Simultaneous Late Stent Thrombosis of Drug-Eluting Stents
Causing Acute Anterior and Inferior Myocardial Infarction

Late stent thrombosis (occurring more than 30 days after stent placement), is a catastrophic complication of drug-eluting stents (DES) that has recently gained heightened awareness. It has been reported to occur at a rate of 0.6% per year after DES placement, and is associated with mortality risk up to 25– 45%.^1–3 This has led to a critical evaluation of the role of DES in the current era of interventional cardiology. In this case report and brief discussion, we describe a patient who had simultaneous late stent thrombosis in two different coronary arteries, causing acute anterior and inferior myocardial infarction.

Case Report. A 46-years-old white male with a past medical history of diabetes mellitus and coronary artery disease presented to our emergency department with sudden-onset retrosternal chest pain. He had stopped taking clopidogrel 5 days previously. The admission electrocardiogram showed marked ST-segment elevations in anterior, lateral and inferior leads (Figure 1).
Four months previously, he had undergone an elective percutaneous coronary intervention (PCI) at an outside hospital to his mid left anterior descending artery (LAD) and mid right coronary artery (RCA) due to complaints of typical exertional angina. At that time, a coronary angiogram showed a chronic total occlusion of the mid RCA and an eccentric 80% lesion of the mid LAD at the bifurcation of second diagonal branch (Figures 2 and 3).

The mid RCA lesion was predilated with a 2 mm balloon and stented with a 3.5 x 33 mm Cypher^™ ( sirolimus- eluting stent; Cordis Corp., Miami Lakes, Florida) DES. Since the lesion did not get fully covered proximal to the stent, another overlapping 3.5 x 8 mm Cypher stent was placed at the proximal edge of the first stent. The stents appeared optimally expanded (inflation pressure of 16 atm) and there was thrombolysis in myocardial infarction (TIMI) 3 flow in the distal vessel (Figure 4). The mid LAD lesion was directly stented with a 3.5 x 23 mm Cypher stent deployed at 16 atm. Following stent deployment, the mid LAD appeared widely patent, but the second diagonal branch was compromised. Thus, the second diagonal was wired through the mid LAD stent and its ostium was dilated with a 2.5 mm balloon at an inflation pressure of 8 atm. The overall results were satisfactory, with no edge dissection and good runoff in the distal LAD and diagonal vessel (Figure 5).

At the time of the current hospitalization, the patient was emergently taken to the cardiac catheterization laboratory where coronary angiography revealed stent thrombosis and complete occlusion of both the mid LAD and mid RCA stents, with TIMI 0 flow distally in both the vessels (Figures 6 and 7). Emergent PCI was performed first on the LAD lesion. Percutaneous balloon angioplasty was performed with a single inflation at a pressure of 6 atm. Mechanical thrombectomy was performed using an Export^® Aspiration catheter (Medtronic Inc., Minneapolis, Minnesota) to partially remove the large angiographically apparent thrombus (Figure 8). A Cypher 3.5 x 23 mm sirolimus-eluting stent (SES) was deployed across the lesion with a single inflation at a maximum pressure of 16 atm. There was 0% residual stenosis and TIMI 2 flow in the LAD following the intervention (Figure 9). Subsequently, PCI was performed on the mid RCA lesion. Balloon angioplasty was performed using 2 inflations at a maximum inflation pressure of 6 atm. A Cypher 3.5 x 18 mm was placed across the lesion and deployed with a single inflation at a maximum pressure of 16 atm. There was 0% residual stenosis, and TIMI 3 flow was achieved following the intervention (Figure 10). Left ventriculography showed an ejection fraction (EF) of 35% with anterolateral, apical and diaphragmatic hypokinesis. The patient had an uncomplicated hospital course after the intervention and was discharged home after 3 days on a dual antiplatelet regimen.

Discussion. DES were approved in the U.S. in April 2003, beginning with the Cypher SES, and followed closely in March 2004, by the Taxus^®(paclitaxel-eluting stent; Boston Scientific Corp., Natick, Massachusetts). The initial pivotal trialsof these stents showed a remarkable 75% relative risk reduction in the rates of target lesion revascularization compared to baremetal stents (BMS).^4,5 This led to the U.S. Food and Drug Administration (FDA) approval of DES for a limited number of indications, but their use quickly grew markedly beyond those indications to the so-called “off-label use”. It is estimated that more than 1 million stents are placed annually in the U.S., and the stent industry has become a multi-billion dollar industry.⁶
The initial excitement associated with reduction in the rates of stent restenosis with DES recently come under tight scrutiny due to multiple reports of late stent thrombosis, increased risk of myocardial infarction (MI) and mortality. Camenzind et al presented a pooled analysis of the published randomized, controlled trials of Cypher and Taxus stents at the 2006 European Society of Cardiology Meeting in Barcelona, which showed a greater incidence of total mortality and Q-wave MI in first generation Cypher SES as compared to the control BMS (6.3% vs. 3.9%; p = 0.03), but not with Taxus PES vs. BMS (2.6% vs. 2.3%; p = 0.30).⁷ Similar findings were reported by the BASKET-LATE registry, which showed that subsequent to the discontinuation of clopidogrel (between 7–18 months), the rates of cardiac death and nonfatal MI were higher in the Cypher SES group than in the BMS group (4.9% vs. 1.3%).⁸

To the contrary, a subsequent patient-level reanalysis of the data from the same 4 trials of Cypher stents (RAVEL, SIRIUS, E-SIRIUS and CSIRIUS) conducted at the Erasmus University in Rotterdam, did not show any increase in death or Q-wave MI with Cypher DES compared to BMS (8.2% vs. 6.5%; p = 0.17).^9,10 There was also no significant increase reported in the risk of stent thrombosis with Cypher DES compared to BMS using the newly-described Academic Research Consortium (ARC) definitions (3.6% vs. 3.3%; p = 0.80). The risk of very late stent thrombosis (after 1 year), though, was noticed to be higher with Cypher DES than BMS, but not statistically significant (2.8% vs 1.7%; p = 0.14).⁹
However, it has definitely become evident that the incidence of late stent thrombosis with both SES and PES is higher than BMS in the real-world registries as compared to the selected population included in the randomized, controlled trials.¹ Some of these registries report a steady rate of late stent thrombosis of 0.4–0.6% per year up to 3 years of follow up with DES. This has been considered to be likely associated with increased complexity of patients and lesions.⁶
Several possible mechanisms have been proposed for latestent thrombosis including inhibition of neointimal growth, stent underexpansion, late-acquired stent malapposition and discontinuation of dual antiplatelet therapy.^11,12 Histopathological evaluations reported by Dr. Virmani show persistent inflammatory changes with delayed or absent stent strut endothelialization in these patients.¹²
We report a unique case of simultaneous late stent thrombosis of DES in two different arteries only a few days after the patient discontinued clopidogrel therapy. Possible risk factors for stent thrombosis in this particular case were bifurcational stenting of the LAD lesion, overlapping stent placement in the RCA, and early discontinuation of clopidogrel. We used DES for management of stent thrombosis in this patient since it was an emergent intervention, and the operator did not have knowledge of the type of stents that the patient had received in the past. Besides, there are no clear guidelines in the literature or evidence from randomized, controlled trials for optimal PCI techniques to manage patients with DES-related stent thrombosis with either balloon angioplasty alone or with the use of DES or BMS. The optimal duration of clopidogrel therapy to treat patients following an episode of stent thrombosis has also not been evaluated in any randomized, controlled trials.
With several recent studies showing the risk of late stent thrombosis post-DES, the current American College of Cardiology( ACC)/American Heart Association (AHA) guidelines now recommend use of clopidogrel following DES placement for a period of up to 6 months, with a consideration for 12 months.¹³ On the other hand, a recent study published by Daemen et al has challenged the role of longer duration of clopidogrel therapy in preventing late stent thrombosis.¹ In their patient cohort, despite the longer duration of clopidogrel prescription (12 months) in the patients from Bern compared with those in Rotterdam (6 months), the incidence of late stent thrombosis was similar in both centers. The optimal duration of use of antiplatelet therapy after DES still remains unclear, and will need to be examined by future clinical trials.
It is hoped that with the advent of the next generation of DES, the incidence of late stent thrombosis will be reduced and indeed initial reports are quite promising. Two-year follow up data from the ENDEAVOR III trial in patients undergoing zotarolimus-coated stent placement showed no stent thrombosis, and equivalent major adverse cardiac events (MACE) rates, target lesion revascularization compared to Cypher DES.¹⁴ Ninemonth follow up of patients in the SPIRIT III trial undergoing everolimus-coated stent placement (XIENCE V) presented at the ACC 2007 Conference, showed a significantly lesser incidence of target vessel failure, 44% reduction in MACE rate versus Taxus DES, and a rare incidence of stent thrombosis.¹⁵
The safety and efficacy of these second-generation DES will need to be evaluated in long-term follow-up studies. In the meantime, it would be prudent to consider longer-term therapy with a dual antiplatelet regimen in patients receiving first-generation polymer-based Cypher and Taxus DES who are at high risk of late stent thrombosis, such as those with a previous history of late stent thrombosis, multiple stents, overlapping stents, bifurcation stents and in those who have a large area of myocardium at jeopardy in cases of left main stenting.

References
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