Stent Thrombosis Following Drug-Eluting Stents: Conflict of Generations

Dear Editor,

We have read with interest the questions that were appropriately pointed out by the reader. Most of them were also our concern when designing and performing the analysis, and writing the final manuscript; thus, to some extent, they have been addressed in the discussion of the original paper.¹

Regarding the lack of information considering the compliance and duration of dual-antiplatelet therapy (DAPT), it is surely of insurmountable importance when the safety of PCI with stent implantation is being addressed. However, in real-world retrospective registries, it is virtually impossible to track and rigorously ascertain treatment compliance for every single patient. This has been previously reported by others and has been a problem in similar studies, including the renowned Swedish Coronary Angiography and Angioplasty Registry (SCAAR).² P2Y12-antagonist status can be easily confirmed in patients with major thrombotic events, but not in those without, especially when late and very-late stent thrombosis (ST) is being considered. At least theoretically, a higher rate of knowledge of DAPT status in patients with ST could lead to an overestimation of the importance of DAPT discontinuation. The recommendations for DAPT duration during the early days of the (first-generation) DES era were based on the same trials that supported their use in clinical practice.^3,4 The optimal duration of DAPT is an unsettled issue. Several meta-analyses of randomized controlled trials involving first-generation DESs (at the time, versus bare-metal stents) showed that, with the recommended pharmacological regimens, the incidence of 12-month ST, although numerically superior with first-generation DESs, was not statistically different from that observed with bare-metal stents. After that period, however, a small but significantly higher number of protocol-defined ST occurred in both sirolimus- and paclitaxel-eluting stent-treated patients.^3,5 Our study did not address very-late ST because, at the time of the original analysis, the number of patients treated with second-generation-DES and with a reliable long-term follow-up was relatively low. Work is underway toward a complete assessment of the risk of very-late ST in our growing patient cohort. Additionally, there is no consistent evidence that prolonging thienopyridine treatment beyond 6 to 12 months will significantly reduce ST. In a prospective analysis of a multicenter registry involving 3086 patients treated with first-generation DESs, Airoldi et al⁶ found that the discontinuation of thienopyridine treatment after 6 months of stent implantation was not an independent predictor of ST (hazard ratio, 0.94; 95% confidence interval, 0.30-2.98; P=.92). Likewise, randomized trials — that have included mixed patients (treated with both first- and second- generation DESs) and may have been underpowered to detect differences on the incidence of this rare endpoint — failed to show a benefit of prolonged DAPT regimens in reducing hard thrombotic events, including ST.^7,8

The explanations for the variation in the incidence of Academic Research Consortium (ARC)-defined definite ST observed between 2007 and 2009 in our cohort¹ are not straightforward. We strongly feel that the unrestricted use of first-generation DES that followed the enthusiastic results of the early trials, outside the “controlled environment” of randomized clinical trials, likely led to an excessive “off-label” use and definitely contributed to the surge of the late ST issue. After the “alarming reports” in 2006 by Camenzind et al and the BASKET-LATE analysis,^9,10 a greater awareness of the “stent-thrombosis phenomenon,” together with modifications in PCI technique, as discussed elsewhere,¹ may have decisively and positively influenced interventional cardiologists toward a more judicious use of both first-generation DES and the newer devices as they came into daily practice. Nevertheless, underreporting cannot be definitely excluded. 

Despite the importance of DAPT, ST, regardless of the timing of its occurrence, is a complex and multifactorial issue. Our aim was to evaluate whether or not the widespread use of a second-generation DES whenever a DES may be indicated (a scenario similar to the one that followed the first DES trials), considering all the potential adverse circumstances and “pitfalls” of real-world PCI (including non-adherence to DAPT, whatever the motive), would translate into lower rates of thrombotic events. In our dataset, despite the landmark analysis after 2007 that showed that the differences did not reach statistical significance, numerically, the incidence of ARC-definite ST was consistently lower in the second-generation group, at all time points. Of note, no mortality benefit was observed.¹ Assessment of cardiac-related death could have definitely produced more reliable information regarding the clinical impact of ST, but actual cause of death is difficult to firmly assess in population-based retrospective registries.

The authors,

Helder Dores, MD and Luís Raposo, MD

References

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