November 10, 2011 (San Francisco, California) — One of the newer drug-eluting stents (DES), the biolimus-eluting Biomatrix Flex stent (Biosensors International), is noninferior to the sirolimus-eluting Cypher (Cordis/Johnson & Johnson) stent, previously considered the "gold standard" in DES but now discontinued, new four-year data from the Limus Eluted from a Durable versus Erodable Stent Coating (LEADERS) trial show [1].

The results, which were reported earlier this week at TCT 2011 by Dr Thomas Ischinger (Kardiologie im Zentrum, Munich, Germany) and published online November 9, 2011 by Dr Giulio G Stefanini (University of Bern, Switzerland) and colleagues in the Lancet, show a significant 80% relative risk reduction in very late stent thrombosis with the biodegradable-polymer platform as compared with the durable-polymer platform of Cypher (p=0.04).

"What this study shows is that the problem of very late stent thrombosis, which was present with old Taxus and Cypher stents, is markedly reduced by the biodegradable-polymer platform, and that translates into a late benefit in terms of cardiac death or myocardial infarction," coauthor of the study, Dr Stephan Windecker (University of Bern, Switzerland), told heartwire .

The problem of very late stent thrombosis is markedly reduced by the biodegradable-polymerplatform, and that translates into a late benefit in terms of cardiac death or MI.

And in order "to validate this finding in a larger data set," Windecker explained that he and his colleagues went on to perform a meta-analysis of these new LEADERS data together with results from two other trials comparing biodegradable-polymer DES with the Cypher stent, ISAR-TEST-3 and ISAR-TEST-4. This showed a significant risk reduction in definite stent thrombosis and target lesion revascularization (TLR) with the biodegradable-polymer DES.

"This finding further strengthens the conclusions of our trial, which contributed most of the accumulated evidence, showing the superiority of a newer-generation DES over durable-polymer sirolimus-eluting stents with respect to both safety and effectiveness," they state.

However, in an accompanying editorial [2], Drs Ron Waksman and Gabriel Maluenda (Washington Hospital Center, Washington, DC) say that while the long-term results of LEADERS are "encouraging," the existing data are not sufficient to claim superiority of biodegradable-polymer DES over even first-generation DES. "LEADERS was not designed as a superiority trial, and the differences in major adverse clinical events recorded in the long-term follow-up, although statistically significant, should be carefully interpreted when translating to clinical practice."

First Randomized Clinical Trial to Show Lower Rate of Very Late Stent Thrombosis Compared With Cypher

Windecker notes that LEADERS is the first randomized clinical trial to show a significant difference with a newer stent in terms of very late stent thrombosis compared with the now-defunct Cypher, which he notes was "the previous gold standard in terms of efficacy and also the risk of stent thrombosis."

Previous trials showing a significant difference in very late stent thrombosis have compared newer stents with paclitaxel-eluting Taxus, "which was an easy comparison," he observes.

Other studies comparing newer stents with Cypher, such as RESET and ISAR-TEST-4, have not shown a significant difference in very late stent thrombosis, he notes, although "it may be that the follow-up [in those trials] is not long enough." This was one of the reasons that he and his colleagues performed the new meta-analysis, he says.

Stent-Thrombosis Concerns Dissipate With Newer DES, But Comparisons Needed

The LEADERS results--along with data from large European registries on the newer everolimus-eluting stents, Xience V (Abbott) and Promus (Boston Scientific)--indicate that concerns about stent thrombosis with DES, which caused a major kerfuffle in the interventional community about five years ago, are waning with the second-generation stents.

But with the many novel options with different drug coatings and stent platforms, the question of whether one newer product is better than another remains unanswered, says Windecker.

"Scientifically, what's interesting is that it was hypothesized that adverse events with the early-generation Cypher and Taxus stents were related to the durable polymer, so the idea was to use a biodegradable polymer, and I think this LEADERS study is kind of proof of concept," he notes.

He adds that Boston Scientific is testing an everolimus-eluting product that has a biodegradable-polymer stent platform, and "most of the new stents coming out have biodegradable polymers, so really the field is going in this direction anyway."

Most of the new stents coming out have biodegradable polymers, so really the field is going in this direction anyway.

But, he stresses, "You can't make any claim. Indeed that would be one important question of whether the biolimus-eluting stent is noninferior or has any advantage compared with the durable everolimus-eluting stent. You would need a separate trial, and there are trials ongoing, but that question is not answered at this point," he told heartwire .

Waksman and Maluenda agree: "Although biodegradable-polymer technology is scientifically appealing, we are not yet in a position to confirm whether biodegradable polymers will replace durable polymer for DES technology," they state.

At the University of Berne, Windecker and his colleagues are currently using the Xience stent, the zotarolimus-eluting Resolute stent (Medtronic), both of which have durable stent platforms, as well as the Biomatrix stent tested in LEADERS and a new sirolimus-eluting stent on a biodegradable-polymer platform, he noted.

Details of Four-Year LEADERS Data

In LEADERS, which was designed to be an "all-comers" trial, patients were randomized to either the biodegradable-polymer biolimus-eluting stent (857 patients, 1257 lesions) or the Cypher stent (850 patients, 1215 lesions).

At four years, the biodegradable-polymer stents were noninferior to Cypher for the primary end point, a composite of cardiac death, MI, or clinically indicated target vessel revascularization (18.7% of patients vs 22.6%; rate ratio 0.81; p for noninferiority <0.0001, p for superiority 0.05).

The rate ratio of definite stent thrombosis was 0.62, which was largely attributable to a lower risk of very late stent thrombosis between years 1 and 4 in the biolimus-eluting-stent group than in the Cypher group (RR 0.20; p=0.04).

This "landmark analysis" shows that beyond one year, "that is between one and four years, there is a significant reduction in the risk of cardiac death or myocardial infarction" with the biolimus-eluting stent compared with Cypher, Windecker reiterated.

Windecker has received research contracts to his institution from Abbott, Boston Scientific, Biosensors, Cordis, and Medtronic. Disclosures for the coauthors are listed in the paper. Waksman has received consulting and speaker fees from Biotronik, Medtronic, and Boston Scientific; research grants from Biotronik, Boston Scientific, the Medicines Company, GlaxoSmithKline, Schering-Plough, and Sanofi-Aventis; and has been on speakers' bureaus for the Medicines Company and AstraZeneca. Maluenda declares that he has no conflicts of interest.


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