ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.
But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.
“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.
In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.
The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.
Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.
In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.
But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.
In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.
But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.
“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.
What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.