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In a broad range of patients undergoing percutaneous coronary intervention (PCI), use of everolimus-eluting stents (EES) provides 9-month angiographic results comparable to those of sirolimus-eluting stents (SES), the standard bearer for the first generation of this device class. The finding, bolstered by similar rates of clinical outcomes at 1 year, appears in the October 25, 2011, issue of the Journal of the American College of Cardiology.

For the EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) trial, a team led by Hyo-Soo Kim, MD, of Seoul National University Main Hospital (Seoul, South Korea), randomized 1,443 patients undergoing PCI at 19 Korean centers between  June 2008 and July 2009 in a 3:1 fashion to Xience V everolimus-eluting stents (n = 1,079; Abbott Vascular, Santa Clara, CA) or Cypher Select sirolimus-eluting stents (n = 364; Cordis/Johnson & Johnson, Miami Lakes, FL).

Quantitative angiographic follow-up was performed at 9 months in 67.4% of the EES group and 64.5% of the SES group. For the primary endpoint of mean in-segment late loss and for mean in-stent late loss, EES met the criteria for noninferiority to SES (table 1).

Table 1. Angiographic Outcomes at 9 Months

^a For noninferiority.

Similar results were seen in the intention-to-treat population.

In addition, at 1 year, no differences were observed between stents for rates of cardiac death, MI, ischemia-driven TLR, Academic Research Consortium-defined definite or probable stent thrombosis, or target lesion failure (TLF; composite of cardiac death, target vessel-related MI, and clinically indicated TLR; table 2).

Table 2. Clinical Outcomes at 1 Year

TLF rates did not differ between patients who did or did not receive routine angiographic follow-up.

In subgroup analyses, among diabetics, EES resulted in higher levels of both in-segment and in-stent late loss at 9 months compared with SES (0.14 ± 0.39 vs. 0.01 ± 0.31; P = 0.0021, and 0.23 ± 0.36 mm vs. 0.10 ± 0.27 mm; P = 0.0034, respectively). Among patients who received multivessel stenting, only in-segment late loss was higher in the EES arm (0.15 ± 0.41 vs. 0.02 ± 0.25; P = 0.0067). No late loss differences were seen between the stents among patients with longer lesions (≥ 20 mm).

On the other hand, for the clinical endpoint of TLF, results for the 2 DES were comparable across subgroups involving diabetes, long lesions, multivessel stenting, acute MI, renal dysfunction (CCr ≤ 60 vs. > 60 mL/min), and reference vessel diameter (≥ vs. < 2.75 mm).

Underpowered for Clinical Endpoints

In an accompanying editorial, Fernando Alfonso, MD, PhD, and Cristina Fernandez, MD, PhD, both of Clinico San Carlos University Hospital (Madrid, Spain), point to several limitations that complicate interpretation of the findings.

First, only two-thirds of patients actually received angiographic follow-up, which “might jeopardize the value of the selected noninferiority margin because dropouts may dilute potential differences between treatments,” Drs. Alfonso and Fernandez write. Additionally, the trial was underpowered to detect differences in clinical endpoints.

They also note that according to the trial design, patients were randomized to 6 or 12 months of dual antiplatelet therapy, but data on whether long-term therapy might have affected the safety results of the 2 stent groups unevenly are not provided. Lastly, the 3:1 randomization scheme may have increased the risk of the play of chance in the smaller, SES arm.

To provide a broader perspective, the editorial presents an analysis of pooled data from 11,351 patients in 8 randomized head-to-head comparisons of EES with SES. Granting the trials’ heterogeneity, the analysis nonetheless found no statistically significant differences between the first- and second-generation DES for any event but clear ‘signals’ favoring the safety and efficacy of EES. “If present, however, it remains questionable whether [the signals] will be considered as ‘clinically relevant’ from a practical perspective,” the editorial acknowledges.

Cypher Bows Out with Head Held High

“I think this is the last of the comparative trials with an angiographic primary endpoint for stents that have already been proven to consistently [provide] low late loss,” David E. Kandzari, MD, of the Piedmont Heart Institute (Atlanta, GA), told TCTMD in a telephone interview. When the first-generation stents were initially introduced, there was an intense focus on late loss and its relationship to clinical outcomes like TLR, he recalled. “But we’ve learned that those relationships don’t really hold up long-term, and that clinical outcomes trump angiographic outcomes.”

For Dr. Kandzari, “the really interesting part of this study” is that it underscores that event rates have improved markedly over the past 5 or 6 years. “Cypher has not changed, but [interventional] practice around it has changed,” he commented. The improvement is probably driven by better technique, optimization of medical therapy, including use of antiplatelets and statins, and even “a bit of gamesmanship” in choice of trial endpoints, moving from patient-oriented to more stent-specific endpoints, he suggested.

Dr. Kandzari predicted that Xience will become the new benchmark for future DES trials, in part because Cypher is no longer available. “But more importantly, Xience and Promus [the same stent but marketed by Boston Scientific; Natick, MA] have already become the standard, given their [broad] market share and the fact that we’re now observing some of the best outcomes with these DES in both trials and practice,” he added.

As for a possible signal of lower EES efficacy in diabetics, the editorial points out that the higher late loss did not translate into a difference in clinical outcomes. Moreover, Dr. Kandzari said that for clinicians, small potential differences in efficacy between DES should take a back seat to recognition that diabetics are at higher risk overall and so warrant aggressive medical management of risk factors.

The trend toward increasingly favorable outcomes means that new stent designs, such as those featuring bioresorbable polymers or platforms, face a formidable challenge in demonstrating superiority to the current crop of DES, Dr. Kandzari observed. In a similar vein, the editorial concludes, “This [trial] may serve as a farewell tribute to this still-unbeaten first-generation SES.”

Study Details

The baseline patient, lesion, and procedural characteristics were mostly similar between the study groups, except that a history of stroke was more common and the final balloon pressure was higher in SES patients, while EES patients received marginally more stents.

Sources:

1. Park KW, Chae I-H, Lim D-S, et al. Everolimus-eluting versus sirolimus-eluting stents in patients undergoing percutaneous coronary intervention: The EXCELLENT (Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting) randomized trial. J Am Coll Cardiol. 2011;58:1844-1854.
2. Alfonso F, Fernandez C. Head-to-head randomized comparisons of limus-eluting coronary stents: Pursuing excellence or flying too high? J Am Coll Cardiol. 2011;58:1855-1858.

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• ESSENCE-DIABETES Published: Xience, Cypher Equally Equipped to Treat Diabetics
• Meta-analysis Finds Equivalence Between First-, Second-Generation DES
• Everolimus-Eluting Stents Found Equivalent to First-Generation Stents in Most Patients at 1 Year