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Update to FDA Statement on Coronary Drug-Eluting Stents

On September 14, 2006, FDA issued an initial statement related to concerns about adverse events related to coronary drug-eluting stents (DES). The statement noted that new data suggested a small but significant increased risk of stent thrombosis in patients who have been treated with the currently approved DES (the CYPHER stent and the TAXUS stent). FDA has made detection of DES thrombosis signals a priority because of the potential for serious harm to patients—even though stent thrombosis occurs at low rates. While the new data raised important questions, the Agency did not have enough information to draw conclusions. FDA announced plans to convene a public panel meeting of outside scientific experts to assist us in a thorough review of all available data and make recommendations about what actions may be appropriate, such as possible labeling changes or additional studies.

On December 7 and 8, 2006, the Circulatory System Devices Advisory Panel met in an effort to fully characterize the risks, timing and incidence of DES thrombosis. The purposes of this meeting were: (1) to provide a forum for the presentation of clinical data relevant to the issue of DES thrombosis (both when DES are used according to their label and in more complex patients beyond their labeled indication) and (2) to address the appropriate duration of antiplatelet therapy (aspirin plus clopidogrel) in DES patients. Panel members and public speakers represented a broad spectrum of interest and expertise including interventional cardiologists, non-interventional cardiologists, cardiovascular surgeons, biostatisticians, and the DES manufacturers.

In response to specific questions posed by FDA, the Panel had the following recommendations regarding DES when they are used in accordance with their approved indications:

Both approved DES are associated with a small increase in stent thrombosis compared to bare metal stents that emerges 1 year post-stent implantation.
However, based on the data available, this increased risk of stent thrombosis was not associated with an increased risk of death or myocardial infarction (MI) compared to bare metal stents. This finding may be due to (1) an insufficient number of patients in currently available studies; or (2) an increase in deaths or MI's was offset by a reduction in events associated with in-stent restenosis and additional revascularization procedures.
When compared to bare metal stents, DES are not associated with an increased rate of all-cause mortality.
The concerns about thrombosis do not outweigh the benefits of DES compared to bare metal stents when DES are implanted within the limits of their approved indications for use.
Larger and longer premarket clinical trials and longer follow-up for post-approval studies are needed, using uniform definitions of stent thrombosis and close attention paid to patient compliance with antiplatelet therapy.

The Panel was also asked to address the broader use of DES in patients with more complex patients and coronary lesions compared to those patients studied to support initial marketing approval. The use of a drug or device outside the FDA-approved indications is known as “off-label use” Although FDA regulates the manufacture, labeling, and promotion of devices, we do not regulate how they are used by individual clinicians in the practice of medicine. However, FDA may take action if safety issues with any use of a device become a public health concern. We felt that DES safety associated with off-label use should be included in the Panel’s deliberations given observations that at least 60% of current DES use is off-label. The Panel had the following comments and recommendations:

With more complex patients, there is an expected increased risk in adverse events. The Panel agreed that off-label use of DES is associated with an increased risk of stent thrombosis, death or MI compared to on-label use.
The available data were insufficient to determine whether the increased risk in adverse events with off-label use was the same or different between the two currently approved DES.
Data on off-label use are limited, and additional studies are needed to determine optimal treatments for more complex patients. Until more data are available, the DES labels should state that when DES are used off-label, patient outcomes may not be the same as the results observed in the clinical trials conducted to support marketing approval.

Regarding the duration of antiplatelet therapy:

Data from several studies suggests that a longer duration of antiplatelet therapy than is currently included in the CYPHER and TAXUS labeling may be beneficial.
The optimal duration of antiplatelet therapy, specifically clopidogrel, is unknown and DES thrombosis may still occur despite continued therapy.
The labeling for both approved DES should include reference to the ACC/AHA/SCAI PCI Practice Guidelines, which recommend that patients receive aspirin indefinitely plus a minimum of 3 months (for Cypher patients) or 6 months (for TAXUS patients) of clopidogrel, with therapy extended to 12 months in patients at a low risk of bleeding.

Following this meeting, FDA has been carefully considering the new data presented at the meeting, the opinions from public speakers, and the Panel’s deliberations and recommendations. We will be working closely with the manufacturers of both approved DES and other DES still under study to incorporate appropriate modifications to labeling and changes to pre- and post-approval studies. Additionally, we will continue to work with professional societies, consumer organizations, and health care providers to provide physicians and patients with the most updated information as quickly as possible.

Update to FDA Statement on Coronary Drug-Eluting Stents

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