SORT OUT III: Higher Risk of Very Late Stent Thrombosis with Cypher vs. Endeavor

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Despite a long-term reduction in major adverse cardiac events (MACE) compared with zotarolimus-eluting stents, sirolimus-eluting stents carry a higher risk of very late stent thrombosis, according to a study published online August 20, 2012, ahead of print in JACC: Cardiovascular Interventions.

For the multicenter SORT OUT III trial, researchers led by Michael Maeng, MD, PhD, of Aarhus University Hospital (Aarhus, Denmark), randomized 2,332 Danish patients with stable CAD or ACS to the Endeavor zotarolimus-eluting stent (n = 1,162; Medtronic, Santa Rosa, CA) or the Cypher sirolimus-eluting stent (n = 1,170; Cordis/Johnson & Johnson, Warren, NJ). Follow-up data were obtained from national administrative and health care registries.

Previously published 9- and 18-month data from SORT OUT III showed Endeavor to be inferior to Cypher with regard to both safety and efficacy endpoints. Specifically, SES were associated with lower rates of stent thrombosis at 9 months, reduced MI at both 9 and 18 months, and lower all-cause mortality at 18 months. For the current analysis, Dr. Maeng and colleagues extended follow-up to 3 years.

Lower MACE with Cypher, but Higher Late Definite ST

Overall, MACE (composite of cardiac death, MI, and TVR) was higher with Endeavor compared with Cypher, as was TVR. Rates of MI, cardiac death, and cumulative definite stent thrombosis were similar between the 2 groups (table 1).

Table 1. SORT OUT III: 3-Year Outcomes

However, between 12 and 36 months, very late definite stent thrombosis occurred in 12 patients in the Cypher group (1.1%) compared with no events in the Endeavor group (P = 0005).

In a landmark analysis, the higher risk of MACE with Endeavor was seen exclusively during the first year (HR 2.06; 95% CI 1.45-2.94; P < 0.01) and was driven by a fourfold higher risk of TLR (HR 3.97; 95% CI 2.29-6.87; P < 0.01). After 1 year, no differences were observed between the 2 DES for either endpoint.

For very late stent thrombosis, the ‘number needed to harm’ was 91 when using Cypher instead of Endeavor. Definite stent thrombosis was associated with 64% of the MIs observed in the first year following stent implantation and 23% of those seen beyond that point.

Long-term Follow-up Key

According to the authors, the findings are in accordance with 5-year data from the ENDEAVOR III trial, which showed that progression of MACE over time was significantly more common in patients receiving Cypher vs. Endeavor. However, in that study, less than 1% of patients experienced stent thrombosis at 5-year follow-up, with no difference between stent types.

“Therefore, our results highlight the importance of long-term follow-up in randomized studies evaluating new DES,” they write, adding that follow-up “far beyond the traditional 1-year primary endpoint, in large-scale clinical trials including all-comer patients are needed to predict the long-term outcome, especially with regard to [stent thrombosis].”

Results Unsurprising

“I don’t really think that [the findings are] surprising at all,” Stephen G. Ellis, MD, of the Cleveland Clinic (Cleveland, OH), told TCTMD in a telephone interview. “If you look at the overall body of data, it’s fair to say that second-generation DES are much safer than first-generation DES when it comes to stent thrombosis, and this study is consistent with that. It’s been clear that there was a risk of very late stent thrombosis with the first-generation stents and this is confirmation of it.”

Cypher stents are no longer being manufactured, Dr. Ellis noted, but the problem facing clinicians and patients is what to do about patients who already have been implanted with them.

“The randomized trials of antiplatelet therapy so far suggest that [overall] a shorter duration of clopidogrel is better than a long one, but there is a continuing concern about very late stent thrombosis in these [Cypher] patients,” Dr. Ellis said. “They certainly should not come off aspirin unless absolutely necessary. [Clinicians] need to be cognizant that stents that were placed several years ago still can thrombose. It’s a tricky situation, though, because typically there does not appear to be much in the way of warning signs, so I’m not sure exactly what follow-up we could even do to mitigate the risk in these patients.”

According to Dr. Ellis, it is unclear which element of Cypher is to blame for the increased risk of very late stent thrombosis. The polymer was implicated in the LEADERS study, but the same conclusion could not be reached in SORT OUT V, he indicated, adding, “It’s really hard to know what to incriminate, but my guess would be the polymer, followed by the stent, followed by the drug.”

 

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Source:
Maeng M, Tilsted H-H, Jensen LO, et al. 3-year clinical outcomes in the randomized SORT OUT III superiority trial comparing zotarolimus- and sirolimus-eluting coronary stents. J Am Coll Cardiol Intv. 2012;Epub ahead of print.

 

 

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