Drug-eluting stents have ushered in a new era in interventional cardiology with the availability of sirolimus-eluting Cypher™ (Cordis Corp., Miami, Florida) and paclitaxel-eluting Taxus® (Boston Scientific Corp., Natick, Massachusetts) stents which have shown a very low restenosis rate associated with a good safety record in randomized studies1–4 and registries.5,6 Despite these encouraging developments, there have been some concerns with the widespread use of these stents. Drug-eluting stents prevent healing and can potentially lead to complications such as stent thrombosis and aneurysm formation. A recent report highlighted the adverse effects of a drug-eluting stent in a patient manifested by localized hypersensitivity and late coronary thrombosis.7 There have been few case reports of coronary aneurysms following drug-eluting stents.8–11 Furthermore, the cause and management of such aneurysms is still not clear. We report two patients who developed coronary aneurysms early after drug-eluting stent implantation requiring surgical intervention to treat the complication. Case Reports Case 1. A 55-year-old hypertensive male suffered anterior wall myocardial infarction in May 2004. He underwent coronary angiography in September 2004 which revealed significant left anterior descending (LAD) artery and right coronary artery (RCA) disease amenable to percutaneous coronary intervention using drug-eluting stents. The LAD artery was stented using 3.0 x 33 mm Cypher Select™ stent (Cordis Corp., Miami, Florida) that was deployed at 14 atmospheres. The stented segment was postdilated with 3.0 x 8 mm Quantum™ Maverick (Boston Scientific) balloon at 18 atmospheres. Similarly, the RCA lesion was stented using a 2.5 x 33 mm Cypher Select stent deployed at 20 atmospheres. There was no residual stenosis, dissection or evidence of an aneurysm at the end of the procedure. The patient was kept on standard dual antiplatelet therapy (aspirin 150 mg and clopidogrel 75 mg once a day). The patient complained of chest pain 6 days postprocedure which was not accompanied by any new changes in the electrocardiogram. In view of his recent percutaneous coronary intervention (PCI) and symptoms, coronary angiography was performed and showed brisk TIMI 3 flow, but areas of small radiolucencies inside the LAD stent suggestive of small nonocclusive thrombi. The RCA stented segment was normal. The patient was started on low-molecular weight heparin and became pain-free within 24 hours. During this period, he had no fever and his white blood cell count, including the eosinophil count (2%), was normal. Coronary angiography was repeated one week later in view of the finding of small filling defects; it showed a large coronary aneurysm in the stented segment of the LAD (Figure 1). He was referred for CABG surgery, but the next day while awaiting surgery, he experienced chest pain followed by hypotension not accompanied by any new ECG changes. Two-dimensional echocardiography revealed evidence of cardiac tamponade. The patient was taken up for emergency surgery. The findings at surgery suggested intense inflammation around the LAD area. There was no purulent material. A culture taken from the scrapings showed no growth of organisms. He received a graft to the LAD artery along with aneurysm repair site, and is asymptomatic at 8-month follow up. Case 2. A 32-year-old dyslipidemic male experienced a non-Q wave anterior wall myocardial infarction in October, 2004 following which he underwent percutaneous transluminal coronary angioplasty (PTCA) and stent implantation in the LAD using 3.0 x 21 mm Duraflex stent (Avantec Vascular, Sunnyvale, California). He developed recurrence of Class III symptoms two months later. Coronary angiography was performed, revealing diffuse in-stent restenosis of the LAD artery. It was decided to treat the in-stent restenosis with a drug-eluting stent. The lesion was predilated with 1.5 x 10 mm Stormer balloon (Medtronic, Inc., Minneapolis, Minneapolis) at 6 atmospheres, followed by dilatation using a 2.5 x 6 mm Cutting Balloon (Boston Scientific) inflated at 8 atmospheres. The lesion was then covered using two overlapping Cypher Select stents (2.75 x 33 mm and 3.0 x 13 mm), and the stented segment was postdilated with 3.0 x 12 mm Maverick balloon at 18 atmospheres with good results. The patient had been administered abciximab during the procedure which was continued on standard dual antiplatelet therapy (aspirin and clopidogrel). There was no residual stenosis and dissection around the stent and the result was good. The patient was discharged in good condition after two days. The patient developed chest pain 1 day after discharge. An ECG revealed a new-onset right bundle branch block. Repeat coronary angiography showed a patent stented segment with small radiolucency in the stented segment at the site of origin of the second septal, which had also become blocked. There was no history of fever, and the patient’s white blood cell counts, including the eosinophil counts (3%), were normal. Also, there was no evidence suggesting systemic infection. The patient was started on low-molecular weight heparin, but 2 days later, he complained of increased intensity of chest pain, with no new ECG changes. Two-dimensional echocardiography and Doppler revealed mild pericardial effusion. In view of our experience in the first case, the patient underwent coronary angiography, which revealed an increase in radiolucency inside the stented segment and a small aneurysm formation in the stented segment (Figure 2). The patient was sent for CABG surgery and received grafts to the LAD and diagonal, along with aneurysm repair. The finding at surgery consisted of intense inflammatory changes and an impending rupture of a thin-walled aneurysm. The scrapings from the site did not grow any organisms. The patient was asymptomatic at 5-month follow up. Discussion Aneurysms related to coronary arteries are infrequently reported entities since their first description by Morgagni in 1761.12 Coronary aneurysms have also been observed following vascular trauma from coronary angioplasty, directional atherectomy and post-stent implantation. Aneurysms after sirolimus-eluting stent implantation are considered rare. The data available from intravascular ultrasound (IVUS) follow up from the RAVEL study and a first-in-man study revealed 1 patient with an aneurysm at 18-month follow up, which presumably developed because of dissolution of thrombus in the area of the stent’s malapposition.8 The surgical findings in both our patients showed inflammation at the site of aneurysm formation. This led us to believe that this inflammation could be a hypersensitivity reaction to the metal, the polymer or the drug, which are the three components of a drug-eluting stent. Inflammation secondary to stainless steel, the metal used in this stent, appears less likely because aneurysm formation after implantation of bare metal stents, which have been used extensively for several years, is very rare. Also, the second patient had already received a bare metal stent at the same site without any aneurysm formation. Finn et al., in an interesting animal study, showed persistent inflammation, fibrin deposition and delayed endothelialization when the surrounding tissue is exposed to inappropriate levels of drug and/or polymer.13 The drug sirolimus, which has anti-inflammatory properties and is used to prevent transplant rejection, seems unlikely to be the primary cause. However, inhibition of the healing process by sirolimus could have contributed to the expansion of the weakened areas of intima and media secondary to the trauma of PCI, thus resulting in aneurysm formation. Polymers, including the one used in Cypher stents, are an area of continuing concern and have shown to induce an inflammatory response leading to incomplete endothelialization, tissue damage, inflammation, poor wound healing and intra-intimal hemorrhage in animal studies.14,15 In a recent report by Virmani et al., localized inflammation by polymer fragments of the Cypher stent was speculated as the cause of late coronary thrombosis at 18 months after Cypher stent implantation.7 The high-pressure dilatation traumatizing and weakening the vessel wall, coupled with an inflammatory response set up by the polymer/drug combination, seems to us a distinct possibility. Mycotic aneurysms after drug-eluting stent implantation have also been reported, and could be a potential cause.16 In our case, however, there were no signs of an infective process. Aneurysms of the coronary arteries as seen in our case can potentially lead to serious problems such as thrombosis, embolization and rupture, which can be fatal. The management of post-stenting coronary aneurysm is challenging, as there are no guidelines. The use of covered stents to exclude the aneurysm from the main vessel is also emerging as a treatment strategy.17 We also considered this strategy, but we favored surgery because of the large intracoronary lucencies and a putative hypersensitivity reaction to the drug, which would still have persisted even after sealing the aneurysm. Although reports of coronary artery aneurysm producing adverse events after drug-eluting stent implantation are considered to be very rare, a meticulous follow up and a low threshold for performing repeat angiography in symptomatic patients is desirable. Problems secondary to drug-eluting stents, especially due to the polymer or drug effect, may be more frequent than what is reported in the literature.
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