Coexistent In-Stent Restenosis, Late Incomplete Stent Apposition and Mural Thrombus in a Zotarolimus-Eluting Stent

ABSTRACT: Drug-eluting stents (DES) have been demonstrated to dramatically reduce the rate of in-stent restenosis (ISR). However, some studies found an increased rate of late incomplete stent apposition (ISA) and late stent thrombosis (ST) in DES compared to traditional bare metal stents (BMS). Endeavor stent, a new cobalt-alloy DES coated with phosphorylcholine and zotarolimus, has been reported to have a very favorable safety profile with few documented late acquired ISA and late ST. In the present report, we described an interesting case with coexistent ISR, late ISA and mural thrombus in an Endeavor zotarolimus-eluting stent 8 months after primary percutaneous coronary intervention.

J INVASIVE CARDIOL 2008;20:423–425

Implantation of coronary metallic stents improved procedural safety and reduced rates of restenosis as compared with balloon angioplasty. But despite the use of coronary stents, the frequency of restenosis remained more than 30 percent in high-risk subgroups. Subsequently, polymer-based local delivery of antiproliferative drugs from eluting stent platforms was developed and drastically reduced restenosis rates.1-5 However, during the current era of drug-eluting stent (DES) implantation, late stent thrombosis (ST) has become a public health issue as evidenced by some recent studies.6-9 The Endeavor® stent (Medtronic, Minneapolis, Minnesota), a new cobalt-alloy stent coated with phosphorylcholine and the antiproliferative agent ABT-578 (zotarolimus), has been reported to have a very favorable safety profile with few documented late acquired incomplete stent apposition (ISA) and late ST.10-12 In the present report, we described an interesting case with coexistent in-stent restenosis (ISR), late ISA and mural thrombus in an Endeavor stent 8 months after primary stenting.

Case report. In October 2006, a 71-year-old man came to the emergency room and complained of abrupt chest pain for 6 hours. The patient had a history of hypertension. ST-segment elevation and pathologic Q-wave was noted at the precordial leads on ECG, and cardiac enzymes were also markedly elevated. Thus, he was diagnosed as acute anterior myocardial infarction and emergent coronary angiography was performed. The angiogram showed total occlusion of the proximal left anterior descending artery (LAD) and a significant stenotic lesion in the proximal segment of the left circumflex artery (LCX) (Figure 1). In the subsequent procedure, a 2.75 x 30 mm zotarolimus-eluting Endeavor stent was implanted in his LAD with the pressure of 14 atm after predilatation. The angiographic result of primary percutaneous coronary intervention (PCI) was excellent and there was no significant residual stenosis in the stented segment with TIMI 3 coronary flow in LAD (Figure 2). The patient was discharged without any complications 8 days later and remained on dual antiplatelet therapy with aspirin 100 mg/day and clopidogrel 75 mg/day.

The patient remained asymptomatic throughout the subsequent clinical follow-up period. In June 2007, he returned to our hospital for repeated coronary angiography by scheduled follow up. To our surprise, the coronary angiogram revealed significant ISR in the proximal stented segment of LAD while a zig-zag phenomenon was found in the middle stented segment (Figure 3). The intravascular ultrasound (IVUS) catheter could not cross the serious ISR segment until the predilatation had been performed. The following IVUS examination showed a very interesting phenomenon with coexistent neointimal proliferation in the proximal stented segment, ISA and mural thrombus in the middle stented segment of proximal LAD (Figure 4). Repeat PCI was then performed with a 2.75 x 32 mm TAXUS Liberté paclitaxel-eluting stent (Boston Scientific Corp., Natick, Massachusetts) in the proximal LAD and another 3.0 x 20 mm TAXUS Liberté stent in left main and proximal LCX. After the final kissing balloon, the angiographic and IVUS results were excellent and there was no significant residual stenosis in stented segments with TIMI 3 coronary flow in both LAD and LCX (Figure 5). The patient was discharged without any complications 3 days later and remained asymptomatic during the subsequent follow up.

Discussion

In recent years, DES has been demonstrated to dramatically reduce the rate of ISR and the need for repeat revascularization.1–5 Despite these promising results, some studies found an increased rate of late ISA and late ST in DES compared to traditional BMS.6–9,13–19 Endeavor is a new DES system based on a new generation thin strut and cobalt-alloy material, coated with phosphorylcholine and the antiproliferative zotarolimus which is a synthetic analogue of rapamycin. In previous trials, the Endeavor stent has been reported to have a very favorable safety profile. No late ST and only 1 late acquired ISA was reported in more than 1300 patients of the ENDEAVOR I, II and III trials within 2 years after stent implantation,10–12 although the incidence of binary ISR at 8-month angiographic follow up in the ENDEAVOR III trial was significantly higher than with sirolimus-eluting stents (SES). The present case was very exceptional as significant ISR, late ISA and mural thrombus were coexistent in the Endeavor stent at 8-month follow up after primary stenting for acute myocardial infarction.

Angiographic restenosis after DES implantation is an infrequent event occurring mainly in association with small vessel size, long lesion length, diabetes mellitus, stent underexpansion, discontinuity in stent coverage, and DES type.20–22 In our case, the adverse anatomical factors such as relatively small vessel diameter (2.75mm), long lesion length (30mm), and the Endeavor stent itself may have contributed to the significant ISR in proximal stented segment, as the other risk factors mentioned above could be excluded by clinical characteristics and IVUS evaluation. Compared to SES in ENDEAVOR III, increased neointimal hyperplasia with the Endeavor stent might be due to differences in biological activity of zotarolimus compared with sirolimus, the more rapid elution kinetics of zotarolimus from the phosphorylcholine polymer (zotarolimus 95% eluted in approximately 2 weeks compared with the slower release of sirolimus 95% eluted in approximately 6 weeks) and differences in biological responses to either the stent or the phosphorylcholine polymer itself.12

ISA is defined as separation of stent struts from the arterial wall with evidence of blood flow behind the strut in the absence of a bifurcation. Several mechanisms of ISA have been proposed as follows: 1) positive arterial remodeling with an increase of EEM out of proportion to the increase of plaque; 2) a decrease in plaque and media due to dissolution of jailed thrombus or plaque debris; 3) ISA not recognized at implantation and detected at follow up; and 4) chronic stent recoil without any change in arterial dimensions. In our case, it was impossible to discern chronic stent recoil and persistent ISA from the other mechanisms because of the omission of postprocedural IVUS. As this patient had undergone primary stenting during acute myocardial infarction, the dissolution of jailed thrombus and the unhealed ulceration might be the most possible mechanism of the late ISA. Additionally, we implanted an undersized stent (2.75 x 30 mm) in the proximal LAD without a higher pressure inflation or post-dilation with a larger balloon. Based on the above technical issues with the implantation of stent, the ISA might represent a persistent ISA which was not recognized at implantation.

Most previous studies had suggested few adverse clinical sequelae from ISA. But in a recent report by Cook et al, ISA was found to be more frequent (77% versus 12%) in patients with very late ST after DES implantation compared with controls.23 As a serious complication, ST usually leads to ST-elevation myocardial infarction or death. Iakovou et al reported a 45% rate of death for patients suffering late ST in DESs, with the majority of others suffering nonfatal myocardial infarction.24 In the present patient, IVUS examination showed a partially organized thrombus loosely attached to the adjacent vessel wall of the ISA in the middle stented segment. Alternatively, significant neointimal proliferation, which led to serious in-stent restenosis and obstructed the lumen with flow reduction, may have contributed to the thrombus formation in our case, whereas the ISA might play a more important role in the pathogenesis of the mural thrombus.

Our case is interesting and exceptional as it is the first case with coexistent ISR, late ISA and mural thrombus in an Endeavor stent for primary PCI of acute myocardial infarction. Further large and prospective studies with routine IVUS follow-up will help answer the question about the definite safety and efficacy of the Endeavor stent in patients with AMI.