Simultaneous Two-Vessel Very Late Stent Thrombosis and Coronary Aneurysm Formation After Sirolimus-Eluting Stent Implantation: An Intravascular Ultrasound Evaluation

ABSTRACT: Very late stent thrombosis is a rare but devastating complication. Several factors are known to contribute to its occurrence, and are related to the patient, procedure, lesion and premature discontinuation of antiplatelet therapy. This report describes the case of a 49-year-old patient with simultaneous two-vessel stent thrombosis (left anterior descending and circumflex arteries) 24 months after sirolimus-eluting stent implantation. The importance of intravascular ultrasound is enhanced. The potential contributing factors to the stent thrombosis are analyzed.

J INVASIVE CARDIOL 2011;23:E128–E131

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Drug-eluting stents (DES) are designed to deliver pharmacological drugs over time and were developed to suppress the mechanisms associated with in-stent restenosis, a problem mainly associated with bare-metal stent (BMS) implantation and balloon angioplasty alone. Therefore, restenosis and target vessel revascularization could be reduced to less than 10% after DES implantation.^1,2 However, stent thrombosis, a potentially fatal event due to acute vessel closure, is one of the most feared complications after percutaneous coronary intervention (PCI). Several reports suggest that stent thrombosis may occur more than 1 year after the index procedure (very late stent thrombosis) in patients treated with DES,³ and efforts are being implemented to uncover variables that potentially increase the risk of thrombus formation. We report the case of a patient who experienced simultaneous two-vessel stent thrombosis 24 months after sirolimus-eluting stent implantation and describe intravascular ultrasound (IVUS) imaging alterations.

Case Report. A 49-year-old man presented to the emergency department with oppressive chest pain 50 minutes after onset of symptoms. His past medical history was significant for dyslipidemia, type 2 diabetes and smoking habits. He had previously undergone cardiac catheterization (24 months prior, event-related details were unknown) and PCI with implantation of 2 sirolimus-eluting stents in the left coronary artery [left anterior descending (LAD) and circumflex (LCX) arteries] was performed. He completed 1 year of dual antiplatelet therapy and stayed on aspirin (100 mg per day) afterward. He was asymptomatic until the current episode.

In the emergency department, an electrocardiogram showed sinus rhythm (65 beats/minute), ST-segment elevation in the anterior and lateral walls (maximum: 4 mm) and Q-waves in the anterior wall. Physical examination was unremarkable. A loading dose of clopidogrel and weight-adjusted unfractionated heparin were administered and the patient was transferred to the catheterization laboratory for emergent left cardiac catheterization. Selective coronary angiography revealed two filling defects: 100% occlusion of the mid-segment of the LAD and 100% occlusion of the mid-segment of the LCX (TIMI 0 flow), consistent with LAD and LCX stent thrombosis (Figure 1). Therefore, a continuous perfusion of abciximab was started. Aspiration thrombectomy was conducted, in both the LAD and LCX, and flow was restored (TIMI 2 flow) (Figure 2). IVUS was performed. In the LAD, there was malapposition of the stent, with a large amount of thrombus detected and an image compatible with severe ectasia and a peri-stent coronary aneurysm [aneurysm cross-sectional area (CSA): 27.25 mm²; minimum lumen diameter (MLD): 1.6 mm; distal reference diameter (DR): 2.8 mm; and proximal reference diameter (PR): 3.5 mm]. The remaining vessel had non-significant fibrolipidic plaque and small calcification areas. In the LCX, thrombus was also evident and peri-stent dilation (aneurysm CSA: 20.36 mm²) with stent malapposition (similar to the LAD) was visible (MLD: 1.9 mm; DR: 2.6 mm; and PR: 2.75 mm) (Figure 3).

PCI was performed. Dilation of the LAD with 4 x 15 mm and 5 x 20 mm noncompliant balloons was conducted, followed by re-evaluation with IVUS. A flow-limiting dissection distal to the previous stent was detected and a 3.5 x 19 mm BMS (Titan 2 Cross Maxx, Hexacath, Paris, France) was deployed with distal overlapping. TIMI 3 flow was restored and no residual stenosis was present (MLD: 2.9 mm). The LCX was dilated with a 3 x 15 mm noncompliant balloon with a good final result (MLD: 2.5 mm) (Figure 4).

The patient was admitted to the coronary care unit asymptomatic and with hemodynamic stability. Peak plasma troponin I was 122.2 ng/ml and peak plasma creatine-kinase was 7661 U/L. No renal dysfunction was detected. A transthoracic echocardiogram was performed and showed a left ventricle with apical akinesia and a small apical aneurysm, hypokinesia of the lateral wall and an ejection fraction of 37%. The patient was discharged 7 days after on dual-antiplatelet therapy.

Discussion. Stent thrombosis is a multifactorial problem. Several factors that contribute to stent thrombosis have been identified. Procedure-related factors include stent malapposition/incomplete expansion at the index procedure, stent length, multiple stent implantation, radiation therapy, residual dissection and late secondary stent malapposition (late resolution of thrombus induces struts displacement on the vessel wall and predisposes to a thrombogenic environment). Patient- and lesion-related factors include low ejection fraction, diabetes mellitus, advanced age, renal dysfunction, acute coronary syndrome as the index event and stenting bifurcation, in-stent restenotic or ostial lesions.^1,4,5 Premature discontinuation of antiplatelet therapy has also been associated with thrombus formation and is reported to be one of the most powerful predictors of thrombosis and of the occurrence of major adverse cardiovascular events.⁶

Hypersensitivity reactions are also described as a potential mechanism for late stent thrombosis and several reports have shown eosinophilic infiltration in the vascular wall (eosinophilic coronary arteritis) that leads to a positive remodeling after sirolimus- and paclitaxel-eluting stent implantation.^3,7 Rapamycin (sirolimus) is a drug with lipophilic properties used in DES, and is known to inhibit proliferation and migration of vascular smooth muscle cells, hence delaying arterial healing and endothelization and potentially provoking a thrombogenic environment. This positive remodeling can induce a late secondary stent malapposition with an increase in the external elastic membrane and thus form aneurysmatic dilations that augment the rate of thrombus formation.⁸ It is still unclear how long it will take for DES to endothelialize in humans.¹

Stent malapposition is a subject of extensive debate, as its increased frequency after DES implantation may lead to several adverse events, including stent thrombosis. In ST-elevation acute myocardial infarction (STEMI), the safety of DES remains unclear, and several trials have reported inconsistent results. The intravascular substudy of the HORIZONS-AMI randomized trial9 enrolled 241 patients with 263 native coronary lesions and evaluated the incidence and mechanisms of acute and late stent malapposition (LSM) after primary paclitaxel-eluting stents (PES) and BMS implantation in STEMI. The authors concluded that LSM was more frequent after PES than BMS. The main cause of LSM was positive remodeling and plaque/thrombus resolution, with post-stent IVUS thrombus/plaque protrusion being an independent predictor of LSM.

Hong and Mintz et al conducted two studies with the purpose of evaluating the incidence, mechanisms, predictors and long-term prognosis of LSM after BMS implantation (881 patients) and DES implantation (557 patients).^10,11 They retrospectively evaluated 992 lesions treated with BMS and 705 lesions treated with DES (IVUS evaluation post-implantation and at follow-up). In this analysis, total stent length, primary stenting in STEMI, and chronic total occlusion lesions were independent predictors of LSM. The incidence of LSM at 6-month follow-up appeared to be higher in DES than in BMS patients, especially in these higher-risk subsets (the incidence of LSM after primary stenting in STEMI was 11.5% after BMS implantation and 31.8% after DES implantation). The main mechanism involved in LSM appeared to be positive remodeling and an out-of-proportion increase in external elastic lamina, and not a decrease in plaque mass.

IVUS is an important diagnostic technique that provides valuable information regarding inadequate stent deployment after stent implantation. In stent thrombosis, after patency of the target vessel has been restored, it can provide information that helps to depict the mechanisms associated with thrombus formation. Incomplete stent apposition refers to the separation of stent struts from the vessel wall, with evidence of blood speckles behind the strut, in the absence of a bifurcation.³ Kang et al recently published a study focusing on the long-term natural history of acquired malapposition and performed serial IVUS evaluations immediately after stent implantation, and at 6-month and 2-year follow-up.¹² This study reported that malapposition detected at 6 months rarely regressed; rather, it continued to progress due to an ongoing positive remodeling. Thus, IVUS follow-up after DES implantation should be extended, as a shorter monitoring period may underestimate malapposition frequency.

In the present case, a two-vessel very late stent thrombosis associated with coronary aneurysms occurring 24 months after sirolimus-eluting stent implantation is described. IVUS proved to be an excellent technique that allowed us to evaluate properly the degree of stent malapposition. The factors leading to this complication in our patient are unclear, as are the details related to the first procedure. Nevertheless, the simultaneous thrombosis of the two-vessel stents and similar IVUS findings in both arteries (peri-stent aneurysm and large amount of thrombus detected behind struts) led us to consider LSM, probably related to a hypersensitivity reaction to sirolimus. Although premature discontinuation of antiplatelet therapy is one of the most important contributors to stent thrombosis, the patient completed 12 months of aspirin and clopidogrel (was it long enough?) and continued on aspirin afterward.

Conclusion. The mechanisms associated with stent thrombosis are not fully understood, but several patient-, procedure- and lesion-related factors appear to have a role. Late stent malapposition can lead to a thrombogenic environment, and IVUS imaging has a primary role in its detection and evaluation. The optimal duration of dual-antiplatelet therapy after DES implantation is still unclear. More prospective and randomized registries are necessary to accurately assess the risk of late stent malapposition and thrombosis associated with DES.

Acknowledgments. Josepa Mauri, PhD, Eduard Fernandez-Nofrerias, MD, Oriol Rodríguez-Leor, MD, and Antoni Bayes-Genis, PhD.

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From the Cardiology Department, University Hospital German Trias i Pujol, Badalona, Barcelona, Spain.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted July 21, 2010, provisional acceptance given September 28, 2010, final version accepted November 1, 2010.
Address for correspondence: Joana Silva, MD, Rua da Chainça, nº 35, Carvalhais de Cima, 3040-690 Coimbra, Portugal. Email: joanadelgadosilva@gmail.com