Author + information
- Received July 23, 2010
- Revision received September 30, 2010
- Accepted October 1, 2010
- Published online December 14, 2010.
- Dean J. Kereiakes, MD⁎,⁎ (, )
- Donald E. Cutlip, MD†,
- Robert J. Applegate, MD‡,
- John Wang, MD§,
- Manejeh Yaqub, MD∥,
- Poornima Sood, MD, MBA∥,
- Xiaolu Su, MS∥,
- Guoping Su, PhD∥,
- Naim Farhat, MD¶,
- Ali Rizvi, MD#,
- Charles A. Simonton, MD∥,
- Krishnankutty Sudhir, MD, PhD∥ and
- Gregg W. Stone, MD⁎⁎
- ↵⁎Reprint requests and correspondence:
Dr. Dean J. Kereiakes, The Christ Hospital Heart and Vascular Center, 2123 Auburn Avenue, Suite 424, Cincinnati, Ohio 45219
Objectives We compared the safety and efficacy of the XIENCE V (Abbott Vascular, Santa Clara, California) everolimus-eluting stent (EES) with the TAXUS Express (Boston Scientific, Natick, Massachusetts) paclitaxel-eluting stent (PES) among the large cohort of randomized diabetic patients enrolled in the SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) trial.
Background Diabetes mellitus remains a significant predictor of adverse clinical outcomes after percutaneous coronary intervention with drug-eluting stents, and the comparative outcomes of different drug-eluting stents in diabetic patients remains ill-defined.
Methods In the SPIRIT IV trial, 3,687 patients with up to 3 de novo native coronary artery lesions were prospectively randomized 2:1 to receive EES or PES. Randomization was stratified by the presence of diabetes and lesion complexity. The primary end point was the occurrence of target lesion failure (TLF) (cardiac death, target-vessel myocardial infarction, or ischemia-driven target lesion revascularization) at 1 year. Clinical outcomes were evaluated in randomized diabetic (n = 1,185 [786 EES; 399 PES]) and nondiabetic patients (n = 2,498 [1,669 EES; 829 PES]).
Results The EES compared with PES reduced TLF in nondiabetic patients (3.1% vs. 6.7%, p < 0.0001), with significant reductions in myocardial infarction, stent thrombosis, and target lesion revascularization. In contrast, no difference in TLF (6.4% vs. 6.9%, respectively, p = 0.80) or any of its components was present among diabetic patients, regardless of insulin use. A significant interaction between the presence of diabetes and stent type on TLF (pinteraction = 0.02) was observed.
Conclusions In the SPIRIT IV randomized trial, EES compared with PES provided similar clinical outcomes in diabetic patients and superior clinical outcomes in nondiabetic patients at 1 year. (SPIRIT IV Clinical Trial: Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With de Novo Native Coronary Artery Lesions; NCT00307047)
Patients with diabetes mellitus have worse clinical outcomes after percutaneous coronary intervention (PCI) compared with their nondiabetic counterparts (1,2). The propensity for adverse outcomes after PCI has been ascribed to smaller-caliber target vessels, a greater degree of underlying vascular inflammation, a pro-thrombotic milieu, and associated cardiovascular risk factors (3). Greater plaque burden and neointimal proliferation also contribute to increased restenosis after coronary stent deployment (4).
Although drug-eluting stents (DES) reduce angiographic and clinical restenosis compared with bare-metal stents in patients both with and without diabetes (5,6), the presence of diabetes remains a significant predictor of adverse outcomes in the DES era (7). Late (2- to 4-year) clinical follow-up from multiple randomized trials and clinical registries of DES versus bare-metal stents have demonstrated reduced target lesion revascularization (TLR) with no appreciable differences in death, myocardial infarction (MI), or stent thrombosis with DES use in diabetic patients (8–10). Although numerous studies have demonstrated less in-stent late lumen loss and reduced neointimal hyperplasia after sirolimus-eluting stents (SES) versus paclitaxel-eluting stents (PES) in diabetic patients, clinical events—including TLR and major adverse cardiovascular events (MACE)—have been similar between stent types (11–13). In the SPIRIT III (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System), no significant differences were observed between PES and everolimus-eluting stents (EES) for the co-primary end points of late loss or target vessel failure among 290 randomized patients with diabetes mellitus, and a significant interaction was noted between stent type and event-free survival (14). It has been proposed that the direct effect of paclitaxel on microtubule function inhibits insulin-regulated signal transduction pathways, thus mitigating the deleterious effect of diabetes on increasing neointimal hyperplasia (15). However, prior studies were not adequately powered to evaluate differences in clinical safety or efficacy between DES types.
The SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) trial was a large prospective randomized trial comparing EES and PES in subjects with de novo native coronary atherosclerosis, with randomization stratified by the presence of diabetes mellitus (16,17). This pre-specified diabetic cohort analysis involves 1,185 diabetic patients enrolled into the SPIRIT IV trial.
The SPIRIT IV trial was a prospective, multicenter, single-blind, active-controlled trial in which 3,687 patients with coronary artery disease undergoing PCI were randomized 2:1 to EES (XIENCE V, Abbott Vascular, Santa Clara, California) or PES (TAXUS Express2, Boston Scientific, Natick, Massachusetts) (16). The trial enrolled 1,185 patients with diabetes, and stratification according to the presence of diabetes occurred before randomization to ensure that the 2:1 (EES vs. PES) randomization ratio was preserved and that measured and unmeasured confounders were likely to be balanced in the diabetic subgroup (17). Routine follow-up angiography was not performed in the SPIRIT IV trial, unlike the SPIRIT III trial (14).
Inclusion and exclusion criteria
After confirmation of angiographic eligibility, telephone randomization was performed, stratified by the presence of diabetes, complex lesions, and study site.
The XIENCE V EES has been described previously (16). In the SPIRIT IV trial, EES were available in diameters of 2.5 to 4.0 mm and lengths of 8, 18, and 28 mm. The full range of commercially available PES was available in diameters of 2.5 to 3.5 mm and lengths of 8, 12, 16, 18, 22, 28, and 32 mm.
Procedure and follow-up
Balloon pre-dilation of the target lesion was mandatory. Additional stents used for bailout purposes were required to be from the same treatment arm. Aspirin ≥300 mg was administered before the procedure, and oral clopidogrel load ≥300 mg was recommended before the procedure and required within 1 h after stent deployment. Aspirin ≥80 mg daily was administered indefinitely, and clopidogrel 75 mg daily was prescribed for ≥12 months. Clinical follow-up was scheduled at 30, 180, 270, and 365 days and then yearly through 5 years. Follow-up angiography was not specified by protocol.
Clinical end points
End point definitions have been described previously (16–18). The primary end point was target lesion failure (TLF) at 1 year (composite of cardiac death, target-vessel MI, or ischemia-driven target lesion revascularization [ID-TLR]). The major secondary end points were ID-TLR and the composite occurrence of cardiac death or target-vessel MI. Additional pre-specified secondary end points included MACE (composite of cardiac death, MI, or ID-TLR), target vessel failure (cardiac death, MI, or ischemia-driven target vessel revascularization) as well as its individual components, and stent thrombosis as defined per protocol (16) and by the Academic Research Consortium criteria (18).
Subgroup classifications according to presence or absence of diabetes and type of diabetic treatment (insulin- vs. noninsulin-requiring) were pre-specified (16). All data are presented on the basis of the intent-to-treat principle. Selected baseline characteristics and 1-year clinical outcomes were compared between treatment groups and various diabetes strata, and adjustments were not made for multiple comparisons. Categorical variables were compared by Fisher exact test. Continuous variables are presented as mean ± 1 SD and were compared by t test.
Baseline characteristics and procedural outcomes
Baseline clinical and angiographic characteristics stratified by the presence of diabetes and randomly assigned stent type are shown in Table 1. Procedural results and angiographic outcomes are shown in Table 2. Due to the limitation in stent lengths available for EES (3 lengths) versus PES (7 lengths), stent length/lesion and stent-length/lesion-length ratio were slightly greater with EES than PES.
Clinical outcomes at 1 year
Among nondiabetic patients, EES compared with PES reduced the primary end point of TLF by 54% (3.1% vs. 6.7%, p < 0.0001) and MACE by 52% (3.2% vs. 6.7%, p < 0.0001). The EES resulted in significantly lower rates of the major secondary end points of ID-TLR and the composite occurrence of cardiac death or target-vessel MI (Table 3). Furthermore, EES resulted in reduced rates of target-vessel MI (both Q-wave and non–Q-wave) as well as stent thrombosis (by both protocol and Academic Research Consortium definitions).
In contrast, among patients with diabetes, clinical outcomes to 1 year were not significantly different between randomly assigned stent types for both TLF and MACE. Nor were significant differences in the components of the composite clinical end points or the rates of stent thrombosis observed between stent types. Clinical event rates to 1 year were not significantly different between randomly assigned stent treatments in both insulin-requiring and noninsulin-requiring diabetic patients (Table 4).
Logistic regression analysis demonstrated a significant interaction between diabetes and stent type on the primary end point of TLF (p = 0.02) (Fig. 1). No interaction between diabetes type (insulin-requiring or not) and stent type with TLF was observed (p = 0.56) (Fig. 2).
The major findings from this pre-specified SPIRIT IV diabetic cohort analysis are: 1) even though EES compared with PES markedly reduced adverse clinical outcomes at 1 year in nondiabetic patients, results in diabetic patients were comparable, regardless of stent type; and 2) no differences in 1-year clinical outcomes after EES versus PES were observed in patients with diabetes, regardless of insulin requirement.
The SPIRIT IV trial confirms and extends the observation made in the SPIRIT III trial of a significant interaction between randomized stent type (EES vs. PES) and the presence of diabetes on the primary composite safety-plus-efficacy clinical end point. However, explanation(s) for the apparent attenuation in the relative benefit afforded by EES versus PES among diabetic patients is unknown.
Of note, TLF to 1 year after PES was similar among nondiabetic patients (6.7%), noninsulin-requiring diabetic patients (6.8%), and insulin-requiring diabetic patients (7.0%). Conversely, TLF after EES treatment occurred in 3.1% of nondiabetic patients, 5.9% of noninsulin-requiring diabetic patients, and 8.0% of insulin-requiring diabetic patients. Similar relative differences were observed for other clinical end points when stratified by stent type as well as the presence and severity of diabetes. Thus, adverse events in diabetic (vs. nondiabetic) patients were increased after PCI with EES. In contrast, PES seems to mitigate both the presence and severity of diabetes as a risk factor for adverse outcomes. This observation seems counter to the findings of the SPIRIT V diabetic randomized trial, which compared the XIENCE V (Abbott Vascular) EES with the TAXUS Liberté (Boston Scientific) PES (19). Important differences between these trials exist. The SPIRIT V diabetic trial had an angiographic primary end point (in-stent late loss at 270 days) with protocol-mandated angiography and follow-up. Although EES (vs. PES) produced in-stent late loss, no statistically significant differences in in-segment late loss or in binary angiographic restenosis were observed, and the study was grossly underpowered for assessment of clinical outcomes. Thus, although the direct effects of paclitaxel in inhibiting insulin-regulated intracellular signal transduction pathways provide theoretic appeal for paclitaxel elution by DES in patients with diabetes (15), everolimus elution provided comparable clinical benefit among diabetic patients with reference vessel diameters ≥2.5 mm enrolled into the current study.
The lower 1-year rates of stent thrombosis after EES (vs. PES) in the SPIRIT IV and COMPARE (Second-generation everolimus-eluting and paclitaxel-eluting stents in real-life practice) randomized trials (17,20) have prompted speculation regarding potential “thromboresistant” properties of the EES biostable fluorocopolymer (21,22). In this regard, an even larger diabetic cohort than was enrolled in the SPIRIT IV trial would be required to determine whether the nonsignificant trend toward fewer stent thrombosis events observed in diabetic patients treated with EES (vs. PES) represents a real difference or is due to chance.
Finally, despite the stratification of randomization for the presence of diabetes mellitus, specific covariate imbalance was observed in baseline angiographic as well as procedural variables among diabetic subjects stratified by stent type. Diabetic subjects treated with PES had a higher prevalence of American College of Cardiology/American Heart Association Type A and a lower prevalence of Type B1/B2/C angiographic lesion morphology than those who received treatment with EES. Furthermore, total stent length/lesion and total stent-length/lesion-length ratio were less in PES-treated diabetic and nondiabetic subjects, whereas the maximum stent deployment pressure was increased. Each of the inequities observed, particularly more complex target lesion morphology and longer stent length, would be expected to disadvantage the EES-treated cohort.
Although EES (vs. PES) reduced the study primary end point of TLF as well as the major secondary end points of cardiac death or target-vessel MI and ID-TLR in patients without diabetes mellitus, no significant differences in outcomes were observed between DES types among diabetic patients, regardless of insulin requirement. These findings suggest the need for further studies to elucidate the mechanistic pathways underlying the poor prognosis of patients with diabetes mellitus, with a focus toward development of novel drugs and stents to improve outcomes in this high-risk patient cohort.
For supplementary methods, please see the online version of this article.
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)
This work was supported by Abbott Vascular, Santa Clara, California. Dr. Kereiakes has received grant/research support from, been a consultant to, and served on the advisory board for Abbott Vascular and Boston Scientific. Dr. Cutlip has received research support from Medtronic. Dr. Applegate has received grant/research support from and served as consultant for Abbott Vascular. Dr. Wang has served on the Speakers' Bureau for Abbott, Boston Scientific, Medtronic, and Cordis. Drs. Yaqub, Sood, Xiaolu Su, Guoping Su, Simonton, and Sudhir are Abbott Vascular employees. Dr. Farhat reports that he has no relationships to disclose. Dr. Stone has received grant/research support from and served on the advisory board for Abbott Vascular and Boston Scientific.
- Abbreviations and Acronyms
- drug-eluting stent(s)
- everolimus-eluting stent(s)
- ischemia-driven target lesion revascularization
- major adverse cardiac event(s)
- myocardial infarction
- percutaneous coronary intervention
- paclitaxel-eluting stent(s)
- sirolimus-eluting stent(s)
- target lesion failure
- target lesion revascularization
- Received July 23, 2010.
- Revision received September 30, 2010.
- Accepted October 1, 2010.
- American College of Cardiology Foundation
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