Recurrence of Late-Acquired Incomplete Stent Apposition following Sirolimus-Eluting Stent Implantation

Author Affiliations: From the *Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, and §Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California. The authors report no conflicts of interest regarding the content herein. Manuscript submitted February 4, 2008, provisional acceptance given April 8, 2008, manuscript accepted April 16, 2008. Address for correspondence: Hiroshi Iwata, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 113-8655 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: hiroiwata-circ@umin.ac.jp

_______________________________________________ ABSTRACT: Stent thrombosis has been recognized as a potentially critical complication in percutaneous coronary intervention. In the bare-metal stent era, stent thrombosis was considered to be an acute or subacute event, occurring within 1 month after stent implantation.1 Recently, late or very late stent thrombosis after drug-eluting stent implantation has been brought into focus;2–4 however, the mechanism underlying this potentially fatal event is largely unknown. We report a case of critical late thrombosis 2 years after sirolimus-eluting stent implantation. Detailed serial intravascular ultrasound analyses revealed that late-acquired incomplete stent apposition, accompanied by extensive positive vascular remodeling, was involved in the pathogenesis of the nearly fatal event described in this case.

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J INVASIVE CARDIOL 2008;20:E265–E268 Case Report. A 71-year-old male with a history of hypertension and hypercholesterolemia was admitted for the treatment of unstable angina. Coronary angiography showed severe stenosis in the left main (LM), left anterior descending artery (LAD) and first diagonal branch (D1) (Figure 1A). Because of the patient’s strong preference, he was treated with sirolimus-eluting stents (SES) (Cypher™, Cordis Corp., Miami Lakes, Florida): 2 SESs (3.5 x 18 mm) in the proximal mid-LAD, 1 (3.5 x 18 mm) in the mid-portion of the LM, and 1 (2.5 x 18 mm) in D1. SES in the LM was postdilated with a 4 mm balloon, and the other stents received high-pressure postdilatation with each stent delivery balloon (Figure 1B). Intravascular ultrasound (IVUS) demonstrated a minimal stent area of 8.6 mm2, with adequate stent apposition to the vessel wall (Figure 2A). Aspirin and ticlopidine were initiated, however, as a skin rash caused by ticlopidine was observed, the antiplatelet regimen had to be changed and ticlopidine had to be discontinued. Because clopidogrel was still not approved for clinical use in Japan, the patient was treated with a dual antiplatelet regimen including daily doses of aspirin 100 mg and cilostazol 200 mg. Follow-up angiography 9 months post PCI showed no restenosis or vessel dilatation (Figure 1C). The patient had a stable clinical course and continued the dual antiplatelet regimen until 23 months after the initial percutaneous coronary intervention (PCI), when he was admitted with ST-elevation acute myocardial infarction complicated by cardiogenic shock. Emergent coronary angiography demonstrated a thrombotic total occlusion in the mid-LM stented segment (Figure 1D). Intracoronary administration of 8,000 IU of tissue-plasminogen activator reconstituted TIMI grade 1 coronary flow. IVUS showed a massive in-stent thrombotic burden within the stented segment. Red and solid thrombi were aspirated with a thrombectomy device, concluding the first treatment for stent thrombosis. Following successful revascularization, clopidogrel 75 mg was added to the antiplatelet regimen. Repeat coronary angiography 3 weeks after the initial presentation of stent thrombosis showed complete resolution of thrombus and marked aneurysmal vessel dilatation at the stented segments. IVUS also revealed a significantly dilated vessel wall accompanied by late-acquired incomplete stent apposition (ISA) (Figure 2 B-1, B-3). Similar IVUS findings were also observed in D1 (Figure 2 B-5). Longitudinal views of IVUS images demonstrated extensive late-acquired ISA accompanied by positive vessel remodeling in the LM. Since there was a concern that unapposed stent struts could predispose the lesion to recurrent thrombosis, additional PCI was performed to improve stent apposition, using a 6 mm balloon for the LM, a 5 mm for the LAD (Figure 2 B-2, B-4) and a 4 mm for the D1. Follow-up coronary angiography and IVUS analysis 3 months after the treatment for stent thrombosis revealed further vessel enlargement accompanied by redevelopment of ISA (Figure 2C). On the contrary, restenosis was observed in the unstented segment in the proximal portion of the LAD. Coronary computed tomography confirmed vessel dilatation in the LM up to 10 mm in diameter, as well as a stenotic lesion between the LM and LAD stents (Figure 3). Lymphocyte stimulation and skin-patch tests were performed to test possible allergic reactions; however, the tests were all negative for SES, bare-metal Bx Velocity stent, or sirolimus. The patient continues to be medically treated without further interventions. Discussion. Here, we present a case with very late stent thrombosis occurring 23 months following SES implantation. The onset of this near-fatal event was presumably precipitated by the presence of late-acquired ISA with significant vascular remodeling following SES implantation. Stent thrombosis is one of the most severe, occasionally fatal complications following PCI. When seen in the bare-metal stent era, the vast majority had been acute or subacute thrombotic events after stent implantation.1 Until the recent introduction of drug-eluting stents (DES) to clinical use, late or very late stent thrombosis had been rarely observed, except in patients undergoing intracoronary brachytherapy.5 Since its first occurrence in a patient,6 late stent thrombosis following DES implantation has been a major concern, gaining increasing clinical attention. A meta-analysis from randomized clinical trials reported that DES did not increase the risk of stent thrombosis under an appropriate antiplatelet regimen;7 however, the follow-up period in this analysis was limited to 1 year. Although still not conclusive, recent analyses, including those with longer follow-up periods, place emphasis on the incremental occurrence of late or very late thrombosis in patients receiving DES.2,4 While clinical risk factors are being reported in ongoing clinical registries,2–4,7,8 a limited number of reports are available regarding the local pathology. Pathological findings, including less complete arterial healing, incomplete endothelial coverage as a result of reduced in-stent cellular hyperplasia, late-acquired ISA and localized hypersensitivity,9 were postulated to be relevant to late stent thrombosis. In a detailed report from 14 autopsies, the main characteristics of pathology seen in these late stent thrombosis cases include local hypersensitivity, ostial/bifurcation stenting, ISA, restenosis and strut penetration into a necrotic core.10 IVUS-based studies have shown a higher incidence of late-acquired ISA in SES implanted lesions than those of bare-metal stents.11 Late-acquired ISA following DES implantation is associated with positive vascular remodeling.11,12 The reported IVUS features of late-acquired ISA (i.e., positive vascular remodeling and unattached stent struts) appear analogous to the pathology observed in stent thrombosis. Although no increase in adverse cardiac events has been reported in ISA patients enrolled in clinical trials so far, it should be noted that the follow-up periods are still relatively limited. Considering the delayed time point of late thrombosis, occurring even years after DES implantation, the length of follow up necessary to evaluate and capture such events remains an open question. Serial IVUS analyses in this present case allowed us to elucidate sequential changes in vascular dimensions. Vascular enlargement, with an external elastic membrane area nearly three times that of baseline, accompanied by severe ISA, was clearly visualized after thrombus dissolution. Even after thrombolysis and thrombectomy, the external elastic membrane and underlying pathology were not readily identifiable without the side-by-side comparison of baseline IVUS images. The possible relationship between ISA and late stent thrombosis should be determined through careful interpretation of serial image comparisons. From a clinical viewpoint, this case poses several difficult questions. First, IVUS confirmed optimal stent deployment, including adequate expansion and stent apposition, at the time of initial stent implantation. Furthermore, this patient remained compliant with the dual antiplatelet regimen until the onset of stent thrombosis. While implantation of multiple stents might have contributed to this event, the patient received relatively adequate precautions to reduce the potential risk for stent thrombosis. In this case, the vessel enlargement presumably developed later than 9 months after stent implantation. Provided that late-acquired ISA may predispose patients to a higher risk of stent thrombosis,13 clinicians might require a more efficient and preferably less invasive measure to detect and diagnose it before serious clinical sequelae ensue. In this patient, no abnormal reaction to either sirolimus or the SES was observed in the skin-patch and lymphocyte stimulation tests. Given the extent of the pathological changes, virtually limited to the stented segment, it may be difficult to detect such changes from systemic reactions, even if hypersensitivity was involved in this local pathology. In addition, 3 months after reintervention to improve stent strut apposition to the vessel wall, further positive vascular remodeling was observed. In a previous case report, untreated late-acquired ISA preceded subsequent late stent thrombosis.13 Until the nature of this vascular pathology is further elucidated, the definitive treatment for such patients is not yet known. In conclusion, we present a case of very late stent thrombosis occurring 2 years after SES implantation. Detailed serial IVUS analysis has shown that late-acquired ISA was presumably involved in the pathogenesis of this near-fatal clinical event. It remains to be clarified how best to identify the patients vulnerable to these vascular reactions and how to treat such lesions. Until we understand the nature of this critical complication sufficiently, the judicious choice of treatment indication and careful longer-term follow up may be warranted to ensure patient safety.

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