March 15, 2010

March 15, 2010 (Updated March 16, 2010) (Atlanta, Georgia) — A head-to-head comparison of two drug-eluting stents has shown that patients treated with the zotarolimus-eluting stent (Endeavor, Medtronic) have more major adverse cardiac events at 18 months than patients treated with sirolimus-eluting stents (Cypher, Cordis) [1].

The investigators, led by Dr Klaus Rasmussen (Aarhus University Hospital, Denmark), presented the findings from the SORT OUT III trial today during the late-breaking clinical-trials session here at the American College of Cardiology 2010 Scientific Sessions/ i2 Summit and showed that differences in outcomes were maintained at 18 months.

As previously reported, the nine-month composite end point favored the "sirolimus-eluting stent above the zotarolimus-eluting stent, mainly because of a reduced risk of target lesion revascularization [TLR], but also because of a lower occurrence of myocardial infarction and stent thrombosis," according to the investigators.

Presenting the results to the media during an afternoon press conference, Dr Michael Maeng (Aarhus University Hospital, Denmark) said the findings confirm the inferiority of the Endeavor stent when compared with Cypher in the context of everyday clinical practice and that his institution no longer uses the zotarolimus-eluting stent.

Dr Michael Maeng

The results of the study are also published online in the Lancet.

Wrench in the Program

Early studies with the zotarolimus-eluting stent suggested it might not have as potent an antiproliferative effect as the first market-approved drug-eluting stents--the Cypher sirolimus-eluting stent and the Taxus paclitaxel-eluting stent (Boston Scientific). Most of these data came from early Endeavor stent trials, which pointed to higher rates of in-stent late loss, leaving interventionalists unsure as to whether this increased late loss would translate into reduced effectiveness as time went on.

Early nine-month data from SORT OUT III, presented at TCT 2008, and reported by heartwire at that time, threw "a wrench in the mechanics of the ENDEAVOR program," according to one expert, when data showed increased rates of MI, stent thrombosis, and TLR with the Endeavor stent. At the time of the presentation, Medtronic called the findings "confoundingly anomalous," saying more long-term data were needed.

Presented during the late-breaking clinical-trials sessions, the 18-month results showed, just like the nine-month findings, that individuals treated with the zotarolimus-eluting stent were more than two times as likely to have a major adverse cardiac event--defined as cardiac death, MI, and clinically driven TLR--as those treated with the sirolimus-eluting stent. Regarding individual end points, there were significant reductions in MI and TLR, as well as target vessel revascularization and all-cause mortality, in those treated with the Cypher stent.

Clinical Outcomes at 18 Months

Clinical events Zotarolimus-eluting stent, n=1162, n (%) Sirolimus-eluting stent, n=1170, n (%) Hazard ratio (95% CI)
Cardiac death, MI, and clinically driven TLR 113 (10) 53 (5) 2.19 (1.58–3.04)
All-cause mortality 51 (4) 32 (3) 1.61 (1.03–2.50)
Cardiac death 18 (2) 12 (1) 1.51 (0.73–3.14)
MI 24 (2) 11 (1) 2.22 (1.09–4.53)
Target vessel revascularization 92 (8) 39 (3) 2.42 (1.67–3.52)
TLR 71 (6) 20 (2) 3.66 (2.23–6.01)

Definite Stent Restenosis and Symptom-Driven Restenosis

Event Zotarolimus-eluting stent, n=1162, n (%) Sirolimus-eluting stent, n=1170, n (%) Hazard ratio (95% CI)
Definite stent restenosis      
0–30 d 8 (1) 3 (<1) 2.66 (0.70-10.0)
0 d–9 mo 13 (1) 4 (<1) 3.28 (1.07–10.1)
0–12 mo 13 (1) 4 (<1) 3.28 (1.07–10.1)
0–18 mo 13 (1) 6 (1) 2.19 (0.83–5.77)
In-stent restenosis      
0 d–9 mo 37 (3) 6 (1) 6.28 (2.65–14.9)
0 d–18 mo 58 (5) 12 (1) 4.98 (2.68–9.28)

The results of SORT OUT III differ from the results observed in the Endeavor clinical trial program. As previously reported by heartwire , major adverse cardiovascular events at two years in ENDEAVOR III were no different between the Endeavor and Cypher stents. In five-year follow-up from ENDEAVOR III, presented as a poster elsewhere at this meeting, rates of TLR appeared to stabilize over time, with rates of major adverse coronary events and death/MI, while underpowered, seemingly superior in the Endeavor arm as compared with the Cypher. In ENDEAVOR IV, the Endeavor stent was "noninferior" at 12 months to Taxus, at least for a composite of cardiac death, MI, and target vessel revascularization. One-year results from the Korean ZEST trial suggested that the Endeavor had higher rates of TLR than the Cypher, but lower rates than the Taxus. A two-year follow-up analysis from the Western Denmark registry, however, did point to an increased risk of all-cause mortality and higher rates of stent thrombosis, TLR, and in-segment restenosis in Endeavor- vs Cypher-treated patients.

Asked about the differences between the studies, Maeng told heartwire the SORT OUT III study differed in that it included patients with complex lesions, such as bifurcations, ostial lesions, left main lesions, long lesions, and chronic total occlusions, as well as patients with acute coronary syndromes and ST-segment-elevation MI, and that it was powered to address clinical end points.

Maeng said the all-cause mortality results showing a benefit with Cypher are surprising but noted the study included more than 2300 randomized patients. "I can't say whether that's a true finding, but that's the finding in our study," he said.

SORT OUT the Differences in the Studies

In an editorial accompanying the published study, Drs Mark Webster and John Ormiston (Green Lane Cardiovascular Service, Auckland, New Zealand) write that disparate findings in the different clinical trials might be explained by the comparator stent. In some studies, but not all, outcomes are better with the sirolimus- or everolimus-eluting stent over paclitaxel [2].

"The study population is also likely to have an effect," they write. "The greater reduction in restenosis with the sirolimus-eluting stent than with the zotarolimus-eluting stent could be most clinically relevant in the most challenging patients and diseases."

Dr Robert Byrne

Results of the ISAR-TEST-2 study were also presented today during the late-breaking clinical-trials session. In that trial, led by Dr Robert Byrne (Deutsches Herzzentrum, Munich, Germany), researchers showed there was some "late catch-up" of restenosis and TLR in Cypher-treated patients between one and two years and that growth of binary restenosis and TLR rates was significantly greater for the Cypher group than in the Endeavor groups. Asked about the studies, Byrne said there are a couple of possible reasons for the findings.

"They are all-comer patients in both of our studies [ISAR-TEST-2 and SORT OUT III], and if you look at our patients they are slightly older," Byrne told heartwire . "The reference vessel diameter was slightly smaller, and there were some differences in the types of lesions. That might have amplified the antirestenotic performances of the Cypher and Endeavor stents. Also, we have a two time-point angiographic follow-up in our study, at six to eight months and two years, and that tends to increase the absolute differences between stent platforms in a manner that is not reflective of real life. However, the relative differences in antirestenotic efficacy are perhaps real."

Also commenting on the results of SORT OUT III for heartwire , Dr David Kandzari (Scripps Clinic, La Jolla, CA) said the "big issue is how clinicians take the information between the Cypher and Endeavor stents and assimilate that into clinical practice."

He said that no one trial should alter clinical practice and that clinicians should look for trends across the different studies. With so many clinical trials performed for drug-eluting stents, there is always the possibility that the findings are the result of chance.

More important, however, Kandzari said the SORT OUT III study should remind interventionalists that no stent to date has demonstrated superior efficacy and safety to the Cypher stent in comparative drug-eluting-stent trials. Its declining use stems mainly from the fact it gets unfairly lumped in as a first-generation stent and suffers from "guilt by association."

Regarding the two stents, Kandzari said both performed very well in these complex patients, with very low TLR and MI rates. Any clinician, he said, should feel comfortable treating patients with Cypher or Endeavor.

Medtronic Responds to SORT OUT III

In response to the findings, Medtronic issued a statement today, criticizing the "unconventional methodology" of the study, drawing attention to the fact that the results are not derived from a randomized clinical trial. Also, the company notes that procedure-related MIs were excluded from the analysis, and adherence rates to dual antiplatelet therapy were unreported. The company also questioned the "unexpectedly low event rates," for the Cypher in SORT OUT III compared with SORT OUT II--2.0% for TLR vs 4.5% in SORT OUT II, for example. Finally, it states that the "long-term deficiencies of the Cypher stent" are not addressed by the short-term SORT OUT III study.

In their editorial, Webster and Ormiston note that the method of detecting clinical events in the registry could have influenced the low event rates, but clinical outcomes, in general, have improved after stent implantation, given the concerns with stent thrombosis. Clinicians are "increasingly meticulous with their technique for stent deployment," they note.

The study was sponsored by unrestricted grants from Medtronic and Cordis. Maeng reports speaking honoraria from Cordis, consulting fees from Medtronic, and travel grants from both companies. Rasmussen reports no conflicts of interest. Ormiston and Webster have received research funding from all the major interventional device companies.