30 novembre, 2006 18:38

Pressure Mounts for FDA Panel to Provide "Concrete Recommendations" for DES as New Late-Stent-Thrombosis Data Published

The study, conducted by researchers at the Cleveland Clinic and appearing in the December 2006 issue of the American Journal of Medicine, was actually presented in 2005, but, according to senior author Dr Deepak Bhatt (Cleveland Clinic, OH), was largely ignored by clinicians and reporters alike.

"In fact one of our fellows, [first author Dr Anthony A Bavry] presented this meta-analysis at the 2005 American Heart Association meeting, and at the time it didn't really generate any interest, certainly not from the media but not even, for that matter, among physicians," Bhatt said. "We thought it was pretty concerning, but at the time it was met with skepticism. People thought it was a small excess risk, and they weren't convinced it was real."

Bavry et al's study combined 14 clinical trials in which a total of 6675 patients were randomized to either a bare-metal stent or a sirolimus- or paclitaxel-eluting stent (the Cypher or Taxus). The trials included the entire TAXUS trial program (five trials), the three SIRIUS studies, the RAVEL, SES-SMART, SCANDSTENT, DIABETES, and STRATEGY trials, plus one additional randomized clinical trial from Germany. The primary end point for the meta-analysis was angiographic stent thrombosis, defined as a filling defect in proximity to a previously placed stent on repeat angiography, with angiography performed either as per protocol or due to a clinical event. Of note, clinical events deemed by study investigators to be caused by thrombosis, even if not confirmed angiographically, were counted as thrombotic events.

In the combined data set, there was no statistically significant difference in the overall rate of stent thrombosis between the DES and bare-metal-stent groups (9.3/1000 patients for DES vs 9.0/1000 per 1000 for bare-metal stents). However, the risk of very late stent thrombosis (greater than one year postprocedure) was five events per 1000 in the DES-treated patients, compared with zero in the bare-metal stent group, a statistically significant difference. Examined separately, the difference in the risk of late stent thrombosis in DES-treated vs bare-metal-stent-treated patients was statistically significant for paclitaxel-eluting stents, but not for sirolimus-eluting stents, but investigators attribute this lack of significance in the sirolimus studies to the smaller numbers of patients in the SIRIUS and RAVEL trials as compared with the TAXUS trials. Of note, time to stent thrombosis was, on average, 15.5 months for sirolimus-eluting stents and 18 months for paclitaxel-eluting stents, but only four months for bare-metal stents.

Very late stent thrombosis rates (>1 year postimplantation)

*No late stent thrombosis occurred in any bare-metal-stent-treated patients

Bhatt emphasized that the absolute difference in risk between DES and bare-metal stents remains low. "We saw a four- to fivefold relative excess risk, but in absolute terms we're talking about approximately a 0.5% excess rate, so about one patient in 200 or so might have a stent thrombosis with a DES vs a bare-metal stent." The stent-thrombosis findings are largely in keeping with those of other meta-analyses presented at the TCT meeting, which looked only at the SIRIUS/RAVEL and TAXUS trial programs, as reported by heartwire.

Bhatt says he hopes the new information will "inform the debate" about DES use, particularly in light of the upcoming FDA discussions.

"I know there has been a lot of heat and noise, with some folks saying there is no problem with stent thrombosis at all and others saying that it's an epidemic and people are dropping dead. I think our paper is taking the middle ground and saying there's a definite hazard here, but in terms of degree of hazard it's not that high for the individual patient. Unless, of course, you're the patient who has stent thrombosis. Then it's a big deal."

Asked what his expectations are for next week's FDA panel meeting, Bhatt said he expects the committee to address the issue of appropriate dual-antiplatelet-therapy duration, and, hopefully, reach some consensus on the degree of risk with DES in the types of patients currently undergoing DES implantation. "I don't have any predictions, but I'll tell you I am looking for some guidance. I'm hoping that they do come out with some concrete recommendations on what to do."

He added that while interventional cardiologists may be preoccupied with the DES safety debate, other physicians are unaware of the issue, a situation that sometimes leads to unwarranted stoppage of dual antiplatelet therapy.

"Even now I see patients who had DES placed, then had some kind of minor procedure for which both their aspirin and clopidogrel were stopped. This is a purposeful decision, and it might be the right thing to do in some cases, but I think most of the time these decisions are uninformed. And those are the folks who really need to know these data, and hopefully publishing a study like this in the American Journal of Medicine will reach the noncardiology audience as well as the cardiology audience. I think that's also one benefit of the FDA having this meeting--that it will reach a very broad audience."

1. Bavry AA, Kumbhani DJ, Helton TJ et al. Late thrombosis of drug-eluting stents: a meta-analysis of randomized clinical trials. Am J Med 2006; 119: in press.
2. 2. Chen MS, John JM, Chew DP, et al. Bare metal stent restenosis is not a benign clinical entity. Am Heart J 2006; 151:1260-1264.