Relative Place of Very Late ST Among MI in Patients With Stable CAD
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).
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
- Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-e164.
- Camenzind E, Steg PG, Wijns W. Stent thrombosis late after implantation of first-generation drug-eluting stents: a cause for concern. Circulation 2007;115:1440-55.
- Räber L, Magro M, Stefanini GG, et al. Very late coronary stent thrombosis of a newer-generation everolimus-eluting stent compared with early-generation drug-eluting stents: a prospective cohort study. Circulation 2012;125:1110-21.
- Wenaweser P, Daemen J, Zwahlen M, et al. Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study. J Am Coll Cardiol 2008;52:1134-40.
- Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369:667-78.
- Claessen BE, Henriques JP, Jaffer FA, Mehran R, Piek JJ, Dangas GD. Stent thrombosis: a clinical perspective. JACC Cardiovasc Interv 2014;7:1081-92.
- Yamaji K, Räber L, Zanchin T, et al. Ten-year clinical outcomes of first-generation drug-eluting stents: the Sirolimus-Eluting vs. Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX) VERY LATE trial. Eur Heart J 2016;37:3386-95.
- Lemesle G, Tricot O, Meurice T, et al. Incident Myocardial Infarction and Very Late Stent Thrombosis in Outpatients With Stable Coronary Artery Disease. J Am Coll Cardiol 2017;69:2149-56.
- Doyle B, Rihal CS, O'Sullivan CJ, et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007;116:2391-8.
- Chechi T, Vecchio S, Vittori G, et al. ST-segment elevation myocardial infarction due to early and late stent thrombosis a new group of high-risk patients. J Am Coll Cardiol 2008;51:2396-402.
- Lemesle G, De Labriolle A, Bonello L, et al. Clinical manifestation and prognosis of early versus late stent thrombosis of drug-eluting stents. J Interv Cardiol 2009;22:228-33.
- Lemesle G, Maluenda G, Collins SD, Waksman R. Drug-eluting stents: issues of late stent thrombosis. Cardiol Clin 2010;28:97-105.
- Taniwaki M, Radu MD, Zaugg S, et al. Mechanisms of Very Late Drug-Eluting Stent Thrombosis Assessed by Optical Coherence Tomography. Circulation 2016;133:650-60.
- Souteyrand G, Amabile N, Mangin L, et al. Mechanisms of stent thrombosis analysed by optical coherence tomography: insights from the national PESTO French registry. Eur Heart J 2016;37:1208-16.
- Nakazawa G, Finn AV, Joner M, et al. Delayed arterial healing and increased late stent thrombosis at culprit sites after drug-eluting stent placement for acute myocardial infarction patients: an autopsy study. Circulation 2008;118:1138-45.
- Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435-41.
- D'Ascenzo F, Bollati M, Clementi F, et al. Incidence and predictors of coronary stent thrombosis: evidence from an international collaborative meta-analysis including 30 studies, 221,066 patients, and 4276 thromboses. Int J Cardiol 2013;167:575-84.
- Adriaenssens T, Joner M, Godschalk TC, et al. Optical Coherence Tomography Findings in Patients With Coronary Stent Thrombosis: A Report of the PRESTIGE Consortium (Prevention of Late Stent Thrombosis by an Interdisciplinary Global European Effort). Circulation 2017;136:1007-21.
- 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.
- Otsuka F, Byrne RA, Yahagi K, et al. Neoatherosclerosis: overview of histopathologic findings and implications for intravascular imaging assessment. Eur Heart J 2015;36:2147-59.
- Mauri L, Kereiakes DJ, Yeh RW, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.
- Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.
Clinical Topics: Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Interventions and Coronary Artery Disease, Interventions and Imaging, Chronic Angina
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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