Thrombosis and Acute Myocardial Infarction as Consequences of Very Late Stent Malapposition after Implantation of a Drug-Eluting

The use of drug-eluting stents (DES) has become popular because of their favorable effects on clinical and angiographic outcomes.^1–5 However, most clinical results have been reported on simple de novo lesions. In real-world practice, more complex lesions are frequently encountered with an increased risk for late cardiovascular events. We have concerns regarding the long-term safety of DES because of the development of late stent malapposition (LSM) and thrombosis.^6,7
LSM has been reported based on intravascular ultrasound (IVUS) studies following implantation of bare-metal stents and brachytherapy.^8,9 It has also been reported in 12% of cases after DES implantation at 6 months. LSM was not reported to be associated with late cardiovascular events during a follow-up period over 10 months in one study.¹⁰ However, there is limited information regarding the possible causal relationship between long-term LSM and stent thrombosis.
Here we report a case of late stent thrombosis and myocardial infarction associated with LSM that developed more than 16 months after stent implantation.

Case Report

A 45-year-old male patient was admitted with exertion-induced chest pain that developed 2 months before admission. His physical examination, blood pressure and heart rate were all normal. An echocardiography showed normal left ventricular wall motion and a normal ejection fraction. The electrocardiogram was normal and the treadmill test showed ST-segment depression at a modified Bruice stage 3. The coronary angiogram revealed a diffuse, tight stenosis at the mid segment of the left anterior descending artery, with a grade 2 collateral flow from the right coronary artery and tubular concentric stenosis, 70% in diameter, at the proximal second diagonal branch (Figure 1A). After crossing a Runthrough guidewire (Terumo, Japan), we performed balloon dilatation with a 2.5 mm diameter Aqua balloon (Cordis Corp., Miami, Florida). Stent implantation was successfully performed with a 2.75 x 33 mm Cypher™ sirolimus-eluting stent (Cordis) at 10 atm (Figure 1B). The patient was discharged with the following medications: aspirin 200 mg/day, clopidogrel 75 mg/day, a beta-blocker and a statin. A routine follow-up angiography was performed at 10 months after the procedure and the stent was noted to be patent (Figure 1C). At 16months after stenting, the patient visited the emergency room with chest pain at rest for 1 hour. The electrocardiogram showed a 5 mm ST-segment elevation on precordial leads V2–V5. The CK-MB and troponin-I were elevated to a maximum 2,567 ng/dl and 270 ng/dl, respectively. Because angiographic equipment was not available, the patient did not undergo primary angioplasty; instead, he received heparin and 75 mg of metylase.
Coronary angiography performed 5 hours after thrombolytic therapy revealed a diffuse irregular luminal dilatation with multiple thrombi in the stented segment (Figure 1D). Anticoagulation therapy with low molecular-weight heparin was administered for 5 more days. Six days after admission, follow-up coronary angiography was performed, revealing diffuse ecstatic changes outside of the DES without a visible thrombus and TIMI 3 flow (Figure 2A). The lesion was crossed with a 0.014 inch Runthrough guidewire and a Galaxy IVUS study (Boston Scientific Inc., Natick, Massachusetts) was performed to determine the apposition status of the stent. The IVUS study demonstrated a diffuse, eccentric echo-free space behind the stent along the entire segment of the stent (Figure 2B). Balloon angioplasty was performed to adhere the stent strut to the vessel wall. Using a 3.0 x 10 mm Aqua balloon, the stent was dilated at high pressure (16 atm). After multiple dilatations with the balloon, stent apposition was improved as shown by IVUS (Figure 2C). The patient was discharged the day after the procedure on aspirin, clopidogrel and cilostazol.

Discussion

The frequency of LSM increased after the introduction of DES, especially in cases with long lesion coverage, acute myocardial infarction and chronic total occlusion.¹⁰ However, it has not been related to any cardiovascular events in short-term follow up.¹⁰ Here, we report a case of LSM that developed late, after 16 months, and led to stent thrombosis and acute myocardial infarction despite long-term dual antiplatelet therapy.
DES was a clinical breakthrough for troublesome restenosis in patients requiring coronary intervention. Recently, safety issues with DES have been raised and stent thrombosis and LSD are currently major concerns.^11,12 The main clinical effect of DES results from the inhibition of neointimal proliferation at the site of arterial injury. DES causes delayed arterial healing and increased inflammatory reaction compared to bare-metal stents. In addition, the DES is more prone to LSM and stent thrombosis.^13,14 LSM is a potential complication of brachytherapy and is associated with positive remodeling and regression of neointimal hyperplasia.^9,15 LSM has been reported to occur in 4–5% of bare-metal stents, usually at the stent edges.⁸ The frequency of LSM after DES procedures has been reported to be double that of bare-metal stents.¹⁰ Many mechanisms have been postulated to explain LSM after DES implantation. These factors include positive vascular remodeling, regression of unstable plaque, dissolution of the thrombotic materials captured behind the stent strut and cell necrosis.¹⁶ In addition, allergic reaction to sirolimus and a possible hypersensitivity reaction to the polymer have been suggested as underlying causes of LSM.¹⁴ Regarding the case presented here, a possible explanation for the LSM was the presence of a large plaque burden in a high-grade stenotic lesion, or perhaps the stent used was too small for the vessel. Consequently, there was long-term inhibition of neointimal hyperplasia accompanied by plaque resolution that progressed to LSM and stent thrombosis. Sirolimus-eluting stents have demonstrated persistent inhibition of neointimal hyperplasia for up to 2 years after implantation.⁴ In our case, the 10-month follow-up angiogram did not reveal any findings suggestive of LSM. However, the LSM and thrombus formation developed 16 months after DES implantation, even with dual-agent antiplatelet therapy. This finding suggests that LSM can occur at any time after DES implantation. The optimal therapeutic strategy for the treatment of LSM has not been established. We could improve stent apposition with multiple balloon dilatations using a 10 mm short balloon. There is no information yet regarding the safety and late outcome of overdilatation of DES using a larger balloon. Further studies are needed to determine the optimal duration and regimens of antiplatelet therapy in patients with LSM. In summary, LSM in a long segment can lead to stent thrombosis and acute coronary syndrome at any time period after the procedure. Also, optimal stenting is mandatory to prevent LSM in cases with long and high-grade stenotic lesions.

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