Very Late Stent Thrombosis after Bare-Metal Stent Implantation: Case Reports and Review of the Literature

From the Department of Internal Medicine, Division of Cardiology, Washington Hospital Center, Washington, D.C. Disclosures: Dr. Waksman reports receiving speaker honoraria from Biotronik, Medtronic, and Boston Scientific, and has received research grants from Biotronik, Boston Scientific, Glaxo-Smith-Kline, Sanofi-Aventis, Schering-Plough, and The Medicines Company. Manuscript submitted August 28, 2008, provisional acceptance given October 13, 2008, manuscript accepted October 22, 2008. Address for correspondence: Ron Waksman, MD, Washington Hospital Center, 110 Irving Street, NW, Suite 4B-1, Washington, D.C. 20010. E-mail: ron.waksman@medstar.net

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ABSTRACT: Stent thrombosis (ST) is a catastrophic complication that frequently presents as an acute myocardial infarction and/or death. The most recently accepted definition established by the Academic Research Consortium classifies ST as: early (occurring within 30 days), late (30 days to 1 year) or very late (after 1 year). Very late ST has been reported following drug-eluting stent implantation with rates up to 0.6% per year and has been attributed to delayed strut endothelialization. However, very late ST is unusual after bare-metal stent (BMS) implantation. We report two cases of patients presenting with ST-elevation myocardial infarction due to very late ST 6 and 8 years after BMS implantation.

J INVASIVE CARDIOL 2009;21:E27–E32

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Stents have improved the safety and efficacy of percutaneous coronary intervention (PCI) compared to conventional balloon angioplasty by reducing periprocedural abrupt vessel closure and restenosis.¹ Stent thrombosis (ST), however, remains a principal limitation of their use. Although rare, ST is associated with 20–40% mortality and 70% incidence of acute myocardial infarction (MI),^2,3 and typically occurs within the first 30 days after initial stent implantation.^3–5 While early ST has been reported with bare-metal stents (BMS), the new phenomenon of very late ST has been reported with drug-eluting stents (DES) and is mainly attributed to delayed strut endothelialization and potential prothrombotic characteristics of the DES itself.^6,7 The incidence of definite very late ST after DES implantation appears to be approximately 0.4–0.6% per year.^3,4 Yet, while this complication is not uncommon after DES implantation, very late BMS thrombosis has rarely been reported outside the setting of brachytherapy.⁸

Case Reports

Case 1. A 66-year-old female with a history of dyslipidemia and tobacco use was admitted to our center with a recurrent acute inferior ST-segment elevation MI (STEMI) related to very late ST 8 years after a BMS implantation. She had suffered a prior acute inferior STEMI in July of 2000 that was treated with early thrombolysis with t-PA and elective PCI 3 days later. The coronary angiogram at that time revealed normal left coronary arteries (Figures 1 A and B) and a severe stenosis in the distal right coronary artery (RCA) (Figures 1 C and D), which was directly stented with a Tristar 3.0 x 13 mm BMS (Guidant Corp., Indianapolis, Indiana), producing excellent angiographic results (Figure 1E). For the next 8 years, the patient did well on optimal medical therapy for coronary artery disease, including 1 year of clopidogrel therapy following the MI and the PCI. In June 2008, the patient was admitted with typical angina, shortness of breath and vomiting. An electrocardiogram (ECG) showed inferior STEMI. Transthoracic echocardiography revealed inferior akinesia. The left ventricular ejection fraction (LVEF) was 45% and there was no valvular disease. Emergent cardiac catheterization revealed occlusion of the distal RCA stent (Figure 2A), with a persistent filling defect at the stent site after thrombus aspiration (Figure 2B). A Taxus^® 2.75 x 16 mm DES (Boston Scientific Corp., Natick, Masssachusetts) was implanted using the direct stenting technique, with excellent angiographic results (Figures 2 C and D). Intravascular ultrasound (IVUS) was performed between thrombus aspiration and stent implantation and demonstrated mild restenosis and no dissection or plaque rupture. Thrombus was noted in the mid-portion of the stent (Figure 3). Case 2. A 56-year-old African-American male with a history of dyslipidemia, hypertension and internal cardiac defibrillator implantation for severe ischemic LV dysfunction (LVEF 25%) was admitted to our center with an acute inferior STEMI related to very late ST 6 years after BMS implantation. He initially presented with unstable angina in May 2002. At that time, the coronary angiogram revealed diffuse atherosclerotic disease in the RCA with multiple severe stenoses in the proximal, mid and distal segments (Figure 4A) and nonsignificant atherosclerotic disease in the left coronary arteries (Figure 4B). In order to treat the RCA, the patient underwent several balloon angioplasties and was then stented with 5 Bx-Velocity 3.5 x 76 mm BMS (Cordis Corp., Miami Lakes, Florida), with satisfactory angiographic results (Figures 4 C and D). In July 2007, he underwent a new coronary angiogram for shortness of breath and a positive ischemic stress test in the anterior territory. At that time, the coronary angiogram revealed a lesion progression in the left anterior descending artery (LAD), with a long significant stenosis including proximal and mid segments (Figure 5A) that was directly stented with a Taxus 3 x 32 mm, producing satisfactory angiographic results (Figures 5 B and C). Interestingly, the coronary angiogram also revealed significant (70%) in-stent restenosis in the mid-segment of the RCA (Figure 5D), which was treated medically in the absence of ischemic evidence in the inferior territory on the stress test. The patient was discharged on optimal medical therapy for coronary artery disease, including dual antiplatelet therapy. In July 2008, the patient was readmitted with typical angina and shortness of breath. He was still on dual antiplatelet therapy of aspirin and clopidogrel with perfect compliance. An ECG showed inferior STEMI. Emergent cardiac catheterization revealed occlusion of the mid-RCA stent (Figure 6A). After coronary artery reperfusion using a wire (Figure 6B), the lesion was treated successfully with implantation of a Xience™ 4 x 28 mm DES (Abbott Vascular, Abbott Park, Illinois) (Figures 6 C and D).

Discussion

Very late ST is rare after BMS implantation outside the setting of brachytherapy.⁸ The incidence of definite very late ST after BMS implantation seems to be very low, as only 21 cases could be identified in the Medline literature, despite the deployment of millions of BMS over the past decade. (Table 1).^9–20 The pathophysiology of very late BMS thrombosis is poorly defined. Among the etiologies could be in-stent restenosis associated with severe narrowing leading to clot formation, chronic inflammation and in-stent atherosclerosis progression.²¹ It is not clear whether cessation of antiplatelet therapy plays a role in the occurrence of very late BMS thrombosis. In our cases, no recent modification of antiplatelet therapy had been made: the patient in Case 1 received aspirin monotherapy for 7 years before the event without experiencing ST, and the patient in Case 2 was still on dual antiplatelet therapy (aspirin-clopidogrel) at the time of the ST. The literature does not support modification of antiplatelet regimen as a cause for very late BMS thrombosis. Indeed, the majority of the patients who presented with very late BMS thrombosis were on aspirin alone, 1 patient was on dual antiplatelet therapy with aspirin and clopidogrel and 1 was chronically off antiplatelet therapy at the time of very late ST (Table 1). Nevertheless, the role of antiplatelet therapy could not be definitely determined because of the small number of events. Given the presence of mild in-stent neointimal formation in Case 1 and the evidence of significant in-stent restenosis 1 year before the event in Case 2, it is most likely that the narrowing caused by neointimal formation was the leading cause of the very late ST in these patients. Although Asakura et al reported regression of neointima over time after BMS implantation, we believe that it is mainly the in-stent neointimal progression or atherosclerosis progression in the stent or at the stent edge that can subsequently lead to very late ST. Indeed, Hasegawa et al reported histopathological evidence of new atherosclerosis progression occurring inside implanted stents.²² Other recent studies have observed that in-stent restenosis after BMS implantation presents as STEMI in around 3% of patients, thus suggesting progression of restenosis as a mechanism for very late ST with less dramatic manifestation as reported with DES, probably due to slow narrowing and occlusion versus abrupt and rapid closure.^23–25 Nevertheless, some authors have suggested other mechanisms. Asakura et al used angioscopy to investigate neointimal coverage of stents and observed that the neointima became thicker within the first 6 months following BMS implantation and then thinned, becoming transparent within 3 years, thus suggesting the regression of neointima as a possible cause of very late ST.²⁶ Also, Hayashi et al reported 2 cases of very late ST after BMS implantation with exposed stent struts visible by angioscopy.¹² Finally, mechanical factors such as stent malapposition or underexpansion and stent fracture are also proposed as possible causes of very late ST after BMS. When performed, IVUS demonstrated stent underexpansion or malapposition in 3 of 6 patients with very late BMS thrombosis.^10,12 Mechanical factors have also been identified as predictors for late ST and very late ST after DES implantation.^27,28 Finally, very late ST is not an exclusive phenomenon to DES and is also seen, albeit at a lower rate, after BMS implantation. Both types of stents share and differ in etiologies for this unpleasant phenomenon.

Conclusion

We report 2 cases of patients who presented with acute STEMI related to very late ST 6 years and 8 years after BMS imvplantation. Very late ST is fortunately very rare following BMS implantation. The etiologies are not completely understood and possibly differ from those for DES. Despite the focus on very late ST after DES implantation, this potential catastrophic complication in patients undergoing BMS implantation should not be overlooked. In this setting, the pivotal role of in-stent restenosis is yet to be determined. Pending more data and better understanding of the mechanisms, we believe that every clinician should be vigilant regarding the possible occurrence of very late ST in patients who have previously undergone BMS implantation.

References

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