Bucking trend, Nobori DES misses noninferiority test vs Cypher

February 07, 2013

Aarhus, Denmark - A biolimus-eluting coronary stent lined with a biodegradable polymer (Nobori, Terumo) didn't fare well enough to be declared noninferior vs a sirolimus-eluting, standard-polymer stent (Cypher Select Plus, Cordis/Johnson & Johnson) with respect to a combined nine-month safety/efficacy end point in a randomized trial of patients with chronic stable angina[1].

The 1229-patient fifth Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT V) trial, published online January 29, 2013 in the Lancet, ended up as something of an outlier among studies with a similar purpose and design. In at least three other trials, the Nobori or similar drug-eluting stents (DES) handily met noninferiority criteria compared with sirolimus- or everolimus-eluting durable-polymer stents in about the same clinical setting.

One of those trials, called COMPARE II [2], was published simultaneously with SORT OUT V but had been presented with the same numbers in May 2012 and covered then by heart wire . In it, note Dr Pieter Cornelis Smits (Maasstad Ziekenhuis, Rotterdam, the Netherlands) and associates, the Nobori was noninferior (p for noninferiority <0.0001) at 12 months compared with the everolimus-eluting Xience V, Prime (Abbott Vascular), or Promus (Boston Scientific) stents.

But in SORT OUT V, the nine-month rate of cardiac death, MI, definite stent thrombosis, or target vessel revascularization (TVR) was 4.1% for Nobori and 3.1% for Cypher by intention to treat, a nonsignificant difference (p=0.22) overall that nonetheless fell short of the trial's prespecified standard for noninferiority (p=0.06).

The authors, led by Dr Evald H ø j Christiansen (Aarhus University Hospital, Denmark), said they had no explanation for why the event rate was higher with the biolimus-eluting stent. "Although nonsignificant, the difference was noted in all elements of the combined end point and across patient subgroups. The differences seemed to occur mainly during the first month and were most pronounced in the end points of stent thrombosis, MI, and new revascularizations," they write.

In an accompanying editorial[3], Dr Adnan Kastrati (Deutsches Herzzentrum, Munich, Germany) and Dr Franz-Josef Neumann (Universitäts-Herzzentrum Freiburg-Bad Krozingen, Germany) write that the Nobori "fell short of being statistically noninferior to the Cypher stent by an absolute difference in nine-month adverse event rates of only 0.9%. The main statistical result of the trial primarily reflects the power provided by the large sample size rather than being a strong indication of a clinically relevant difference between the compared devices."

SORT OUT V randomized 1229 patients with 1532 ultimately treated lesions to receive the Nobori and 1239 patients (who went on to have 1555 treated lesions) to receive the sirolimus-eluting stent. The 12-month results followed the same pattern as those at nine months: 5.4% for the Nobori and 4.4% for the Cypher.

With some irony, the primary-end-point difference appeared largely attributable to the definite-stent-thrombosis component, which was 0.7% for Nobori and 0.2% for Cypher at both nine and 12 months (p=0.034). A possible decrease in risk of stent thrombosis has been one of the theoretical advantages of biodegradable polymers over durable polymers. (In COMPARE II, the stent-thrombosis rates were 0.7% for the biolimus-eluting stent and 0.4% for the everolimus-eluting stents.)

According to Kastrati and Neumann, "With only 11 cases of definite stent thrombosis, [SORT OUT V] was underpowered to assess this event in a reliable manner," and the difference may be clinically relevant only if it persists over a much longer time than one year.

Significance of one-year noninferiority

Trials other than COMPARE II that pit Nobori or Nobori-like stents against stents with durable polymers, as covered by heart wire , include the LEADERS trial, in which the biolimus-eluting, biodegradable-polymer Biomatrix Flex stent (Biosensors) was found noninferior to the Cypher.

And in the 2603-patient ISAR-TEST 4 , a custom-made sirolimus-eluting stainless-steel stent with a biodegradable polymer was declared noninferior to Cypher and Xience stents at 12 months. The end point was a composite of cardiac death, MI related to the target vessel, or target lesion revascularization (TLR). Definite or probably stent thrombosis developed in 1% of the biodegradable-polymer group and 1.5% of the durable-polymer group.

In an editorial accompanying the COMPARE II paper[4], Dr Julinda Mehilli (Klinikum der Universitaet Munich, Germany) writes that its authors "should be encouraged to follow COMPARE II patients for up to five years, because the hypothesized advantage of biodegradable-polymer DES is that noninferiority at one year should transform into long-term clinical superiority over durable-polymer DES. Only then can we be certain that a stent with a disappearing polymer provides lasting clinical benefit for patients treated in routine practice."

SORT-OUT V was supported by Terumo and Cordis (Johnson & Johnson), from which Christiansen discloses receiving honoraria and travel grants; disclosures for the coauthors are listed in the paper . Kastrati discloses receiving lecture fees from Abbott, Biotronik, Cordis, and Medtronic and having submitted patent applications involving DES technology. Neumann had no disclosures. COMPARE II was funded by Terumo Europe; Smits discloses being a consultant for Blue Medical and receiving lecture and travel fees from Abbott Vascular, while his coauthors had no disclosures. Mehilli discloses receiving lecture fees from Abbott Vascular, Terumo, Translumina, Lilly/Daiichi Sankyo, and t he Medicines Company.




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