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Comparison of Stainless-Steel Stents Coated with Turbostratic Carbon and Uncoated Stents for Percutaneous Coronary Interventions
October 2003
Implantation of stainless-steel stents has improved the results of percutaneous coronary revascularization.1,2 However, in various subsets of lesions, especially in the presence of complex lesion morphology, in-stent restenosis due to late neointimal hyperplasia occurs in up to 50% of cases3–5 requiring repeated coronary interventions including intravascular brachytherapy.6,7 Various passive stent coatings have been proposed to reduce thrombus formation and intimal hyperplasia following stent implantation.8–10 However, none of these stent coatings have proven to prevent in-stent restenosis. Although the recent use of antiproliferative drugs loaded on coronary stents has shown to efficiently control intimal hyperplasia in de novo coronary lesions as demonstrated by the landmark RAVEL study,11 long-term clinical experience with this approach is still limited. In the setting of in-stent restenosis, primary results on the efficacy of drug-eluting stents remain conflicting.12,13 Turbostratic carbon is a highly biocompatible material that has been used to coat stainless-steel stents and gave only mild platelet deposition and neo-intimal formation in an animal model.14 We conducted a prospective, randomized study to assess whether implantation of stainless-steel stents coated with turbostratic carbon can reduce the incidence of clinical events and restenosis when compared to uncoated stainless-steel stents.
Methods
Patients. A consecutive series of patients with symptomatic coronary artery disease treated with stenting between October 1999 and March 2002 were eligible for this study. Exclusion criteria included patients in whom more than 1 lesion had to be treated, lesion length > 15 mm, vessel diameter 4.0 mm, ostial lesions or lesions located in an unprotected left main, in-stent restenoses, lesions located in a bend > 60° or at the take-off of a major sidebranch, lesions located in a saphenous vein or arterial bypass graft, lesions requiring more than 1 stent based on a pre-procedure estimation, and unwillingness or inability of the patient to provide written informed consent. All patients were randomly assigned to receive either a stainless-steel or carbon-coated stent by means of sealed envelopes before the intervention. The study was carried out according to the principles of the Declaration of Helsinki and approved by the institutional ethics committee.
Stenting procedure and medical regimen. Prior to stent placement, patients received heparin (7,500 U) and aspirin (500 mg) intravenously, as well as an oral loading dose of clopidogrel (300 mg). After the procedure, all patients were treated with aspirin (100 mg) and clopidogrel (75 mg) every day for 4 weeks. Patients randomized to a carbon-coated stent received a CarboStent (SORIN, Saluggia, Italy) either 9, 15 or 25 mm in length. Patients randomized to an uncoated stainless-steel stent received a Tristar, Tetra or Penta Multi-Link stent (Guidant Corporation, Santa Clara, California) either 13, 18 or 23 mm in length. Stent diameters were 3.0, 3.5 or 4.0 mm. Both types of stent are manufactured from 316 L stainless-steel and have tubular architecture. While the CarboStent has a closed-cell design, the Multi-Link stent has an open-cell design. There were also slight differences in strut thickness among the stents (CarboStent, 76 µm; Tristar, 140 µm; Tetra, 91 µm; Penta, 91–124 µm). The CarboStent is homogeneously coated with a 0.3–0.5 µm layer of turbostratic carbon. The stents come pre-mounted on semi-compliant percutaneous transluminal coronary angioplasty (PTCA) balloons. Prior to stent implantation, pre-dilatation was carried out using a standard PTCA balloon. If residual dissections were visible after implantation of the primary stent, one or more additional stents of equal quality (either coated or uncoated) were implanted, aiming at an optimal angiographic result.
Angiographic evaluation. Coronary angiography was performed prior to PCI and stent implantation, immediately after stent implantation and at follow-up. We attempted to visualize the coronary lesion in at least 2 projections. Lesions were classified according to the modified American College of Cardiology/American Heart Association score.15 Geometric coronary measurements were carried out offline using the computer-assisted contour detection system CAAS (PieMedical, Maastricht, The Netherlands). Parameters of geometric coronary measurements were lesion length, reference diameter (RD), minimal luminal diameter (MLD) and percent diameter stenosis (DS). Acute elastic recoil was assessed as the difference between MLD at maximal ballon pressure during stent expansion and MLD at the stented segment directly after stent implantation. Acute lumen gain was the difference between MLD at the end of the intervention and MLD before balloon dilatation. Late lumen loss was calculated as the difference in MLD between measurements after the procedure and at follow-up. An intravascular ultrasound substudy was not performed in this series.
Definitions and endpoints. The primary endpoint of the study was the binary angiographic restenosis rate 6 months after stent implantation. Secondary endpoints were the MLD as well as the major adverse cardiac events (MACE) at 6 months (death, myocardial infarction, bypass operation and repeat PCI). Diagnosis of myocardial infarction was based on at least 1 of the following electrocardiographic criteria: 1) appearance of new pathological Q-waves; and 2) CK elevation of more than two times the upper limit of the normal range including a significant elevation of CK-MB-fraction. Target vessel revascularization was performed in the presence of angiographic restenosis and symptoms or signs of ischemia. Cardiac events were monitored throughout the follow-up period and analyzed after the first 30 days following PCI as well as 6 months after the primary procedure. The assessment was made on the basis of the information provided by hospital readmission records, the referring physician or by a telephone interview with the patient.
Statistical analysis. Assuming an angiographic restenosis rate of 23% in patients treated with the uncoated stainless-steel stents and 11% in patients treated with carbon-coated stents, a sample size of 306 patients was calculated with a statistical power of 80% for detecting a difference with an alpha-level of 0.05. In order to accommodate possible losses at follow-up, we enrolled 339 patients. Analysis was performed on an intention-to-treat basis and results are expressed as mean values ± standard deviation or as proportions (%). Differences between groups were assessed by t-test for continuous data and by chi-square test or Fisher’s exact test for categorical data. The frequency of event-free survival was calculated with the Kaplan-Meier method. Differences in survival parameters were assessed for significance using the log-rank test. Statistical significance was accepted at p Thirty-day clinical outcomes. Acute occlusion due to stent thrombosis occurred in 1 patient of the C group (0.6%) and in 3 patients of the S group (1.9%). In all 4 cases, the occlusion could be recanalized immediately. There were no acute myocardial infarctions or deaths in either group. MACE during the first 30 days after intervention are listed in Table 4.
Angiographic follow-up. Angiographic follow-up data were obtained for 87.2% of the eligible patients and are listed in Table 5. The MLD was 1.67 ± 0.64 mm in the C group and 1.68 ± 0.57 mm in the S group (p = 0.878). Late lumen loss was 0.93 ± 0.63 mm in the C group and 1.05 ± 0.59 mm in the S group (p = 0.93). The cumulative distribution of MLD measured in both study arms before intervention, after intervention and at follow-up is depicted in Figure 1. The binary angiographic restenosis rate was 18.1% in the C group versus 20.6% in the S group (p = 0.591).
Clinical outcomes at 6 months. Clinical follow-up 6 months after stent implantation was obtained in 295 patients (89.7%). MACE during the follow-up period are listed in Table 6. The target lesion revascularization rate was 16.4% in the C group versus 21.5% in the S group (p = 0.341). The Kaplan-Meier curves depicting the frequency of event-free survival in both patient cohorts are shown in Figure 2.
Discussion
Chemically inert coatings of stainless-steel implants prevent the release of heavy metal ions to surrounding tissue and may contribute to inhibition of inflammatory hypersensitivity reactions and allergic reactions to metal which in turn lead to platelet adhesion and fibroproliferative response around the implant.16 When inserted in pig coronary arteries, stents coated with turbostratic carbon provided a reduction of thrombus formation and reactive intimal hyperplasia.14 An initial clinical series using coronary stents coated with turbostratic carbon reported no stent thromboses and a restenosis rate of 11%.17
Our study represents the first randomized comparison between stents coated with turbostratic carbon and uncoated stainless-steel stents. In this study, a wide range of clinical indications for stenting, including complex lesion morphology, unstable angina and acute myocardial infarction, were included to provide a representative clinical scenario for stent to stent comparisons.18 We achieved a 100% procedural success rate in both groups and an angiographic follow-up rate of 87.2%, which allowed a largely unbiased restenosis analysis.
Carbon coating and stent restenosis. Despite the promising data from animal experiments and initial clinical experiences, no significant differences were found with regard to angiographic restenosis or clinical event rates between patients treated with carbon-coated stents and those treated with uncoated stainless-steel stents. Obviously, the biological potential of stent surface coating with turbostratic carbon does not translate into relevant clinical advantage within a widely unselected patient cohort. It cannot be overlooked, however, that a selective investigation of patients with allergic reactions against heavy metal ions19 or of patients especially prone to stent thromboses, such as in the setting of acute coronary syndromes, might reveal a clinical benefit of carbon coating. Nevertheless, it should be pointed out that out of the 4 stent thromboses occurring in our study population, three cases happened in patients treated with uncoated stainless-steel stents, while only 1 stent thrombosis occurred in the carbon-coated stent group. None of these cases were associated with an acute coronary syndrome or angiographically visible dissections.
Study limitations. Optimal conditions for comparison of stent coatings would include the use of stents with identical design and mechanical properties in both groups. This idea was supported by a previous study showing a higher rate of restenosis with thick strut stents compared to thin strut stents.20 In 2 randomized multicenter trials, however, a thick strut stent with closed-cell architecture recently demonstrated angiographic outcomes superior to both stent types used in our study.11,21 Based on these considerations, the observed trend toward a lower incidence of angiographic restenosis and clinical events with the carbon-coated stent could potentially be explained by either the closed-cell design providing better scaffolding of the intima compared to the open-cell design of the Multi-Link architecture or by the chemically inert properties of the surface coating. The observed difference in acute angiographic outcomes between the 2 groups might in part be related to variations in mechanical stent properties. Acute elastic recoil after stent deployment tended to be slightly more expressed in the carbon-coated stent group (9.6%) compared to the stainless-steel stent group (8.5%). In previous restenosis studies, the MLD immediately after the intervention as well as the acute lumen gain appeared to be important predictors of late restenosis.20,22 Interestingly, this observation is not confirmed by the findings of our study. Despite the initially lower final MLD (2.59 mm versus 2.72 mm) and the smaller acute lumen gain (1.82 mm versus 1.88 mm) among the carbon-coated stents, this group was not found to be associated with a higher incidence of in-stent restenosis. Thus, it cannot be excluded that an even more favorable late angiographic outcome in the carbon-coated stent group due to surface coating and closed-cell architecture might have been masked by slightly less favorable mechanical properties.
Conclusion. From the results of our comparison, no clinically relevant advantage of stents coated with turbostratic carbon over uncoated stainless-steel stents can be derived. The observed trend toward lower rates of clinical events and restenosis among patients treated with the carbon-coated stent could potentially be related to either a beneficial effect of the stent surface coating or the scaffolding properties of the closed-cell design.
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