Chronic total coronary occlusions (CTO) constitute one of the most complex and challenging therapeutic scenarios for an interventional cardiologist, due not only to the technical complexity of the lesion and the need for specific operator skills, but also to the many complications that can occur during and after the procedure.1–4 Stent thrombosis (ST) represents the most important clinical complication due to the high rate of death and/or myocardial infarction.5 Its pathophysiology includes various factors related to the device itself, the procedure and the patient.6

It has been traditionally considered that one the factors associated with increased risk of ST is, as suggested by some studies,7,8 the implantation of a drug-eluting stent (DES) in the context of a CTO. The aim of this study is to assess the incidence, clinical significance and timing of DES thrombosis in the treatment of CTO, given the lack of clear knowledge concerning the safety of these devices in this context. For this purpose, data on ST from the CIBELES trial9 were studied.

ST is an uncommon event, with a variable clinical presentation but generally unfavorable course, resulting in high rates of myocardial infarction (50–70%) or death (20–40%). The data in the literature on its incidence are inconsistent, but it is estimated at between 0.5% and 2.5%. These figures are slightly lower and with earlier clinical presentation for bare-metal stents (BMS).9

The essential pathophysiology is closely related to various parameters and chronological stages: early events often depend on variables associated with the procedure itself, including the presence of residual thrombus, dissection in the proximity of the target lesion, stasis, stent under-expansion, stent length, or a combination of the above. Late events are most frequently associated with delayed scarring or incomplete and/or inadequate neointimal covering. Additionally, underlying vascular inflammation and the length of the implanted devices have also been shown to be important, with patients who had received longer stents or experienced an allergic reaction to the polymer most often suffering ST.11–13

Traditionally, percutaneous revascularization of a CTO is considered to be at high risk for ST. This is due to the complexity of the procedure and the intricate histopathology of these lesions, which contain varying amounts of collagen, lipid, calcifications and intraluminal microchannels. All this leads to increased vulnerability and susceptibility to vascular damage.14,15 Numerous clinical studies have demonstrated the superiority of DES (mainly SES) compared with BMS in the treatment of CTO,16–21 with a lower restenosis rate and fewer major adverse cardiac events. There are no data in the literature that conclusively demonstrate increased rates of ST in this context. However, ST is slightly more frequent in patients treated with first-generation DES.

The new generations of DES have been developed to improve safety and biocompatibility, optimizing the three main components: the platform, the polymer and the drug. They have been shown to be more effective than the first generation, mainly due to a reduction in the rate of medium-term target vessel revascularization. They have also shown a better safety profile, with lower rates of ST. These findings have been supported by the results of numerous clinical trials published in recent years (SPIRIT II,22 SPIRIT III,23 SPIRIT IV,24 COMPARE I25), which compared the two generations of DES.

So the results of the CIBELES trial, which demonstrates the non-inferiority of EES versus SES, should not surprise us. They corroborate the previously published data and establish the safety of EES in the context of CTO. Although it is not possible to draw definite conclusions concerning differences in ST between the two treatment groups, there were no cases of definite or probable thrombosis in the EES arm. Other second-generation stents, such as zotarolimus-eluting stents, have been proven to be at least as effective as SES in the treatment of CTO, offering similar results in terms of numbers of ST.26

As noted above, ST usually presents as an acute event with a variable spectrum, but usually with high rates of morbidity and mortality. However, in our study the clinical course was relatively benign, presenting in all cases as an episode of unstable angina or a nonfatal non-ST-elevation myocardial infarction. The particular angiographic scenario probably contributed significantly to this clinical course, as pre-existing collateral circulation may have played a protective role in the event of an ischemic event caused by ST.

The data obtained suggest that the only independent predictor of ST is minimal luminal diameter immediately after the procedure. This suggests that stents implanted in small vessels or malpositioned or under-expanded (due to, for example, the existence of underlying calcium) are at higher risk of thrombosis. Recently published data emphasize the low use of non-compliant balloons in the treatment of CTO. In the CIBELES trial, post-dilatation was only performed in 25% of patients, a figure that is surprising given the expected proportion of malpositioning or under-expansion of the implanted stents according to the type and length of the treated lesions. Invasive imaging techniques such as IVUS guided the procedure and its outcome in only 6% of cases.27

It is known that the same precipitating factors are predictors of ST after revascularization with DES in other coronary lesions.28,29 Analyzing the timing of the event rate, there is no evidence of a clear grouping, with one acute, one subacute, and one late ST in our study. The two early events were presumably related to the procedure itself and associated local complications. Stenting often leads to areas of dissection along the artery, and together with the presence of organized thrombotic material, areas of calcification and suboptimal end TIMI flow, would provide the pathophysiological basis for increased incidence of ST. However, and despite the complexity of the procedure, the frequency of acute and subacute ST is very low, representing only 0.97% of all our cases.

Furthermore, thrombosis associated with DES occurs later than with BMS.28 The main cause of this phenomenon is delayed endothelialization of the device, caused by the antiproliferative action of the drug, as indicated by various angioscopy, optical coherence tomography and autopsy studies, although no definite conclusions can be drawn.30,31 We found only one case of late ST, but the follow-up in our study was only 12 months after revascularization. Hence, possible very late thrombosis events were not recorded.

In light of the above, we consider that this substudy of the CIBELES trial shows that ST in the context of CTO treated with DES is an uncommon phenomenon, similar to that of other coronary lesions. The previously known predisposing factors account for the majority of the risk, although the importance of certain local factors, such as the frequent presence of underlying calcium or areas of arterial dissection, should be borne in mind. Our data are similar to those published by other groups, in which the efficacy of EES32 and other second-generation stents33,34 was assessed, suggesting the existence of a class effect.

Moreover, second-generation DES have tended to diminish ST and are probably better in this regard than the first generation. The clinical presentation is in this context milder than in other circumstances, as the abundant collateral circulation acts as insurance and protects possible at-risk myocardial territory. Therefore, and given the available scientific evidence, we believe that DES stenting in CTO – and even more with second-generation stents – does not lead to added risk of ST, and presents a clear benefit in restenosis rates.21 Invasive imaging techniques such as IVUS or optical coherence tomography, and the use of non-compliant balloons after stent implantation, are useful tools to predict and correct malpositioning or under-expansion, thereby alleviating some of the main triggers of thrombosis.

Our study has some limitations. First, the CIBELES trial was designed to compare stent restenosis with EES and SES, and not to study ST. However, it is not really feasible to perform a specific clinical trial to assess ST in the context of CTO. Secondly, CTO were defined as those with estimated occlusion time >2 weeks (and not >3 months as recommended in recent consensus documents). The data are thus comparable to those of other trials of DES in CTO, such as PRISON II.21 In any case, in our study the estimated duration of occlusion was not related to the rate of ST. Thirdly, since the choice of antiplatelet therapy was at the discretion of the operator, there was no uniformity concerning the dose and type of drug administered. Finally, the clinical monitoring of patients was conducted over a 12-month period, so events after this period were not recorded. Consequently, despite its low incidence, possible very late ST is not included in this study.

The rate of thrombosis of DES in patients with CTO is low (1.4%), especially in those treated with EES compared to SES. In this context, the only independent predictor is minimal luminal diameter after the procedure. The clinical presentation in all cases was relatively benign (unstable angina or nonfatal non-ST-elevation myocardial infarction). The use of DES in the treatment of CTO is a safe option and should not be considered to increase risk of thrombosis.

This study was supported by the Spanish Society of Cardiology, with an unrestricted grant by Abbott Vascular.