TAXUS Liberté Attenuates the Risk of Restenosis in Patients With Medically Treated Diabetes MellitusResults From the TAXUS ATLAS Program
Ehtisham Mahmud, MD, FACC*,*,
John A. Ormiston, MBChB ,
Mark A. Turco, MD, FSCAI ,
Jeffrey J. Popma, MD ,
Neil J. Weissman, MD||,
Charles D. O'Shaughnessy, MD¶,
Tift Mann, MD#,
Jack J. Hall, MD**,
Thomas F. McGarry, MD,
Louis A. Cannon, MD,
Mark W.I. Webster, MD,
Lazar Mandinov, MD||||,
Donald S. Baim, MD||||
* University of California, San Diego, San Diego, California
Mercy Angiography Unit, Mercy Hospital, Auckland, New Zealand
Center for Cardiac & Vascular Research, Washington Adventist Hospital, Takoma Park, Maryland
Angiographic Core Laboratory, Brigham and Women's Hospital, Boston, Massachusetts
|| Cardiovascular Research Institute, Washington Hospital Center, Washington DC
¶ North Ohio Research Center, Elyria, Ohio
# Wake Heart Associates, Wake Medical Center, Raleigh, North Carolina
** The Heart Center, St. Vincent's Hospital, Indianapolis, Indiana
Oklahoma Heart Hospital, Oklahoma City, Oklahoma
Cardiac & Vascular Research Center, Northern Michigan Hospital, Petoskey, Michigan
Auckland City Hospital, Auckland, New Zealand
|||| Boston Scientific Corporation, Natick, Massachusetts
 |
Abstract
|
|---|
Objectives: The aim of this study was to assess the relative efficacy and safety of the second-generation TAXUS Liberté paclitaxel-eluting stent (PES) in patients with and without diabetes mellitus.
Background: Diabetic patients suffer from accelerated atherosclerosis and increased risk of restenosis after coronary interventions; however, prior data suggest that PES might blunt this effect, providing equal benefit in diabetic and nondiabetic patients.
Methods: A pooled analysis of all 4 TAXUS ATLAS studies was conducted that included 413 diabetic and 1,116 nondiabetic subjects treated with the TAXUS Liberté stent for de novo coronary lesions. Angiographic and intravascular ultrasound outcomes at 9 months and clinical outcomes at 9 and 12 months were compared in patients with and without diabetes. Propensity score and multivariate adjustments were performed to correct for baseline differences.
Results: In-stent angiographic restenosis (13.0% vs. 9.6%, p = 0.12), late luminal loss (0.40 mm vs. 0.38 mm, p = 0.58), and intimal hyperplasia (14.8% vs. 13.4%, p = 0.29) were similar for diabetic and nondiabetic subjects. After propensity adjustment, 12-month target lesion revascularization rates were similar for diabetic and nondiabetic subjects (6.4% vs. 4.7%, p = 0.18), with no differences in mortality, myocardial infarction, or stent thrombosis. However, the rate of target vessel revascularization (TVR) was higher for diabetic subjects due to increased TVR outside the target lesion (TVR Remote).
Conclusions: Similar clinical, angiographic, and intravascular ultrasound outcomes were observed for both diabetic and nondiabetic subjects treated with TAXUS Liberté, suggesting that this PES attenuates the effect of diabetes on restenosis after percutaneous coronary intervention, yielding comparable efficacy and safety in diabetic and nondiabetic patients. (TAXUS ATLAS; NCT00371709, NCT00371423, NCT00371748, and NCT00371475)
Key Words: coronary artery disease • diabetes • drug-eluting stent • paclitaxel
|
Abbreviations and Acronyms
| | %DS = percent diameter stenosis | | CI = confidence interval | | HR = hazard ratio | | MACE = major adverse cardiac events | | MI = myocardial infarction | | MLD = minimum lumen diameter | | PES = paclitaxel-eluting stent(s) | | RVD = reference vessel diameter | | TLR = target lesion revascularization | | TVR = target vessel revascularization |
|
There is an increased prevalence of atherosclerosis in patients with diabetes mellitus (1). Diabetic patients thus tend to have more advanced coronary artery disease compared with nondiabetic patients, with greater plaque burden, and longer lesions in smaller (or more diffusely diseased) vessels (2–5). Patients with diabetes are also more likely to develop restenosis after treatment with bare metal stents and are at greater risk for myocardial infarction (MI) and stent thrombosis compared with those without diabetes (6–9). The use of drug-eluting stents, including the TAXUS (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) and the CYPHER (Cordis, Miami, Florida) sirolimus-eluting stent (SES), has resulted in significantly lower rates of restenosis as compared with bare metal stents (10–15). However, the relative efficacy and safety of drug-eluting stents in diabetic versus nondiabetic patients has not been well studied. In this regard, in vitro studies have suggested a selective benefit of paclitaxel in suppressing the neointimal hyperplasia in a diabetic model (16). This study examines whether that observation is supported clinically from data for diabetic versus nondiabetic patients treated with the second-generation, thin-strut PES, TAXUS Liberté.
The TAXUS Liberté stent, designed specifically to improve deliverability and conformability and provide more homogeneous drug distribution, has recently been evaluated in 4 prospective, controlled studies enrolling patients with de novo coronary lesions: TAXUS ATLAS (17), TAXUS ATLAS Direct Stent (18), TAXUS ATLAS Long Lesion (19), and TAXUS ATLAS Small Vessel (19). In the TAXUS ATLAS study, the TAXUS Liberté PES was shown to be similarly effective to the TAXUS Express PES in reducing restenosis and the need for repeat revascularization in an overall sample containing both diabetic and nondiabetic patients (17). The current integrated analysis was undertaken to compare the angiographic, intravascular ultrasound, and clinical outcomes in medically treated diabetic patients treated with the TAXUS Liberté stent in all 4 TAXUS ATLAS studies with those of the nondiabetic cohort in the same studies. The objective of this analysis was to evaluate the effect of the TAXUS Liberté PES on neointima development and the need for repeat revascularization in patients with and without diabetes.
|
Methods
|
|---|
Device description.
The TAXUS Liberté stent (Boston Scientific Corporation, Natick, Massachusetts) consists of a balloon-expandable Liberté stent with a biostable poly(styrene-b-isobutylene-b-styrene) polymer coating that contains 1 µg/mm2 of paclitaxel in a slow-release formulation. Drug-dosing and release kinetics are virtually identical to that of the TAXUS Express PES, but the different stent geometry and thinner strut (0.0038 inch/0.096 mm vs. 0.0052 inch/0.132 mm) design allows for enhanced deliverability and more uniform wall coverage.
Patient selection, procedure, and follow-up.
The study protocols were approved by local ethics review committees for included studies, and all patients provided written informed consent. Trials are registered on the National Institutes of Health website (identifiers NCT00371709, NCT00371423, NCT00371748, and NCT00371475) (20).
Subjects were pooled from the 4 TAXUS ATLAS studies. A summary of the individual TAXUS ATLAS study designs is presented in Table 1. Eligibility criteria and procedural requirements were the same in all 4 studies (17–19). After stent implantation, all patients were prescribed thienopyridine therapy for a minimum of 6 months. Aspirin therapy was mandated for at least 9 months and was recommended indefinitely.
Diabetic subjects were identified as those treated with at least 1 hypoglycemic agent (oral or insulin) at the time of enrollment. By this criterion, the 1,529 subjects enrolled in the 4 TAXUS ATLAS trials were divided into 2 groups: 413 patients with medically treated diabetes and 1,116 without diabetes (Table 1). Clinical follow-up was at 1, 4, 9, and 12 months. Quantitative coronary angiography at 9-month follow-up was planned for all patients in the Direct Stent, Long Lesion, and Small Vessel studies plus 543 randomly selected patients in TAXUS ATLAS trial. Intravascular ultrasound analysis was prespecified for randomly selected patients in 3 studies—TAXUS ATLAS, Direct Stent, and Long Lesion—for a total intravascular ultrasound cohort of 624 patients. Patient follow-up through 12-months is outlined in Figure 1.
View larger version (24K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Patient Flow Through 9- and 12-Month Follow-Up
Patient flow of all diabetic and nondiabetic subjects enrolled in the TAXUS ATLAS, Direct Stent, Long Lesion, and Small Vessel Studies. mo = month; QCA = quantitative coronary angiography; IVUS = intravascular ultrasound.
|
|
Quantitative coronary angiographic and intravascular ultrasound analyses.
Quantitative coronary angiographic analyses were performed by the same core laboratory (Brigham and Women's Hospital, Boston, Massachusetts) for all studies. Standard image acquisition was performed at the clinical sites with 2 or more angiographic projections of the stenosis, and all procedural and follow-up angiograms were reviewed with standard morphologic criteria (21,22). With the contrast-filled injection catheter as the calibration source, quantitative coronary angiography was performed with a validated automated edge detection algorithm (MEDIS CMS, Version 5.0, Leiden, the Netherlands) (22). A 5-mm segment of reference diameter proximal and distal to the stenosis was used to calculate the average reference vessel diameter (RVD) at baseline, after stent implantation. Minimal lumen diameter (MLD) was measured at these same time points within the stent (in-stent analysis), within the 5-mm proximal and distal edges of the stent and within the segment between the proximal and distal reference vessel (in-segment analysis). Angiographic percent diameter stenosis (% DS) was defined as: (1–[MLD/RVD]) x 100. Binary angiographic restenosis was defined as the incidence of % DS  50% at the qualifying angiographic follow-up. Late loss was defined as MLD immediately after the procedure minus MLD at 9-month follow-up. Restenosis patterns were qualitatively assessed with the Mehran classification system (23). Lesion length was defined as the axial extent of the lesion that contained a shoulder-to-shoulder lumen reduction by 20%. Angiographic follow-up was performed 9 months (±14 days) after the index procedure unless earlier angiography was required clinically.
Volumetric intravascular ultrasound analyses were performed by the same core laboratory (Washington Hospital Center, Washington DC) for all studies. Detailed methods have been previously described (24). Images were obtained immediately after stent implantation and at 9-month follow-up in patients designated for intravascular ultrasound follow-up. Images with technically inadequate quality, inconsistent pullback speed, and incomplete visualization of the vascular interface were not analyzed.
The angiographic and intravascular ultrasound Core Laboratories were blinded to all clinical characteristics, including the diabetic status.
Definitions.
Major adverse cardiac events (MACE) and stent thromboses were adjudicated by an independent Clinical Events Committee. The clinical and angiographic end point definitions were identical for all TAXUS ATLAS studies (17,18). Stent thrombosis adjudicated by the Academic Research Consortium definite/probable definition is also reported (25).
Statistical methodology.
All end points were analyzed with the intent-to-treat analysis set. Homogeneity tests were performed to justify pooling across the 4 TAXUS ATLAS studies. The Breslow-Day test was used for binary data and 2-way analysis of variance was employed for continuous variables. Values of p > 0.05 (the lowest p value was 0.31) suggested that the treatment effect between the diabetic and nondiabetic patients across studies is homogeneous and that all 4 TAXUS ATLAS studies can be pooled together.
Baseline, post-procedure, and follow-up data are summarized with descriptive statistics, with data presented as proportions (%, count/sample size) or mean ± SD. The Student t test was used for comparing continuous variables. The chi-square test or Fisher exact test, as appropriate, was used for comparing 2 proportions. Kaplan-Meier product-limit method and log-rank test were used to assess time-to-event end points between the 2 groups.
Due to significant differences in baseline characteristics between diabetic and nondiabetic patients, clinical, angiographic, and intravascular ultrasound outcomes were adjusted with propensity score analysis. In addition, 1-year clinical outcomes were also adjusted with multivariate modeling, to confirm the results of the propensity analysis.
Propensity score analysis (26–29) is used to balance 2 nonrandomized groups on the basis of observed covariates in order to equalize the baseline differences associated with a treatment or disease state and give a more accurate estimate of the effect of the treatment or the disease (30). Use of this propensity score allows for adjustment of baseline differences (other than the presence of diabetes) between the diabetic and nondiabetic groups. Propensity score analysis was performed with a hierarchical logistic regression model with a stepwise selection process and an entry/exit criterion of 0.10. The logistic regression model creates a score on the basis of the propensity that a patient belongs to 1 of the 2 groups being compared. The propensity score for the likelihood of belonging to the diabetic group ordered patients of the 2 analysis sets into quintiles. Each quintile contained patients with similar scores and more balanced baseline characteristics, thus allowing for more like-to-like comparisons between the 2 groups and adjustment of the outcomes. All demographic data and lesion characteristics listed in Table 2
and the following procedural characteristics were considered for adjustment: pre-procedure Thrombolysis in Myocardial Infarction flow; nontarget lesion treated; maximum balloon/artery ratio; maximum overall pressure; glycoprotein IIb/IIIa inhibitor use during index procedure; and pre-procedure aspirin and thienopyridine use.
Multivariate adjustment was also performed for 1-year clinical outcomes, with the same variables that were considered for propensity score adjustment. In addition, event-free survival estimates/diabetic status were produced by stratification of multivariate Cox regression models in a 2-stage multivariate analysis.
Multivariate analyses were used to determine predictors of 12-month mortality, MI, target vessel revascularization (TVR), TVR Remote, and target lesion revascularization (TLR) in all subjects. All characteristics listed in the preceding text along with diabetes were considered. A 2-stage multivariate analysis was conducted for each outcome with the Cox regression model. In the first stage, the predictors were determined by stepwise selection with an entry and exit criterion for each candidate of p  0.05. In the second stage, a multivariate model was created only considering the variables found to be significant predictors in the first stage for each outcome.
Differences were considered to be statistically significant when the p value was <0.05.
|
Results
|
|---|
Baseline characteristics and procedural outcomes.
Baseline demographic data and angiographic lesion characteristics are shown in Table 2. Subjects with medically treated diabetes were more likely to be women and to have a history of previous revascularization (both percutaneous coronary intervention and coronary artery bypass graft surgery), congestive heart failure, hyperlipidemia, hypertension, and chronic renal insufficiency but were less likely to be smokers. Diabetic subjects had smaller angiographic reference diameter and smaller final implanted stent size. All other baseline clinical and angiographic lesion characteristics were matched between the 2 groups (Table 2). Procedural characteristics and antiplatelet use are shown in Table 3. Use of dual antiplatelet therapy was similar between diabetic and nondiabetic patients pre-procedure, at discharge, and at 9-month follow-up. However, diabetic patients had significantly higher dual antiplatelet therapy use at 1 year compared with nondiabetic patients.
Angiographic end points at 9 months.
There were no significant differences in 9-month in-stent angiographic outcomes, regardless of propensity-adjustment. Late loss was similar for diabetic and nondiabetic subjects and nearly identical after propensity score adjustment (Table 4). In addition, the distribution curves of late loss for diabetic and nondiabetic subjects were virtually superimposable (Fig. 2). Binary in-stent restenosis rate and in-stent % DS, whether adjusted or unadjusted, were not statistically different between diabetic and nondiabetic patients. The pattern of in-stent restenosis was also similar between the 2 groups with <2% of the study sample presenting with proliferative hyperplasia or total occlusion at follow-up regardless of diabetic status (Fig. 3).
View larger version (22K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2 Cumulative Frequency Distribution of 9-Month In-Stent and In-Segment Late Loss by Quantitative Coronary Angiography
Subjects with and without diabetes treated with the TAXUS Liberté Stent in the TAXUS ATLAS studies. (A) In-stent; and (B) in-segment. Intent-to-treat, angiographic subset (n = 1,201; diabetic: 334; nondiabetic: 867).
|
|
View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3 ISR Patterns in Diabetic and Nondiabetic Patients
The frequency of individual patterns of in-stent restenosis (ISR) in subjects with and without diabetes treated with the TAXUS Liberté Stent in TAXUS ATLAS studies. Intent-to-treat, angiographic subset (n = 1,201; diabetic: 334; nondiabetic: 867).
|
|
In-segment late loss was similar for the 2 patient groups regardless of adjustment. There was a trend toward higher rates of in-segment binary restenosis in subjects with diabetes; however, after propensity score adjustment the rates were similar for the 2 groups. In-segment % DS was significantly increased in patients with diabetes; this difference became nonsignificant after propensity score adjustment. Edge analysis was used to evaluate the difference in the in-segment % DS between the 2 groups. Although there were no differences in % DS or restenosis rates at the proximal edge between the 2 groups, both % DS and restenosis at the distal edge were significantly increased in diabetic compared with nondiabetic subjects (Fig. 4).
View larger version (15K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 Angiographic Edge Analysis
Frequency of percent diameter stenosis (A) and binary restenosis (B) 5 mm proximal and distal to each stent edge in subjects with and without diabetes mellitus treated with the TAXUS Liberté Stent in TAXUS ATLAS studies. Intent-to-treat, angiographic subset (n = 1,201; diabetic: 334; nondiabetic: 867).
|
|
Intravascular ultrasound end points at 9 months.
A total of 427 patients (68% of the intravascular ultrasound cohort) completed 9-month intravascular ultrasound follow-up (Fig. 1), and 413 of these patients had analyzable films. The TAXUS Liberté stent suppressed neointima growth similarly in diabetic and nondiabetic subjects with similar % intimal hyperplasia in both groups (Table 4). Intima-free length of the stent was also similar for the 2 groups. Unadjusted and adjusted results were concordant.
Clinical efficacy of TAXUS Liberté in diabetic subjects at 9 and 12 months.
Clinical follow-up at 9 and 12 months demonstrated a higher rate of overall TVR for diabetic subjects as compared with nondiabetic subjects, a difference that remained statistically significant after propensity adjustment (Table 5). The 9- and 12-month rates of both TLR and remote TVR were also significantly higher for diabetic subjects versus nondiabetic subjects. However, after propensity adjustment (Table 5), the TLR rates were similar between the 2 cohorts with a trend toward a higher rate of remote TVR (in the target vessel but outside the target lesion) in the diabetic cohort. The results at 12-month follow-up were corroborated by multivariate adjustment (Fig. 5) demonstrating that the diabetic subjects had significantly increased risk of TVR, driven by a higher risk of TVR Remote (non-TLR TVR); however, the risk of TLR was comparable for the 2 groups.
View larger version (32K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5 12-Month Freedom From Adverse Outcomes
Unadjusted (A, C, E, G) and multivariate-adjusted (B, D, F, H) freedom from all-cause mortality (A, B), target vessel revascularization (TVR) (C, D), TVR Remote (non-target lesion revascularization [TLR] TVR) (E, F), and TLR (G, H). Diabetic (n = 413) and nondiabetic (n = 1,116) intent-to-treat subjects treated with the TAXUS Liberté Stent in TAXUS ATLAS studies. Event-free survival ± 1.5 SEM. CI = confidence interval.
|
|
Safety of TAXUS Liberté in diabetic subjects at 12 months.
Subjects with diabetes had comparable rates of all-cause mortality, cardiac death, and MI at 9 and 12 months compared with nondiabetic subjects (Table 5). The rates of stent thrombosis by protocol and Academic Research Consortium definition were also similar between the 2 groups (Table 5). Unadjusted/protocol stent thrombosis rates at 12 months were concordant with those after multivariate (hazard ratio [HR]: 1.37; 95% confidence interval [CI]: 0.34 to 5.5; p = 0.66) and propensity score adjustment (Table 5).
Multivariate predictors of clinical outcomes at 12 months.
Multivariate analysis was performed for numerous clinical and procedural variables to determine the risk factors for overall mortality, cardiac mortality, MI, TVR, TLR, and remote TVR (Table 6). Diabetes was not found to be a risk factor for death, MI, or TLR 12 months after TAXUS Liberté stent implantation. However, the presence of diabetes remained a predictor of repeat TVR (HR: 1.77; 95% CI: 1.24 to 2.52; p = 0.002) and remote (nontarget lesion) TVR (HR: 1.71; 95% CI: 1.03 to 2.82; p = 0.04) at 12 months.
|
Discussion
|
|---|
This study has a number of important findings that pertain to medically treated diabetic patients treated with the second-generation TAXUS Liberté PES. First, angiographic and intravascular ultrasound analyses both demonstrate that this stent reduces neointimal proliferation in diabetic subjects to a level that is comparable to that seen in nondiabetic subjects. Second, when restenosis develops, its pattern is dominated by focal restenosis in both diabetic and nondiabetic subjects. Third, these angiographic and intravascular ultrasound findings are accompanied by rates of clinical restenosis of the target lesion (TLR) that are similar for diabetic and nondiabetic subjects. Fourth, the increased rates of overall TVR and MACE seen in diabetic subjects are driven predominantly by TVR Remote (i.e., TVR outside the stented lesion) rather than events driven within the stented segment. Fifth, at 12-month follow-up, no increase in the likelihood of stent thrombosis, MI, or death exists with this stent in diabetic subjects.
The active ingredient in the TAXUS Liberté stent, paclitaxel, effectively blocks smooth muscle cell proliferation and migration through multiple mechanisms, including stabilization of microtubules to cause G1 arrest (31–33) and inhibition of the Ras/mitogen-activated protein kinase pathway (16,34). When these pathways are affected, the alternative pro-survival mechanism for the smooth muscle cell is through modulation of the AKT-dependent mTOR (35–37) and/or FoxO3a signaling pathways. The ability to not promote activation of AKT under the hyperglycemic state typically seen in the diabetic metabolic state (16), and to strongly inhibit insulin-dependent AKT phosphorylation (35,36), allows paclitaxel to maintain its inhibition of restenosis in diabetic models.
The current study supports the translation of these in vitro findings to the clinical realm by showing that paclitaxel can provide a similarly low degree of neointimal proliferation in diabetic subjects and nondiabetic subjects. Indeed, the angiographic in-stent parameters of late luminal loss and % DS were found to be very similar in diabetic and nondiabetic patients treated with this second-generation PES. Despite slightly smaller reference vessels at baseline in the diabetic patients, their in-stent binary restenosis rates were comparable to those of nondiabetic subjects and the pattern of restenosis at the time of repeat revascularization for both groups was predominantly focal in nature, a pattern easier to treat than proliferative or diffuse restenosis (23). Angiographic findings were corroborated by intravascular ultrasound results, which demonstrated that the in-stent intimal hyperplasia was similar between diabetic and nondiabetic subjects, further supporting that this PES can inhibit neointimal growth even in the diabetic state. This is consistent with a recent meta-analysis of the TAXUS IV, V de novo, and VI trials that also shows comparable suppression of neointimal hyperplasia by quantitative intravascular ultrasound analysis in diabetic subjects and nondiabetic subjects with the first generation PES TAXUS Express (38).
Whereas there were no significant differences between diabetic and nondiabetic patients in any in-stent measures, % DS in the analysis segment was significantly increased in patients with diabetes, driven by a greater % DS at the distal edge. The increased rate of distal edge restenosis in diabetic patients as compared with nondiabetic subjects might be caused by more pronounced restenotic response within the injured vessel segments that remained uncovered by the PES or more rapid disease progression outside the stent in patients with diabetes. However, in-segment % DS was not significantly different between groups after propensity score adjustment. Similarly, the unadjusted TLR rates were higher in the diabetic cohort, which presented with smaller diameter vessels, slightly longer lesions, increased comorbidities, and more edge restenosis than the nondiabetic cohort. Importantly, no significant difference in the likelihood of TLR remained after propensity score or multivariate adjustment correcting for baseline differences between the 2 groups. These findings corroborate the results from a meta-analysis of 5 TAXUS Express randomized studies that demonstrated TLR reduction for the first-generation PES compared with bare metal stents in cohorts with diabetes (HR: 0.42; 95% CI: 0.30 to 0.60) and without diabetes (HR: 0.47; 95% CI: 0.38 to 0.59) (15).
The higher MACE rate seen in the diabetic cohort was accounted for by the increased TVR Remote (non-TLR) in diabetic subjects. Because diabetes is a systemic disease, progression of atherosclerosis or formation of new lesions remote from the index treated lesion is expected, as is the inability of focal treatment by a drug-eluting stent to reduce progressive disease beyond the treated vessel segment. In patients treated with the paclitaxel-eluting TAXUS Liberté stent, diabetes thus remained a significant risk factor for repeat TVR at 1 year due to revascularization outside the target lesion.
In a meta-analysis of 5 TAXUS Express randomized studies with a follow-up 4 years after stenting, diabetic patients treated with the TAXUS Express stent compared with those receiving bare metal stents demonstrated similar rates of all-cause mortality (8.4% TAXUS vs. 10.3% bare metal stent, p = 0.61), Q-wave MI (0.5% TAXUS vs. 1.5% bare metal stent, p = 0.26), and Academic Research Consortium definite/probable stent thrombosis (2.2% TAXUS vs. 1.4% bare metal stent, p = 0.74) and thus demonstrated a similar safety profile (15). The present study demonstrates that patients with and without diabetes had similar rates of death, MI, and stent thrombosis at 1 year after TAXUS Liberté PES implantation. This suggests a similar safety profile for the TAXUS Liberté stent in diabetic and nondiabetic patients. Although diabetes has been recognized as a cardiovascular risk factor (30) and higher rates of death and MI can be anticipated in diabetic patients with longer follow-up beyond 1 year, the current analysis did not identify any incremental risk of using PES in patients with diabetes at 1 year.
Study limitations.
The TAXUS ATLAS, Direct Stent, Long Lesion, and Small Vessel studies are prospective studies evaluating the TAXUS Liberté stent in patients with strict inclusion/exclusion criteria; because patients enrolled in these trials were carefully selected, the results might only apply to the types of patients and lesions included in these 4 studies. Assessment of diabetic status in these subjects was also not ideal, because plasma glucose, hemoglobin A1c, and glucose-tolerance data were not obtained. Biological indicators of diabetic status might have detected more patients with early-stage diabetes than the currently used definition of "treatment with oral hypoglycemic agents or insulin." In addition, because the analysis of diabetic patients was restricted to those receiving medical treatment, the results might not be extrapolative to patients with pre-diabetes or hypoglycemia managed by change in lifestyle or diet. Furthermore, within these constraints, the comparison of the diabetic versus nondiabetic cohort was a post-hoc analysis and might be underpowered to detect differences in low-frequency safety events such as stent thrombosis, death, or MI. In this study, significant differences in baseline characteristics also existed between the 2 cohorts that might be related to diabetes. However, several of these variables are also independent predictors of adverse events after coronary interventions, and metabolic features of the diabetic state confer additional risks that are unique to the diabetic condition. Therefore, propensity score and multivariate adjustment were used to partially compensate for baseline differences. Although this might be suboptimal, it provides a method to adjust for baseline imbalance when randomization is not possible. It is important to note that the intent of reporting propensity- and multivariate-adjusted results is not to suggest "new" rates but rather to ensure more like-to-like comparisons between the 2 patient groups so that a less biased assessment of paclitaxel's ability to inhibit in-stent restenosis in the diabetic metabolic state can be ascertained.
|
Conclusions
|
|---|
The TAXUS Liberté is a second-generation paclitaxel-eluting stent with reduced stent strut thickness and a better delivery system compared with the first-generation PES. When used for treatment of single simple and complex de novo native coronary lesions, this stent is associated with nearly identical late luminal loss, restenosis, and neointimal hyperplasia in both diabetic and nondiabetic subjects. This was accompanied by similar and low rates of adjusted TLR at 12-month follow-up in both groups and provides clinical evidence that the paclitaxel-eluting TAXUS Liberté stent blunts any deleterious effect of diabetes on the development of restenosis within the stented segment. The increased need for repeat intervention in diabetic subjects as compared with nondiabetic subjects, however, is due to higher rates of remote TVR likely due to accelerated atherosclerosis in diabetic subjects. The safety profile of the TAXUS Liberté stent is comparable for diabetic and nondiabetic subjects as evident by similar rates of death, MI, and stent thrombosis in the 2 patient subsets. Therefore, the TAXUS Liberté PES is an effective treatment option for de novo coronary lesions in patients with diabetes but has no effect on the development and progression of atherosclerosis beyond the treated lesion.
|
Acknowledgments
|
|---|
The authors thank Kristin L. Hood, PHD (Boston Scientific Corporation) for assistance with manuscript preparation and Carola Alfaro, MS, Brian Johnson, MPH, Joe Bero, MS, and Alan Yu, MS (all Boston Scientific Corporation) for providing the statistical analysis.
|
Footnotes
|
|---|
This study was supported by Boston Scientific Corporation, Natick, Massachusetts. The authors wish to disclose the following conflicts of interest related to Boston Scientific: research grant support (to Drs. Mahmud, Turco, Popma, Weissman, O'Shaughnessy, and Webster); consulting fees/honoraria (to Drs. Ormiston, O'Shaughnessy, and Cannon); advisory board (to Drs. Ormiston, Turco, Popma, O'Shaughnessy, and Cannon); Speakers' Bureau (to Drs. Turco, Popma, O'Shaughnessy, and Cannon); stock options/equity interest (to Drs. Mandinov and Baim); and salary/full-time employee (to Drs. Mandinov and Baim).
* Reprint requests and correspondence: Dr. Ehtisham Mahmud, UC San Diego Medical Center, Cardiovascular Catheterization Labs, 200 West Arbor Drive, San Diego, California 92103-8784 (Email: emahmud{at}ucsd.edu).
Manuscript received July 30, 2008;
revised manuscript received November 19, 2008,
accepted December 16, 2008.
|
REFERENCES
|
|---|
- Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035-2038.[Abstract/Free Full Text]
- Feskens EJ, Kromhout D. Glucose tolerance and the risk of cardiovascular disease: the Zutphen Study J Clin Epidemiol 1992;45:1327-1334.[CrossRef][Web of Science][Medline]
- Kip KE, Faxon DP, Detre KM, Yeh W, Kelsey SF, Currier JW. Coronary angioplasty in diabetic patients: The National Heart, Lung, and Blood Institute percutaneous transluminal coronary angioplasty registry Circulation 1996;94:1818-1825.[Abstract/Free Full Text]
- Mathew V, Gersh BJ, Williams BA, et al. Outcomes in patients with diabetes mellitus undergoing percutaneous coronary intervention in the current era: a report from the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial Circulation 2004;109:476-480.[Abstract/Free Full Text]
- Mahmud E, Bromberg-Marin G, Palakodeti V, Ang L, Creanga D, DeMaria A. Clinical efficacy of drug eluting stents in diabetic patients: a meta-analysis J Am Coll Cardiol 2008;51:2385-2395.[Abstract/Free Full Text]
- Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation J Am Coll Cardiol 1998;32:584-589.[Abstract/Free Full Text]
- Carrozza Jr. JP, Kuntz RE, Fishman RF, Baim DS. Restenosis after arterial injury caused by coronary stenting in patients with diabetes mellitus Ann Intern Med 1993;118:344-349.[Abstract/Free Full Text]
- Chen C, Fang CC, Chen Y, Yu CL, Wang SP. Comparative study of angiographic outcomes following coronary stenting between diabetic and non-diabetic patients Acta Cardiologica Sinica 2002;18:119-124.
- Elezi S, Kastrati A, Pache J, et al. Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement J Am Coll Cardiol 1998;32:1866-1873.[Abstract/Free Full Text]
- Daemen J, Garcia-Garcia HM, Kukreja N, et al. The long-term value of sirolimus- and paclitaxel-eluting stents over bare metal stents in patients with diabetes mellitus Eur Heart J 2007;28:26-32.[Abstract/Free Full Text]
- Hermiller JB, Raizner A, Cannon L, et al. Outcomes with the polymer-based paclitaxel-eluting TAXUS stent in patients with diabetes mellitus: the TAXUS-IV trial J Am Coll Cardiol 2005;45:1172-1179.[Abstract/Free Full Text]
- Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004;350:221-231.[CrossRef][Web of Science][Medline]
- Dawkins KD, Stone GW, Colombo A, et al. Integrated analysis of medically treated diabetic patients in the TAXUS program: benefits across stent platforms, paclitaxel release formulations, and diabetic treatments Euro Intervention 2006;2:61-68.
- Spaulding C, Daemen J, Boersma E, Cutlip DE, Serruys PW. A pooled analysis of data comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:989-997.[CrossRef][Medline]
- Kirtane AJ, Ellis SG, Dawkins K, et al. Paclitaxel-eluting coronary stents in patients with diabetes mellitus: pooled analysis from 5 randomized trials J Am Coll Cardiol 2008;51:708-715.[Abstract/Free Full Text]
- Patterson C, Mapera S, Li HH, et al. Comparative effects of paclitaxel and rapamycin on smooth muscle migration and survival: role of AKT-dependent signaling Arterioscler Thromb Vasc Biol 2006;26:1473-1480.[Abstract/Free Full Text]
- Turco MA, Ormiston JA, Popma JJ, et al. Polymer-based, paclitaxel-eluting TAXUS liberte stent in de novo lesions: the pivotal TAXUS ATLAS trial J Am Coll Cardiol 2007;49:1676-1683.[Abstract/Free Full Text]
- Ormiston JA, Mahmud E, Turco MA, et al. Direct stenting with the TAXUS Liberte drug-eluting stent: results from the TAXUS ATLAS DIRECT STENT study J Am Coll Cardiol Intv 2008;1:150-160.[Abstract/Free Full Text]
- Turco MA, Ormiston JA, Popma JJ, et al. Reduced risk of restenosis in small vessels and reduced risk of myocardial infarction in long lesions with the new thin-strut TAXUS Liberté stent: one-year results from the TAXUS ATLAS program J Am Coll Cardiol Intv 2008;1:699-709.[Abstract/Free Full Text]
- ClinicalTrials.gov: A service of the U.S. National Institutes of Health www.clinicaltrials.gov 2008Accessed February 22, 2008.
- Ellis SG, Vandormael MG, Cowley MJ, et al. Multivessel Angioplasty Prognosis Study Group Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease. Implications for patient selection. Circulation 1990;82:1193-1202.[Abstract/Free Full Text]
- van der Zwet PM, Reiber JH. A new approach for the quantification of complex lesion morphology: the gradient field transform; basic principles and validation results J Am Coll Cardiol 1994;24:216-224.[Abstract]
- Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome Circulation 1999;100:1872-1878.[Abstract/Free Full Text]
- Weissman NJ, Koglin J, Cox DA, et al. Polymer-based paclitaxel-eluting stents reduce in-stent neointimal tissue proliferation: a serial volumetric intravascular ultrasound analysis from the TAXUS-IV trial J Am Coll Cardiol 2005;45:1201-1205.[Abstract/Free Full Text]
- Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions Circulation 2007;115:2344-2351.[Abstract/Free Full Text]
- D'Agostino Jr RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group Stat Med 1998;17:2265-2281.[CrossRef][Web of Science][Medline]
- Rosenbaum PR, Rubin DB. Reducing bias in observational studies using subclassification on the propensity score J Am Stat Assoc 1984;79:516-524.[CrossRef][Web of Science]
- Rubin DB. Estimating causal effects from large data sets using propensity scores Ann Intern Med 1997;127:757-763.[Abstract/Free Full Text]
- Winkelmayer WC, Glynn RJ, Mittleman MA, Levin R, Pliskin JS, Avorn J. Comparing mortality of elderly patients on hemodialysis versus peritoneal dialysis: a propensity score approach J Am Soc Nephrol 2002;13:2353-2362.[Abstract/Free Full Text]
- Schramm TK, Gislason GH, Kober L, et al. Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people Circulation 2008;117:1945-1954.[Abstract/Free Full Text]
- Axel DI, Kunert W, Goggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery Circulation 1997;96:636-645.[Abstract/Free Full Text]
- Blagosklonny MV, Darzynkiewicz Z, Halicka HD, et al. Paclitaxel induces primary and postmitotic G1 arrest in human arterial smooth muscle cells Cell Cycle 2004;3:1050-1056.[Web of Science][Medline]
- Blagosklonny MV, Demidenko ZN, Giovino M, et al. Cytostatic activity of paclitaxel in coronary artery smooth muscle cells is mediated through transient mitotic arrest followed by permanent post-mitotic arrest: comparison with cancer cells Cell Cycle 2006;5:1574-1579.[Web of Science][Medline]
- Okano J, Rustgi AK. Paclitaxel induces prolonged activation of the Ras/MEK/ERK pathway independently of activating the programmed cell death machinery J Biol Chem 2001;276:19555-19564.[Abstract/Free Full Text]
- Le XF, Hittelman WN, Liu J, et al. Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis Oncogene 2003;22:484-497.[CrossRef][Web of Science][Medline]
- MacKeigan JP, Taxman DJ, Hunter D, Earp III HS, Graves LM, Ting JP. Inactivation of the antiapoptotic phosphatidylinositol 3-kinase-Akt pathway by the combined treatment of taxol and mitogen-activated protein kinase kinase inhibition Clin Cancer Res 2002;8:2091-2099.[Abstract/Free Full Text]
- Mitsuuchi Y, Johnson SW, Selvakumaran M, Williams SJ, Hamilton TC, Testa JR. The phosphatidylinositol 3-kinase/AKT signal transduction pathway plays a critical role in the expression of p21WAF1/CIP1/SDI1 induced by cisplatin and paclitaxel Cancer Res 2000;60:5390-5394.[Abstract/Free Full Text]
- Kimura M, Mintz GS, Weissman NJ, et al. Meta-analysis of the effects of paclitaxel-eluting stents versus bare metal stents on volumetric intravascular ultrasound in patients with versus without diabetes mellitus Am J Cardiol 2008;101:1263-1268.[CrossRef][Web of Science][Medline]
This article has been cited by other articles:
|
|
|
|
 
M. J. Mack, A. P. Banning, P. W. Serruys, M.-C. Morice, Y. Taeymans, G. Van Nooten, G. Possati, F. Crea, K. L. Hood, K. Leadley, et al.
Bypass Versus Drug-Eluting Stents at Three Years in SYNTAX Patients With Diabetes Mellitus or Metabolic Syndrome
Ann. Thorac. Surg.,
December 1, 2011;
92(6):
2140 - 2146.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. W. Stone, S. G. Ellis, A. Colombo, E. Grube, J. J. Popma, T. Uchida, J. S. Bleuit, K. D. Dawkins, and M. E. Russell
Long-Term Safety and Efficacy of Paclitaxel-Eluting Stents: Final 5-Year Analysis From the TAXUS Clinical Trial Program
J. Am. Coll. Cardiol. Intv.,
May 1, 2011;
4(5):
530 - 542.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Kereiakes, D. E. Cutlip, R. J. Applegate, J. Wang, M. Yaqub, P. Sood, X. Su, G. Su, N. Farhat, A. Rizvi, et al.
Outcomes in Diabetic and Nondiabetic Patients Treated With Everolimus- or Paclitaxel-Eluting Stents: Results From the SPIRIT IV Clinical Trial (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System)
J. Am. Coll. Cardiol.,
December 14, 2010;
56(25):
2084 - 2089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Kereiakes, L. A. Cannon, R. L. Feldman, J. J. Popma, R. Magorien, R. Whitbourn, I. M. Dauber, A. C. Rabinowitz, M. W. Ball, B. Bertolet, et al.
Clinical and Angiographic Outcomes After Treatment of De Novo Coronary Stenoses With a Novel Platinum Chromium Thin-Strut Stent: Primary Results of the PERSEUS (Prospective Evaluation in a Randomized Trial of the Safety and Efficacy of the Use of the TAXUS Element Paclitaxel-Eluting Coronary Stent System) Trial
J. Am. Coll. Cardiol.,
July 20, 2010;
56(4):
264 - 271.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Dixon, C. L. Grines, and W. W. O'Neill
The Year in Interventional Cardiology
J. Am. Coll. Cardiol.,
May 18, 2010;
55(20):
2272 - 2286.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Banning, S. Westaby, M.-C. Morice, A. P. Kappetein, F. W. Mohr, S. Berti, M. Glauber, M. A. Kellett, R. S. Kramer, K. Leadley, et al.
Diabetic and Nondiabetic Patients With Left Main and/or 3-Vessel Coronary Artery Disease: Comparison of Outcomes With Cardiac Surgery and Paclitaxel-Eluting Stents
J. Am. Coll. Cardiol.,
March 16, 2010;
55(11):
1067 - 1075.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods