Evolving Use of Drug-eluting Stents in Diabetic Patients

There are more than 150 million adults worldwide estimated to have diabetes mellitus (DM), with Type 2 diabetes accounting for up to 95% of all cases.¹ In 2001, the prevalence of DM in the United States was 8%, a relative increase of approximately 61% over a 10-year time span.² Coronary artery disease (CAD) is virtually ubiquitous in adults with DM compared with non-diabetic patients and portends a worse prognosis. Diabetic patients are 2 to 4 times more likely to develop CAD than non-diabetic patients and have the same likelihood of experiencing a myocardial infarction (MI) as those without DM but who have a previous history of MI.³ As the prevalence of DM increases, the challenges for the health care of these individuals are magnified. In addition to optimal medical therapy, a significant proportion of DM patients with CAD are candidates for revascularization. Among the nearly 1.5 million revascularization procedures performed each year in the United States (CABG or PCI), approximately 25% occur in diabetic patients.⁴ The propensity of diabetic patients to experience adverse outcomes following revascularization has been ascribed to smaller-caliber target vessels, a greater degree of underlying vascular inflammation, a prothrombotic state, and more frequent associated risk factors.^4–6 Recent data also suggest that immunity, inflammation, and heredity are related central pathogenic mechanisms in the development of insulin resistance that characterizes the metabolic syndrome.⁷ Insulin resistance may be further involved in the development of atherothrombotic disease through stimulation of plasminogen activator inhibitor-1 and alteration of endothelial function, as well as through a direct mitogenic/growth factor-like effect of insulin on both vascular smooth muscle and neointimal cells.⁸ Maladaptive arterial remodeling (vessel scarring or shrinkage) may contribute to more frequent restenosis following balloon angioplasty in diabetic patients. Although coronary stent deployment has improved late outcomes (versus balloon angioplasty) following PCI, both angiographic restenosis and the requirement for repeat revascularization are increased in diabetic patients and limit the durability of PCI compared to surgery.⁹ Polymer-based drug-eluting stents (DES) have markedly reduced late coronary lumen loss and angiographic restenosis, as well as the need for repeat revascularization when compared to bare metal stents (BMS). The Cypher™ sirolimus-eluting stent (Cordis Cardiology, Miami Lakes, Florida) has demonstrated durable clinical and angiographic benefit for diabetic patients in both randomized clinical trials and post-market surveillance registries.^10–21 More recent data on the paclitaxel-eluting Taxus™ stent (Boston Scientific, Natick, Massachusetts) suggest similar efficacy for the treatment of diabetic patients.^22–26 By markedly reducing restenosis, DES significantly improve or eliminate the major limitation of conventional stenting/PCI and may herald a paradigm shift from surgical revascularization to PCI in diabetic patients. In this issue of the Journal, Aoki et al. add to the real world experience of utilizing DES for diabetic patients undergoing PCI.27 During 11 months of enrollment, sirolimus-eluting stents (SES) were evaluated in a consecutive group of diabetic patients (n = 112) undergoing elective PCI and compared to a historical control group (n = 118) receiving BMS. Diabetic status was determined by medical documentation or by utilization of insulin or oral hypoglycemic agents. All patients received life-long aspirin and clopidogrel for 1 month in the BMS group and for at least 3 months in the SES group. The use of platelet glycoprotein IIb/IIIa blockade was at the discretion of the operator and was significantly higher in the BMS group (31% versus 13%; p = 0.001). Significant differences in angiographic and procedural characteristics in the SES group included more bifurcation stenting, smaller mean stent diameter, and longer total stent length per patient. Twenty-nine of 60 patients treated during the first 6 months of SES utilization underwent angiographic follow-up between 6 and 9 months for complex lesion characteristics (bifurcations, left main disease, chronic total occlusions, very small vessels [2.25 mm diameter], and long stent length [> 36 mm]). The primary outcome was the occurrence of major adverse cardiac events (MACE) defined as death (cardiac and non-cardiac), non-fatal MI, or any repeat revascularization. At 30 days, there was no significant difference in the frequency of MACE between the 2 groups. The cumulative incidence of MACE at 1 year was significantly lower in the SES group (17.3% versus 30.2%; hazard ratio, 0.54 [95% CI, 0.32–0.91]; p = 0.02), mainly due to a marked reduction in repeat revascularization (10.2% versus 23.5%; hazard ratio = 0.40 [95% CI, 0.21–0.78]; p = 0.007). There was no significant difference in death or MI. The 1-year incidence of repeat revascularization in SES patients enrolled in the first 6 months (48% had mandated angiographic follow-up) was 15.6% compared with 23.5% in the BMS group (hazard ratio = 0.62 [95% CI, 0.30–1.26]; p = 0.18). SES patients treated in the last 5 months (clinical angiographic follow-up only) had significantly less repeat interventions compared to the BMS group (3.9% versus 23.5%; hazard ratio = 0.15 [95% CI, 0.04–0.61]; p = 0.009). The authors conclude that the routine utilization of SES in diabetic patients effectively reduces the incidence of MACE at 1 year compared to BMS, primarily due to a marked reduction in the incidence of repeat intervention. The authors of the present study should be commended for adding to our growing database on the utilization of DES in the diabetic patient. As pointed out by the authors, the study is limited by its non-randomized, single center design and relatively small sample size. In addition, while historical controls have been utilized in both device and pharmacotherapy studies, these type of comparisons are limited in the inability to account for confounders unique to each group within the time period analyzed. For example, the effect of more prolonged antiplatelet therapy in the SES group (as well as other systemic therapies that may modulate inflammation, endothelial function, and the need for repeat revascularization) cannot be excluded in the present study. Another factor to consider is that the majority of patients in this study were non-insulin-requiring diabetics. Only 37 insulin-requiring diabetic (IRDM) patients were treated with SES, and 29 with BMS during the respective time periods. One-year cumulative MACE for IRDM patients was 26.3% in the SES group and 35.5% in the BMS group demonstrating no significant difference (hazard ratio 0.63 [95% CI, 0.27–1.44]; p = 0.28). Insulin requirement (versus non-insulin requirement) has been associated with an increased incidence of restenosis and need for repeat revascularization. Previous randomized DES trials have demonstrated efficacy in reducing binary restenosis and revascularization rates for IRDM patients.^{10,13,16–19,22–25} However, similar to prior studies, the total number of IRDM patients in the current study is too small for definitive conclusions and randomized trial data with larger number of IRDM patients are required to evaluate this issue. As one would expect, the increased rate of revascularization driven by mandated angiographic follow-up was significant. The SES cohort was prospectively evaluated according to different follow-up strategies. Diabetic patients enrolled during the first 6 months of SES utilization underwent protocol-mandated late (6- to 9-month) angiographic follow-up (48% of total population), while patients treated during the last 5 months had only clinically driven angiographic follow-up. As pointed out by the authors, the different follow-up strategies certainly contributed to the marked difference in revascularization outcomes (15.6% with angiographic follow-up, 3.9% without) seen within the SES group compared with the revascularization rate in the BMS group (23.5%). This finding is consistent with prior studies and demonstrates the difficulty in comparing trials of DES, which by design, have different clinical follow-up strategies. Previous randomized clinical trials have demonstrated efficacy of DES for diabetic patients with relatively simple lesions. Recent registry data support the use of both Cypher and Taxus stents in unselected patient populations, including diabetics.^21,26 The REALITY trial, the largest head-to-head study to compare the two FDA approved DES, demonstrated less late loss and in-stent percent stenosis with the Cypher stent compared with Taxus, but no significant difference in the primary endpoint of binary restenosis at 8 months.²⁸ Some speculate that the lower late loss with Cypher may become more clinically relevant in small vessels, including patients with diabetes. The ISAR-DIABETES trial recently compared Cypher versus Taxus in 250 diabetic patients undergoing elective PCI.²⁹ Diabetic patients in the Cypher arm of the study had significantly lower late loss and angiographic restenosis at 6 months; however, target lesion revascularization (TLR) at 9 months was no different between the two groups. Long-term clinical follow-up will be needed before any definitive conclusions can be drawn between the different DES platforms in this patient population. In addition, the majority of patients with DM have multivessel coronary disease and previous randomized trials have shown lower mortality rates following CABG than after PCI. Two ongoing clinical trials (BARI 2D and FREEDOM) will help evaluate the utility of SES in this scenario.^30,31 Drug-eluting stents offer a major advance in the percutaneous revascularization of diabetic patients. Although vitally important, randomized clinical trials provide data on carefully selected patient populations and may not reflect “real world” use in high-risk patient subsets. Ongoing registry data, careful post-market evaluation, and single-center studies as presented by Aoki et al, help define the appropriate strategies for use and importantly, the true incidence of adverse events in large populations. It is important to remember that no DES trial to date has had a demonstrable effect on death or MI. Careful attention must be paid to optimal periprocedural and late adjunctive pharmacotherapy following coronary revascularization to improve durability and clinical outcome. Thus, the optimal strategy for percutaneous revascularization in diabetic patients must include DES in combination with adjunctive pharmacotherapies. youngj@ohioheart.org

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