Diabetes is associated with an increased risk of major adverse cardiac events after percutaneous coronary intervention. We compared clinical outcomes in patients with and without diabetes mellitus treated with the second-generation Endeavor zotarolimus-eluting stent (ZES) or the first-generation Cypher Select+ sirolimus-eluting stent (SES). We randomized 2,332 patients to treatment with ZESs (n = 1,162, n = 169 diabetics) or SESs (n = 1,170, n = 168 diabetics) and followed them for 18 months. Randomization was stratified by presence/absence of diabetes. The primary end point was major adverse cardiac events defined as a composite of cardiac death, myocardial infarction, or target vessel revascularization. Secondary end points included these individual end points plus all-cause mortality and target lesion revascularization. In diabetic patients, use of ZES compared to SES was associated with an increased risk of major adverse cardiac events (18.3% vs 4.8%, hazard ratio 4.05, 95% confidence interval 1.86 to 8.82), myocardial infarction (4.7% vs 0.6%, hazard ratio 8.09, 95% confidence interval 1.01 to 64.7), target vessel revascularization (14.2% vs 3.0%, hazard ratio 4.99, 95% confidence interval 1.90 to 13.1), and target lesion revascularization (12.4% vs 1.2%, hazard ratio 11.0, 95% confidence interval 2.59 to 47.1). In patients without diabetes differences in absolute risk decrease were smaller but similarly favored SES. In conclusion, implantation of ZESs compared to SESs is associated with a considerable increased risk of adverse events in patients with diabetes at 18-month follow-up.
Diabetic patients have been shown to have the greatest benefit of drug-eluting stents and diabetic patients may thus serve as a stress test subjects for differences between comparator stents. The Endeavor zotarolimus-eluting stent (ZES), a second-generation drug-eluting stent, has been shown to produce more uniform neointima formation than the Cypher sirolimus-eluting stent (SES). The ZES has been compared primarily to the first-generation drug-eluting stent in patients with a noncomplex single lesion. A subgroup analysis of diabetic patients with such lesions in the ENDEAVOR IV study has shown similar outcomes between the ZES and the Taxus paclitaxel-eluting stent. Since then we and others have found the ZES to be inferior to the SES in patients receiving routine clinical care including those with complex lesions. To date no randomized data comparing ZES to SES performance in the high-risk diabetic subgroup have been available. In the present study we used the Danish Organization for Clinical Trials with Clinical Outcome (SORT OUT) III database to compare clinical outcomes using ZES versus SES in patients with and without diabetes.
Methods
Within the framework of the SORT OUT Organization we undertook a multicenter, open-label, randomized, all-comer trial from January 2006 through August 2007 in 5 Danish high-volume percutaneous coronary intervention centers. The trial included patients ≥18 years old with stable chronic coronary artery disease or acute coronary syndromes. Patients were eligible if they had ≥1 target lesion defined as a lesion to be treated with a drug-eluting stent. Exclusion criteria were inability to provide informed consent, life expectancy of <1 year, allergy to acetylsalicylic acid, clopidogrel, ticlopidine, sirolimus, or zotarolimus, or participation in another randomized trial. Patients were considered to have diabetes if they received active treatment with insulin, an oral antidiabetic medication, or reported diet-treated diabetes. A subgroup of diabetic patients (n = 127) participated in a substudy (Diabetes and Drug-Eluting Stent [DiabeDES] III) with 10-month angiographic and intravascular ultrasound follow-up.
Patients were randomized in block fashion according to center, and the allocation sequence was generated by computer and stratified by presence/absence of diabetes and by gender. Patients were assigned 1:1 to ZESs (Endeavor, Medtronic, Santa Rosa, California) or SESs (Cypher Select or Cypher Select+; Cordis, Johnson & Johnson, Warren, New Jersey).
Patients were pretreated with acetylsalicylic acid ≥75 mg, clopidogrel 300- to 600-mg loading dose, and unfractionated heparin (5,000 IU or 70 to 100 IU/kg). Glycoprotein IIb/IIIa inhibitors were used at the discretion of the operator. Dual antiplatelet regimens included recommendations of lifelong acetylsalicylic acid (75 mg/day) and clopidogrel (75 mg/day) for 1 year in accord with Danish guidelines.
Data on mortality (cardiac and noncardiac), hospital admissions, coronary angiography, repeat percutaneous coronary intervention, and coronary bypass surgery were obtained from national Danish registries (Danish Civil Registration System, National Registry of Causes of Death, Danish National Registry of Patients, local heart registries in the 5 percutaneous coronary intervention centers, and the Danish Heart Register). These cover the entire Danish population.
Outcome measurements in subgroup analysis were the composite of cardiac death, myocardial infarction (MI), and target vessel revascularization (TVR) and of all-cause death, cardiac death, MI, TVR, target lesion revascularization (TLR; stent plus 5-mm edge), symptom-driven observation of restenosis (stent plus 5-mm edge), and angiographically verified (definite) stent thrombosis (ST) assessed at 18 months. The definitions of these end points have been described previously. According to the Academic Research Consortium definition of definite ST, we also report ST events at 30-day and 12-month follow-ups.
Distributions of continuous variables in the ZES and SES groups were compared using a 2-sample t test (or Cochran t test for unequal variance) or Mann–Whitney U test depending on whether the data followed a normal distribution. We compared distributions of categorical variables using chi-square test. We counted end-point events occurring during the follow-up period and compared rates for the 2 groups of patients according to presence/absence of diabetes. Follow-up began on the date of the index percutaneous coronary intervention. In analyses of each outcome follow-up continued until the date of an end-point event, death, emigration, or 18 months after implantation, whichever came first. Cumulative incidence curves were constructed based on the cumulative incidence of end-point events taking into account the competing risk of death. Hazard ratios between groups were estimated using Cox proportional hazards regression analysis. Patients treated with SESs were used as the reference in all analyses. All analyses were performed according to intention-to-treat principles. A p value <0.05 was considered statistically significant. We used SAS 9.2 (SAS Institute, Cary, North Carolina) for all analyses.
Results
In the diabetes group the assigned study stent could not be implanted in 6 patients (4%) in the ZES arm and in 4 patients (2%) in the SES arm (p = 0.53). In patients without diabetes the study stent could not be implanted in 24 patients (2%) in the ZES arm and in 38 patients (3%) in the SES arm (p = 0.07).
Baseline patient ( Table 1 ) and procedure ( Table 2 ) characteristics were well balanced between the ZES and SES groups in the diabetic and nondiabetic subgroups. Patients with diabetes compared to patients without diabetes were more frequently treated for hypertension (72% vs 49%, p <0.0001) and hypercholesterolemia (80% vs 67%, p <0.0001) before the index percutaneous coronary intervention. Diabetic patients received treatment with a glycoprotein IIb/IIIa inhibitor during the index percutaneous coronary intervention more frequently than nondiabetics (22% vs 17%, p = 0.014). They also had higher rates of previous percutaneous coronary intervention (27% vs 18%) and a higher body mass index (29 ± 6 vs 27 ± 5 kg/m 2 , p = 0.0001).
| Variable | Diabetes Mellitus | |||||
|---|---|---|---|---|---|---|
| Yes | No | |||||
| ZES (n = 169) | SES (n = 168) | p Value | ZES (n = 993) | SES (n = 1,002) | p Value | |
| Age (years), median (quartiles 1–3) | 65 (59–73) | 67 (59–74) | 0.68 | 65 (57–29) | 64 (57–29) | 0.92 |
| Men | 121 (72%) | 120 (71%) | 0.97 | 731 (74%) | 742 (74%) | 0.82 |
| Previous myocardial infarction | 72 (43%) | 61 (37%) | 0.27 | 354 (37%) | 376 (39%) | 0.34 |
| Previous percutaneous coronary intervention | 47 (29%) | 42 (26%) | 0.56 | 186 (19%) | 153 (16%) | 0.048 |
| Treatment for hypercholesterolemia | 134 (82%) | 129 (78%) | 0.42 | 647 (67%) | 628 (66%) | 0.41 |
| Treatment for hypertension | 118 (72%) | 118 (72%) | 0.86 | 487 (51%) | 451 (47%) | 0.11 |
| Active smoker | 51 (33%) | 38 (25%) | 0.16 | 296 (32%) | 303 (33%) | 0.80 |
| Body mass index (kg/m 2 ), mean ± SD | 29 ± 6 | 29 ± 6 | 0.92 | 27 ± 6 | 27 ± 6 | 0.90 |
| Indication for intervention | 0.20 | 0.087 | ||||
| ST-segment elevation myocardial infarction | 5 (3%) | 12 (7%) | 65 (7%) | 88 (9%) | ||
| Unstable angina pectoris or non–ST-segment elevation myocardial infarction | 66 (39%) | 60 (36%) | 370 (37%) | 386 (39%) | ||
| Stable angina pectoris | 96 (57%) | 91 (54%) | 518 (52%) | 501 (50%) | ||
| Other | 2 (1%) | 5 (3%) | 40 (4%) | 27 (3%) | ||
| Variable | Diabetes Mellitus | |||||
|---|---|---|---|---|---|---|
| Yes | No | |||||
| ZES | SES | p Value | ZES | SES | p Value | |
| Total number of lesions | 229 | 236 | 1,390 | 1,375 | ||
| Number of treated lesions in each patient | 0.46 | 0.13 | ||||
| 1 | 125 (74%) | 116 (69%) | 687 (69%) | 708 (71%) | ||
| 2 | 28 (17%) | 39 (23%) | 202 (20%) | 215 (22%) | ||
| ≥3 | 16 (4%) | 13 (8%) | 104 (11%) | 78 (8%) | ||
| Number of treated vessels in each patient | 0.48 | 0.23 | ||||
| 1 | 139 (82%) | 134 (80%) | 788 (79%) | 798 (80%) | ||
| 2 | 24 (14%) | 31 (19%) | 164 (17%) | 176 (18%) | ||
| 3 | 6 (4%) | 3 (2%) | 41 (4%) | 28 (3%) | ||
| Target lesion coronary artery | 0.64 | 0.50 | ||||
| Left main | 5 (2%) | 5 (2%) | 21 (2%) | 24 (2%) | ||
| Left anterior descending | 90 (39%) | 96 (41%) | 595 (43%) | 554 (40%) | ||
| Left circumflex | 54 (24%) | 67 (28%) | 342 (25%) | 376 (27%) | ||
| Right | 77 (34%) | 66 (28%) | 423 (30%) | 413 (30%) | ||
| Bypass graft | 3 (1%) | 3 (1%) | 9 (1%) | 8 (1%) | ||
| Length of stented segment per lesion, median (quartiles 1–3) | 18 (12–25) | 18 (13–23) | 0.79 | 18 (12–25) | 18 (13–23) | 0.16 |
| Length of stented segment per patient, median (quartiles 1–3) | 24 (15–36) | 23 (13–39) | 0.34 | 24 (15–36) | 23 (13–34) | 0.59 |
| Maximal stent diameter, mean ± SD | 3.2 ± 0.5 | 3.2 ± 0.5 | 0.21 | 3.2 ± 0.5 | 3.2 ± 0.5 | 0.34 |
| Lesion type | 0.82 | 0.06 | ||||
| A | 36 (16%) | 43 (18%) | 280 (20%) | 235 (18%) | ||
| B | 99 (44%) | 102 (44%) | 611 (45%) | 650 (49%) | ||
| C | 88 (40%) | 89 (38%) | 482 (35%) | 456 (34%) | ||
| Use of glycoprotein IIb/IIIa inhibitors | 37 (22%) | 38 (23%) | 0.87 | 151 (15%) | 183 (18%) | 0.07 |
Results of the primary and secondary end points are presented in Table 3 . Time courses of major adverse cardiac events and TLR events are illustrated in Figure 1 . Major adverse cardiac events, the primary end point, occurred more frequently in patients treated with ZESs than SESs in the diabetic and nondiabetic subgroups. The corresponding numbers needed to treat were 7 for diabetic patients and 26 for nondiabetic patients in favor of SESs. These differences were mainly driven by higher rates of TLR in the ZES group than in the SES group in the diabetic and nondiabetic subgroups. Similar differences were observed for TVR. Only in the diabetic group did MI occur more often in the ZES group than in the SES group. The other secondary end points did not differ significantly. We also tested for interaction between diabetes status and type of drug-eluting stent and found no significant interaction for any end points assessed (major adverse cardiac events, p = 0.07; TLR, p = 0.09; TVR, p = 0.10; all others, p >0.10).
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
