LEADERS: Solid Nine-Month Data on Biolimus-Eluting Stent With Biodegradable Polymer

September 01, 2008

September 1, 2008 (Munich, Germany) — A drug-eluting stent with a biodegradable polymer fared just as well as an older-generation sirolimus-eluting stent in the Limus Eluted from a Durable versus Erodable Stent Coating (LEADERS) trial, a head-to-head study that investigators say is representative of real-world clinical practice [1]. The novel stent platform, which elutes a sirolimus analog from a biodegradable platform, was noninferior to the sirolimus-eluting stent in terms of the primary end point of cardiac death, MI, and target-vessel revascularization (TVR).

"The biolimus-eluting stent with an abluminal biodegradable polymer compared against the sirolimus-eluting stent with a durable polymer resulted in noninferior safety, efficacy, and angiographic outcomes at nine months," said lead investigator Dr Stephan Windecker (Bern University Hospital, Switzerland). The results, he added, can be generalized outside the clinical-trial setting, as investigators took on all-comers, including those with multivessel disease and those who had previously undergone revascularization.

The results of the study were presented today during a press conference and hotline session here at the European Society of Cardiology Congress 2008 and are published simultaneously in the Lancet.

Reducing the Risk of Stent Thrombosis

Speaking with heartwire , Windecker explained that biolimus is a highly lipophilic sirolimus analog that is immersed into a polylactic acid biodegradable polymer and applied to the abluminal surface of a stainless-steel stent. The polymer breaks down after six to nine months, and the rationale for the biodegradable stent is to reduce the risk of late stent thrombosis.

The LEADERS study was conducted in 10 European centers and enrolled 1707 patients with chronic stable coronary artery disease or acute coronary syndromes to treatment with the biolimus-eluting or the sirolimus-eluting stent. There was no limitation on the number of treated lesions, vessels, or lesion length.

The primary end point--a composite of cardiac death, MI, or clinically indicated TVR--occurred in 9.2% of patients treated with biolimus stent and 10.5% of patients treated with the sirolimus-eluting stent, meeting the statistical definition of noninferiority.

LEADERS: Clinical Outcomes at Nine Months

Clinical Outcome Biolimus-Eluting Stent, n=857 (%) Sirolimus-Eluting Stent, n=850 (%) Odds Ratio (95% CI)
Cardiac death, MI, or clinically indicated TVR 9.2 10.5 0.88 (0.64–1.19)
Death 2.6 2.8 0.91 (0.51–1.62)
Cardiac death 1.6 2.5 0.66 (0.34–1.30)
MI 5.7 4.6 1.25 (0.82–1.92)
Clinically indicated TVR 4.4 5.5 0.79 (0.52–1.22)
Any TVR 5.7 7.3 0.77 (0.53–1.13)

LEADERS: Angiographic Outcomes

Angiographic Outcomes at 9 mo Biolimus-Eluting Stent, n=168 (%) Sirolimus-Eluting Stent, n=167 (%) Estimated Difference (95% CI)
In-stent diameter stenosis 17.5 19.6 -2.2 (-6.0 to 1.6)
In-segment diameter stenosis 16.4 18.5 -2.7 (-6.2 to 0.9)

The trial was not powered to address individual components of safety and efficacy. The overall findings were consistent across all subgroups, including those with diabetes and multivessel and small-vessel disease, and in off-label use. In patients with ST-segment-elevation MI (STEMI), however, the primary end point occurred significantly less frequently in patients treated with the biodegradable stent.

Stent-Thrombosis Risks

Investigators also reported data on stent-thrombosis rates. At 30 days, definite or probable stent thrombosis occurred in 2.1% of patients treated with the biolimus stent and in 1.9% of patients treated with sirolimus-eluting stent, a nonsignificant difference. At nine months, 2.6% and 2.2% in the biolimus- and sirolimus-treatment arms, respectively, had a definite or probable stent thrombosis, also a nonsignificant difference.

"I think any trial, even studies that compare drug-eluting stents against bare-metal stents, need to be at least one year," Windecker told heartwire . "That's what we've learned from the safety debate. The real cause of stent thrombosis nobody knows, but one of the explanations is a hypersensitivity reaction to the polymer. So if we get rid of it, we might be able to see an advantage. But this is just a hypothesis. Nobody really knows the answer to that question just yet."

Dr Laura Mauri (Harvard Medical School, Boston, MA), the scheduled discussant during the late-breaking clinical-trials sessions, noted that the hypothesis that the biolimus stent offers long-term safety over the older stents is not yet proven. The sirolimus-eluting stent, for example, has four-year data at this point, while the biolimus stent is still novel, and nine months is not sufficient to detect safety concerns or catch-up restenosis.

In an editorial accompanying the published study [2], Dr Ron Waksman (Washington Hospital Center, Seattle) also urged caution against generalizing these results to off-label use, as well as to routine clinical practice, as further study of the biolimus stent is needed. The stent-thrombosis risk especially will need to be looked at again at 12 months and further out, but he notes there is no control of bare-metal stents in the LEADERS trial, so investigators will be unable to know whether the stent-thrombosis rates at 9 months, which he believes are high, are the result of the stent or the broad inclusion criteria.

Waksman questioned the value of noninferiority studies when comparing these next-generation stents and their older predecessors. "If one wants to prove that these new-generation stents are better, a superiority study design is needed," he writes.

Are They Better Stents, or Just Newer?

In his editorial, Waksman notes that the LEADERS trial is the first randomized trial in drug-eluting stents to enroll "all-comers," avoiding the traditional route of testing the new device in "so-called vanilla cases," such as noncomplicated patients with simple lesions. This has led to only limited labeling and an increase in off-label use often associated with "unpleasant surprises of unanticipated events when the technology was approved commercially.

"LEADERS could serve as an opportunity to call on both sponsors and regulatory bodies to consider a similar approach in future trials by broadening labeling and inclusion criteria," according to Waksman. In her discussion of the trial, however, Mauri pointed out that many of the subgroups are underpowered to detect clinical differences in outcomes, and heterogeneity in an all-comers study can weaken the overall findings, she noted.

The LEADERS trial is ongoing, and one-year data will be presented at the upcoming TCT meeting in Washington, DC, next month. Follow-up is expected for five years, and the investigators hope to be able to answer the question about the potential benefit of eliminating the polymer, such as reductions in the risk of stent thrombosis or different durations of antiplatelet therapy.

Biosensors Europe SA sponsored the LEADERS study.

  1. Windecker S, Serruys PW, Wandel S, et al. Biolimus-eluting stent with biodegradable polymer versus sirolimus-eluting stent with durable polymer for coronary revascularization (LEADERS): a randomized noninferiority trial. Lancet 2008; DOI: 10.1016/S0140-6736(08)61244-1. Available at: www.thelancet.com.

  2. Waksman R. Drug-eluting stents: is new necessarily better? Lancet 2008; DOI: 10.1016/S0140-6736(08)61244-1. Available at: www.thelancet.com.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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