Sirolimus-Eluting, Bioabsorbable Polymer-Coated Constant Stent (Cura‚Ñ¢) in Acute ST-Elevation Myocardial Infarction: A Clinical a

Drug-eluting stents (DES) have emerged as a novel technology in coronary revascularization. Ample evidence has shown that polymer-based DES effectively reduce in-stent restenosis and repeat revascularization after percutaneous coronary intervention (PCI).^1,2 However, there have been safety concerns over the current polymer-based DES on the possible delayed healing process and adverse reactions to the polymer when drug elution is completed, resulting in adverse events, including late stent thrombosis.^3–6 Therefore, DES with bioabsorbable drug/polymer composite coating are an attractive technology for improved safety and efficacy.
Cura™ (Orbus Neich, Fort Lauderdale, Florida) is a sirolimus-eluting, bioabsorbable, polymer-coated constant stent. Absorbable composite coatings are applied to the abluminal surface of the constant stent, which is a stainless-steel balloon-expandable stent. The coating consists of sirolimus (170 µg/cm²), which is combined with conform (PLA and PLGA) bioabsorbable polymer in a fixed ratio. In vivo assays have shown that the drug-polymer coating is eroded over a period of 45 days and there is no residual polymer after drug elution.
In this first-in-man registry of CURA in Myocardial Infarction (CURAMI), we sought to assess: (1) the feasibility and safety of implanting the Cura stent for the treatment of ST-elevation myocardial infarction (STEMI), and (2) the impact of the Cura stent on the development of in-stent restenosis.

Methods

Study design. This study was carried out at an Asian University teaching hospital. Under the CURAMI registry, from March 1 to June 30, 2005, Cura stent implantation was instituted as the default strategy for percutaneous treatment of STEMI within 12 hours after symptom onset. With the exception of cardiogenic shock (systolic blood pressure <90 mmHg or requiring inotropic support), all clinical characteristics and lesion morphologies were considered eligible. The institutional review board of the local institution approved the study and all patients gave informed consent before the procedure.
With the exception of Cura stent utilization, all procedures were performed according to standard techniques, and the final interventional strategy was left to the discretion of the operator. Cura stents were available in diameters of 2.5, 2.75, 3.0, 3.5, and 4.0 mm, as well as lengths of 9, 17, 24, 28, and 32 mm. There was no restriction on the use of thrombectomy or distal protection devices. Weight-adjusted heparin was administered to achieve an activated clotting time of >300 seconds, or 200–250 seconds when a platelet glycoprotein IIb/IIIa inhibitor was used. The postprocedural antiplatelet regimen consisted of aspirin at 100 mg per day indefinitely and clopidogrel at 75 mg per day for 3 months.
Clinical follow up. The investigators at the outpatient clinic reviewed all recruited patients at 1, 4, and 9 months. Patients were evaluated for the occurrence of death, reinfarction (clinical symptoms or new electrocardiographic changes, associated with re-elevation of the creatine kinase, and creatine kinase-MB levels of >1.5 times the previous value if within 48 hours, >3 times the upper limit of normal if after 48 hours), and target lesion revascularization (surgical or percutaneous reintervention motivated by a significant stenosis located within the stent or in the 5 mm segments proximal or distal to the stent).
Angiographic follow up. To determine the late loss and incidence of restenosis after Cura stent implantation for STEMI, angiographic follow up was scheduled at 8 months for all living patients. Offline quantitative coronary angiography (QCA) analysis was performed immediately postprocedure and at 8-month angiographic follow up. All angiograms were performed after administration of 200 µg intracoronary nitroglycerin. Late loss was defined as the difference between the minimal lumen diameter immediately after the procedure and at follow up. Binary restenosis was defined as a stenosis diameter >50% within the stent or in the 5 mm segments proximal or distal to the stent.
Statistical analysis. The statistical analyses were generated using SPSS software, version 14.0. The descriptive statistics and percentages with a 95% confidence interval (CI), calculated using Wilson recommendation method (Wilson EB, 1927), were presented where appropriate.

Results

After 4 months of enrollment, a total of 49 (primary, n = 48; rescue, n = 1) consecutive STEMI patients underwent Cura stent implantation for treatment of the infarct-related artery; these patients comprised the present study population. As per hospital policy, only the infarct-related artery was treated in the acute setting. The baseline clinical and demographic characteristics of the patients are shown in Table 1. The angiographic and procedural characteristics are shown in Table 2. All culprits were de novo lesions in a native coronary artery. Infarct location was anterior in 34 cases (69%). Periprocedural glycoprotein IIb/IIIa inhibitor (abciximab, 10%; eptifibatide, 12%) was used in 22% of the patients. There was 1 case of Cura stent dislodgement in the left anterior descending artery (LAD) just proximal to the target lesion. The stent was successfully snared, and another Cura stent of the same size was deployed over the lesion. There was no other intraprocedural complication, including acute stent thrombosis. Before the procedure, TIMI flow 0–1 was present in 76% of the cases. Postprocedural TIMI 3 flow was achieved in 96% of patients.
In-hospital outcomes. In-hospital death occurred in 1 patient (2%). He was a 71-year-old diabetic patient who presented with anterior STEMI due to ostial LAD occlusion. He developed acute pulmonary edema and cardiac arrest after balloon predilatation, and required resuscitation and intubation. After stabilization, 2 Cura stents (2.75 x 28 mm and 3.0 x 24 mm) were successfully deployed over the lesion. However, he developed progressive cardiac failure and eventually succumbed the following day.
On discharge, aspirin was prescribed in 98% (1 patient was found to have allergy aspirin after the procedure), clopidogrel in 100%, beta-blockers in 90%, angiotensin-converting enzyme inhibitors in 77%, and statins in 96% of the 48 living patients.
Clinical follow up. At 30-day follow up, a 65-year-old patient who underwent successful Cura stent implantation in the proximal LAD for anterior STEMI was readmitted on day-11 due to heart failure. Reinfarction and stent thrombosis were excluded. He was stabilized with medications and discharged uneventfully. There were no incidences of acute or subacute stent thrombosis or urgent revascularization. With the exception of the in-hospital death, all patients attended clinic follow up according to the schedule. All recruited patients were compliant with the prescribed antiplatelet therapy. All except 1 patient (2%) were asymptomatic. A 58-year-old diabetic patient developed inferior STEMI 6 months after the index procedure, at which time a Cura stent (3 x 30 mm) was implanted in the ostial LAD. Urgent angiography showed an occluded right coronary artery (RCA), and the Cura stent in the LAD had developed significant in-stent restenosis. A bare-metal stent implantation to the RCA was performed. Three months later, repeat angiography showed the RCA stent again developed in-stent restenosis and the patient was submitted for coronary artery bypass graft surgery (CABG). There was no incidence of late stent thrombosis at 9-month follow up. None of the patients had clinical restenosis at follow up.
Angiographic follow up. Eight-month angiographic follow up was performed in 27 patients (56%). The angiographic outcomes are shown in the Table 3 and Figure 1. Late loss was 0.74 ± 0.89 mm, and there were 6 cases (22%) of binary restenosis. Among patients with binary restenosis, 2 underwent repeat PCI, 2 underwent CABG, and 2 were treated medically. The target lesion revascularization rate was 8.3%. Only 1 (patient #30) out of the 6 cases of restenosis underwent intravascular ultrasound interrogation which showed aneurysmal dilatation at the mid portion of the stent, as well as severe focal restenosis at the proximal stent edge.

Discussion

This is the initial experience of SES with a bioabsorbable polymer (Cura) in STEMI. In this pilot registry, Cura stent implantation appears to be feasible and safe in the treatment of STEMI. However, the binary restenosis rate and late loss at 8-month angiographic follow up compare unfavorably with other proven benchmark DESs. From the available evidence, for a DES to be effective in reducing restenosis, a polymer is essential for the drug to be released in a controlled manner.⁷ However, after drug elution is completed, the remaining durable polymer has no therapeutic role in maintaining vessel patency, but potentially becomes a nidus for future adverse events. The Cura stent made use of the bioabsorbable polymer-sirolimus complex coated on the constant stent. The composite coating is eluted over a period of 45 days. The bioabsorbable coating has the advantage of providing a controlled-release mechanism for the drug, while at the same time obviating future risks of adverse events related to the polymer.
The most untoward adverse reaction to durable polymer is stent thrombosis. Patients with STEMI undergoing primary stenting are known to be at particularly high risk of stent thrombosis. We therefore postulated that the Cura stent would be particularly beneficial in the patients who presented with STEMI. Since the Cura stent had been available for general clinical use in a few Asian countries during the design phase of the registry, we decided to evaluate the safety and feasibility of the Cura stent in STEMI rather than in stable patients with simple lesions. In this regard, our data confirmed the safety of the principle of DES with a bioabsorbable polymer. Apart from the death due to progressive heart failure, there were no deaths or stent thromboses during the acute and follow-up period.
Sirolimus, when coated on the Bx-Velocity^® stent (Cordis Corp., Miami, Florida) with a durable polymer has been demonstrated to be highly effective in reducing restenosis and repeat revascularization rates.¹ In the RESEARCH registry, a binary restenosis rate of 0% and a late loss of -0.04 mm were demonstrated in 96 STEMI patients undergoing Cypher stent implantation.⁸ However, the initial enthusiasm was hampered by the occurrence of late stent thrombosis.⁶ Underlying mechanisms for late thrombosis remain unclear, but delayed allergic reaction to the residual polymer has been proposed as a plausible mechanism.
It is intriguing that the Cura stent failed to achieve comparable angiographic results to those of the Cypher stent. The drug used in the 2 stents is the same, and the doses are similar (170 µg/cm² for Cura versus 140 µg/cm² for Cypher). Both the stent strut (100 µm versus 140 µm) and coating (3.5 µm versus 5–10 µm) thickness were thinner for the constant stent than the Bx-Velocity stent, favoring the Cura stent. We therefore postulate that a different drug elution profile is the reason for the failure of the Cura stent to produce “Cypher-like” angiographic results. In the Cypher stent, the drug is eluted slowly over a period of 90 days, and approximately 50% of the drug is eluted in the first 10 days. In contrast, for the Cura stent, the drug-polymer composite coating is eluted much faster, over 45 days, with 70% of the coating being eluted over the first 10 days.
Study limitations. There are a number of limitations in this study. The number of patients in the study was small, and the design was a single-arm registry. Reluctance to undergo a repeat invasive procedure is a common observation in Asian patients. As a result, only slightly more than half of the treated patients returned for repeat angiography. All of these factors hinder a definitive conclusion on the efficacy of the Cura stent in reducing restenosis. QCA analysis was not performed by an independent core laboratory, and an intravascular ultrasound study was not performed; this is because the study was physician-driven, and funding from industry was limited.
In conclusion, at 9-month follow up, Cura stent implantation appears to be feasible and safe in the treatment of STEMI. However, the binary restenosis rates and late loss at angiographic follow up were similar to those of bare-metal stents,^9,10 and therefore compare unfavorably with other proven benchmark DES.

Acknowledgement. The authors are indebted to Cindy Lau, and to the nurses and technicians of the cardiac catheterization laboratory of the National University Hospital.

References

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