Stent Thrombosis Through the Generations

Stent thrombosis (ST), while infrequent, remains a dreaded complication of percutaneous coronary revascularization because of the associated rates of major myocardial infarction (60%-70%) and early mortality (20%-25%).¹ As coronary stents became more widely used in clinical practice during the late 1990s to treat acute vessel closure and to reduce restenosis, the emergence of ST redirected the efforts of the cardiology community to mitigate or eliminate this potentially catastrophic event. Advances in stent design and strut thinness, the advent of drug-eluting stent (DES) options, and more potent antithrombotic therapy have been substantial influences on ST. DESs have been associated with higher ST rates as compared to their bare-metal counterparts, particularly when utilized among high-risk groups and high-risk lesions. More recently, early meta-analyses of smaller studies have suggested reduced ST rates with newer-generation DESs versus prior versions.² Similarly, observations from a randomized trial suggested lower ST rates with the newer-generation everolimus-eluting stent (<1%) compared to rates for the older-generation paclitaxel-eluting stent (3%).³ So while this uncommon but catastrophic complication persists in contemporary practice, its low frequency has made it difficult to study, particularly in the real-world setting. 

In the current issue of the Journal of Invasive Cardiology, Dores et al have analyzed the outcome data from a large-volume, single-center prospective registry evaluating the incidence of definite ST.⁴ The study consisted of 3806 patients who underwent percutaneous coronary intervention between January 2003 and December 2010. In the registry, a total of 2388 patients (62.7%) were treated with first-generation DESs (sirolimus-eluting and paclitaxel-eluting stents), while 1418 patients (37.3%) were treated with second-generation DESs (everolimus-eluting and zotarolimus-eluting stents). The overall occurrence of Academic Research Consortium (ARC)-defined definite ST at 12 months was 1.2% (46 events). After correction for baseline differences between study groups and other variables deemed to influence the occurrence of ST, Dores et al concluded that the use of first-generation DESs was associated with a 2.4-fold increase in the risk of definite ST. Among the cases receiving a first-generation DES, the risk of ST was higher for paclitaxel-eluting versus sirolimus-eluting stents.

The observations from Dores et al are consistent with prior reports, in that the rates of definite ST are low and decreasing in recent years. As can be seen in Dores’s Figure 3 considering annual frequency of definite ST, the numerically highest years were 2003 and 2004, and over the most recent years, rates have averaged closer to 1%. Questions will remain in the field of ST, some of which will require large-scale registry data to help consider their relevance and possible answers. The underlying challenge remains how to afford to study such low-frequency events with multifactorial and variable etiologies. Beyond the events during the interventional procedure and device utilized (ie, type of DES), many other factors that affect the rate of ST (eg, patient genotype and phenotype) are still being unraveled. Considerable research has gone into finding predictive subsets for those at increased risk for ST.⁵ Among identified factors are the timing and acuity of presentation. Patients presenting with an ACS are known to be more vulnerable to early ST than patients with chronic stable disease. The initial plaque rupture of ACS triggers a prothrombotic avalanche of events, from platelet activation to local thrombus formation and occlusion, spasm, and distal embolization of microcirculatory debris.⁶ It is interesting to note in the Dores et al. registry that patients receiving second-generation DESs more often presented with an ACS, making their observations reassuring that ST rates can be kept low with evolving care strategies. 

In an analysis of the ACUITY trial, which particularly enrolled patients with ACS,⁷ early ST occurred with similar frequency after anticoagulation with either heparin plus glycoprotein IIb/IIIa inhibitors or bivalirudin (with or without IIb/IIIa inhibitors), and not surprisingly was predicted by diffuse atherosclerosis, suboptimal angiographic results, and inadequate pharmacotherapy. Such patients also had a higher incidence of renal insufficiency and insulin-dependent diabetes mellitus. The ACUITY subanalysis found that the rate of ST within 30 days was 1.4%, significantly higher than the 0.3%-0.5% ST rates reported among patients with stable coronary artery disease.

Among the most critical factors in mitigating the risk of ST are adequate and consistent dual-antiplatelet therapy (DAPT). A remarkable interpatient variability in the antiplatelet response to clopidogrel has been well documented. The frequency of clopidogrel hyporesponsiveness has been reported among as many as 30% of patients undergoing PCI, yet the clinical relevance of antiplatelet responsivity is modest,⁸ again since the factors related to ST are many. Loss-of-function alleles have been identified for clopidogrel metabolism, and these have been associated with an increased risk of adverse cardiovascular events, including ST. Among patients with ACS, the need for more rapid and potent pharmacological suppression of platelet reactivity in the prevention of early ST is highlighted in clinical trials testing newer antiplatelet therapies. 

In a landmark trial, prasugrel, a more potent, consistent, and faster-acting third-generation thienopyridine has shown a significant reduction in overall ST rates compared to clopidogrel (1.1% vs 2.4%).⁹ Similarly, ticagrelor, an oral, reversible, direct-acting inhibitor of the ADP receptor P2Y12 that has a more rapid onset and greater potency of platelet inhibition than clopidogrel was recently studied in a large clinical trial. In the Platelet Inhibition and Patient Outcomes (PLATO) study, there was a significant reduction in ST in the ticagrelor group vs the clopidogrel group, with definite ST rates of 1.3% and 1.9%, respectively.¹⁰

It is becoming clear that there has been a generational improvement in DESs that has reduced the risk of ST. This has been paralleled by advances in DAPT regimens and interventional techniques that have collectively reduced the risk of ST. While the field will continue to search for answers to the optimum duration of DAPT, and whether this is dependent on stent type and acuity of patient presentation, DES polymers, design characteristics, and the antiproliferative drugs will also continue to evolve. Understanding incremental improvements in techniques, devices, and drugs will remain quite challenging as the rate of ST slowly moves closer to zero.

References

1. Cutlip DE, Baim DS, Ho KK, et al. Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials. Circulation. 2001;103(15):1967-1971.
2. Palmerini T, Biondi-Zoccai G, Della Riva D, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet. 2012;379(9824):1393-1402.
3. Kedhi E, Joesoef KS, McFadden E, et al. Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice (COMPARE): a randomised trial. Lancet. 2010;375(9710):201-209.
4. Dores H, Raposo L, Teles RC, et al. Stent thrombosis with second versus first generation drug eluting stents in real world coronary percutaneous intervention. J Invasive Cardiol. 2013;25(7):330-336.
5. Holmes DR Jr, Kereiakes DJ, Garg S, et al. Stent thrombosis. J Am Coll Cardiol. 2010;56(17):1357-1365.
6. Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol. 2010;30(7):1282-1292.
7. Aoki J, Lansky AJ, Mehran R, et al. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation. 2009;119(5):687-698.
8. Holmes DR Jr, Dehmer GJ, Kaul S, Leifer D, O’Gara PT, Stein CM. ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning.” A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the American Heart Association. J Am Coll Cardiol. 2010;56(4):321-341.
9. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371(9621):1353-1363.
10. 1Wallentin L, Becker RC, Budaj A, et al; the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2009;361(11):1045-1057.

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