Steroid-Eluting Stents in Patients with ACS. Angiographic Results of DESIRE: Dexamethasone-Eluting Stent Italian REgistry

From the ^aDepartment of Biomedical Sciences and Surgery of the Università di Verona, Verona, the ^bEuropean Hospital, Rome, the ^cOspedale Santo Spirito, Pescara, the ^dPoliclinico San Marco, Zingonia, the ^eUniversità di Catania, Ospedale Ferrarotto, Catania, and the ^fUniversità di Napoli, Policlinico Federico II, Naples, Italy. ^*The DESIRE (Dexamethasone-Eluting Stent Italian Registry) investigators are listed in the Appendix at the end of this manuscript. Disclosures. This study was partially supported by Abbott Vascular Devices (Redwood City, California, USA) and Endotech (Como, Italy). The study sponsors had no role in the data analysis, statistical analysis, data interpretation, writing the report or in the decision to submit the article for publication. The authors report no conflicts of interest regarding the content herein. Dr. F. Ribichini received a research grant from the study sponsors and was reimbursed of travel expenses for presentation of the results of the study at scientific meetings. Manuscript submitted September 25, 2008, provisional acceptance given October 6, 2008, manuscript accepted October 13, 2008. Address for correspondence: Prof. Flavio Ribichini, MD, Director Catheterisation Laboratories, University of Verona, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. E-mail: flavio.ribichini@univr.it

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ABSTRACT: Background. Steroids have known powerful anti-inflammatory effects. This study was designed to assess the possible antiproliferative action of the Dexamet™dexamethasone-loaded stent. Methods. This was a prospective, controlled registry performed in 20 Italian centers that enrolled 332 patients with acute coronary syndromes (ACS) treated according to an early-invasive approach with the implantation of 420 dexamethasone-eluting stents in 387 coronary lesions. Six of the enrolling centers participated in the angiographic substudy: elective 6-month follow-up angiography was performed in 140/151 patients (92.7%). Quantitative coronary analysis (QCA) was performed at a centralized core laboratory on 156 lesions treated with the Dexamet stent. Results. One hundred forty patients (156 lesions) underwent elective QCA. Patients presented with either unstable angina (80%) or Non-ST-elevation myocardial infarction (20%); 70 patients (50%) had ST-T segment changes, 81 (58%) had troponin elevation and 31 (22.1%) were diabetic. One hundred twenty-five patients had a single lesion, 117 of which were treated with a single stent, while 8 received multiple stents. Mean lesion and stent lengths were 11.94 ± 6.30 and 17.30 ± 6.08 mm, respectively. In-segment binary restenosis (percent [%] diameter stenosis ≥ 50%) was 34.3% per patient (48/140), or 33.3% per lesion (52/156); the mean late lumen loss was 0.95 ± 0.64 mm in-stent and 1.02 ± 0.59 mm in-segment. At multivariate analysis, baseline minimum luminal diameter (MLD) (MLD – odds ratio [OR] = 0.18; 95% confidence interval [CI] = 0.04–0.72; p = 0.01) and lesion length (OR = 1.12; 95% CI = 1.04–1.2; p Conclusions. This is the first large, multicenter analysis of the angiographic outcome obtained with Dexamet. Our results do not support any effective antiproliferative action of this device implanted in patients with ACS.

J INVASIVE CARDIOL 2009;21:86–91

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Current recommendations for the treatment of patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) indicate that an early-invasive approach is superior to a conservative strategy in patients with either ST-segment depression, troponin elevation or other high-risk indicators.¹ Such results have been obtained by means of surgical or percutaneous coronary intervention (PCI) using bare-metal stents (BMS)^2,3 and the favorable short- and mid-term outcomes observed have been confirmed over the long term.^4,5 The powerful antirestenotic properties of drug-eluting stents (DES) may further improve the efficacy of PCI in ACS patients according to preliminary observations.^6,7 However, this assumption remains in part speculative and deserves dedicated investigation. Inflammation plays a major role in the onset and development of atherosclerosis.^8,9 Furthermore, the evolution of the disease toward either plaque passivation, healing and stabilization or towards plaque rupture and the occurrence of major events is strongly influenced by inflammatory mechanisms. The local elution of a potent anti-inflammatory agent at the plaque level represents the theoretical background for the use of a dexamethasone DES in these patients. This is supported by previous clinical studies in which the systemic administration of high-dose prednisone was shown effective in reducing clinical events after PCI,^10–14 a clinical finding strongly supported by preclinical experiments comparing the efficacy of the commercially available Taxus® DES (Boston Scientific Corp., Natick, Massachusetts) and high-dose oral prednisone in the atherosclerotic animal model.¹⁵ The Dexamet-Eluting Stent Italian REgistry (DESIRE) was designed to test the clinical safety and efficacy at 6 months of the commercially available dexamethasone-eluting stent Dexamet™ (Abbott Vascular Devices, Galway, Ireland). The clinical results of the study have been recently published elsewhere.16 The study was also designed to investigate the angiographic outcomes with Dexamet at 6 months, which is the aim of the present investigation.

Materials and Methods

A total of 334 patients presenting with NSTE-ACS at 20 Italian interventional centers were enrolled in DESIRE. Clinical events were analyzed and adjudicated by an independent clinical events committee (Appendix). Patients entering this prospective registry were informed of the study aims and all gave their informed consent to participate according to the ethical regulations of the relevant institutions. Study design and protocol. All patients included in the study were admitted with a diagnosis of NSTE-ACS and categorized according to the revised Braunwald’s classification of unstable angina. Patients presenting with elevation of creatine kinase [CK]-MB levels > 3 times the upper limit of normal (ULN), and without ST-segment elevation were considered as having NSTE-myocardial infarction (MI). Patients presenting with myocardial ischemia and troponin elevation on admission, but with CK-MB levels 17 All patients were pretreated before angiography with either intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin (according to each center’s standard of practice) and aspirin (300–500 mg/day). Pretreatment with a thienopyridine, either ticlopidine (250 mg b.i.d. at least 24 hours before PCI) or clopidogrel (300 mg loading at least 6 hours before PCI), was recommended. The thienopyridine was continued for at least 1 month and aspirin indefinitely after intervention. Statins were recommended in all patients. The use and choice of glycoprotein (GP) IIb/IIIa inhibitors was left to the operator’s discretion. Inclusion and exclusion criteria. Patients had to be over 18 years of age and present with NSTE-ACS (either NSTEMI or unstable angina) and show evidence of single- or multi-vessel coronary disease amenable to PCI. When the informed consent to enter the registry was obtained and exclusion criteria were ruled out, patients were treated during the same hospitalization with PCI and at least 1 dexamethasone-DES implanted in the culprit lesion. The exclusion criteria were as follows: in-stent restenosis, saphenous vein graft or a totally occluded vessel as the culprit lesion; acute ST-segment elevation MI; life expectancy 2 mg/dl; vessel diameter 30 mm (according to visual estimation). Percutaneous coronary intervention and quantitative coronary analysis. Interventions were performed through either the femoral or the radial approach. Staged multivessel procedures were performed during the same hospitalization. D-DES platform and usage. The Dexamet stent was available during the study period in different diameters (2.75, 3.0 and 3.5 mm) and lengths (10, 15, 18, 22, 28 mm). Dexamet is a stainless-steel stent coated with a phosphorylcholine polymer and loaded with 0.5 µg of dexamethasone/mm2 on the stent’s surface. At least 1 dexamethasone-DES had to be implanted in the culprit lesion and direct stenting was allowed. PCI was considered successful when a percent (%) diameter stenosis ≤ 30% and a thrombolysis in myocardial infarction (TIMI) flow ≥ 2 were obtained in the culprit lesion. Six centers participated in the angiographic substudy (Appendix). Angiographic recordings for QCA were obtained in at least two orthogonal views of each of the treated coronary segments, after the administration of intracoronary nitroglycerin. At follow-up angiography, the same orthogonal views were obtained. The compact discs containing the angiographic images were sent to an independent core laboratory (Appendix) for centralized QCA using the CMS automated edge-detection system (Medis Medical Imaging Systems, Leiden, The Netherlands). All the lesions treated with Dexamet recorded at baseline, after PCI and at follow up were of adequate quality for QCA. Biochemical measurements: Troponin I (ULN 0.1 µg/L), fibrinogen (ULN 350 mg/dL), C-reactive protein level (UNL 0.5 mg/dl), white blood cells (ULN 10.11 cells x 10^9/L) and neutrophiles (ULN 6.6 cells x 10^9/L) were measured before PCI, and after 48–72 hours. The ULN cut-off used for statistical analysis were selected according to previous studies that correlated these biochemical variables with clinical outcome and restenosis after PCI.^10,11,18Endpoints and definitions. The primary endpoint and results of the study have been described in detail elsewhere.16 The secondary endpoint was the incidence of binary restenosis at follow-up angiography, defined as a stenosis of at least 50% of the minimal diameter inside the stent or within 5 mm of the stent edges of the lesions treated with Dexamet, according to QCA. Stenosis length (defined as the axial extent of the treated lesion that contained a shoulder-to-shoulder lumen reduction by ≥ 20%), reference vessel diameter (calculated analyzing segments of 5 mm length proximal and distal to the lesion) and minimum luminal diameter (MLD) were measured at baseline post stent implantation and at follow up. Late lumen loss was calculated as the difference in millimeters between post procedural and follow-up MLD. All parameters were treated according to the standard and widely-accepted definitions for QCA as reported elsewhere.¹⁹Follow up. All patients were evaluated clinically at 30 days and 6 months after the procedure. In the 6 centers that participated in the DESIRE angiographic substudy, angiography was performed at 6 months after the PCI to assess the occurrence of angiographic restenosis. Statistical analysis. Continuous data are expressed as means and standard deviations; discrete variables are given as absolute values and percentages. The Student’s t-test was used to compare differences between continuous variables and between continuous variables and categorical grouping variables. The chi-square statistics with Yates’ correction, or Fisher’s exact test when appropriate, were used to test associations of categorical data. A logistic multivariate regression model was used to assess the predictive value of factors related to the occurrence of restenosis. The variables of the models included those found to be statistically significant in the univariate analyses. The distribution of the late lumen loss of the treated lesions at follow up was analyzed by a frequency distribution curve (Figure 1) and checked for normality with the Kolmogorov-Smirnov test. Calculations and graphs were made using Microsoft Excel and the SPSS software (version 11.5 for Windows). A probability value of ≤ 5% was considered significant.

Results

Patient characteristics. The baseline characteristics of the 332 patients entered in the study were reported previously.¹⁶ Of the 151 patients enrolled in the angiographic substudy, follow-up angiography was obtained in 140 patients (92.7% or 42.2% of the whole DESIRE sample), with 156 lesions treated with Dexamet. One hundred eight of the 140 patients were male (77%) with an average age of 62.5 ± 9.2 years. Seventy-four (53%) were hypertensive, 70 (50%) were current smokers, 75 (54%) had high blood cholesterol and 31 (22%) were diabetic. The diagnosis at admission was NSTEMI in 19.3% of patients and acute (type III) unstable angina in 27.8%. Forty-three percent of the patients had a previous MI and 17.1% had undergone previous myocardial revascularization. Troponin I was elevated in 58% of patients, C-reactive protein (CRP) in 86%, and electrocardiographic (ECG) changes (ST depression or T-wave inversion) were observed in 50%. According to the TIMI risk stratification,¹⁸ the risk score was intermediate-to-high in 50% of patients. These data are summarized in Table 1 and do not differ significantly from the characteristics of the entire DESIRE population. Clinical results. Clinical follow up at 6 months was obtained in 328/332 DESIRE patients (98.8%). The composite endpoint of death and MI was observed in 10 patients (3%). Twenty-eight patients underwent ischemia-driven target vessel revascularization (TVR) (8.5%). The primary endpoint was therefore reached in 38/328 patients (11.6%). Repeat TVR was also performed in 9 additional patients undergoing per-protocol coronary angiography at 6 months. All these subjects were asymptomatic, had no ECG signs of ischemia, but presented with a stenosis of the target vessel > 50% and n = 140), none died, 23 underwent TVR, 2 patients experienced new non-Q-wave MI, while 1 had a Q-wave MI. The TVR rate was significantly higher than in the non-QCA group (16.4 vs. 7.4%; p 16 Angiographic results. The mean time to angiographic follow up was 195 ± 43 days after PCI. Five patients showed a totally occluded vessel (3.6%), and edge restenoses were seen in 4 cases: 2 proximal and 2 distal to the stent borders (2.9%). The angiographic endpoint of binary restenosis inside the stent or within 5 mm of the stent edges implanted in the culprit lesion was observed in 34.3% of patients (48/140), or 33.3% of lesions (52/156). The mean in-stent late lumen loss was 0.95 ± 0.64 mm, the mean in-segment late lumen loss was 0.99 ± 0.59 mm and the mean lesion length was 11.39 ± 1.28 mm (Table 2). The frequency distribution curve of the late loss showed a normal pattern (Figure 1: Kolmogorov-Smirnov p = 0.52). In the total DESIRE population, 24% of treated vessels were smaller than 2.75 mm before PCI. The average interpolated reference diameter (IRD) at the lesion site was 2.7 ± 0.51 mm. The average baseline and post-PCI in-stent and in-segment MLDs were 0.83 ± 0.40, 2.59 ± 0.42 and 2.16 ± 0.49 mm, respectively. These and other relevant data derived from QCA analysis are reported in Tables 1 and 2. Subgroup analysis. Among the analyzed variables, age, baseline lesion length, baseline MLD, post-procedural in-stent/in-segment MLD and elevated troponin I levels on admission were associated with the presence of binary restenosis at follow up (Table 1). Figure 2 shows the additive effect of troponin I elevation and lesion length on the incidence of binary restenosis. Lesions with a lower MLD at baseline angiography (0.65 ± 0.24 vs. 0.91 ± 0.43 mm; p p = 0.04) and in-segment (2.05 ± 0.49 vs. 2.22 ± 0.48 mm; p p p = 0.01) remained strongly associated with the event. The predictive value of Troponin I elevation on admission was close to significance (OR 0.42, 95% CI: 0.17–1.03; p = 0.058). These data are plotted in Figure 4.

Discussion

Our study reports the first multicenter angiographic analysis of the dexamethasone-eluting stent Dexamet in the specific setting of patients with NSTE-ACS undergoing early invasive revascularization with PCI. Our results suggest that the early elution of dexamethasone at the plaque level in the acute phase of plaque destabilization yields rather unpredictable angiographic results. Unlike sirolimus- or paclitaxel-eluting stents, whose late lumen loss values have been invariably replicated in several different trials, the angiographic results of the Dexamet-DES observed in the few available studies have yielded widely varied values. The first clinical study performed with Dexamet was the STRIDE trial,²⁰ which analyzed 71 nondiabetic patients, 42% of whom had ACS. The stent was loaded with 0.5 µg of dexamethasone/mm² of stent surface and despite the small sample size of this study, the authors reported significantly better angiographic outcomes in the unstable patients (late lumen loss at 6 months 0.32 ± 0.39 mm) compared to the stable patients (late lumen loss 0.60 ± 0.55 mm; p = 0.067). Another initial experience was reported by Hoffmann et al^21,22 30 in which dexamethasone-DES were implanted in ­­­­­­­mostly stable patients (90%) who underwent repeat QCA at 6 months. In that sample, 5 patients (17%) were diabetic, 3 (10%) had unstable angina, 12 (40%) had multivessel disease and 18 (60%) had complex lesions. Unlike the commercially available Dexamet-DES used in DESIRE, the stents used by Hoffmann et al were manually loaded with dexamethasone. Using this rudimentary method, the estimated dose density at the abluminal stent surface was calculated to be 2.2 µg/mm². The restenosis rate was 31%, the % diameter stenosis was 43 ± 22 mm, and in-stent late lumen loss was 0.96 ± 0.63 mm. The mean intimal hyperplasia thickness assessed by intracoronary ultrasound at 6 months in 18 of the 30 patients was similar to that observed in patients receiving a BMS.²² More recently, two randomized studies have reported on the angiographic outcomes of the dexamethasone-DES compared to its BMS counterpart, the BiodivYsio stent (Abbott Laboratories, Abbott Park, Illinois), which has the same metallic platform.^23,24 The first study compared 71 manually loaded dexamethasone-DES (similar to the stents tested by Hoffman et al) and 27 BiodivYsio metallic stents in 92 patients with ACS. Late lumen loss values at 6 months (controlled on 59 dexamethasone-DES and 21 BMS patients) were 0.77 ± 0.66 and 1.34 ± 0.65 mm, respectively, a significant difference that also translated into a net clinical benefits in favor of the dexamethasone-eluting stent. The second study enrolled 2 arms of 60 patients each treated either with the Dexamet-DES or the BiodivYsio BMS (control group) in the setting of ACS. At 6 months, the Dexamet-DES yielded a significant reduction in late lumen loss (0.55 ± 0.65 mm) compared to the controls (1.07 ± 0.92 mm; p = 0.001) a difference that, like in the previous study, retained clinical relevance. The wide discrepancy between the late lumen loss values reported in different studies of dexamethasone-DES requires some considerations. The first consideration concerns the different method used for drug absorption and elution from the stent in the manually loaded stent and the Dexamet-DES. The unpredictable drug dosage and elution profile of the former stent makes comparison with the latter fairly unreliable. Second is the sample size ranging between 30^21,22 and 156 patients.¹⁶ The third consideration involves the different clinical and angiographic settings: mostly simple type-A lesions²⁰ versus mostly complex type-B2 and -C lesions,^16,23,24 and stable^20,22 versus unstable patients.^16,23,24 Last, but not least, is the possible publication bias of positive results. Although all these variables can explain the contrasting results obtained with dexamethasone-DES in different studies, it has already been well established that other DES do not show such a wide variability in angiographic efficacy, even in different clinical settings^6,7 and loading conditions.^25,26 On the contrary, our study yielded worse angiographic results in older patients, in long and tight lesions and in patients presenting with troponin-positive ACS (Table 1), which are well-known predictors of restenosis for nonmedicated stents. However, the anti-inflammatory effects of dexamethasone showed efficacy in reducing the occurrence of clinical events in unstable patients and in reducing the recurrence of angina at 6 months compared to previous studies of patients with NSTE-ACS treated with PCI and BMS.¹⁶ Thus, the locally eluted steroid may exert a beneficial effect on the “passivation” of the unstable plaque in patients with ACS. Higher drug concentrations may be needed to obtain an effective antiproliferative effect with steroids after stent implantation, since not only anti-inflammatory actions, but immunosuppression, are required to achieve this goal. Indeed, previous studies have demonstrated that the efficacy of steroids after PCI is dose-sensitive;^10–14 therefore, the possibility of also obtaining a reduction in the degree of neointimal hyperplasia by administering high systemic doses of corticosteroids after the implantation of a dexamethasone-DES may deserve further investigation.

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