Transient Coronary Aneurysm Formation After Nevo Stent Implantation Versus Persistent Coronary Aneurysm After Cypher Select Stent Implantation

ABSTRACT: We implanted a Cypher Select™ coronary stent and two months later a Nevo™ sirolimus-eluting coronary stent in another vessel. At a prescheduled angiographic follow-up, coronary aneurysms were seen in the two stented segments, 6 and 8 months after stent implantation, respectively. Six months later, the aneurysm had healed in the Nevo, but was still present in the Cypher stented segment. We hypothesize that aneurysm formation was induced by sirolimus and the polymer of the implanted stents, and that subsequent healing was possible in the Nevo stent after degradation of the polymer.

J INVASIVE CARDIOL 2011;23:E158–E160

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Case Report. A 47-year-old male with an acute anterior ST-segment elevation myocardial infarction (STEMI) was admitted for primary percutaneous coronary intervention (PCI). The patient had no previous history of coronary artery disease, arterial hypertension, hyperlipidemia, or diabetes mellitus. The risk factors were a family history of coronary artery disease and smoking. Coronary angiography showed a proximal left anterior descending artery (LAD) occlusion and a significant, mid right coronary artery (RCA) stenosis (Figures 1A and 1C). The circumflex artery was normal. The LAD occlusion was treated by thrombus aspiration and implantation of a 3.5 x 23 mm Cypher Select™ stent (Cordis Corporation, Bridgewater, New Jersey) (Figure 1B). The stent was postdilated with a 4.0 mm compliant balloon at 14 atm. Left ventricular function was evaluated with echocardiography after the procedure and apical hypokinesia was found. The ejection fraction was 55%. Two months later, the RCA stenosis was treated electively by enrollment in the Res-Elution I trial¹ and randomization to treatment with the Nevo™ sirolimus-eluting coronary stent (Cordis Corporation). A 3.0 x 28 mm Nevo stent was implanted at 12 atm (Figure 1D), and no post-dilation was performed. The left coronary artery was not evaluated at this procedure. Per protocol, the patient had a 6-month angiographic follow-up (Figure 2A). Unexpectedly, angiography and intravascular ultrasound (Eagle Eye Gold Catheter, Volcano Corporation, San Diego, California) showed a coronary aneurysm at both stented segments (Figure 2B). Coronary aneurysm was defined as an external elastic membrane (EEM) cross-sectional area (CSA) > 50% larger than the proximal reference segment with all 3 vessel layers intact (true aneurysm). Six months later, we performed another angiography and an optical coherence tomography (OCT) using the C7 Dragonfly™ Imaging Catheter and the C7XR system (LightLab Imaging, Westford, Massachusetts). Angiography (Figures 3A and 3B) and OCT showed complete healing of the aneurysm related to the Nevo stent (Figure 4), while there was a persisting aneurysm with relation to the Cypher stent (Figure 5). The patient remained asymptomatic after the primary PCI procedure and was on continuous dual-antiplatelet medication.

Discussion. This is the first report on development of a coronary aneurysm after implantation of the Nevo stent with subsequent spontaneous healing and disappearance of the aneurysm.

Coronary aneurysm formation after coronary intervention with both bare-metal and drug-eluting stents is rare. Data from the SIRIUS, C-SIRIUS, and E-SIRIUS trials reported a very low incidence of aneurysm formation at 8-month follow-up of 0.37% (2/546) in the Cypher arm and 0.91% (5/552) in the BX Velocity bare-metal stent arm (Christian Spaulding, personal communication, data on file at Cordis Corporation). The cause of aneurysm formation is not clear, and different pathological mechanisms may be involved. In a review by Aoki et al,² a causal classification of aneurysms was proposed: type-I aneurysms demonstrate rapid early growth with pseudoaneurysm formation detected within 4 weeks after stent implantation. It is likely that arterial injury at the stent procedure is a contributor to aneurysm formation. Type-II aneurysms are true aneurysms and typically are detected incidentally during angiographic follow-up ≥ 6 months after stent implantation. It seems likely that type-II aneurysm formation is a chronic arterial response to a metal stent, polymer, and/or drug. Positive vessel remodeling is a potential explanation.³ Also, a hypersensitivity reaction to the polymer and/or drug, with a local inflammatory response, is a possible cause.⁴ The ability to determine whether aneurysms resolve, persist, or otherwise change morphology over time is often difficult to determine due to the need for repeat invasive angiography in the same patient. In the present case, the occurrence of aneurysms in relation to the implanted stents suggests a relationship between aneurysm development and components of the implanted Nevo and Cypher stents. In theory, the use of biodegradable polymers may reduce the risk of aneurysm formation. Our case illustrates that a stent with a biodegradable polymer (Nevo), may be associated with adverse reactions to the polymer and/or to the drug, leading to aneurysm formation, but that subsequent healing and disappearance of the aneurysm is possible. In contrast, the first-generation drug-eluting Cypher stent with a permanent polymer coating led to a persistent condition of aneurysm and stent strut malapposition. Both aneurysms in this case can be classified as type-II. The rare type-III aneurysms proposed by Aoki et al² are mycotic or infectious aneurysms. These patients typically present with systemic manifestations and fever. Our patient remained asymptomatic after the primary PCI procedure, and a mycotic or infectious etiology is unlikely.

The Nevo stent is a third-generation drug-eluting stent. The platform is a cobalt-chromium alloy. Its bioresorbable polymer is completely metabolized within 90–120 days following implantation, and reservoir technology which concentrates sirolimus-polymer blend in laser-drilled holes in the stent struts leaves the stent surface free from polymer coating. Sirolimus is used in a dosage and with release kinetics similar to the Cypher stent. The drug is completely released by 90 days and the polymer is completely absorbed in a similar time-course so that the Nevo stent converts into a bare-metal stent after 3 months. In the first-in-man assessment of the efficacy and safety of the Nevo stent, the randomized Res-Elution I,¹ the Nevo stent was compared to the Taxus Liberté^® stent (Boston Scientific Corporation, Natick, Massachusetts). After 6 months, in-stent late lumen loss was significantly lower in the Nevo stent patients as compared with Taxus Liberté patients (0.13 ± 0.31 mm versus 0.36 ± 0.46 mm, respectively; p < 0.001).¹ This present case is the only case of aneurysm formation at 6-month angiographic follow-up in the Res-Elution I trial¹ (Christian Spaulding, personal communication, data on file at Cordis Corporation). In this study, no stent thromboses were observed at 12-month follow-up in the Nevo group while 2 late thromboses occurred in the Taxus Liberté group.⁵

Our case indicates a possible relationship between polymer and safety. Polymers have been hypothesized to cause inflammation related to hypersensitivity reactions with chronic eosinophillic infiltration of the arterial wall and delayed healing and increased risk of stent thrombosis, although none of the patients with aneurysm formation in the Cypher pivotal trials had stent thrombosis (Christian Spaulding, personal communication, data on file at Cordis corporation). The chemical structure and location of the polymers in the Cypher and Nevo stent differ.  The Cypher coating is a mixture of two durable polymers, poly(n-butyl)methacrylate (PBMA) and poly(ethylene-co-vinyl acetate) (PEVA) and sirolimus, which are on the surface of the stent. The Nevo polymer is incorporated in the reservoirs of the stent and the bioresorbable polymer poly(DL-lactic-co-glycolic acid).

In conclusion, our report of coronary aneurysm development and subsequent healing after implantation of the sirolimus-eluting absorbable polymer Nevo stent, contrasted to demonstration of a persistent aneurysm after Cypher stent implantation in the same patient, suggests a favorable long-term safety profile for the Nevo stent.

Acknowledgment. We thank Christian Spaulding, MD, Cordis Corporation; Sidney Cohen, MD, Cordis Corporation; and Leif Thuesen, MD, DrMSci, Department of Cardiology B, Aarhus University Hospital, Skejby, Denmark for their contributions to this manuscript.

References

1. Spaulding C. NEVO™ sirolimus-eluting coronary stent: First clinical results and future development of RES technology. Circ Cardiovasc Inverv, in press.
2. Aoki J, Kirtane A, Leon MB, Dangas G. Coronary artery aneurysms after drug-eluting stent implantation. JACC Cardiovasc Interv 2008;1:14–21.
3. Mintz GS, Shah VM, Weissman NJ. Regional remodeling as the cause of late stent malapposition. Circulation 2003;107:2660–2663.
4. Cook S, Ladich E, Nakazawa G, et al. Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation 2009;120:391–399.
5. Abizaid A. The NEVO RES-I: Twelve-month outcomes. Presented at EuroPCR, Paris, France; May 25, 2010.

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From the Department of Cardiology, Aarhus University Hospital, Skejby, Aarhus, Denmark.
EHC has received speaking honoraria and a travel grant, JFL has received speaking honoraria and travel grants, and LOJ has received speaking honoraria from Cordis Corporation.
Manuscript submitted August 17, 2010, provisional acceptance given August 24, 2010, final version accepted December 2, 2010.
Address for correspondence: Evald Høj Christiansen, MD, Department of Cardiology, University of Aarhus, Skejby Hospital, Denmark. Email: evald.christiansen@dadlnet.dk