Although stent thrombosis is currently a rare complication of percutaneous coronary intervention (PCI), it can cause devastating clinical results such as acute myocardial infarction (AMI) and death.1 The peak incidence of stent thrombosis usually occurs within the first 48 hours post-PCI, and is rarely encountered after the first week of stent implantation.1 Late stent thrombosis (> 30 days) is an even more unusual phenomenon, and has been demonstrated to be associated with brachytheraphy2 and radioactive or drug-eluting stents.3 Recently, late stent thrombosis more than one month after stenting has been reported in patients who underwent intracoronary brachyheraphy, perhaps due to a radiation-induced delay in the formation of an endothelial monolayer on the stent surface.2 Exercise testing, which is used to investigate myocardial ischemia in patients undergoing coronary stent placement, has been associated with a transient activation of the coagulation system4 and hemodynamic changes, inducing thrombosis in the presence of triggering factors. Following the widespread acceptance of high-pressure post-dilatation with antiplatelet agents in PCI, the additional benefits of intravascular ultrasound (IVUS) have been debated.5 However, some investigators have proposed that IVUS-guided therapy could improve procedural results.6 We present a case of a 43-year-old man who underwent stenting in the left anterior descending artery (LAD) 16 months ago, and presented with AMI due to late stent thrombosis two hours after exercise electrocardiography. Case report. In June 2003, a 43-year-old man had undergone successful stent deployment in the mid-LAD lesion for exertional chest pain. A slotted tube coronary stent (Ephesos, Nemed, Istanbul, Turkey), 2.5 x 15 mm had been placed at 14 atm inflation pressure with an optimal angiographic result. The patient’s hospital stay had been uneventfull and he was discharged two days post-PCI. We had prescribed a daily dose of 100 mg aspirin (for life), 75 mg clopidogrel (for three months) and 40 mg atorvastatin at hospital discharge. Six months later, the asymptomatic patient underwent control angiography which showed no evidence of significant in-stent restenosis. In October 2004, the patient presented with chest pain which began during walking and lasted several minutes. Thus, he was reevaluated with an exercise ECG for inducible ischemia. Unfortunately, two hours after a negative exercise test, he developed sudden, severe, typical chest pain associated with excessive sweating. He was immediately transferred to our hospital. Upon hospital admission, the ECG revealed ST-segment elevation in the anterior leads; his arterial blood pressure and heart rate were 120/70 mmHg and 80 bpm, respectively. Physical examination showed a 1/6 grade systolic murmur auscultated in the apical region, but was otherwise normal. Bedside transthoracic echocardiography showed severe hypokinesis in the anterior wall. Left ventricular systolic functions were depressed, and his ejection fraction, calculated with modified Simpson method, was 45%. Mild mitral regurgitation was detected in a Doppler study. He was emergently taken into the catheterization laboratory. Coronary angiography revealed massive in-stent thrombosis in the LAD (Figure 1). Thrombectomy was perfomed using a 1.5 mm X-Sizer catheter (EndiCOR Medical Inc., San Clemente, California), in combination with an adjunctive glycoprotein IIb/IIIa antagonist (tirofiban), which completely removed filling defects in the stented segment (Figure 2A). Twenty-four hours later, IVUS imaging (Atlantis 40 mHz, Boston Scientific, Maple Grove, Minnesota) of the LAD was peformed to determine the cause of late stent thrombosis (Figure 2B, C, D). IVUS clearly demonstrated that the stent was under-expanded, and that a large atheromatous plaque burden remained in the stented segment of the coronary artery. Additional balloon inflations with a 2.5 mm balloon were also performed following IVUS imaging. Early peak of creatine kinase MB isoform was observed at the eighth hour (293 U/l). The patients was discharged five days later and was advised to take aspirin and clopidogrel for life. Discussion. Although late stent thrombosis is very rarely seen in patients undergoing bare stent placement after PCI, when it occurs, it may cause catostrophic clinical sequelae, including AMI and death.7 The most common risk factors for late stent thrombosis are stent length and number, post-procedure minimal lumen diameter (stent underexpansion), residual coronary dissection, and early withdrawal of antiplatelet therapy.8 The IVUS study of our patient demonstrated that the stent was not optimally expanded in the vessel wall despite the fact that post-procedure coronary angiograms at the time of stent deployment showed good results, with a perfect lumenal appearence. We believe that stent under-expansion may have caused late stent thrombosis in this case. Heller et al. reported that late stent thrombosis is an unusual, but serious, complication in patients who have not received coronary brachytherapy according to the results of a large study which included over 1,800 patients.7 In that study, 12 patients presented with late stent thrombosis between 33 and 270 days post-procedure (mean 72.9 ± 23 days). Late stent thrombosis was found to be associated with a 16.7% mortality rate and very high morbidity rates in that study. Up to now, only two late stent thrombosis cases occurring one year after stent implantation have been reported in the literature.9 Hayashi et al. reported two cases of AMI caused by late thrombotic occlusion at the conventional stented site two years after stenting.9 Parodi et al. reported a case of late stent thrombosis that occurred six months after the primary stenting of the LAD for AMI in a 75-year-old man. After exercise stress testing, the patient developed acute anterolateral myocardial infarction. However, our patient presented with AMI two hours following exercise stress testing due to late stent thrombosis which occurred 16 months after stent placement. It is now widely accepted that high-pressure deployment of stents with dual antiplatelet therapy, including clopidogrel, reduces the incidence of subacute stent thrombosis.5 Subsequently, routine high-pressure deployment without IVUS imaging became the standard of therapy.5 Studies demonstrating that stent thrombosis could be limited with a combination of high-pressure balloon dilatation and antiplatelet drugs evaluated 30-day clinical end points, and therefore did not address the issue of late stent thrombosis.10 To the best of our knowledge, late stent thrombosis is a negligible phenomenon, though its sequela may be fatal. The concerns about the occurrence of in-stent restenosis may mask the importance of late stent thrombosis. Because all of the studies have focused on in-stent restenosis and its clinical results, there is no large-scale study on late stent thrombosis. Although it has been shown that IVUS-guided stent placement did not reduce restenosis rates,11 the role of IVUS in the prevention of late stent thrombosis has been largely unknown. Even if a post-procedure coronary lumenogram at the time of stent placement indicated a perfect angiographic appearance, an IVUS study 16 months later revealed that the stent was under-expanded. Thus, we believe that optimal stent sizing with the use of IVUS imaging could be essential in preventing late stent thrombosis which could lead to catastrophic complications. The cost-effectiveness of this approach is open to debate, but when the clinical results of late stent thrombosis are taken into account, it seems reasonable to perform IVUS-guided stent placement to prevent late stent thrombosis, especially in patients in whom stent sizing was difficult. The PCI-CURE (Percutanous Coronary Intervention-Clopidogrel in Unstable Angina to prevent Recurrent ischemic Events) and CREDO (Clopidogrel for the Reduction of Events During Observation) trials have shown that long-term (one-year) clopidogrel therapy is effective in reducing adverse cardiovascular events, including death, AMI and stroke.12,13 We believe that long-term clopidogrel treatment may improve cardiovascular outcomes by preventing late stent thrombosis. The role of exercise testing in the occurrence of stent thrombosis is not well-delineated. It was found that platelet activation increases during exercise testing in sedentary patients.4 Dash et al. found that the increased vessel wall stres associated with exercise increases coronary pressure and flow, which may traumatize an already disrupted intima.14 Cooper at al. found that fibrinolysis increases with acute exercise and decreases rapidly during the post-exercise period.15 Consistent with these data, our patient developed AMI two hours after exercise testing. The decrease in fibrinolysis and activation of the coagulation system may have triggered stent thrombosis when combined with the relatively low-flow during exercise in our patient. Also, because the stent was not sufficiently expanded, the relative residual stenosis may have caused blood stagnation around the stent struts, resulting in stent thrombosis. In conclusion, late stent thrombosis, though relatively uncommon, is a serious complication in the patients undergoing stent placement. Thus, we believe that prolonged administration of clopidogrel (> 1 year) for selected cases could prevent this potentially fatal complication.
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