Clinical and Angiographic Outcomes in Diabetic Patients following Single or Multivessel Stenting in the COSTAR II Randomized Tr
- Volume 20 - Issue 7 - July, 2008
- Posted on: 8/1/08
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The prevalence of diabetes has reached epidemic proportion in many sectors of the world.1 Atherosclerotic cardiovascular disease has been correlated with the presence, duration and severity of diabetes.2,3 In addition, both clinical and angiographic outcomes following percutaneous coronary intervention (PCI) are worse in patients with diabetes when compared with their nondiabetic counterparts.4,5 Although coronary stent implantation improved the outcomes of diabetic patients compared with balloon angioplasty due to a reduction in periprocedural and late (restenosis) complications,6–8 restenosis following bare-metal stent (BMS) deployment remained a significant limitation to PCI in this patient population.9,10 Stent-based elution of either paclitaxel or sirolimus from biostable polymers has been demonstrated to reduce angiographic and clinical restenosis compared with BMS deployment in patients both with or without diabetes mellitus.11–14 However, the safety and efficacy of paclitaxel elution from a stent-based bioresorbable polymer in patients with diabetes mellitus has not been studied. Furthermore, the importance of hyperglycemia in the absence of diagnosed diabetes mellitus as a determinant of clinical and/or angiographic outcomes following coronary stent deployment is inadequately defined.15,16 Therefore, prespecified subgroup analysis of outcomes in patients with diagnosed diabetes mellitus, and of those with elevated glycolated hemoglobin (HbA1c) in the absence of known diabetes was undertaken from all patients enrolled in the CObalt chromium STent with Antiproliferative for Restenosis (COSTAR) II trial. Study design and patient population. The COSTAR II study design has been described.17,18 Briefly, COSTAR II is a prospective, multicenter, single-blind, asymmetric (3:2), randomized trial comparing clinical and angiographic outcomes following deployment of the CoStar (Conor MedSystems, Menlo Park, California) compared with the Taxus (Boston Scientific, Natick, Massachusetts) paclitaxel drug-eluting stent (DES) for elective PCI in patients with de novo single- or multivessel coronary artery disease (CAD). The central hypothesis of the COSTAR II trial was that the CoStar stent is noninferior to the Taxus stent for the treatment of patients with symptomatic CAD.
Prespecified subgroup analyses included patients with diabetes, multivessel (versus single-vessel) stented cohorts as well as patients who required the provisional use of overlapping stents. Subject inclusion and exclusion criteria have been described17,18 and were similar to those of the Taxus IV study,12 with the exception being the inclusion of patients with 1-, 2- or 3-vessel CAD. Dual antiplatelet therapy (aspirin plus thienopyridine) was prescribed by protocol for 6 months following stent deployment. The study protocol compiled with the Declaration of Helsinki and was approved by the institutional review boards of all participating centers. All participating subjects signed an informed consent.
CoStar stent. The CoStar stent is a novel, thin-strut (0.0035 inch) cobalt chromium alloy metal platform with multiple laser-cut holes within the stent struts that serve as reservoirs for a bioresorbable (poly-lactic-co-glycolic acid; PLGA) polymer matrix. The polymer is loaded with paclitaxel, and the kinetics of both polymer resorption as well as paclitaxel elution are programmable by altering the ratio of copolymer (lactic or glycolic acid) constituents. Based on precedent clinical evaluations, a 10 µg paclitaxel dose eluted over 30 days (in vitro) dose kinetic was used in the present study.19
Data collection, follow up and core laboratory analyses. All data were submitted to the data coordinating center (Duke Clinical Research Institute) and all clinical events (30 days, 8 and 12 months) were adjudicated by an independent and blinded clinical events committee. All patients underwent baseline angiography. Angiographic (n = 250 multivessel; n = 100 single-vessel PCI patients) and intravascular ultrasound (IVUS) substudies (n = 70 single-vessel PCI patients) were performed. Cardiovascular Research Foundation (New York, New York) served as the angiographic core laboratory and Cardiovascular Core Analysis Lab (Stanford University, Palo Alto, California) served as the IVUS core laboratory. The clinical primary endpoint assessment was completed at 8 months following enrollment, while angiographic endpoints were analyzed 1 month following clinical assessment (at 9 months) to avoid confounding clinical endpoint measures in this single-blind study. An HbA1c level was obtained on all patients at baseline prior to stent deployment.
Endpoint definitions. The primary endpoint of the trial was the aggregate occurrence of MACE out to 8 months including death not attributed to a noncardiac cause or a nonintervention vessel; new Q- or non-Q-wave myocardial infarction (MI) not clearly attributed to a nonintervention vessel (the diagnosis of MI required a CK level > 2 times the upper limit of normal in the presence of elevated CK-MB fraction); and clinically-driven target vessel revascularization (TVR). Key secondary clinical endpoints included device, lesion and procedural success;17 MACE at 30 days and 12 months post procedure; target lesion revascularization (TLR), clinically-driven TLR and target vessel failure (TVF), defined as the composite of TVR, recurrent MI or cardiac death not attributed to a vessel other than the target vessel. The primary angiographic endpoint of the trial was in-segment late lumen loss with secondary endpoints including in-stent late lumen loss, in-stent and in-segment binary (> 50%) restenosis as well as in-stent and in-segment minimum luminal diameter. An HbA1c level > 6.5% in the absence of previously diagnosed diabetes was felt to be consistent with unrecognized hyperglycemia.20 Acute stent thrombosis was defined as abrupt vessel closure of the treatment site resulting in clinical manifestations of ischemia and angiographic evidence of occlusion or flow-limiting thrombosis in a treated vessel in which the investigational device was successfully implanted and that occurred after the procedure, but before the patient left the catheterization laboratory. Subacute stent thrombosis was defined as abrupt vessel closure of the treatment site that resulted in clinical manifestations of ischemia and occlusion occurring after the patient left the catheterization laboratory, but within 30 days of the interventional procedure. Late stent thrombosis was defined as MI attributable to the target vessel, with angiographic documentation of thrombus or total occlusion at the target lesion > 30 days following successful implantation of the device. Statistical analyses. Prespecified subgroups classified according to presence or absence of diabetes, diabetes treatment and elevated HbA1c levels were studied. Treatment assignments used in these comparisons were based on the intent-to-treat principal.
Continuous data are presented as means and categorical variables are presented as percentages, unless otherwise stated. Selected baseline characteristics, clinical and angiographic outcomes were compared between treatment groups and various diabetes strata by the chi-square test in instances of discrete variables and t-test in instances of continuous variables. Relative risk reduction and 95% confidence intervals (CI) were used for comparisons of major clinical outcomes. A p-value < 0.05 was considered statistically significant. No statistical adjustment was made for multiple comparisons. All statistical analyses were done using SAS version 8.0 or higher.