FDA warns of adverse effects from use of drug-eluting stent

Negative reactions taint Cordis product

The safety of drug-eluting stents was called into question Oct. 29, when the FDA issued a warning that one such device, the only one approved for sale in the U.S., can cause clotting and death.

Its manufacturer, Cordis, a subsidiary of Johnson & Johnson, has shipped about 450,000 units of the product, called Cypher. They have been implanted in 300,000 patients, about 60% of them in the U.S. Some have been accompanied by severe adverse effects.

The FDA has received more than 290 reports of thrombosis occurring within 30 days after implanting Cypher. At least 60 resulted in death. The remaining patients suffered injury requiring medical or surgical intervention.

The agency has also received more than 50 reports of possible hypersensitivity reactions, some leading to death. Symptoms included pain, rash, respiratory problems, hives, itching, fever, and changes in blood pressure.

The FDA warning at the end of October is the second time the medical community was cautioned about the Cordis stent. The first warning came July 8 from Cordis in a letter stating that the FDA had received 47 Medical Device Reports (MDRs) of stent thrombosis occurring within a few days of implantation. At the time, more than 50,000 patients had been implanted with the stent.

"It was noted there was a risk of rare cases of thrombosis," said Rochelle Ellis, an analyst with Front Line Strategic Consulting in San Mateo, CA. "The doctors we interviewed were aware of this, and they said it didn't affect the use of the product."

Ellis was the lead analyst for a report on drug-eluting stents published days before the October FDA warning. The report predicted that sales of the stents would triple in the next five years from $2.1 billion this year to $6.3 billion by 2008. Leading this growth would be the U.S. market, according to the report.

The October FDA warning, however, could affect those numbers, Ellis said. How much is hard to gauge.

"Obviously, this warning was more intense (than the previous one) and will have more negative consequences, but at this point it is unclear if the thrombosis rate (for drug-eluting stents) is any different from that for bare metal stents," she said.

The rate of clotting is between 1% and 2% for conventional stents, according to reports about these products. That's about 10 times more frequent than the adverse reactions reported to the FDA regarding the Cordis product.

The 50-plus cases of hypersensitivity, however, have some in the medical community concerned. Prior to the FDA warning, hypersensitivity was believed to be extremely rare, if a threat at all.

The Cypher stent is coated with a thin polymer containing the drug sirolimus, an immunosuppressant intended to reduce restenosis. The drug, some suspect, could be the source of the hypersensitivity.

Although the Cypher is the only drug-eluting stent now available in the U.S., others are being readied for market. Boston Scientific expects its Taxus product to be commercially available by the end of this year or early next. Medtronic is targeting the launch of its own such product for Europe late next year and the U.S. in late 2005. Guidant could have one out sometime in 2006, according to Ellis.

For some patients, such as those with blockages in multiple vessels, drug-eluting stents may offer an alternative to bypass surgery. Demand for this technology will be bolstered by increased reimbursement rates from the Centers for Medicare and Medicaid and private third-party payers. Rising demand and increasing reimbursement will make the U.S. the dominant market for drug-eluting stents, accounting for more than 70% of sales by 2008, according to Front Line. The total market size in the EU will be relatively small, hindered by pricing limits and lower reimbursement rates overseas.

The FDA warning will likely affect sales in the U.S. How much depends on what is found to be causing the adverse effects.

The FDA and Cordis are working together to examine the circumstances surrounding events reported in the U.S. The agency is also working with foreign regulators to get information about any such events overseas that may have involved Cypher. Investigators are looking particularly at product characteristics, patient characteristics, and procedural factors that might be involved in adverse outcomes.

"Until the FDA gets to the root of the problems, the agency is encouraging doctors to follow the instructions for use of the stent, and urging them to be vigilant for any patient symptom that may be attributed to hypersensitivity," the FDA warning said.

Investigations using intravascular ultrasound have found that stents are often poorly deployed or underexpanded. Both of these factors could predispose a patient to subacute thrombosis, whether a stent is bare metal or drug-eluting. Research suggests that the risk for thrombosis due to stent implantation may be higher for certain patient types, such as those receiving bifurcational stenting in both the parent and branch vessels.

The FDA request that practitioners pay attention to instructions for use of the stent alludes to the already burgeoning off-label use of the product. Physicians are directed to use Cypher to improve the diameter of coronary arteries with diminished blood flow. It shouldn't be used to treat patients with restenosis, acute myocardial infarction, saphenous vein graft lesions, or bifurcation lesions. But reports indicate that the stent is being used for these purposes.

This may be one reason sales of Cypher have taken off. If the medical community becomes wary of such practices, it could foretell a moderation in the sale of what has been a blockbuster new product.