PROTECT: No Difference in Stent Thrombosis With Endeavor and Cypher Stents

August 27, 2012

August 27, 2012 (Munich, Germany) — There is no difference in the incidence of stent thrombosis among patients treated with the Endeavor zotarolimus-eluting stent (Medtronic) and the Cypher sirolimus-eluting stent (Cordis/Johnson & Johnson), according to the results of a new study [1].

At three years, the rate of definite or probable stent thrombosis among the Endeavor- and Cypher-treated treated patients was 1.4% and 1.8%, respectively, a difference that was not statistically significant. In a time-specific analysis, the rate of definite or probable stent thrombosis was similar between both stents in the first 30 days, but higher among the Endeavor-treated patients between one month and one year. In contrast, the rate of stent thrombosis was higher among the Cypher-treated patients between one and three years.

Dr William Wijns

Presenting the results of the study, known as the Patient Related Outcomes with Endeavor versus Cypher Stenting Trial (PROTECT) today at the European Society of Cardiology (ESC) 2012 Congress in Munich, Germany, Dr William Wijns (Cardiovascular Center Aalst, Belgium) said that the trial retains its significance despite both stents no longer being widely used in clinical practice.

"Hundreds of thousands of patients have been implanted with these permanent devices, so from a patient perspective, data like these on long-term safety are essential," Wijns told the media during the ESC press conference. "From a physician's perspective, the hypothesis of the trial was a comparison between two devices with very different antiproliferative properties."

The Cypher stent, he explained, is known to have an increased risk of late stent thrombosis compared with bare-metal stents, while the vascular healing response of the Endeavor stent is closer to that of bare-metal rather than other drug-eluting stents, thus reducing the risk of very late stent thrombosis. "From a mechanistic viewpoint, the study shows, and this is very relevant from a physician's perspective, that the trade-off between efficacy and safety is different when comparing first-generation drug-eluting stents with bare-metal stents vs two different drug-eluting stents."

In an editorial accompanying the study [2], Drs Robert Byrne, Adnan Kastrati, and Jörg Hausleiter (Deutsches Herzzentrum, Munich, Germany) praise the researchers for conducting the trial and for having the conviction of waiting three years to fully look for differences between the Endeavor and Cypher stents, even though a shift in usage has seen both stents largely fallen out of favor worldwide.

"This shift undoubtedly limits the immediate clinical relevance of these findings. However, the data remain of interest to physicians caring for the millions of patients already treated with these stents," write the editorialists.

The study, with lead investigator Dr Edoardo Camenzind (University of Geneva, Switzerland), and the editorial are now published online in the Lancet to coincide with the ESC late-breaking clinical-trials sessions.

PROTECT Powered to Detect Stent-Thrombosis Differences

The PROTECT open-label study included 4357 patients randomized to treatment with the Endeavor stent and 4352 patients randomized to receive the Cypher stent. The trial used broad inclusion criteria, randomizing patients 18 years or older who were undergoing stenting for elective, unplanned, or emergency procedures in native coronary arteries. The study was designed as a superiority trial and based on the hypothesis that the Endeavor stent, which has more potent antiproliferative properties, would be superior to treatment with the Cypher stent for the reduction in stent thrombosis. Most important, the study was powered to detect significant differences in the rate of stent thrombosis between the two drug-eluting stents.

After the stenting procedure, all patients were treated indefinitely with aspirin and prescribed thienopyridine therapy for a minimum of three months and as long as one year (or longer based on physician discretion).

Despite the different vascular healing responses between the two stents, the rate of definite or probable stent thrombosis was equivalent after three years. In terms of the main secondary end points, which looked at different combinations of death and cardiac death with nonfatal MI, including large nonfatal MI, there was no difference between the Endeavor and Cypher stents. The rate of definite stent thrombosis was lower in the Endeavor-treated patients compared with those who received a Cypher stent (0.7% vs 1.2%; p=0.03) while target lesion revascularization (TLR) was lower in the Cypher-stent arm than in the Endeavor arm (3.5% vs 5.6%, p<0.0001).

"The lesson we've taken from these results is that large pragmatic trials such as PROTECT are essential to determine differential outcomes between drug-eluting stents," said Wijns, "and also they're needed if we want to capture the impact of improved procedures in clinical practice on stent-thrombosis rates over time." The PROTECT investigators also observed a difference in the rate of definite or probable stent thrombosis over time, with a higher rate of late stent thrombosis in the Endeavor-treated patients compared with a higher rate of very late stent thrombosis in the Cypher arm. The researchers note that just four cases of stent thrombosis were reported in the Cypher arm between 30 days and one year, a period when more than 85% of patients were treated with dual antiplatelet therapy. The rate of stent thrombosis increased substantially once dual antiplatelet therapy decreased to less than 40% between one and three years. In contrast, the rate of stent thrombosis decreased over time in the Endeavor-treated patients, even though the use of dual antiplatelet therapy was also decreasing.

For the PROTECT investigators, this suggests that the use of dual antiplatelet therapy has a very different long-term clinical relevance according to the type of stent used.

In their editorial, however, Byrne, Kastrati, and Hausleiter caution that a temporal analysis of these data is inadvisable, as there was no difference between the stents in terms of the primary end point or in any of the main secondary end points, so the probability of a chance finding is high. While the editorialists are reluctant to accept such conclusions without further evidence, they say there is little doubt the Cypher stent is associated with some incidence of device-specific late hypersensitivity reactions, which can cause stent thrombosis. Overall, they say the device's safety profile is good, and "it has proven a difficult, if not impossible, comparator to beat." The findings of PROTECT are in line with previous efficacy analyses between the two stents, including studies with clinical and angiographic end points, they add.