Simultaneous Very Late Stent Thrombosis in Multiple Coronary Arteries

Abstract

We report 2 noteworthy cases of very late stent thrombosis presenting as ST-segment-elevation myocardial infarction, with vastly different manifestations. Both patients were women who had histories of multivessel percutaneous coronary intervention with first-generation sirolimus-eluting stents, in 2005 and 2006. On the more recent occasions reported here, one underwent successful multivessel primary percutaneous coronary intervention, while the other underwent successful multivessel “plain old balloon angioplasty.” Both were discharged from the hospital with advice to stop smoking and to follow a lifelong regimen of aspirin and clopidogrel.

On the basis of these two cases and our review of the current literature, we ask whether it is now prudent to recommend lifelong dual antiplatelet therapy after drug-eluting stent deployment. Moreover, in order to account for cases of stent thrombosis that occur ≥5 years after drug-eluting stent implantation, should we perhaps suggest the addition of “extremely late stent thrombosis” to the existing Academic Research Consortium classification?

Stent thrombosis after percutaneous coronary intervention (PCI) remains a serious concern for both cardiologists and patients. The incidence of stent thrombosis within the first 30 days in patients randomized to receive sirolimus-eluting stents (SES) in clinical trials is reported to be no different from that in patients randomized to a control group receiving bare-metal stents.¹ Stent thrombosis has been reported as late as 17 months,² and more recently as late as 26 months, after SES implantation.³ We report 2 cases of simultaneous very late stent thrombosis in multiple coronary arteries ≥5 years after drug-eluting stent (DES) implantation, presenting as an ST-segment-elevation myocardial infarction (STEMI) despite a regimen of aspirin in patient 1 and both aspirin and clopidogrel in patient 2.

Case Reports

Patient 1

In 2010, a 77-year-old woman presented with acute inferior STEMI in the setting of previous multivessel PCI. She had a 2.5 × 13-mm first-generation Cypher® sirolimus-eluting stent (Cordis Corporation, a Johnson & Johnson company; Miami Lakes, Fla) deployed in her mid left anterior descending coronary artery (LAD) and a 2.5 × 18-mm Cypher stent in her proximal right coronary artery (RCA) in 2005. Since 2005, she had undergone follow-up coronary angiography 7 times, and each time the images had shown patent stents in both the LAD and the RCA. Background medical problems included treated hypertension, hypercholesterolemia, and hypothyroidism, together with ongoing smoking. Her current medications were aspirin 81 mg daily, metoprolol 25 mg twice daily, enalapril 2.5 mg daily, methimazole 30 mg daily, simvastatin 40 mg daily, and ipratropium 2 inhalations twice daily. Her last echocardiogram, in 2010, showed normal left ventricular (LV) function with LV hypertrophy and an ejection fraction of 0.65. The rest of the study was unremarkable.

Coronary angiography showed a fresh occlusion of the mid LAD (Fig. 1) and a fresh occlusion of the proximal RCA (Fig. 2). Both lesions were in-stent thromboses. The mid-LAD lesion was crossed with a Luge™ Guide Wire (Boston Scientific Corporation; Natick, Mass) and serially predilated with a 2.5 × 12-mm Apex® PTCA Dilatation Catheter (Boston Scientific), followed by a Quantum™ Maverick® 3.25 × 20-mm balloon (Boston Scientific). Due to the patient's questionable compliance and ongoing smoking, we deployed a 3.5 × 22-mm Integrity® bare-metal stent (BMS) (Medtronic, Inc.; Minneapolis, Minn) at 16 atm of pressure for 15 seconds and postdilated it with a Quantum Maverick 3.75 × 15-mm balloon at 20 atm of pressure for 15 seconds, with good result (Fig. 3). The proximal RCA lesion was crossed with a Luge wire and predilated with an Apex 2.5 × 20-mm balloon. We deployed a 2.5 × 26-mm Integrity BMS at 16 atm of pressure for 15 seconds and postdilated it with a Quantum Maverick 2.75 × 20-mm balloon at 20 atm of pressure for 15 seconds, with good result (Fig. 4). An intravenous abciximab infusion was continued for 12 hours. Testing for hypercoagulation abnormalities and clopidogrel resistance yielded noncontributory results. The patient was discharged from the hospital with advice to follow a lifelong aspirin and clopidogrel regimen and to stop smoking.

Fig. 1 Patient 1. Coronary angiography shows occlusion (arrow) of the mid left anterior descending coronary artery before stent deployment.

Fig. 2 Patient 1. Coronary angiography shows occlusion (arrow) of the proximal right coronary artery before stent deployment.

Fig. 3 Patient 1. Coronary angiography shows lesion (arrow) of the left anterior descending coronary artery after stent deployment.

Fig. 4 Patient 1. Coronary angiography shows lesion (arrow) of the right coronary artery after stent deployment.

Patient 2

In 2011, a 62-year-old woman presented with cardiogenic shock in the setting of an acute anterior and inferior STEMI, with a history of previous multivessel PCI. In 2006, she had 4 stents implanted: a 2.5 × 8-mm first-generation Cypher SES in the proximal LAD, a 3 × 18-mm in the proximal RCA, a 3 × 18-mm in the mid RCA, and a 2.5 × 15-mm in the first obtuse marginal branch (OM1). Her background medical problems included treated hypertension, hypercholesterolemia, and hypothyroidism, together with ongoing smoking. Her current medications were aspirin 81 mg daily, clopidogrel 75 mg daily, metoprolol 25 mg twice daily, lisinopril 10 mg daily, and simvastatin 40 mg daily. Since 2006, she had undergone no follow-up coronary angiographic studies.

Coronary angiography showed occlusion of the proximal LAD and OM1 (Fig. 5), together with occlusion of the distal RCA (Fig. 6). Both the LAD and RCA occlusions were instances of in-stent thrombosis.

Fig. 5 Patient 2. Coronary angiography shows occlusion of the proximal left anterior descending coronary artery (arrow) and mid first obtuse marginal branch (arrowhead).

Fig. 6 Patient 2. Coronary angiography shows occlusion (arrow) of the distal right coronary artery.

Right-sided cardiac catheterization showed a cardiac index of 1.55 L/min/m² and a pulmonary capillary wedge pressure of 32 mmHg. Mechanical hemodynamic support was achieved by using the Impella® 2.5 (Abiomed, Inc.; Danvers, Mass).

The proximal LAD lesion was crossed with a Luge wire and serially predilated with 2.5 × 15-mm and 2.75 × 15-mm Apex balloons with good angiographic results (Fig. 7). The OM1 was crossed with a Luge wire and dilated with a 2.75 × 15-mm Apex balloon with good angiographic results (Fig. 7).

Fig. 7 Patient 2. Coronary angiography shows the left anterior descending coronary artery (white arrow) and the first obtuse marginal branch (black arrow) after balloon angioplasty, with the Impella 2.5 device (arrowhead) in situ.

During the procedure, the patient had several episodes of ventricular fibrillation that necessitated direct-current cardioversion. The right coronary lesion was not attempted because of the patient's hemodynamic instability. The Impella device was left in situ, and the patient was transferred to the coronary care unit. Repeat right-sided heart catheterization showed improved hemodynamic values (coronary index, 2.2 L/min/m²; and pulmonary capillary wedge pressure, 18 mmHg). The Impella device was removed 12 hours later. She remained in a stable condition throughout her hospital stay.

In this case, our primary goal was to establish Thrombolysis in Myocardial Infarction (TIMI) 3 flow. We did consider stenting, but in light of the episode of stent thrombosis, we thought that adding more metal to a previously stented segment might increase the risk of another thrombotic episode. In addition, there is evidence that stenting in primary PCI increases the chances of coronary slow flow. Given the presence of cardiogenic shock, our primary goal was to achieve TIMI 3 flow without a chance of slow flow. Hence, we stopped with “plain old balloon angioplasty.”

Discussion

Acute STEMI secondary to stent thrombosis is a catastrophic event that commonly presents as an acute myocardial infarction (in 70% of cases) and can result in death (20%–40% mortality rate).^4,5 It is typically seen within the first 30 days after stent implantation.^5–7 The Academic Research Consortium classifies stent thrombosis as early (occurring within 30 d of stent deployment), late (31 d–1 yr) or very late (after 1 yr). Late stent thrombosis is an infrequent but serious complication of DES implantation.^8,9 Although rare, it is fatal in almost 50% of all cases.¹⁰ Stent thrombosis can develop immediately or a year after implantation.¹¹ Discontinuation of antiplatelet therapy has been strongly associated with DES thrombosis and is usually seen within 2 weeks after cessation.² Cases of stent thrombosis have occurred several months after stopping clopidogrel and aspirin.^2,12 This has led us to question the optimal duration of dual antiplatelet therapy after DES implantation.

Identified predictors of stent thrombosis in patients with SES are advanced age, premature antiplatelet discontinuation, clopidogrel resistance, insulin-dependent diabetes mellitus, low LV ejection fraction, moderate or heavy calcification, multivessel disease, postprocedural TIMI <3, and a totally occluded lesion as the first manifestation.¹³

Very late stent thrombosis, a new phenomenon, has been reported more often in association with DES than with BMS. The incidence appears to be between 0.4% and 0.6% per year.^14,15 It is of interest that very late stent thrombosis is rarely seen in BMS implantation, outside the setting of brachytherapy.¹⁶ The mechanism of very late stent thrombosis is not fully understood. A delay in the healing process, late hypersensitivity reaction to polymers and consequent chronic inflammatory changes,^1,17,18 incomplete neointimal coverage over stent struts,¹² late stent malapposition,^19–21 stent under-expansion,²² stent fracture,^23,24 delayed strut endothelialization, and the prothrombotic characteristics of the DES^19,25 are thought to play a role several years after initial deployment.

Endothelial dysfunction may well be a contributor to very late stent thrombosis. An intriguing observation is that, in an SES subgroup, paradoxical exercise-induced vasoconstriction occurred in both proximal and distal segments of the vessel adjacent to SESs. In comparison, a BMS subgroup displayed normal exercise-induced vasodilation.²⁶ This suggests drug-induced endothelial dysfunction.

Inoue and colleagues²⁷ studied histopathologic samples of coronary arteries at necropsy of 36 patients after SES implantation. Around the stent struts, they found fibrin deposition and infiltration of chronic inflammatory cells (that is, T-lymphocytes and macrophages) despite adequate endothelial coverage by the stents, with the exception of the coverage surrounding bifurcation stenting of side branches. They postulated that severe peri-strut chronic inflammation after SES implantation might accelerate neointimal vulnerability and that this in turn might be followed by very late stent thrombosis, despite endothelial coverage and continuous antiplatelet therapy. Finally, they emphasized the importance of stabilizing atheromatous plaque with statins, which might prevent very late stent thrombosis after SES implantation.²⁷

A recent study by Nakazawa and colleagues²⁸ illustrated the pathological basis of stent thrombosis in both first-generation SESs and paclitaxel-eluting stents. They described the clear difference in the underlying composition of the neointima post stent deployment. Hypersensitivity seems to play a significant role in SESs, whereas for paclitaxel-eluting stents, the cause of thrombosis seems to be excessive fibrin deposition on the abluminal surface in the presence of malapposition.²⁸ In our patient 1, although the mechanism of stent thrombosis was multifactorial, it seems possible that chronic malapposition due to inadequate stent size may well have been a critical contributing factor to the stent's late failure.

The mystery of stent thrombosis is slowly unraveling. These cases raise serious questions regarding the current recommendations for the duration of dual antiplatelet therapy after DES deployment and, perhaps, prompts a call for the addition of “extremely late stent thrombosis” to the existing Academic Research Consortium classification, to account for cases of stent thrombosis that occur ≥5 years after DES implantation. In consideration of the new cases of very late (or “extremely late”) stent thrombosis and the increasing frequency of multivessel PCI, is it now prudent to recommend lifelong dual antiplatelet therapy? In selected cases, perhaps the newer hybrid myocardial revascularization²⁹ should be considered.

Acknowledgment

We would like to thank Katrina McKay, RN, MHS, for helping with the preparation of this manuscript.