Recent data on drug-eluting stents have shown improved clinical outcomes in patients with diabetes mellitus. However, the relative efficacy and safety of sirolimus-eluting stents (SES) compared with paclitaxel-eluting stents (PES) remains controversial. Therefore, a meta-analysis of randomized trials was performed to compare SES with PES exclusively in patients with diabetes. The published research was scanned by formal searches of electronic databases (PubMed, EMBASE and the Cochrane Central Register of Controlled Trials) from January 2001 to April 2009. All randomized trials involving head-to-head comparison of SES versus PES in patients with diabetes were examined for analysis. A total of 5 randomized trials were included in the present meta-analysis, involving 1,173 patients (594 in the SES group, 579 in the PES group). SES were significantly more effective in the reduction of target lesion revascularization (5.1% vs 11.4%, odds ratio [OR] 0.41, 95% confidence interval [CI] 0.26 to 0.64, p <0.001) and angiographic binary (≥50%) restenosis (5.6% vs 16.4%, OR 0.30, 95% CI 0.19 to 0.48, p <0.001) compared to PES. In contrast, the differences between SES and PES were not statistically significant with respect to cardiac death (2.2% vs 2.9%, OR 0.71, 95% CI 0.34 to 1.47, p = 0.35), myocardial infarction (1.5% vs 2.6%, OR 0.58, 95% CI 0.26 to 1.31, p = 0.19), and stent thrombosis (0.6% vs 1.2%, OR 0.57, 95% CI 0.18 to 0.84, p = 0.35). In conclusion, SES are superior to PES in reducing the incidences of restenosis and target lesion revascularization in patients with diabetes, with nonsignificant differences in terms of cardiac death, myocardial infarction, and stent thrombosis.
The presence of diabetes mellitus is often associated with complex coronary anatomy, with small and diffusely diseased vessels, an increased risk for restenosis, and unfavorable clinical outcomes in patients with coronary artery disease (CAD). Recent data have demonstrated that sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES), the most studied drug-eluting stents, dramatically reduce the incidence of restenosis and the need for repeated revascularization compared with bare-metal stents in patients with diabetes. With regard to the relative safety and efficacy of SES compared with PES, however, controversy remains. We therefore performed a meta-analysis of randomized trials to compare head to head SES and PES in patients with diabetes and CAD.
Methods
The published research was scanned by formal searches of electronic databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials) from January 2001 to April 2009. All randomized trials involving head-to-head comparisons of SES and PES in patients with diabetes were examined using the following key words: “randomized trial,” “diabetes mellitus,” “drug-eluting stent,” “sirolimus-eluting stent,” “paclitaxel-eluting stent,” and “percutaneous coronary intervention.” To be selected for this meta-analysis, studies comparing SES with PES in patients with diabetes had to be randomized and have their results reported by the trial investigators. All studies meeting the requirements, regardless of the language or form of publication, were considered eligible for this meta-analysis. When there were multiple reports from the same trial, we used the most complete and/or recently reported data.
The primary outcome of interest was target lesion revascularization (TLR), which was defined as any revascularization procedure, percutaneous or surgical, involving the target lesion. Other clinical outcomes of interest were cardiac death, myocardial infarction, and stent thrombosis. We accepted the individual protocol definitions of clinical events and did not attempt to retrospectively recategorize them. The angiographic outcome of interest was binary (≥50%) restenosis. Two investigators (FZ, LD) independently performed data abstraction. Disagreements were resolved by consensus.
All analyses were performed on the basis of the intention-to-treat principle. Odds ratios (OR) with 95% confidence intervals (CIs) were computed as summary statistics. The pooled OR was calculated with the Mantel-Haenszel method for fixed effects and the DerSimonian and Laird method for random effects. To assess heterogeneity across trials, we used Cochran’s test and means of the I 2 statistic. A funnel plot and the adjusted rank correlation test, according to the method of Begg and Mazumdar, were used to assess publication bias with respect to the primary outcome of interest. A sensitivity analyses was performed by comparing the treatment effects obtained with each trial removed consecutively from the analysis with the overall treatment effects. Results were considered statistically significant at a 2-sided p value <0.05. Statistical analyses were performed using Stata version 9 (StataCorp LP, College Station, Texas).
Results
Of the 687 potentially relevant reports initially screened, a total of 8 trials (10 relevant reports) were initially identified. Two intravascular ultrasound studies were then excluded because no data were available on angiographic and clinical outcomes, and another trial was excluded because the SES and PES were simultaneously implanted in the same patient with diabetes with multiple coronary artery lesions, which precluded the ability to compare the clinical outcomes between the 2 different drug-eluting stents. Thus, a total of 5 trials (7 relevant reports) were ultimately included in this meta-analysis, involving 1,173 patients with diabetes and CAD (594 randomized to the SES group and 579 randomized to the PES group). The main characteristics of these trials are listed in Table 1 , and baseline characteristics of enrolled patients in the individual trials are listed in Table 2 .
| Study | Trial Name (Year of Publication) | Enrollment Period | Study Site | No. of Centers | No. of Enrolled Patients | Primary End Points | Angiographic Follow-Up (mo) | Clinical Follow-Up (mo) |
|---|---|---|---|---|---|---|---|---|
| Dibra et al | ISAR-DIABETES (2005) | June 2003 to March 2004. | Germany | 2 | 250 (125 sirolimus-eluting stents, 125 paclitaxel-eluting stents) | In-segment late luminal loss | 8 | 9 |
| Billinger et al | SIRTAX (2008) | April 2003 to May 2004 | Switzerland | 2 | 201 (108 sirolimus-eluting stents, 93 paclitaxel-eluting stents) | Major adverse cardiac events | 8 | 24 |
| Kim et al | — (2008) | April 2005 to January 2006 | Korea | 6 | 169 (85 sirolimus-eluting stents, 84 paclitaxel-eluting stents) | In-segment late luminal loss | 6 | 6 |
| Maeng et al, Jensen et al | DIABEDES (2009) | February 2005 to March 2006 | Denmark | 4 | 153 (76 sirolimus-eluting stents, 77 paclitaxel-eluting stents) | In-stent late luminal loss | 8 | 8 |
| Lee et al | DES-DIABETES (2009) | May 2005 to March 2006 | Korea | 5 | 400 (200 sirolimus-eluting stents, 200 paclitaxel-eluting stents) | In-segment restenosis | 6 | 24 |
| Variable ⁎ | ISAR-DIABETES | SIRTAX | Kim et al | DIABEDES | DES-DIABETES | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| SES | PES | SES | PES | SES | PES | SES | PES | SES | PES | |
| (n = 125) | (n = 125) | (n = 108) | (n = 93) | (n = 85) | (n = 84) | (n = 76) | (n = 77) | (n = 200) | (n = 200) | |
| Age (years) | 68 ± 10 | 68 ± 10 | — | — | 63 ± 8 | 62 ± 9 | 66 ± 8 | 65 ± 10 | 61 ± 9 | 61 ± 9 |
| Women | 32 (26%) | 36 (29%) | 33 (31%) | 26 (28%) | 24 (28%) | 20 (24%) | 12 (16%) | 20 (26%) | 78 (39%) | 90 (45%) |
| Insulin-dependent diabetes mellitus | 46 (37%) | 36 (29%) | — | — | 16 (19%) | 11 (13%) | 31 (41%) | 29 (38%) | 32 (16%) | 33 (17%) |
| Glycosylated hemoglobin (%) | 7.4 ± 1.6 | 7.3 ± 1.1 | — | — | 7.5 ± 1.4 | 7.6 ± 1.2 | 7.7 ± 1.3 | 7.5 ± 1.4 | 7.7 ± 1.8 | 7.8 ± 1.6 |
| Current smokers | 16 (13%) | 16 (13%) | 25 (23%) | 16 (17%) | 17 (20%) | 22 (26%) | 29 (38%) | 18 (23%) | 54 (27%) | 57 (29%) |
| Hypertension | 70 (56%) | 82 (66%) | 71 (66%) | 52 (56%) | 54 (64%) | 61 (73%) | 48 (63%) | 58 (75%) | 114 (57%) | 124 (62%) |
| Hypercholesterolemia | 73 (58%) | 78 (62%) | 71 (66%) | 52 (56%) | 26 (31%) | 26 (31%) | — | — | 55 (28%) | 63 (32%) |
| Previous myocardial infarction | 39 (31%) | 49 (39%) | 38 (35%) | 32 (34%) | 13 (15%) | 12 (14%) | — | — | — | — |
| Previous percutaneous coronary intervention | — | — | — | — | 11 (13%) | 9 (11%) | 10 (13%) | 19 (25%) | 25 (13%) | 25 (13%) |
| Previous coronary artery bypass graft | 16 (13%) | 13 (10%) | — | — | 0 (0) | 3 (4%) | 4 (5%) | 6 (8%) | 4 (2%) | 3 (2%) |
| Left ventricular ejection fraction (%) | 50 ± 13 | 52 ± 14 | — | — | — | — | 65 ± 24 | 62 ± 22 | 59 ± 10 | 58 ± 10 |
| No. of target lesions | 125 | 125 | 158 | 134 | 95 | 95 | 122 | 114 | 200 | 200 |
| Complex (type B2/C) lesions | 102 (82%) | 92 (74%) | 59 (37%) | 48 (36%) | 72 (76%) | 70 (74%) | — | — | — | — |
| Reference diameter (mm) | 2.7 ± 0.5 | 2.8 ± 0.6 | 2.9 ± 0.4 | 2.7 ± 0.4 | 2.7 ± 0.4 | 2.8 ± 0.5 | 2.8 ± 0.7 | 2.7 ± 0.5 | 2.8 ± 0.4 | 2.8 ± 0.4 |
| Lesion length (mm) | 14 ± 8 | 12 ± 8 | 11 ± 5 | 12 ± 8 | 13 ± 7 | 13 ± 6 | 19 ± 15 | 18 ± 11 | 26 ± 13 | 27 ± 14 |
| Minimal luminal diameter (mm) | 1.0 ± 0.4 | 1.1 ± 0.4 | 0.6 ± 0.5 | 0.5 ± 0.5 | 0.8 ± 0.5 | 0.8 ± 0.5 | 0.9 ± 0.5 | 0.8 ± 0.6 | 0.8 ± 0.5 | 0.7 ± 0.5 |
| Diameter stenosis (%) | 61 ± 13 | 59 ± 12 | 81 ± 15 | 81 ± 16 | 68 ± 19 | 70 ± 16 | 69 ± 17 | 71 ± 19 | 68 ± 15 | 70 ± 13 |
| Length of stented segment (mm) | 24 ± 10 | 22 ± 9 | 19 ± 11 | 19 ± 12 | 26 ± 6 | 25 ± 6 | 25 ± 17 | 22 ± 13 | 33 ± 14 | 33 ± 15 |
| No. of stents | 1.2 ± 0.4 | 1.1 ± 0.4 | 1.1 ± 0.5 | 1.1 ± 0.4 | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.4 ± 0.8 | 1.4 ± 1.0 | 1.3 ± 0.5 | 1.3 ± 0.6 |
| Glycoprotein IIb/IIIa inhibitors | 25 (20%) | 24 (19%) | — | — | — | — | 38 (50%) | 39 (51%) | 11 (6%) | 7 (4%) |
⁎ The definitions of all variables were according to the prespecified protocols of the individual studies included.
TLR, the primary outcome of interest, was needed in 30 of 594 patients (5.1%) assigned to the SES group, significantly less than the 66 of 579 patients (11.4%) assigned to the PES group (OR 0.41, 95% CI 0.26 to 0.64, p <0.001) by the fixed-effects model ( Figure 1 ). There was no significant heterogeneity between trials (p = 0.91). No evidence of publication bias with respect to TLR was found using the Begg funnel plot and rank correlation test (p = 0.81). The omission of individual trials from the analysis did not have any relevant influence on the overall results of the analysis.
SES were significantly more effective in the reduction of angiographic binary restenosis than PES ( Figure 2 ). The incidence of angiographic restenosis was 5.6% (27 of 482 lesions) in patients treated with SES and 16.4% (74 of 451 lesions) in those treated with PES. The pooled OR in favor of SES was 0.30 (95% CI 0.19 to 0.48, p <0.001) by the fixed-effects model. There was no significant heterogeneity between trials (p = 0.44).
