Secondary prevention and antithrombotic management are key issues for outpatients with stable coronary artery disease (CAD).¹ Any physician's goal is, indeed, to protect these patients from recurrent ischemic events and their related mortality, especially from incident myocardial infarction (MI). A critical evaluation of the residual risk of incident MI in patients with stable CAD (i.e., several years after the last event) is therefore crucial. In addition, since the widespread use of first-generation drug-eluting stents (DES), very late stent thrombosis (ST) has been shown to be something to worry about in stabilized patients.² To date, a large proportion of patients with stable CAD have a history of percutaneous coronary intervention (PCI) with, in most cases, implantation of at least one coronary stent. In these patients, the contribution of very late ST to incident MI may be of importance.

After first-generation DES appearance, initial publications of late outcomes (4-5 years maximum) have shown that very late ST (i.e., occurring >1 year after stent implantation) is a possible (although uncommon) complication of PCI and reported a linear risk of definite very late ST around 0.5-0.6% per year.^3-6 More recently, the 10-year follow-up of the SIRTAX (Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization) trial (n = 1,012 patients) showed that the risk of very late ST after implantation of first-generation DES was 0.67% per year between 1 and 5 years and 0.23% per year between 5 and 10 years.⁷ In the past, literature on very late ST was therefore mainly issued from the follow-up of prospective cohorts/registries of patients undergoing first-generation DES implantation mostly in academic and/or expert centers.^3-5 Although these studies are useful to assess yearly rates of stent thrombosis and to compare this information among several types of stents, they might be limited when it comes to analyzing the importance of very late ST far after (>5 years) the initial stent implantation in a real-life setting (unselected patients and broad centers, different stent types including new-generation DES, and wide indications). Last year, we attempted to report the importance of this phenomenon in a real-life multicenter registry of stable CAD outpatients: the 5-year CORONOR (Suivi d'une cohorte de patients COROnariens stables en region NORd-Pas-de-Calais) registry.⁸ This registry included 4,184 stable CAD outpatients with no exclusion criteria in the north region of France, among whom 2,883 had prior stent implantation at least 1 year before inclusion (median 4 years [Inpatient Quality Indicator = 2-7]). In this registry, we reported a linear residual risk of MI of ≈1% per year, in accordance with the previous literature, and we found out that very late ST accounted for 1/5 of all incident MI events (0.15% per year). This rate of 0.15% per year was therefore similar to (although a bit lower than) the one observed in academic/expert centers. Of note, the time interval between PCI and very late ST was long (median 5.2 years with a maximum of 17 years) in our study, and the risk of very late ST appeared to be constant over time (Figure 1).

Figure 1

Of main importance, stent thrombosis has been related to poor outcome in the past.^6,9 However, to the best of our knowledge, the CORONOR study was the first to directly compare the mortality of very late ST with the mortality of MI at non-stented site within the same cohort. After adjustment on confounders, the mortality after very late ST was 4 times higher (crude rate of 18% per year) than the one observed after MI related to a non-stented site, highlighting the importance to avoid such critical events in daily practice.⁸ The exact reasons for the worse outcome in case of very late ST are unknown. Noteworthy, very late ST presented more often as ST-segment elevation myocardial infarction (STEMI) than MI related to non-stented site; this might explain our results, at least in part. The mechanism of incident MI was indeed very late ST in 1/5 of the cases, a ratio that rises to 1/3 of the cases when the incident MI was a STEMI. In addition, a lower successful reperfusion rate has previously been reported in patients with STEMI related to stent thrombosis in the literature.^10-12 Therefore, very late ST might lead to bigger MI with larger scar.

Our results showed that in patients with stable CAD, although a rare event, very late ST is the cause of incident MI in a non-negligible proportion of the cases and is associated with poor outcome. Therefore, an understanding of the mechanisms of very late ST appears important for the prevention of MI overall and patient's prognosis. In our study, no baseline characteristics allowed us to differentiate patients who experienced very late ST during the follow-up from those who experienced MI at a non-stented site. It should, however, be acknowledged that detailed data on previous PCI procedures were lacking and that we suffered from a certain lack of power. In the past literature, intracoronary imaging (using intravascular ultrasound and optical coherence tomography) and post-mortem studies have associated very late ST after DES implantation with malapposition, uncovered struts, stent underexpansion, and, more recently, neoatherosclerosis.^13-20 Malapposition and uncovered struts have been often restricted to DES in the past because of delayed endothelialization, lack of polymer biocompatibility and local inflammation.^15,16 It is, however, important to note that very late ST was not limited to DES in our study, and 40% of the cases occurred in bare-metal stents. To date, with new-generation stents, very late ST is more influenced by the presence of diffuse atherosclerosis, multivessel disease, multiple and long stent (>30 mm) use, and the presence of highly calcified lesions rather than by the type of stent used.¹⁹

In a contemporary practice, very late ST occurs at a rate of 0.15-0.2% per year in stable CAD outpatients and arises in 1/5 of all MI cases in unselected patients. Although low, the risk seems to be strictly linear and never disappears. Importantly, very late ST is frequently associated with STEMI (rather than non-STEMI) and a higher risk of death. In this context, prolonged dual-antiplatelet therapy should be considered in patients at risk because it has shown to decrease very late ST occurrence.^21,22

References

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19. Nakamura D, Attizzani GF, Toma C, et al. Failure Mechanisms and Neoatherosclerosis Patterns in Very Late Drug-Eluting and Bare-Metal Stent Thrombosis. Circ Cardiovasc Interv 2016;9:e003785.
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Keywords: Angina, Stable, Drug-Eluting Stents, Myocardial Infarction, Coronary Artery Disease, Paclitaxel, Sirolimus, Incidence, Tomography, Optical Coherence, Secondary Prevention, Outpatients, Cicatrix, Inpatients, Percutaneous Coronary Intervention, Thrombosis, Registries, Atherosclerosis, Inflammation

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