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European Heart Journal Advance Access published online on November 5, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn479
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Angiographic and clinical outcome of invasively managed patients with thrombosed coronary bare metal or drug-eluting stents: the OPTIMIST study

Francesco Burzotta1,*, Antonio Parma2, Christian Pristipino3, Alessandro Manzoli4, Flavia Belloni5, Gennaro Sardella6, Stefano Rigattieri7, Alessandro Danesi8, Pietro Mazzarotto9, Francesco Summaria10, Enrico Romagnoli1, Francesco Prati4, Carlo Trani1 and Filippo Crea1

1 Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
2 U.O. of Interventional Cardiology, A.O. San Camillo-Forlanini Hospital, Rome, Italy
3 Department of Cardiology, San Filippo Neri Hospital, Rome, Italy
4 Catheterization Laboratory, S. Giovanni Hospital, Rome, Italy
5 Department of Cardiology, San Pietro FBF Hospital, Rome, Italy
6 Department of Cardiovascular and Respiratory Sciences, Policlinico Umberto I, ‘La Sapienza’ University, Rome, Italy
7 UOSD Emodinamica e Cardiologia Interventistica, ‘Sandro Pertini’ Hospital, Rome, Italy
8 U.O.C. of Cardiology, S. Spirito Hospital, Rome, Italy
9 U.O. Cardiologia Invasiva e Interventistica Endovascolare, S. Carlo—I.D.I. Hospital, Rome, Italy
10 Catheterization Laboratory, Division of Cardiology, Policlinico Casilino Hospital, Rome, Italy

Received 4 January 2008; revised 1 September 2008; accepted 9 October 2008.

* Corresponding author. Tel: +39 0349 4295290, Fax: +39 06 3055535, Email: f.burzotta{at}rm.unicatt.it


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 
Aims: Stent thrombosis (ST) is a major complication of percutaneous coronary interventions (PCIs). An invasive management by re-PCI is the commonly adopted treatment for ST, but data on outcome are limited.

Methods and results: We performed a 2-year multicentre registry enrolling consecutive patients with angiographically confirmed ST undergoing PCI. The primary angiographic endpoint was optimal angiographic reperfusion (TIMI 3 + blush grade 2 or 3). The primary clinical endpoints were death and major adverse coronary and cerebrovascular events (MACCEs) at 6 months. A total of 110 patients underwent 117 urgent PCI during the study. Patients with drug-eluting stent (DES) thrombosis, compared with those with bare metal stent (BMS) thrombosis, exhibited a higher rate of late or very late presentation and of anti-platelet therapy withdrawal. Optimal angiographic reperfusion was obtained in 64% of the patients. Death and MACCE rates at 6 months were 17 and 30%, respectively. Clinical outcome was similar for BMS and DES thrombosis. Very late ST, implantation of stent during PCI for ST, and failure to achieve optimal angiographic reperfusion were the independent predictors of 6-month mortality.

Conclusion: DES and BMS thromboses have different clinical features, but a similar poor outcome. Indeed, PCI for ST is associated with a low rate of reperfusion and to a high rate of death and MACCE, calling for action in order to prevent its occurrence and to improve its management.

Key Words: PCI • Stent • Stent thrombosis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 
Stent thrombosis (ST) is a major complication limiting the clinical efficacy of percutaneous coronary interventions (PCIs). After stent implantation, ST is reported to happen with an early incidence ranging from 0.5 to 2.0%.1–5 As the number of stent-based PCIs is expanding worldwide, the absolute number of patients experiencing ST is expected to increase. Moreover, the introduction of drug-eluting stents (DESs) has been reported to be associated with a 0.6% rate of late and very late ST per year,6 so that ST risk might be extended over time and increased compared with bare metal stents (BMSs).7–10

An early invasive strategy by urgent re-PCI represents the most adopted strategy to manage patients presenting with ST. However, despite its evident clinical relevance, available data on ST derive from substudies3 or single-centre experiences.11–14

Thus, we conceived a multicentre registry enrolling consecutive patients with angiographically confirmed ST undergoing PCI aimed at providing an updated, detailed description of the angiographic and clinical outcome of patients with ST treated by PCI.15


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 
Study design
The Outcome of PCI for Stent-Thrombosis Multicentre Study (OPTIMIST) is a registry enrolling consecutive patients with ST treated by PCI. The study protocol has previously been published.15 Briefly, the recruiting period comprised a fixed 2-year time between 1 January 2005 and 31 December 2006. The study protocol was conceived in October 2005, and prospective enrolment of patients started in January 2006. Each centre, to be activated for the study, had to warrant (fully describing the search process as well as the characteristics of the internal database) ability to provide detailed clinical and procedural data (including a copy of the cine films and the 6-month outcomes), regarding all patients with ST treated with PCI since the start of the retrospective arm study period. Eleven centres, all located in the urban area of Rome and listed in the Appendix section, met these requirements and entered the study.

The study protocol complied with the Declaration of Helsinki and was approved by the Ethics Committee of the coordinating centre. Informed consent to both the PCI procedure and the clinical follow-up has been obtained for each patient enrolled in the study.

Inclusion and exclusion criteria
Included patients, irrespective of type of stent previously implanted and date of its implantation, had to have angiographically confirmed ST of a previously implanted stent associated with rest angina or new ischaemic ECG changes or cardiac biomarker elevation and have undergone an attempt of PCI on ST as target lesion within hospitalization.

The exclusion criteria were surgical or medical management (i.e. no attempt of PCI) of ST and development of ST during stent implantation (i.e. intraprocedural ST).

Clinical data set and clinical outcome measures
A structured case report form has been created to collect the data regarding the patient profile (including the presence of oncological and haematological diseases and timing for previous interruption of antiplatelet drug therapy), the main characteristics of the procedure in which the stent was implanted (date, bifurcation involvement, and type and number of the stent implanted), and the detailed description of the index PCI (peri-intervention medical therapy, target lesion site, number of diseased vessels, presence of severe calcifications, stent underexpansion, revascularization strategy including balloon dilation, additional stent implantation, and use of thrombectomy or distal filter protection). The following ARC definitions16 of ST according to the time interval between implantation and thrombosis of the stent were adopted: ‘early’, 0–30 days; ‘late’, >30 days to 1 year; and ‘very late’, >1 year.

All major adverse coronary and cerebrovascular events (MACCEs) have been recorded at 30 days and at 6 months. MACCE comprised death, myocardial infarction (MI), target vessel revascularization (by either repeat PCI or coronary artery bypass graft surgery), and cerebrovascular accident. MI was defined as ischaemic symptoms and/or ischaemic ECG changes + elevation of creatine-kinase MB or troponin T or I levels above the normal laboratory values.17 Cerebrovascular accident was defined as a specific neurological dysfunction with morphological substrate confirmed by computer tomography or nuclear magnetic resonance imaging. The following ARC definitions16 of recurrent ST during follow-up were adopted: ‘definite’, angiography- or autopsy-confirmed ST; ‘probable’, any unexplained death within first 30 days or any MI in the territory of the stent and in the absence of any other obvious cause; and ‘possible’, any unexplained death after 30 days.

Angiographic analyses
All cine films of PCI on ST were sent to the coordinator centre, where baseline and final post-PCI views were selected and extracted. Then, these selected views only were sent to the core laboratory for centralized, blind analyses. This process was in the opinion of the OPTIMIST's steering committee the best way to warrant angiographic analyses fully independent of knowledge of PCI strategy and course. The validated core laboratory responsible for the angiographic analyses was the Rome Heart Research, Rome, Italy. Coronary angiograms have been analysed before intervention and at the end of the procedure to assess:

  • anterograde coronary flow according to standard Thrombolysis In Myocardial Infarction (TIMI) criteria;18
  • occurrence of angiographic distal embolization defined as an occlusion with abrupt ‘cut-off’ appearance at angiography of a branch of the infarct-related artery distal to the culprit lesion;19
  • corrected TIMI frame count (CTFC) according to Gibson et al.;20
  • thrombus score (TS) according to the TIMI study group21 (0 = no angiographic characteristics of thrombus are present; 1 = possible thrombus is present, with angiography characteristics such as reduced contrast density, haziness, irregular lesion contour, or a smooth convex ‘meniscus’ at the site of total occlusion suggestive but not diagnostic of thrombus; 2 = definite thrombus, with greatest dimensions ≤1/2 the vessel diameter; 3 = definite thrombus, with greatest linear dimension >1/2 but <2 vessel diameters; 4 = definite thrombus, with the largest dimension ≥2 vessel diameters; 5 = total occlusion);
  • myocardial blush grade (MBG) according to van't Hof et al.;22
  • quantitative coronary angiography analysis (CMS Medis Imaging System, Wallingford, CT, USA) of the target lesions before and after PCI according to previously validated methods.23
Before starting the angiographic analyses, the operators of the core laboratory assigned a quality score to each film, according to the chances to appropriately assess CTFC and MBG; films with insufficient score were excluded from the MBG and CTFC analyses (see Burzotta et al.15 for scoring system details).

Primary endpoints
The pre-defined primary angiographic endpoint was the rate of ‘optimal angiographic reperfusion’ defined as the combination of TIMI 3 with MBG 2 or 3.24

The pre-defined primary clinical endpoints were death and MACCE rate at 6 months.

Sources for assessment of numbers of procedures performed by enrolling centres
The total number of procedures with any stent implantation (DES or BMS) and the total number of urgent (primary or rescue) PCIs for ST-elevation acute MI (STEMI) performed by each centre during the study period were obtained from the official website of the Italian Society of Interventional Cardiology (SICI-GISE, www.gise.it), which prospectively collects data from all Italian catheterization laboratories belonging to the society. PCIs carried out in 2004 were used for the sample size calculation,15 whereas PCIs in 2005 and 2006 were used for the current analyses.

Statistical analyses
The sample size of the study has been calculated to enrol more than 100 patients.15 In particular, we observed that the hospitals participating in the study performed together about 6000 PCIs during 2004: thus it has been estimated that at least 12 000 PCIs have been performed during the 2-year (2005–06) study period. Then, we anticipated a 1.5% rate of ST and a rate of attempted PCI on ST of 60%, thus anticipating the enrolment of 108 patients in the study. According to the study design, as a preliminary validation stage of the overall study cohort, baseline clinical (risk factors and clinical presentation) and angiographic characteristics (number of disease vessels, target vessel, and pre-intervention TIMI flow) of retrospectively enrolled patients were planned to be compared with those of the prospectively enrolled patients.15

Pre-intervention clinical, angiographic, and procedural characteristics, angiographic results, and clinical follow-up data are presented for the whole population and for subgroups of patients with BMS and DES thrombosis.

Continuous variables are presented as median and interquartile ranges and compared by the Student's t-test or Wilcoxon–Mann–Whitney test as appropriate. Categorical variables are summarized as counts and percentages and compared using the {chi}2 test or Fisher's exact test when appropriate. The incidence of events over time was studied with the use of the Kaplan–Meier method and compared with log-rank tests.

Univariable and multivariable logistic regression analyses were used to estimate the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). As anticipated in the study protocol,15 the baseline clinical and angiographic and procedural variables that affected the univariable analysis (cut-off for entry 0.10) were included in the multivariable models to assess independent predictors of the primary study endpoints (failure to achieve optimal angiographic reperfusion, 6-month death, and 6-month MACCE). The goodness-of-fit testing (Hosmer and Lemeshow {chi}2) was used to assess how well the final model was calibrated. The predictive value of the variables that emerged from the stepwise analysis was confirmed in a multivariable analysis model corrected for a series of factors that are known, on epidemiological ground, to be relevant predictors of myocardial reperfusion (sex, age, diabetes mellitus, renal failure, STEMI at presentation, IIb/IIIa inhibitors administration, three-vessel disease, target vessel, TIMI flow 0–1, cardiogenic shock, thrombectomy, slow flow or transient no-reflow, post-procedural thrombus-score >1, distal embolization, and failure to achieve optimal angiographic reperfusion) and of clinical outcome (sex, age, diabetes mellitus, renal failure, STEMI at presentation, very late ST, type of thrombosed stent, double simultaneous ST in different vessels, severe calcification, IIb/IIIa inhibitors administration, three-vessel disease, target vessel, TIMI flow 0–1, cardiogenic shock, thrombectomy, stent implantation during PCI for ST, slow flow or transient no-reflow, post-procedural thrombus score >1, distal embolization, and failure to achieve optimal angiographic reperfusion).

A two tailed P-value less than 0.05 was established as the level of statistical significance for all tests. Analyses were carried out using SPSS for Windows 12.0 (SPSS, Chicago, IL, USA).

Role of the funding source
There was no funding source for the present study.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 
Study population
A total of 110 patients underwent PCI for ST in the 2-year protocol period and constituted the study population. No significant differences in either clinical, angiographic, or procedural characteristic were observed between patients enrolled prospectively (n = 58) or retrospectively (n = 52), so that the study population was considered as a whole. The baseline clinical and angiographic characteristics of the study patients are reported in Table 1. Most of the patients presented with STEMI (73%) and occluded (TIMI 0–1) arteries before interventions (85%). High risk clinical features such as diabetes mellitus, renal failure, and cardiogenic shock were present in 30, 20, and 17% of the patients, respectively. Seven patients (6%) had a second episode of ST treated by PCI during the study period (so that the number of PCI required for ST was 117 during the study) and three patients, previously treated by multivessel stenting, presented with simultaneous thrombosis of stents placed in two different vessels. The rate of IIb/IIIa inhibitor use was very high (71%), whereas a minority of patients (7%) were treated by thrombolytic drugs (in referring hospitals) before the rescue PCI in the enrolling hospitals.


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  		Table 1 Baseline clinical and angiographic characteristics of the overall study population and of subgroups of patients presenting with drug-eluting or bare-metal stent thrombosis

 
Prevalence of percutaneous coronary intervention for stent thrombosis
During the study period, the OPTIMIST centres performed a total of 12 280 PCIs with stent implantation: 7318 (60%) with at least one DES implantation and the remaining 4962 (40%) with BMS implantation. Among all stenting procedures, the observed rate of urgent procedures for ST was 0.95%. No significant difference was observed between DES and BMS in the ratio between number of PCI for ST and number of PCI with the corresponding type of stent implantation: 0.85% (62 of 7318) for DES vs. 1.05% (52 of 4962) for BMS; P = 0.24.

During the study period, 89 of 2484 primary or rescue PCIs were performed in patients with ST presenting with STEMI. Accordingly, ST accounted for 3.58% of the urgent PCI for STEMI during the 2-year study period.

Characteristics of drug-eluting vs. bare metal stent thrombosis
The type of thrombosed stent was DES in 55 (50%) patients (27 sirolimus-eluting stents, 16 paclitaxel-eluting stents, five tacrolimus-eluting stents, one zotarolimus-eluting stent), BMS in 43 (39%) patients, and an unascertained type of stent in 12 (11%) patients. Clinical and angiographic characteristics of patients with DES or BMS thrombosis are reported in Table 1. Among all investigated clinical features, patients with DES thrombosis had significantly younger age, more common late or very late presentation, higher prevalence of diabetes mellitus, and platelet therapy withdrawal within the last 15 days when compared with those treated with BMS (Table 1). Moreover, thrombosed DESs had a smaller diameter and were more often located on left anterior descending artery or at bifurcation sites when compared with thrombosed BMSs and all other angiographic features being similar (Table 1).

Procedural details and angiographic outcome of percutaneous coronary intervention for stent thrombosis
PCI procedure details are reported in Table 2. The mainly adopted strategy of PCI was balloon dilation. Adjunctive devices were used in a subgroup of patients and included thrombectomy (30%), whereas only 3% of the patients underwent distal filter protection. Thrombectomy was performed using mainly thrombus-aspirating catheters (30 of 33 patients), whereas a minority (3 of 33) received Angiojet (Possis Medical Inc., Minneapolis, MN, USA) rheolytic thrombectomy. During the procedure, 45% of the patients were treated by additional stent implantation (Table 2). As Table 3 shows, patients who received stent implantation during PCI for ST did not differ significantly from the remaining patients.


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  		Table 2 Procedural characteristics and angiographic results of the whole study population and of subgroups of patients presenting with drug-eluting or bare metal stent thrombosis

 

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  		Table 3 Key pre-intervention characteristics of patients treated or not by stent implantation during PCI for stent thrombosis

 
The angiographic results obtained after PCI are reported in Table 2. The overall quality of cine films was satisfactory as the core laboratory was able to judge post-PCI TIMI flow in all procedures and MBG and CTFC in the majority of them (95% pre-PCI and 83% post-PCI). Failure to re-establish anterograde flow (post-PCI TIMI 0–1) occurred in as high as 12%, whereas optimal angiographic reperfusion (TIMI 3 + MBG 2 or 3) was obtained in 64% of the patients. As shown in Table 4, using the stepwise multivariable analysis (which included the following predictors emerged from the univariable analysis: diabetes mellitus, current smoker, hypertension, double simultaneous ST in different vessels, three-vessel disease, target vessel, cardiogenic shock, distal embolization, and post-procedural thrombus score >1), the variables that were significantly associated with failure to obtain optimal angiographic reperfusion were distal embolization (OR 23.3, 95% CI 1.3–40.0), cardiogenic shock (OR 10.7, 95% CI 2.0–56.9), target left anterior descending artery (OR 7.0, 95% CI 1.7–29.1), post-procedural TS >1 (OR 5.7, 95% CI 1.4–22.9), and multivessel disease (OR 5.06, 95% CI 1.4–18.5). The non-significant Hosmer–Lemeshow goodness-of-fit P-value (0.56) indicated that the model was adequate.


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  		Table 4 Predictors of primary angiographic (lack of optimal angiographic reperfusion = TIMI 3+MBG 2 or 3) and clinical (death and major adverse coronary or cerebrovascular events) endpoints at 6 months emerging from the multivariable analysis

 
Clinical outcome of percutaneous coronary intervention for stent thrombosis
The completeness of follow-up was 100% at 30 days and 95% at 6 months (five patients lost to late follow-up). The number of adverse events observed during follow-up is reported in Table 5. The death rate was 12% at 30 days and 17% at 6 months. MACCEs observed during follow-up were mainly due to cardiac events (one stroke only) and occurred in as high as 21% of the patients at 30 days and in 30% at 6 months.


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  		Table 5 Clinical outcome at 30-day and 6-month observed in the overall study population and in subgroups of patients presenting with drug-eluting or bare metal stent thrombosis

 
The type of thrombosed stent (DES or BMS) did not influence the clinical outcome: survival curves free of death and MACCE for BMS and DES thrombosis are reported in Figure 1. Conversely, the stepwise multivariable analysis (which includes the following predictors emerged from univariable analysis: cardiogenic shock, very late ST, double simultaneous ST in different vessels, severe calcification, stent implantation during PCI for ST, slow flow or transient no-reflow, post-procedural thrombus score >1, and failure to achieve optimal angiographic reperfusion) showed that the independent predictors of 6-month mortality were very late presentation of thrombosis (OR 9.3, 95% CI 1.2–70.7), implantation of stent during PCI for ST (OR 6.1, 95% CI 1.1–16.6), and failure to achieve an optimal angiographic reperfusion (OR 4.6, 95% CI 1.3–16.4) (Table 4). These data did not deviate significantly from the logistic model, as indicated by the non-significant Hosmer–Lemeshow goodness-of-fit test (P = 0.87).


Figure 1
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  		Figure 1 Kaplan–Meier survival curves for patients who presented with thrombosis of drug-eluting stents and those who presented with thrombosis of bare metal stents. (A) shows overall survival and (B) freedom from MACCE.

 
Survival curves according to the timing of ST presentation (early, late, and very late), to further stent implantation during index PCI, and to the achievement of optimal angiographic reperfusion at the end of the procedure are reported in Figure 2. Stepwise multivariable analysis (which includes the following predictors emerged from univariable analysis: renal failure, very late ST, two or more overlapping stents, three-vessel disease, target vessel, severe calcification, TIMI flow 0–1, stent implantation during PCI for ST, and failure to achieve optimal angiographic reperfusion) also showed that the only independent predictors of 6-month MACCE (Table 4) were stent implantation during PCI for ST (OR 5.3, 95% CI 1.7–16.4), three-vessel disease (OR 4.9, 95% CI 1.2–21.0), failure to achieve optimal angiographic reperfusion (OR 4.5, 95% CI 1.5–13.5), and two or more overlapping stents (OR 4.4, 95% CI 1.4–13.6). The non-significant Hosmer–Lemeshow goodness-of-fit P-value (P = 0.61) indicated that the model was adequate.


Figure 2
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  		Figure 2 Kaplan–Meier survival curves after PCI for stent thrombosis. (A) shows overall survival of patients who received or not implantation of stent during PCI for stent thrombosis; (B) shows overall survival of patients who had or not had post-PCI optimal angiographic reperfusion (TIMI 3 + MBG 2 or 3); (C) shows overall survival of patients with different types of stent thromboses according to timing (early, late, and very late).

 
Applying the ARC criteria for ST, the overall 6-month rate of recurrent ST was 16.2% (definite: 6.7%, probable: 5.7%, and possible: 3.8%), with a median interval between PCI for ST and recurrent ST of 45 days (range: 2–175 days). Interestingly, a higher rate of recurrent ST at 6 months was observed in patients who received stent implantation during PCI for ST compared with the remaining patients (26 vs. 10%, respectively, P = 0.04), whereas the type of implanted stent during PCI for ST did not influence the recurrent ST (20% in DES vs. 30% in BMS, P = 0.45).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 
In the present report, we describe the results of the first multicentre registry assessing the angiographic and clinical outcomes of patients with angiographically confirmed ST undergoing urgent PCI in the contemporary DES era. This was the result of a cooperative effort performed by a series of different hospitals well distributed in the same urban area. No sponsorship was endorsed to avoid any possible source of bias in data collection, analysis, and interpretation. Moreover, the study design was published as a full paper before the first data analysis is undertaken.

Overall, the study allowed to assess: (i) the prevalence of PCI on angiographically confirmed ST; (ii) the comparison between DES and BMS thrombosis presentation and outcome; and (iii) the angiographic and the 6-month clinical outcome of invasively managed ST.

Prevalence of percutaneous coronary intervention for angiographically confirmed stent thrombosis
During a 2-year period, we found that PCI for angiographically confirmed ST occurred in less than one every 100 stent implantation procedures. The ratio between stent implantation procedure and PCI for ST was not different between BMSs and DESs. This figure is in keeping with other reports, showing the absence of significant differences in the ST rate between them.25 However, as the length of study recruitment and follow-up were limited and DES might mainly affect late thrombotic events, the hypothesis of an increased very-late DES-related hazard26 cannot be discarded. Interestingly, although angiographically confirmed ST was a low frequency event, it accounted for 3.6% of the primary or rescue PCI (as in 73% of the cases ST caused STEMI) performed by the study centres.

Comparison between drug-eluting and bare metal stent thrombosis presentation and outcome
The comparison between DES and BMS thrombosis showed some differences in the clinical, procedural, and angiographic characteristics. Patients with DES thrombosis, compared with those with BMS, were significantly younger, exhibited higher prevalence of diabetes mellitus, and presented ST more frequently in left anterior descending artery, small vessels, and bifurcated lesions. These associations are difficult to interpret. They might simply be the result of a selection bias in favour of DES usage when such conditions are present. In contrast, the significantly higher prevalence of platelet therapy withdrawal within last 15 days and of late and very late presentation found in DES, compared with BMS thrombosis, might be causally related to the stent type. Indeed, a series of observations from studies with different designs strongly suggest that premature antiplatelet therapy discontinuation may play a key role in DES thrombosis3,8,27–29 and that late and very late STs are more often observed after DES implantation when compared with BMS implantation.16,26 These data reinforce the perception that patient compliance and the absence of contraindications to dual anti-platelet treatment should be pivotal during the decision-making process of stent selection. Moreover, during future assessments of safety and efficacy, individual patient follow-up after DES implantation should probably be extended well beyond the classical 6- or 9-month study period adopted in the BMS era.

Outcome of invasively managed stent thrombosis
Our study shows that ST represents a high-risk clinical scenario. The patient presenting with ST has known history of ischaemic heart disease, has been previously exposed to the risk of peri-PCI myonecrosis, and has sometimes developed conditions that may interfere with his compliance or tolerance to medical therapies. Moreover, the target lesion during ST is composed of a variable (and usually huge) amount of thrombus and is often complex (including bifurcation, restenosis, and diffuse disease). Finally, the initial stent deployment might have been suboptimal.2,12,30,31 In the DES era, all these issues are likely to be exacerbated by the inclusion of difficult coronary anatomies and patients (previously usually not considered for percutaneous treatments). All these factors may contribute to explain the poor angiographic and clinical results observed in the present study.

Overall, the observed clinical outcome of patients with ST in this study is disappointing, as it is associated with both a high early mortality (12% at 30 days) and the occurrence of further adverse events during the later follow-up period leading to 17% death rate and 30% MACCE rate at 6 months. Such figures are in line with the results of early smaller reports,11–14 as well as with that of a recent Spanish registry.32 Of note, the outcome was similar for ST caused by BMSs or DESs. Furthermore, based on the ARC criteria, the rate of recurrent ST at 6 months was remarkable (16%). In a recent intravascular ultrasound study, it has been suggested that re-PCI on thrombosed stent is able to correct important technical difficulties (including stent underexpansion and stent struts ‘malapposition’ to the vessel wall) that could have occurred at the time of stent implantation.33 It follows that in patients presenting with recurrent ST, persistent thrombogenesis at the stent site is more likely to reflect a systemic pro-thrombotic state rather than a local phenomenon. Some systemic features recently recognized as risk factors for ST such as hypersensitivity to the different stent components34 and low responsiveness to anti-platelet drugs35 may also play a role for persistent thrombogenesis.

Despite a liberal adoption of all the most effective resources of contemporary invasive management (high rates of IIb/IIIa inhibitor administration, systematic intra-aortic balloon pumping in patients with cardiogenic shock, and a high usage of thrombectomy devices), the angiographic markers of no reflow were often present after PCI. Such suboptimal post-PCI angiographic results are clinically relevant as they may translate in a poor outcome. Indeed, in our study, lack of a optimal angiographic reperfusion was independently associated with worse 6-month survival. As a consequence, the direct relation between post-PCI reperfusion assessed by blush grade and survival previously reported in patients with de novo occlusion of native coronary arteries22,24 can be extended to this high-risk patient subset. In addition to lack of optimal reperfusion, implantation of a stent during PCI for ST and very late presentation of ST were found to independently predict 6-month survival. The implantation of another stent during PCI for ST is frequently required as a bail-out option to manage dissections, plaque or thrombus shift outside the previously implanted stent and previously untreated adjacent atherosclerotic disease. However, the strong relation with late mortality and MACCE observed in our study as well as in another independent study32 deserves attention. It can be speculated that patients who developed ST represent a selected subgroup with high tendency to thrombus formation over metallic stent struts, so that further augmentation of metal amount is not well tolerated. Taken together with the positive influence on late mortality associated with angiographic reperfusion, these data suggest that during PCI for ST, interventionalists should focus on the goal of achieving optimal myocardial reperfusion rather than an optimal residual stenosis by further stent implantation. Finally, the observed increased risk associated with very late presentation of thrombosis has not been previously reported. However, it is worth noting that, due to its rarity, the investigation on the mechanisms and outcome of very late ST are actually in its former stages,36 and the present observation calls for further studies on this emerging clinical entity.

Study limitations
A major limitation of the present study is represented by the inclusion of a remarkable number of patients retrospectively enrolled: as sources of confounding factors and bias are more common in retrospective data collections, their occurrence cannot be excluded. Nevertheless, as no appreciable difference between retrospectively and prospectively collected patients was detected in the preliminary validation step of the analyses, the accuracy of retrospective cohort recruitment is supported.

Another important limitation of the present study is represented by the absence of IVUS data as technical factors such as strut fracture, stent underexpansion, or even stent overexpansion leading to ST cannot be ascertained by angiography. Moreover, resistance to antiplatelet therapy and patient's compliance to antiplatelet therapy during follow-up were not assessed so that the relation between drug resistance or incompliance and risk of re-thrombosis could not be investigated.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Appendix: list of institutions...
 Acknowledgements
 References
 
Within its limitation of being an observational investigation, the present study provides unique information about the prevalence, the procedural characteristics, and the outcome of patients with angiographically confirmed ST treated by urgent PCI in the contemporary DES era. The staggering high rate of mortality and morbidity associated with ST, even when treated by primary PCI in high volume centres, calls for action in order to prevent its occurrence and further improve its treatment. With regard to the first issue, the best prevention perhaps remains to avoid PCI when it is not indicated, as in oligo-asymptomatic stable patients.37 With regard to treatment, the current study provides useful information on possible strategies to improve PCI for ST, including a greater emphasis on myocardial reperfusion than on residual stenosis.


   Appendix: list of institutions participating in the study
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix: list of institutions...
Acknowledgements
 References
 
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy (Prof. Giovanni Schiavoni); U.O. of Interventional Cardiology, A.O. San Camillo-Forlanini Hospital, Rome, Italy (Dr Roberto Violini); Department of Cardiology, San Filippo Neri Hospital, Rome, Italy (Dr Giuseppe Richichi); Catheterization Laboratory, S. Giovanni Hospital, Rome, Italy; Department of Cardiology, San Pietro FBF Hospital, Rome, Italy (Dr Roberto Serdoz); Department of Cardiovascular and Respiratory Sciences, Policlinico Umberto I, ‘La Sapienza’ University, Rome, Italy (Dr Riccardo Colantonio); UOSD Emodinamica e Cardiologia Interventistica, ‘Sandro Pertini’ Hospital, Rome, Italy (Dr Paolo Loschiavo); U.O.C. of Cardiology, S. Spirito Hospital, Rome, Italy (Dr Alessandro Ferraioni); U.O. Cardiologia Invasiva e Interventistica Endovascolare, S. Carlo - I.D.I. Hospital, Rome, Italy (Dr Francesco Gemelli); Catheterization Laboratory, Division of Cardiology, Policlinico Casilino Hospital, Rome, Italy (Dr Ernesto Lioy).


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
References
 
The authors are indebted to Giovanni Paolo Talarico who has been responsible for the organization of the electronic database of the study.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Appendix: list of institutions...
 Acknowledgements
 References
 

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