Author + information
- Marco Valgimigli, MD, PhD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Marco Valgimigli, Thoraxcenter, Ba 587, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands.
- intravascular imaging
- myocardial infarction
- recurrent stent thrombosis
- stent thrombosis
Errare umano est, sed perseverare diabolicum. (To err is human, but to persist in the error is diabolical.)
The threat of early (i.e., within the first 30 days) stent thrombosis (ST) has accompanied percutaneous coronary intervention since the early days of stent intervention. The initial attempts to mitigate that risk with aspirin, a single antiplatelet therapy, in conjunction with parenteral and oral anticoagulant medications, paved the way to the dual-antiplatelet therapy (DAPT) regimen consisting in a P2Y12 inhibitor and aspirin, an irreversible cyclooxygenase-1 inhibitor (2,3). Because the vast majority of ST cases were noted to occur within the first weeks after stent implantation, an arbitrary 30-day to 6-week duration of DAPT has been investigated and a 30-day duration of therapy has become the standard of care approach after uncoated stent implantation.
Yet proper stent expansion was also acknowledged in these early days as a key factor to minimize the risk of stent reocclusion (4), and optimal stent expansion in some DAPT studies even a prerequisite for patients’ eligibility (2,3).
The advent of the first-generation drug-eluting stent (DES) has triggered renewed interest in reassessing optimal DAPT duration after stent placement. DES per se have been initially regarded more as thrombogenic devices. This was due to their intrinsic capability to minimize late loss and as such potentially compromise stent coverage. Inflammation was also noted in experimental animal models. In the pivotal studies designed for stent approval, DAPT was recommended for 2 (5) or 3 (6) months after sirolimus-eluting stent placement or 6 months (7) after paclitaxel-eluting stent placement. No safety issues were noted early on up to at least 1 year compared with the uncoated stents.
After several anecdotal observations that first-generation DES were associated with the occurrence of very late ST, an entity that was at that time hardly known to exist after bare-metal stents (BMS), the community reacted by endorsing a long-term, or even an indefinite, DAPT regimen after DES implantation.
An extraordinary amount of scientific scrutiny has been devoted to the safety profile of first-generation DES (Figure 1). There has been not 1 single randomized, controlled study or meta-analysis of randomized studies showing that the risk of early, including either acute or subacute, as well as late (from 30 days to 1 year) ST is higher after first-generation DES compared with BMS (8). Some meta-analyses have actually provided evidence that the risk of ST within the first year may be lower after first-generation DES compared with BMS (9).
On the other hand, undoubtedly, first-generation DES were consistently shown later to be associated with a 4- to 5-fold higher risk of very late (i.e., after the first year) ST compared with BMS (8,9). This observation corroborated the perception of increased thrombogenicity of DES compared with BMS and fueled the “longer the better” notion for DAPT duration in DES-treated patients (10).
First-generation DES have been entirely replaced by newer generation devices. Emerging evidence of superior safety with respect to ST and target vessel myocardial infarction has been generated for some of the newly introduced devices compared with first-generation DES (11–13). Importantly, most of these second-generation stents were approved in noninferiority trials compared with first-generation DES. Therefore, few studies have directly compared second-generation DES with BMS. There is a growing literature suggesting that at least some second-generation devices may be safer not only when compared with first-generation but also with the corresponding BMS counterparts (13–15).
Still, the last chapter of the first-generation DES saga needs to be written, including answering the question of how long will the enhanced risk of ST remain such after implantation as well as identifying how to best treat patients presenting with ST.
Unlike the vast amount of rigorous statistics generated on the incidence and distribution of ST events over time after first-generation devices, the complete absence of randomized data to inform on the best management strategy for patients presenting with ST is notable.
In this issue of JACC: Cardiovascular Interventions, Armstrong et al. (16) report on a combined retrospective and prospective observational California registry of angiographic definite ST at 5 academic hospitals from 2005 to 2013. The entry criterion was the occurrence of a definite ST, which was observed in 221 patients of an unknown number of patients at risk. With the important caveat of not knowing the exact timing of first ST event after the index procedure for each stent type, 104 (47%) patients had received a first-generation DES, 51 (23%) a BMS, and 19 (9%) a second-generation DES. After a median follow-up of 3.3 years, definite or probable recurrent ST (rST) developed in 29 patients, whereas 19 presented with angiographic definite rST.
The cumulative hazard ratio of definite or probable rST was 16% at 1 year and 24% at 5 years. The cumulative hazard ratio of angiographic definite rST was 11% at 1 year and 20% at 5 years. Taken together, these findings confirm the high risk of ST recurrences after the occurrence of the first ST and call for dedicated treatment protocols for patients presenting with ST.
A second key piece of information that is conveyed by this important analysis is that the risk of recurrence is highest in the first few months after the first event, but it does not abate entirely over time. This study suggests that ∼50% of events are clustered within the first year after reintervention, whereas the remaining 50% of events occur from the second to the fifth year of follow-up. This observation carries important implications with respect to the duration of secondary preventive measures in this relatively small yet challenging patient population.
Two procedural and 1 post-procedural management strategies deserve specific comments.
At the time of the index ST event, intravascular ultrasound was used in ∼1 in every 4 patients. Given the well-known capability of intravascular ultrasound to shed new light on the reasons underlying an ST event, including undersizing, malapposition, and residual untreated vessel dissection, I tend to believe that an intravascular imaging modality should be offered to all patients experiencing this catastrophic scenario. Importantly, large proximal vessel diameter and initial ST at bifurcation were identified as independent rSTs. These findings emphasize the need for optimal stent deployment and apposition as a key procedural factor to mitigate the risk of recurrences. These observations are consistent with the Dutch stent thrombosis registry that showed undersizing to be among the most important predictors of ST, second only to clopidogrel discontinuation within the first 30 days (17).
A second remarkable procedural aspect is that >1 patient in every 2 underwent restenting in the setting of the first ST event. New stent deployment was not identified as a predictor of rST in this registry. Yet, given the relatively low number of recurrent ST events, caution should be used in interpreting current findings, especially considering that the reasons for restenting were not collected. It is noteworthy that 2 independent studies previously suggested an association between restenting and mortality after the first ST event (17,18). While acknowledging that only a prospective, randomized, controlled trial could conclusively ascertain the risk-benefit ratio of restenting, based on available retrospective data (17,18), additional stent implantation in the setting of ST should probably be restricted to a bailout strategy. Because stent underexpansion or undersizing is known to frequently contribute to ST, optimal, ideally imaging-guided, further expansion of the originally implanted stent should most likely be the goal of reintervention beyond vessel recanalization.
The majority of patients were discharged on aspirin and clopidogrel in this registry. This reflects the limited availability of more potent and consistent P2Y12 inhibitors during the study period. Both prasugrel and ticagrelor have been shown to be associated with a significant reduction of definite and definite or probable ST compared with clopidogrel (19,20). Moreover, both studies indicated that the number of recurrent events is also significantly decreased by treatment with ticagrelor or prasugrel compared with clopidogrel. Hence, the use of clopidogrel after ST cannot be regarded as an effective treatment option. Considering the long-term risk of recurrence after the first ST, it may be reasonable in this highly selected high-risk patient population to make any effort to maintain DAPT in the very long term, if tolerated.
Finally, all attempts should be made to retrieve any possible driver of ST, including inspection of the index procedure and careful assessment of a patient’s history, focusing on compliance with antiplatelet therapy and appraisal of possible triggers, which also comprise prothrombotic morbidity and concomitant medications.
If ST avoidance is the mind-set of every interventional cardiologist during every stent procedure, prevention of recurrences requires even more commitment from all potential stakeholders.
↵∗ Editorials published in the JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology.
Dr. Valgimigli has received honoraria for lectures from, is on the Advisory Board of, and has received research grants from AstraZeneca, Medtronic, Terumo, and The Medicines Company; has received honoraria for lectures from; and is on the Advisory Board of St. Jude, Abbott Vascular, and CID Vascular.
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