University of Turin,
Corso Bramante 88/90, 10126, Turin, Italy Phone: +39.011.633.6022
Fax: +39.011.633.6769
ABSTRACT
Objectives. To compare the effectiveness and safety of self-expanding, sirolimus-eluting
Stentys stents and second-generation drug-eluting stents (DES-II) for the treatment of the unprotected left main (ULM).
Background. Stentys stents may provide a valuable option to treat distal ULM, particularly
when significant caliber variations with the side branches are observed.
Methods. Patients from the multicenter SPARTA (clinicaltrials.gov: NCT02784405) and
FAILS2 registries were included. Propensity-score with matching was performed to account for the lack of randomization. Primary end-point was the rate of major adverse cardiovascular events (MACE, a composite of all cause death, myocardial infarction, target lesion revascularization [TLR], unstable angina and stent thrombosis [ST]). Single components of MACE were the secondary end-points.
Results. Overall, 151 patients treated with Stentys and 1270 with DES-II were included;
no differences in the rate of MACE at 250 days were observed (9.8% vs. 11.5%, p=0.54). After propensity score with matching, 129 patients treated with Stentys and 258 with DES-II, of whom about two-thirds were women, were compared. After a follow-up of 250 days, the rate of MACE did non differ between the two groups (9.9% vs. 8.5%, p=0.66), as well as the rate of ULM TLR (1.6% vs. 3.1%, p=0.36). No ST were reported in patients treated with Stentys. These results were confirmed also after controlling for patients treated with a provisional or 2-stents strategy for the ULM bifurcation.
Conclusion. Stentys stents may be safely and effectively adopted have similar effectiveness and safety compared to DES-II for the treatment of ULM and represents thus a valuable option in this setting. This finding needs to be confirmed in a Randomized Controlled Trial.
Key-words: percutaneous coronary intervention; unprotected left main; self-expandable
stent; second-generation drug-eluting stent.
ABBREVIATIONS LIST
DES, drug-eluting stent LAD, left anterior descending LCX, left circumflex
MACE, major adverse cardiovascular events MI, myocardial infarction
PCI, percutaneous coronary intervention ST, stent thrombosis
STEMI, ST-elevation myocardial infarction TLR, target lesion revascularization
INTRODUCTION
Critical stenosis of the unprotected left main (ULM) have a detrimental impact on short and long term survival.1,2 Surgical revascularization has been for many years the first-choice treatment, while in the last decade percutaneous coronary intervention (PCI) has affirmed itself as a viable option, showing similar long-term results as compared to coronary artery bypass graft, especially in patients with low-intermediate Syntax score values.3 Both first and second-generation drug eluting stents (DES) have reported satisfactory safety and effectiveness results at the short and long-term follow-up.4,5,6,7 Undertaking a PCI of the ULM presents some technical challenges. Particularly, caliber discrepancies between the ULM and its side branches (left anterior descending [LAD], left circumflex [LCX], ramus intermedius) may expose to the risk of stent under-sizing in the ULM, with a potential risk of restenosis and stent thrombosis, or of stent oversizing in the side branch, with a potential risk of dissection or even of perforation.8,9
The self-expanding Stentys® stent represents a potential solution for these issues. This nitinol (nickel and titanium alloy) sirolimus-eluting (in his latest versions) stent exerts, upon deployment, a constant outward force, which allows it to correctly appose against the vessel wall even in case of sudden caliber changes. This device has been tested in various settings, from ST-elevation myocardial infarction (STEMI) to everyday clinical practice with good demonstration of safety and efficacy10,11,12.
Only few data have been reported about the performance of Stentys for the treatment of the ULM13 with promising results. Moreover, few data are available regarding the sirolimus-eluting version of the device and no comparisons with second-generation DES have been provided. Consequently, we conducted the present study to compare the
sirolimus-eluting Stentys stents and the second-generation DES in the treatment of the ULM.
METHODS.
The Safety and effectiveness of the self-aPposing, bAlloon-delivered, siRolimus-eluting stent for the Treatment of the coronary Artery disesase (SPARTA: ClinicalTrials.gov Identifier: NCT02784405) registry is a multicenter retrospective registry enrolling consecutive patients treated with a sirolimus-eluting Stentys stent (both the Stentys SES stent and the Xposition S stent). Patients from the SPARTA registry undergoing PCI of ULM were included in the present analysis. The Failure in Left Main Study with 2nd generation stents-Cardiogroup III (FAILS2) study14 is, as already reported, a multicenter retrospective registry enrolling all consecutive patients treated with conventional second-generation DES. (see Appendix web only for sites of enrolment)
Clinical and procedural data
For each registry, burden of cardiovascular risk factors, along with clinical presentation were collected from electronic charts at each Center on pre-specified forms and recorded online (http://www.cardiogroup.org/FAIL2/index.php?cat=home).
Extent of the coronary artery disease (evaluated with the Syntax score), site of the ULM lesion (ostial, mid-shaft, distal), involvement of side branches, use of intracoronary imaging (IntraVascular UltraSound or Optical Coherence Tomography) or Fractional Flow Reserve were collected, along with the main features of the implanted stents and the reasons that led to the choice of a Stentys stent.
Follow-up and clinical end-points
Rate of major adverse cardiovascular events (MACE, a composite of all cause death, myocardial infarction [MI], target lesion revascularization [TLR], unplanned hospitalization for unstable angina and stent thrombosis[ST]) was the primary end-point,
while the single components of MACE were the secondary end-points. MI was defined according to the current universal definition of MI (type 1, 2 and 4b was considered as MI at follow up for the purpose of the present study).15 TLR was defined as any repeat PCI of the lesions, or surgical bypass of a target vessel, performed for restenosis or other complication involving the target lesion. The length of the target lesion is inclusive of the treated section and the 5 mm proximal and distal to the treated section.16 ST was defined according to the ARC criteria.17 Events were adjudicated at the treating centers. Follow-up was performed at each treating center through dedicated clinical assessment, telephonic follow-up or formal queries to primary care physicians for both registries. Data regarding clinical events and follow-up were centrally reviewed and in case of unclear or doubtful reports, treating centers were contacted for clarification.
Subgroup analyses were performed for patients treated with provisional or 2-stents strategy for the distal ULM bifurcation.
Statistical analysis.
Continuous variables are presented as means ± standard deviation or median with the interquartile range and categorical variable are presented as frequency and percentage (%). Categorical variables were compared with the Fisher’s exact test. Parametric distribution of continuous variables was tested graphically and with the Kolmorogov Smirnov test, and the appropriate analyses were used in accordance with the results.
Given the longer follow-up of the patients included in the FAILS2 study, only events occurring in the first 250 days (the median value of follow-up of the SPARTA) were included, while the others were censored.
Multiple imputation was used to address missing data (http://www.jstatsoft.org/v45/i07/). Due to lack of randomization regards the choice of the stent for the ULM, a propensity score (PS) was generated for each patient from a multivariable logistic regression model based on pre-treatment covariates as independent variables with Stentys vs. second-generation DES as a binary dependent variable. Pairs of patients were derived using a greedy 2:1 (2 DES: 1 Stentys) matching with a caliper of width of 0.2 standard deviation of the logit of the PS (http://CRAN.Rproject.org/package=nonrandom). The quality of the match was assessed by comparing selected pre-treatment variables in propensity score–matched patients using the standardized mean difference, for which an absolute standardized difference of greater than 20% is suggested to represent meaningful covariate imbalance. A Cox regression model, stratified on the matched pairs and adjusted for interventional feature, was used to estimate the treatment effect (i.e. Stentys vs. DES) on the outcomes of interest. This approach accounts for the within-pair homogeneity by allowing the baseline hazard function to vary across matched sets (http://CRAN.R-project.org/package=survival). All p-values <0.05 were considered to indicate statistical significance. Moreover also Cox multivariate analysis were performed on overall dataset before propensity score with matching with MACE as dependent variable and all clinical and angiographic features with a difference of p <005 at univariate analysis, along with kind of stents.
All statistical analyses were performed using R Statistical Software (version 3.2.3; R Foundation for Statistical Computing, Vienna, Austria) and SPSS 21.0 (IBM, Armonk, NY, USA).
RESULTS.
One hundred and fifty one patients were treated for ULM lesions with Stentys (out of 278 patients with sirolimus-eluting Stentys included in the SPARTA registry) and 1270 from the FAILS-2 registry with second-generation DES (Figure 1). Baseline features before propensity score are reported in Supplementary Table 1. Patients treated with Stentys reported a lower prevalence of previous MI and were more frequently admitted with a diagnosis of unstable angina or non-STEMI. From an interventional point of view, Stentys patients were less frequently treated by radial access, presented more frequently a stenosis of the distal ULM and less frequently a trifurcated ULM and reported a lower rate of 2-stent treatment of the ULM bifurcation (Supplementary Table 2). After 250 (170-340) days, the rate of MACE did not differ between patients treated with Stentys and with second-generation DES (9.8% vs. 11.5%, respectively p 0.54), as well as the rates of TLR on ULM (2.0% vs. 2.3%, p 0.81, Supplementary Table 3)
After propensity score with matching (Figure 1), 129 patients treated with Stentys and 258 with second-generation DES were included.
Baseline features were balanced, with a prevalence of women of 67% in both groups (Table 1 and Table 2). Most of the patients presented a distal ULM lesion (121, 94% v. 231, 92%, p 0.56). The frequency of provisional stenting strategy was similar (107, 83% vs. 207, 80%, p 0.52), while a marked vessel tapering was the most frequent reason to use Stentys (76%) and ectasia was the leading reason to use Stentys in the other patients. Regarding second-generation DES, everolimus-eluting stents were the most used (67%), followed by zotarolimus-eluting stents (13%).
curves (p 0.91). Moreover, at Cox multivariate analysis performed on overall population, use of Stentys did not impact on risk of MACE, OR 0.92: 0.52-1.6, 0.78, while only STEMI as clinical presentation did (2.1:1.1-3.5, p 0.03). Rates of TLR on the left main were similar (1.6% vs. 3.1%, p 0.36), as those on the LAD or LCX.
In the subgroup of patients treated with a 2-stent strategy for the ULM bifurcation, rates of MACE did not differ between Stentys and second-generation DES (7.0% vs. 5.9%, p 0.71), as well as those of TLR on ULM (4.5% vs. 3.9%, p 081, see Figure 4). Similarly, for ULM bifurcations treated with a provisional approach, the rate of MACE was 10% in both groups, without differences in TLR on the left main (0.9% vs. 2.9%, p 0.42, see
Figure 5). Rates of MI were higher in the Stentys group, both in overall analysis and in the
DISCUSSION
The main result of the present large, propensity-matched registry is that sirolimus-eluting, self-apposing Stentys stents can be safely and effectively adopted in the treatment of the ULM lesions. The rate of short and long-term adverse events at follow-up was not different when compared with currently commercially available second-generation DES.
The self-expanding Stentys stents, with their innovative design, may provide a valuable therapeutic option in several instances where the short-comings of conventional DES may pose some procedural challenges. Particularly, in the setting of the distal ULM, its ability to adapt to sudden caliber changes and to properly appose to ectatic or irregular vessel profiles can solve the problems related to the choice of the appropriate stent size18,19. For example, a 3.5/4.5 mm stent can accommodate in to a vessel with a caliber ranging from 3.5 to 6.5 mm. Moreover, the presence of “interconnectors” within the stent scaffold allows creating openings after the release of the stent and to easily access the side branches, a potentially advantageous feature in the treatment of the distal ULM.
Despite the promising features and early results,20 very few clinical data exist to date to support the use of the sirolimus-eluting Stentys stents in the ULM setting. Encouraging results have been provided for the previous and outdated paclitaxel-eluting Stentys stent21, while the present is the first study reporting long-term clinical results for the sirolimus-eluting Stentys stents on the ULM. Moreover, our study was conducted in a real-life, multicenter setting, outside of the controlled boundaries of randomized clinical trials, and it therefore reflects the results we would expect after the implantation of these stents in a routine clinical setting. The sirolimus-eluting Stentys stents tested in our analysis showed overall satisfactory clinical results and, more importantly, they reported a
DES, with similar rates of MACE and, more specifically, of TLR. The nitinol structure, coupled with a polysulphone polymer eluting sirolimus, which constitute the peculiarity of this stent, proved to be safe at both the short and long-term follow-up.
Stentys stents present a dedicated release system, different from the balloon-delivery systems of currently available DES. Of note, in the present study we included both the Stentys SES stent with the traditional Stentys release system and the more recent balloon-delivered Xposition Stentys. As previously reported,22,23 these peculiar release systems do not appear to determine significant implantation-related issues, as documented by the absence of early ST and early adverse events in the Stentys group.
Beyond than in female patients, the Stentys stents proved to be effective in several different clinical scenarios. The patients included in our analysis, particularly in the propensity matched groups, reported a relevant prevalence of cardiovascular risk factors and comorbidities. The clinical presentation varied, with more than half of the patients presenting with acute coronary syndromes. More than half of the patients underwent Stentys implantation via radial access, confirming the safety of this arterial access for the ULM treatment also with this peculiar device24. The sirolimus-eluting Stentys stents may therefore be safely used in various clinical contexts without an increased risk of adverse events at the short and long-term follow-up.
Study limitations
This study presents some limitations. First, the analysis of retrospectively collected data implies the introduction of several biases and a limited power to account for such biases, even if propensity score was performed to overcome this limitation. Second, despite the considerable sample size, the propensity-matched cohort could present inadequate power to detect some differences in the study outcomes. Third, choice of the
type of stent was left to the operator’s decision, as the study population is represented by patients coming from two distinct large, multicenter registries and therefore no randomization was performed. Last, a randomized controlled trial is the only kind of evidence allowing inferential aims.
Conclusions
The self-expanding, sirolimus-eluting Stentys stents may be safely and effectively adopted to treat ULM lesions, as they reported comparable rates of adverse cardiovascular events at follow-up as compared to second-generation DES. The Stentys stents may provide a valuable option for the treatment of ULM stenosis in several clinical scenarios, particularly in female patients.
1 Rodriguez AE, Fernandez-Pereira C, Mieres J, Mendoza J, Sartori F. Can We Improve the
Outcomes of Multivessel Disease Using Modified SYNTAX and Residual SYNTAX Scores? Curr Cardiol Rep 2017;19(3):20.
2 D'Ascenzo F, Presutti DG, Picardi E, et al. Prevalence and non-invasive predictors of left main or three-vessel coronary disease: evidence from a collaborative international meta-analysis
including 22 740 patients. Heart 2012;98(12):914-9.
3 Serruys PW, Morice MC, Kappetein AP, et al.; SYNTAX Investigators.. Percutaneous coronary
intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360(10):961-72
4 Espinola-Klein C, Rupprecht HJ, Erbel R, Nafe B, Brennecke R, Meyer J. Ten-year outcome
after coronary angioplasty in patients with single-vessel coronary artery disease and comparison with the results of the Coronary Artery Surgery Study (CASS). Am J Cardiol 2000;85(3):321-6
5 Gaudino M, Puskas JD, Di Franco A, et al. Three Arterial Grafts Improve Late Survival: A
Meta-Analysis of Propensity-Matched Studies. Circulation 2017;135(11):1036-1044.
6 D'Ascenzo F, Iannaccone M, Giordana F, et al. Provisional vs. two-stent technique for unprotected left main coronary artery disease after ten years follow up: A propensity matched analysis. Int J Cardiol 2016;211:37-42
7 Mahmoud AN, Elgendy IY, Mentias A, et al. Percutaneous coronary intervention or coronary
artery bypass grafting for unprotected left main coronary artery disease. Circ Cardiovasc Interv 2017 Mar 15; doi: 10.1002/ccd.26970
8 Byrne RA, Joner M, Kastrati A. Stent thrombosis and restenosis: what have we learned and
where are we going? The Andreas Grüntzig Lecture ESC 2014.Eur Heart J 2015;36(47):3320-31
9 Iannaccone M, D'Ascenzo F, Templin C, et al. Optical coherence tomography evaluation of
intermediate-term healing of different stent types: systemic review and meta-analysis. Eur Heart J Cardiovasc Imaging 2017;18(2):159-166
10 Kidawa M, Chiżyński K, Kacprzak M, Ledakowicz-Polak A, Zielińska M. Self expanding stentys
stent in daily routine use. Kardiol Pol 2017 Mar 29; doi: 10.5603/KP.a2017.0039
11 Silenzi S, Grossi P, Mariani L, Aimi A, Marchese P, Moretti L. A real world single centre
experience using the STENTYS self-expanding coronary stent. Int J Cardiol 2016;209:57-9
13 Smolka G, Wańha W, Roleder T, Pluta A, Ochała A. Treatment of left main coronary artery
stenosis with the STENTYS self-expandable drug-eluting stent - a pilot registry. Postepy Kardiol Interwencyjnej 2014;10(4):226-30
14 D'Ascenzo F, Chieffo A, Cerrato E, et al. Incidence and Management of Restenosis After
Treatment of Unprotected Left Main Disease With Second-Generation Drug-Eluting Stents (from Failure in Left Main Study With 2nd Generation Stents-Cardiogroup III Study). Am J Cardiol 2017;119(7):978-982
15 Thygesen K, Alpert JS, Jaffe AS, et al; ESC Committee for Practice Guidelines (CPG). Third
universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551-67
16 icks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP, Jaff
MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE, Smith EE, Targum SL. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data
Standards). J Am Coll Cardiol. 2015 Jul 28;66(4):403-69
17 Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, Steg PG, Morel MA, Mauri
L, Vranckx P, McFadden E, Lansky A, Hamon M, Krucoff MW, Serruys PW; Academic Research Consortium. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007 May 1;115(17):2344-51
18 Montefusco A, Gili S, D'Ascenzo F, Omedé P, Moretti C. Minding the gap between left main and
branch vessels: Second-generation self-apposing, balloon-expandable, drug-eluting stent on trifurcated unprotected left main. Int J Cardiol 2016;214:151-3
19 Buccheri D, Orrego PS, Cortese B. Drug-eluting stent treatment of left main coronary artery
disease: the case for a sirolimus-eluting, autoexpandable alternative. An optical coherence tomography analysis. Int J Cardiol 2015;199:119-20
20 van Geuns RJ, Yetgin T, La Manna A, et al. STENTYS Self-Apposing sirolimus-eluting stent in
ST-segment elevation myocardial infarction: results from the randomised APPOSITION IV trial. EuroIntervention 2016;11(11):e1267-74
21 Briguori C, Visconti G, Donahue M, et al. The STENTYS® paclitaxel-eluting stent in the
treatment of unprotected distal left main. Catheter Cardiovasc Interv 2015;86(3):E131-9.
22 Amoroso G, van Geuns RJ, Spaulding C, et al. Assessment of the safety and performance of the
STENTYS self-expanding coronary stent in acute myocardial infarction: results from the APPOSITION I study. EuroIntervention 2011;7(4):428-36
24 Gili S, D’Ascenzo F, Di Summa R, et al. Radial Versus Femoral Access for the Treatment of Left
Main Lesion in the Era of Second-Generation Drug-Eluting Stents. Am J Cardiol 2017 Apr 12; doi: 10.1016/j.amjcard.2017.03.262
FIGURE LEGENDS
Figure 1. Study Design (DES-II, second-generation drug-eluting stent; ULM, unprotected
left main)
Figure 2. Study outcomes after propensity score with matching (DES-II,
Figure 3. Kaplan-Meier curves showing freedom from major adverse cardiovascular
events (MACE; blue: Stentys; red: second-generation drug-eluting stents).
Figure 4. Study outcomes after propensity score with matching in the sub-group of
patients with distal unprotected left main stenosis treated with a 2-stent strategy (DES-II, second-generation drug-eluting stent; LAD, left anterior descending coronary artery; LCX, circumflex coronary artery; LM, left main coronary artery; MACE, major adverse
cardiovascular events; MI, myocardial infarction; ST, stent thrombosis; TLR, target lesion revascularization)
Figure 5. Study outcomes after propensity score with matching in the sub-group of
patients with distal unprotected left main stenosis treated with a provisional strategy (DES-II, second-generation drug-eluting stent; LAD, left anterior descending coronary artery; LCX, circumflex coronary artery; LM, left main coronary artery; MACE, major adverse cardiovascular events; MI, myocardial infarction; ST, stent thrombosis; TLR, target lesion revascularization)
