Case Report. A 64-year-old male was transferred from an outside facility after sustaining a non-ST-elevation myocardial infarction (STEMI). Cardiovascular risk factors included noninsulin- dependent diabetes mellitus and hypertension. Additionally, his past medical history was significant for a stent placed in the left anterior descending artery in the remote past, as well as bladder cancer status post cystectomy 5 months prior and chemotherapy completion a few weeks ago. He was hemodynamically stable and symptom-free at the time of admission to our hospital. Physical examination revealed normal vital signs, as well as normal pulmonary and cardiovascular findings. Electrocardiography demonstrated normal sinus rhythm and anterolateral Twave inversions. Laboratory values included: creatine kinase (CK) of 411 U/L, creatine kinase-MB isozyme (CK-MB) of 41.36 ng/mL, troponin I (TROP-I) of 0.869 ng/mL, total cholesterol of 131 mg/dL, low-density lipoprotein of 80 mg/dL, highdensity lipoprotein of 27 mg/dL, and triglycerides of 76 mg/dL.
Cardiac catheterization revealed significant stenoses in the mid left circumflex (LCX) and first obtuse marginal arteries (Figure 1), with a patent previous left anterior descending stent. Left ventricular function and size were within normal limits. Subsequent percutaneous coronary intervention (PCI) of the obtuse marginal branch with a 2.0 x 12 mm Voyager balloon (Abbott Vascular, Abbott Park, Illinois) reduced the lesion to less than 20% residual stenosis. Attention was then turned toward the LCX stenosis, which was successfully stented with a 2.5 x 12 mm Taxus® (Boston Scientific, Natick, Massachusetts) DES, with a good final result (Figure 2). The patient had an uneventful recovery and was discharged after 2 days. A beta-blocker, angiotensin-converting enzyme inhibitor, statin, along with daily dual antiplatelet therapy (DAT) of clopidogrel 75 mg and aspirin (ASA) 325 mg were added to his previous medical regimen.
Eight days post-PCI, he presented with an acute inferolateral STEMI, with a CK of 621 U/L and a CK-MB isozyme of 43.7 ng/mL. After failure of initial thrombolytic therapy, he underwent emergent salvage angiography by a different interventionalist. Although the LCX artery demonstrated Thrombolysis in Myocardial Infarction (TIMI)-3 flow, an area of haziness was seen within the previous stent, consistent with residual clot from subacute thrombosis (SAT) (Figure 3). The patient’s left ventricular ejection fraction was now reduced at 40%, with inferolateral akin esis.Balloon angioplasty resulted in a dissection at the distal stent edge. This was repaired with additional deployment of a 2.5 x 8 mm Taxus DES, overlapping the previous distal stent edge, with an excellent final result (Figure 4). Again, the patient had an uncomplicated recovery and was discharged on the third hospital day on his previous medical regimen.
Five days after the second PCI, the patient again underwent unsuccessful thrombolytic therapy for another inferolateral STEMI at an outside facility. The CK level was 120, CK-MB was 15, and TROP-I was 4.01. After transfer to our hospital, emergent salvage catheterization by a third cardiologist revealed LCX stent thrombosis, with total vessel occlusion (Figure 5). After Export catheter (Medtronic, Minneapolis, Minnesota) thrombectomy and subsequent balloon dilatation, a 2.25 x 12 mm MiniVision (Abbott) BMS was deployed, overlapping the previous distal DES edge. The final result revealed no residual stenosis or dissection and excellent TIMI-3 flow (Figure 6). The patient’s clopidogrel dose was increased to 75 mg twice a day. Unfortunately,despite staff recommendations, the patient signed out against medical advice after 2 days.
On day 31 following his third PCI, the patient once again presented with an acute inferolateral STEMI. Repeat emergent coronary angiography revealed a patent LCX stent; however, there was a possible non-flow-limiting linear dissection within the stent lumen (Figure 7). Given the very complicated recent course, no further mechanical interventions were undertaken.The patient emphatically claimed compliance with his twice daily clopidogrel and adult-strength ASA regimen. Hypercoagulable evaluation revealed normal protein C and S levels. After 2 uneventful hospital days, he was discharged on his previous medical regimen. He continues to smoke, despite prescriptions of bupropion and nicotine patches, but has remained infarct-free.
Discussion. DES, like BMS during the balloon angioplasty era, represent a quantum leap in combating coronary restenosis. This dramatic innovation, however, has been recently overshadowed by the specter of thrombosis, especially late angiographic stent thrombosis (LAST), defined as occurring > 30 days. Mechanistically, there is convincing pathological evidence of incomplete or absent neointimal healing, as well as hypersensitivity reactions. As opposed to the gradual process of restenosis, stent thrombosis not infrequently results in acute STEMI or death. However, recurrent DES-SAT (defined as 1 to 30 days), as occurred in our patient, has not been previously reported as a risk.
The seminal RAVEL (Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de novo Native Coronary Artery Lesions)1 and SIRIUS (Sirolimus-Eluting Stent in De Novo Native Coronary Lesions)2 trials reported dramatically decreased restenosis rates of sirolimus-eluting stents (SES) (Cypher™, Cordis Corp., Miami Lakes, Florida) over control BMS. Subsequently, the TAXUS (Treatment of De Novo Coronary Disease Using a Single Paclitaxel-Eluting Stent) trials demonstrated similarly impressive major adverse cardiovascular event (MACE) reductions for paclitaxel-eluting stents (PES) (Taxus, Boston Scientific) versus BMS controls.3–7 In particular, the pivotal TAXUS IV trial reported a 3.0% binary in-stent restenosis (ISR) rate, compared to 11.3% for BMS at 9 months (p < 0.001).7
Early safety concerns regarding early thrombosis (ET, < 24 hours) and SAT were allayed by equivalent thrombotic rates in the relatively short initial follow-up periods in these studies.1–7 Furthermore, the post-marketing E-Cypher (European - Cypher) registry found similar SAT rates for SES versus BMS. In this 12-month follow-up, three-fourths of all stent thromboses were seen within 3 weeks.8 In their review of 2,512 patients, of whom 506 received BMS, 1,017 SES, and 989 PES, Ong and others reported a uniform 1% SAT seen in all 3 groups.9 Available data suggest that while the risk of DESLAST is slightly increased, that of DES-SAT is equivalent to that for BMS. Thus, repeated SAT, as seen in our patient, is quite rare.
The pathophysiology of stent thrombosis involves a complex cascade, with platelets as the central element. When exposed to nonendothelialized metallic struts, platelets adhere through binding of von Willebrand’s factor, glycoprotein (GP) IB, GP-IA/IIA and collagen. Next, activation occurs via the release of vasoactive factors including thrombin, adenosine diphosphate, thromboxane A2, serotonin and CD40L. Subsequently, activated platelets aggregate into a meshwork by GP IIb/IIIa, serotonin and fibrinogen; the resultant platelet plug may then progress to thrombotic stent occlusion.10 At 6 months, pathological specimens demonstrate surface areas of 30 mm2 and 10–15 mm2 for BMS and DES, respectively.3 In one angioscopic series, complete endothelialization was observed in 100% of BMS, but in only a striking 13.3% of DES.11
Clopidogrel resistance is a potential etiology of stent thrombosis. This phenomenon can result from alterations or abnormalities in intestinal absorption or in hepatic conversion to active metabolites. Drug-drug interactions as well as receptor polymorphisms may also contribute.12 Concurrent glycoprotein IIb/IIIa inhibition likely augments the actions of clopidogrel. Gurbel and coinvestigators compared various inflammatory and platelet aggregation parameters in poststent implantation patients who received either clopidogrel alone or combined clopidogrel/eptifibatide. They found marked reductions in platelet aggregation, active glycoprotein IIb/IIIa expression, C-reactive protein and tumor necrosis factor-alpha. Perhaps more importantly, individuals in the combined therapy arm had lower postprocedural levels of cardiac markers.13 In our case, the patient received eptifibatide during the first and fourth infarcts. The second and third presentations, however, were treated unsuccessfully with thrombolytic therapy. Paradoxically, these agents can potentially enhance platelet aggregation.
Additionally, allergic reactions may be an underrecognized cause of stent thrombosis and can occur with the antirestenotic agent, the bonding polymer and even the stent metal itself.14 Furthermore, DES-induced negative remodeling creates a gap between the deployed stent and aneurysmal vessel wall, which may act as a nidus for platelet adherence/ activation.15 While reports of DES thrombosis continue to surface, few have been observed while on DAT. Discontinuation of DAT with clopidogrel and ASA has emerged as a reliable predictor of DES thrombosis at any time interval.
As long-term DES follow-up became available, isolated reports of DES-LAST began to surface. Stabile and associates reported 2 cases of DES-LAST at 11 and 12 months postimplantation after DAT cessation. Ironically, in both patients, preexisting BMS in other vessels were widely patent.16 On “Black Sunday” at the 2006 European Society of Cardiology, Camenzind reported a significantly higher 6.3% combined death/MI rate of SES over the 3.9% observed for BMS.17 This announcement further solidified the growing public concern regarding the possibility of increased DESLAST. Additionally, The BASKET-LATE [Basel Stent Kosten Effiktivitats (Basel Stent Cost-Effectiveness) Trial- LATE] trial found an increase in major adverse cardiac events (MACE) from 6–18 months post-DES-implantation, when compared to BMS controls. However, DAT was continued for only 6 months in these patients, and no difference in cumulative MACE was observed, owing to the early (< 6 months) benefit conferred by DES.18
The exact scope and clinical significance of this trend, however, remained unclear. In a large meta-analysis of 9 major DES trials, the Cardiovascular Research Foundation found an 86% decrease in in-stent restenosis (ISR), with no differences in combined death or MI for either SES or PES versus BMS controls. However, there were nonsignificant mortality excesses of 5 versus 0, and 9 versus 2 for SES versus BMS and PES versus BMS, respectively.19 Baim presented data pooled from randomized trials involving 3,445 PES patients, demonstrating a 0.5% increase of LAST over BMS patients (p = 0.02) without increases in MI or in cardiac or noncardiac deaths. He theorized that this small excess was offset by the notable morbidity and mortality benefit from the 10% absolute reduction in reintervention.20 A meta-analysis of all 4 randomized SES trials [RAVEL, SIRIUS, C-SIRIUS (Canadian-SIRIUS), and E-SIRIUS (European-SIRIUS)], however, revealed no significant differences in thrombosis for any time interval, or cumulatively for 4 years.21
Conclusion. Thus, while the DES-LAST controversy continues to flood the media, there has been no reported increase in DES-SAT, as was repeatedly seen in our patient. Several factors may have contributed to this patient’s unfortunate course. First, the stents were of small diameter, a known risk factor for SAT. Since the patient did not follow up with any cardiologist, he was admitted to a different oncall cardiologist during each hospitalization. Thus, regrettably, a comprehensive platelet function evaluation was not performed, and we did not ascertain the degree of platelet inhibition afforded by DAT in this case. Although protein C and S levels were within normal range, these compounds have little impact on platelet activity.
Additionally, given the patient’s relatively uncooperative demeanor, it is conceivable that his medication compliance, despite claims to the contrary, may have been less than perfect. Even a single omitted dose of DAT, especially early post-PCI, can potentially lead to SAT. Although not the standard recommendation, twice-daily clopidogrel seemed an appropriate management strategy in this case. While DES safety in acute MI-PCI has previously been demonstrated,22,23 it is possible that the thrombotic milieu may have enhanced our patient’s proclivity for SAT. The patient’s oncological status, as well as chemotherapy, may have also played a role in alterations of platelet function and coagulation.
Interestingly, only the BMS remained patent at 31-day repeat angiography. Spontaneous thrombolysis was likely the explanation. A thrombus may have formed at the nonocclusive dissection site within the stented segment. Thus, for our patient, even in the presence of a potential mechanical cause of SAT, the sequelae for BMS thrombosis appeared less dramatic than those for DES. Additionally, the twice-daily dosing of clopidogrel may well have contributed to prompt thrombus resolution during the third infarction. We recognize that intravascular ultrasound may have provided additional information in this patient; nonetheless, all 3 PCIs demonstrated excellent angiographic results. As each PCI was performed by a different seasoned interventionalist, a common technical problem would be an unlikely cause for the recurrent thrombosis.
Thus, our patient serves as a reminder that, in addition to late angiographic stent thrombosis, DES-SAT (and recurrent SAT) remains a rare, but real, concern. Previous subgroup analyses identifying risk factors, both epidemiologic and angiographic (including small vessel diameters), for DES thrombosis demonstrate significant overlap with those for BMS restenosis. Unfortunately, like anticoagulation for atrial fibrillation in the elderly, those most likely to benefit from a specific therapy, also paradoxically experience the greatest risk.
On December 7 and 8, 2006, the U.S. FDA (Food and Drug Administration) convened an elite 21-member advisory panel to address the safety and utility of DES. Among their conclusions were that DES were associated with a slight but likely real increase in risk of LAST. However, they are associated with significant decreases in target lesion/vessel revascularization rates. When DES are used according to “on-label” indications, the overall MACE rates (including rates of death and MI) are comparable to those of BMS. DAT should be continued for at least 1 year in patients at low risk of bleeding, and patients unlikely to comply with this regimen (for financial or clinical reasons) should be considered for BMS or balloon angioplasty.25
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