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The Efficacy of Sirolimus-eluting Stents Versus Bare Metal Stents in Diabetic Patients Undergoing Elective Percutaneous Coronary
July 2005
Several clinical studies have demonstrated that diabetes mellitus is an important predictor of angiographic restenosis and late mortality after conventional balloon angioplasty.1,2 Stent implantation has been shown to improve the clinical outcomes for diabetic patients,3 however, patients with diabetes mellitus still continue to have increased clinical events and restenosis after coronary stenting.4–6 Endothelial dysfunction, increased platelet reactivity and thrombogenicity, and dysregulation of growth factors may contribute to the exaggerated neointimal hyperplasia occurring in diabetic patients.7,8
Recently, drug-eluting stents have been shown to prevent neointimal hyperplasia and dramatically reduce the restenosis rate in elective patients with de novo lesions.9,10 Sub-studies of the RAVEL, SIRIUS, and TAXUS IV trials have indicated that drug-eluting stents significantly decreased the risk of restenosis in diabetics.11–13 However, the impact of drug-eluting stents outside the context of randomized trials is presently unknown.
Methods
Patient population. Since April 2002, we have adopted a policy of DES implantation for all percutaneous coronary interventions requiring stents at our center, irrespective of clinical presentation or lesion morphology. Sirolimus-eluting stents (SES) were exclusively used until March 2003. From April 2002 to March 2003 (11 months), 112 consecutive diabetic patients with de novo lesions were electively treated solely with SES (SES group) and composed the present study population. Diabetic status was assessed as documented on the medical report or by the utilization of insulin or oral hypoglycemic drugs. Elective cases were defined as patients without recent (14 In total, post procedural cardiac enzymes were measured in 150 patients (65%). Repeat revascularization was defined as all repeat surgical or percutaneous intervention, including revascularization procedures performed to address segments not treated in the index procedure. Clinically-driven repeat revascularization was defined as any intervention (target lesion, target vessel, and non-index vessel) motivated by a significant luminal stenosis (> 50% diameter stenosis) in the presence of anginal symptoms and/or proven myocardial ischemia by non-invasive testing. Stent thrombosis was angiographically documented as a complete occlusion (TIMI flow 0 or 1) or a flow-limiting thrombus (TIMI flow 1 or 2) of a previously successfully treated artery.
Information regarding repeat interventions was prospectively collected by means of an electronic database. Survival status was assessed by written inquiries to the Civil Registry. Questionnaires to assess clinical status were sent to all living patients. The patient, referring physician, and peripheral hospitals were directly approached whenever necessary for additional information.
Angiographic follow-up. Patients treated during the first 6 months of utilization of SES were approached for late angiographic re-evaluation according to the following “complex” characteristics: SES implanted in bifurcations, left main coronary, chronic total occlusions, very small vessels (2.25 mm stent diameter), and long stented length (> 36 mm). In total, 29 of the 60 patients enrolled in the first 6 months (48% of the patients treated in this period) had angiographic re-study between 6 and 9 months of follow-up. For the remaining patients in the pre-SES group and the last subgroup of patients treated with SES (i.e. last 5 months enrollment), follow-up angiography was obtained as clinically indicated by symptoms or documentation of myocardial ischemia.
Statistical analysis. Continuous variables were compared with the Student’s t-test, and the Fisher’s exact test was used for categorical variables. The cumulative incidence of adverse events was calculated according to the Kaplan-Meier method, and Cox proportional hazard models were used to assess risk reduction of adverse events. All statistical tests were two-tailed, and p values less than 0.05 were considered statistically significant.
Results
Patient characteristics. The baseline, angiographic, and procedural characteristics are presented in Tables 1 and 2. There were no statistical differences between the 2 groups with respect to the baseline and angiographic characteristics. Patients in the SES group had a longer stented length and were treated with stents of smaller diameters. The use of glycoprotein IIb/IIIa inhibitors was less frequent in the SES group than in the pre-SES group (13% versus 31%, p = 0.001).
30-day and 1-year clinical outcomes. At 30 days, there were no significant differences in the frequency of major adverse cardiac events between the 2 groups. The 30-day incidence of any MACE was 5.9% in the pre-SES group and 4.5% in the SES group (p = 0.61). Angiographically documented stent thrombosis occurred in 1 patient (0.8%) in the pre-SES group and 2 patients (1.8%) in the SES group (p = 0.77).
The cumulative incidence of major cardiac events at 1 year is shown in Table 3. Both the cumulative incidence of death, and the composite of death or non-fatal MI were not statistically different between the 2 groups (Figure 1A, 1B). However, the incidence of overall MACE was significantly lower in the SES group than in the pre-SES group (17.3% versus 30.2%, respectively; hazard ratio = 0.54 [95% confidence interval = 0.32–0.91]; p = 0.03), mainly due to a decrease in the incidence of repeat revascularization in the SES group (10.2% versus 23.5% in the pre-SES group; hazard ratio = 0.40 [95% confidence interval = 0.21–0.78]; p = 0.007) (Figures 1C and 2A).
To better evaluate the impact of protocol-mandated angiographic follow-up on the clinical outcomes, patients treated with SES in the first 6-month enrollment period (48% had elective control angiography), and those treated with SES in the last 5 months were separately compared to the pre-SES group. The 1-year incidence of repeat revascularization in patients included in the first half of the SES group was 15.6%, compared with 23.5% in the pre-SES group (hazard ratio = 0.62 [95% confidence interval = 0.30–1.26]; p = 0.18). Conversely, patients treated in the last phase of the SES period had significantly less re-interventions than patients treated with bare stents (3.9% versus 23.5%, respectively; hazard ratio = 0.15 [95% confidence interval = 0.04–0.61]; p = 0.009) (Figure 2B, 2C).
Patients with insulin-requiring diabetes mellitus (IRDM). In this study, 37 patients with IRDM were treated with SES and 29 patients with IRDM were treated with BMS. The 1-year cumulative MACE rate was 26.3% in the SES group, and 35.5% in the BMS group, which was not statistically significant (hazard ratio = 0.63 [95% confidence interval = 0.27–1.44], p = 0.28).
Discussion
The present study shows that, in comparison to bare metal stents, utilization of sirolimus eluting stents for diabetic patients treated in the daily practice was safe and effective in reducing major cardiac events at 1 year, mainly due to a marked decrease in the incidence of repeat intervention.
In our series, the SES-treated cohort was composed by two groups prospectively evaluated according to different followed-up strategies. Specifically, a subset of diabetic patients enrolled in the first half of the SES phase underwent protocol-mandated late angiographic re-study, while patients treated in the last half had only clinically driven angiographic re-evaluation. This contrasted with the pre-SES control group, where only clinically driven angiographic follow-up was obtained for the entire group. The different follow-up strategy applied for the two SES subgroups could have accounted for the marked difference in outcomes seen between these subsets. High prevalence of silent ischemia in diabetic patients might decrease the incidence of clinically driven repeat revascularization, and the increase in the incidence of re-intervention due to the so-called “oculo-stenotic reflex” is a well-known phenomenon occurring among patients undergoing protocol-mandated angiographic follow-up.15,16 In the BENESTENT II trial, the one-year incidence of repeat revascularization in the stented group was 18.3% with angiographic follow-up, compared with 7.8% without angiographic follow-up.16 In our series, the effect of the angiographic follow-up on repeat interventions was clearly observed in the SES group: patients in the SES subgroup with re-study had a rate of repeat intervention of 15.6%, while in patients without re-study the incidence of re-intervention was 3.9%. It is worth noting that, although not assessed in the present study, diabetics may be more prone to be influenced by a potential “oculo-stenotic reflex.” The presence of diffuse coronary artery disease, incomplete relief of symptoms related to microcirculation disease, and extra-cardiac co-morbidities, features commonly seen in this high-risk group of patients, may lead to a more aggressive treatment strategy by the time of the repeat catheterization.
Previous randomized trials have shown the effect of drug-eluting stents for diabetic patients with relatively simple lesions.12,13 In the RAVEL trial, sirolimus-eluting stents effectively inhibited neointimal hyperplasia in diabetic patients.13 Similarly, in the SIRIUS trial, SES implantation for diabetic patients was associated with reduction of 9-month MACE from 25.0% with bare metal stent to 9.2%.17 The present study assessed the impact of routine utilization of drug-eluting stents for diabetics treated in daily practice. Despite of the fact that our patients had more complex lesion types and were treated with longer stent lengths and smaller stent diameters than previous randomized trials,9,18 SES implantation was associated with an overall 60% risk reduction of any repeat revascularization in the present study. Furthermore, it must be recognized that this risk reduction may actually be an underestimate due to the unbalanced frequency of angiographic follow-up between patients treated with SES and patients treated with bare metal stents.
Insulin-requiring diabetes mellitus (IRDM) is associated with a high adverse cardiac event rate after coronary stenting in the diabetic population.4–6 The efficacy of the DES for patients with IRDM requires further evaluation. In the SIRIUS trial, the 9-month MACE rate for patients with IRDM who were treated with SES were not significantly different from patients with IRDM who were treated with bare metal stents (MACE; 15.8% versus 22.7%; p = 0.58).17 This result is in agreement with our study. A randomized trial enrolling more patients is required to further evaluate this issue.
In our study, the vast majority of diabetic patients had multi-vessel coronary disease. Diabetic patients with multi-vessel disease have been shown to be at high risk for future cardiac events. Moreover, the best therapeutic approach for these patients is still a matter of ongoing debate. Previous randomized trials of diabetics have shown lower mortality rates following bypass surgery than after balloon angioplasty.19,20 However, more contemporary studies with coronary stents have failed to show any difference in mortality between the surgical and percutaneous treatments.21–23 In these studies, both modalities differed mainly with regards to an excessive incidence of repeat revascularization after stenting, a complication frequently related to the occurrence of late restenosis. According to the analysis of diabetic patients in the ARTS trial, the 1-year incidence of repeat revascularization was 22.3% in the stented group and 3.1% in the CABG group.21 The significantly lower incidence of repeat revascularization in SES-treated patients compared to the bare stent group indicates the promising role of SES for the management of diabetics with advanced atherosclerotic disease. Two clinical trials (the FREEDOM trial and the BARI-2D) are currently ongoing to further evaluate the value of sirolimus-eluting stents in this scenario.24
This study is limited by its non-randomized, single-center design and moderate sample size. It is, however, the first study to evaluate the efficacy of drug-eluting stents for diabetic patients outside the context of randomized trials.
Conclusions
Routine utilization of sirolimus-eluting stents for diabetic patients effectively reduced the incidence of adverse cardiac events at 1 year compared to bare metal stents. Sirolimus-eluting stent implantation seems to be a promising strategy for diabetic patients treated in daily practice.
Acknowledgement. We thank Drs. Pedro A. Lemos and Angela Hoye for their careful review of the manuscript and constructive suggestions.
p.w.j.c.serruys@erasmusmc.nl
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