FDA panel: Drug-eluting stents safe if used as labeled

A much-publicized risk for late stent thrombosis is primarily confined to off-label use and warrants further study.

An FDA advisory panel concluded that drug-eluting stents present no greater risk for late stent thrombosis than bare metal stents, given the available data. Newer stents should stay in use with continued caution about off-label use, the panel said.

The Circulatory System Devices Panel heard two days of testimony and data from physician researchers, advocacy groups and two major manufacturers as members sought to answer the safety question posed by recent reports of increased risk for stent thrombosis with drug-eluting stents.

“There appears to be a risk for adverse outcomes for drug-eluting stents, but it is not clear that it is any worse for drug-eluting stents than it is for bare metal stents,” George Vetrovec, MD, chairman of the division of cardiology at the Medical College of Virginia, told Cardiology Today.

Vetrovec, who served as a panel member at the hearing and is an editorial board member of Cardiology Today’s Interventional Cardiology section, said his views are not necessarily representative of FDA policy.

The FDA routinely convenes advisory panels for expert advice, but often these panels are asked to vote on a proposed indication for a new drug or device. Vetrovec said the panel did not take a vote at this meeting.

However, the panel recommended that physicians remain cautious about off-label use, that patients continue clopidogrel (Plavix, Sanofi Aventis;Bristol-Myers Squibb) for up to one year, and that a better definition and further study of the risk for stent thrombosis is needed.

“One of the complications of a meeting like this is that the FDA does not regulate medical practice, so any suggestions of a black box warning about off-label use, for example, would be immaterial,” Vetrovec said.

FDA policy

Following the meeting, the FDA released the following updated statement: “The FDA believes that coronary drug-eluting stents remain safe and effective when used in patients having clinical and coronary anatomic features similar to those treated in the pivotal trials conducted by the manufacturers for FDA approval.

“New data were released recently that suggest a small but significant increased risk for stent thrombosis in patients who have drug-eluting stents. The agency is keenly interested in this issue because of the potential for serious harm to patients — even though stent thrombosis occurs at low rates.

“Although the new data are of interest to the FDA and raise important questions, we do not have enough information yet to draw conclusions. It is unclear, for example, what causes drug-eluting stent thrombosis, how often it occurs, under what circumstances it occurs or what the risk for occurrence is in a given patient.

“The FDA has been monitoring coronary drug-eluting stents closely since they came on the U.S. market in 2003 and 2004, and will continue to do so.”

There are currently two approved drug-eluting stents, with a number of others in development. The sirolimus-eluting stent (Cypher, Cordis) is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of no more than 30 mm in native coronary arteries with reference vessel diameter of at least 2.5 mm but no more than 3.5 mm.

Paclitaxel-eluting stents (Taxus, Boston Scientific) are indicated for improving luminal diameter in the treatment of de novo lesions no more than 28 mm in length in native coronary arteries of at least 2.5 mm, but not greater than 3.75 mm in diameter.

During the meeting, the FDA panel heard presentations from Cordis and Boston Scientific representatives who used stent thrombosis definitions from the Academic Research Consortium. This includes definite stent thrombosis, defined as confirmation of thrombosis by angiogram or autopsy at follow-up; probable, defined as an MI in the treated vessel in patients who did not have an angiographic confirmation of a thrombosis; and possible, defined as sudden, unexplained death that cannot be attributed to another cause.

Bare metal stent risk

Under this definition the stent thrombosis rate at four years was 3.5% (30/848) among patients treated with the sirolimus-eluting stent and 3.3% for the bare metal comparator stents (28/843), which was not a significant difference (P=.894).

Similar results were seen for the paclitaxel-eluting stents. Patients treated with paclitaxel-eluting stents had a 3.5% rate of stent thrombosis compared with 3.6% with bare metal stents (P=.84).

George Vetrovec

“There was a lot of discussions about these findings because, as of yet, we do not have a clear definition of stent thrombosis, but it was agreed that the ARC definitions probably captured as many as possible,” Vetrovec said.

Although the panel was persuaded that the risk for stent thrombosis in on-label use was no greater than that seen with bare metal stents, the question of off-label use still loomed.

Unanswered questions

“The problem with the question of off-label use is that there are no comparator data in these patients. It’s all registry data, so we don’t know for certain that there is an increased risk,” Vetrovec said.

At least one panel member suggested putting all patients with stent thrombosis into a registry, but the rate of events is still low and it is not clear how many of these patients developed stent thrombosis due to clopidogrel resistance rather than any side effect of the drug-eluting stent, Vetrovec said.

The FDA panel also weighed in on the question of clopidogrel duration. David F. Kong, MD, a cardiologist at Duke University, presented data that suggested physicians consider clopidogrel use beyond six months.

The researchers followed 4,666 consecutive patients with drug-eluting and bare metal stents. At two years, there was a 3.1% rate of mortality and MI among drug-eluting stent patients taking clopidogrel and a 7.2% rate of the same events among those not taking clopidogrel. The death and MI rates for bare metal stent patients were 5.5% and 6% with and without clopidogrel, respectively.

“The panel was reluctant to endorse lifetime antiplatelet therapy because of the bleeding risk, and there are still some data from sets other than what was seen at Duke that show some patients have risk for stent thrombosis in the presence of dual antiplatelet therapy,” Vetrovec said.

Vetrovec said the attention focused on the FDA panel would help make cardiologists and other physicians aware of the potential risk for late stent thrombosis, but it was unlikely to cause these doctors to stop using the drug-eluting stents.

“The risk for restenosis with bare metal stents is so substantial compared with what we see with drug-eluting stents that physicians are still likely to use the newer devices,” Vetrovec said. – by Jeremy Moore

Dr. Vetrovec is a paid consultant for Johnson & Johnson and owns stock in Bristol-Myers Squibb and Johnson & Johnson.