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Updated December 7, 2006

FDA Statement on Coronary Drug-Eluting Stents (September 14, 2006)

FDA is providing the following information in response to inquiries asking for the agency’s position on adverse events related to coronary drug-eluting stents (DES). This information describes our position at this time and does not represent new agency policy.

FDA has been closely monitoring DES since they came to the United States market in 2003 and 2004 – and will continue to do so.

We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES. The specific studies that have prompted recent media inquiries are the BASKET-LATE study (presented at the March 2006 American College of Cardiology Scientific Sessions in Atlanta, Ga.) and more recently, the Camenzind meta-analysis (presented at the September 2006 European Society of Cardiology Annual Meeting/World Congress of Cardiology Meeting in Barcelona, Spain). The small but significant increase in the rate of death and myocardial infarction observed in these studies was noted in patients followed 18 months to 3 years after stent implantation.

While the studies presented at the Atlanta and Barcelona meetings have raised important questions, the data we currently have do not allow us to fully characterize the mechanism, risks, and incidence of DES thrombosis. A more formal evaluation of the data in these studies is necessary, and any conclusions are dependent upon a thorough peer review. FDA intends to more formally evaluate the studies presented in Atlanta and Barcelona.

Stent thrombosis in patients who receive DES is a primary area of interest for the agency because of the potential for serious adverse outcomes—even though stent thrombosis occurs at low rates. Over the past two months, the agency has met with both manufacturers of the FDA-approved approved DES to discuss any information and perspectives they have that may be pertinent to this issue. In assessing the risk of stent thrombosis, we remain keenly interested in the long-term follow-up of patients enrolled in the original pivotal DES randomized trials as well as those in the more complex patient and lesion subsets (for example, patients with diabetes; acute myocardial infarction or multiple vessel disease; or lesions involving arterial bifurcations, the left main coronary artery, and long arterial segments) who are currently being treated in “real world” randomized and registry studies. 

FDA also continues to closely evaluate information related to the duration of treatment with clopidogrel (Plavix), a drug used in combination with aspirin to reduce/prevent clotting in DES patients.  Although the duration of clopidogrel appeared to be adequate for the selected patients in the original clinical trials conducted to support FDA approval, the agency recognizes that the optimal duration of clopidogrel in more complex patients has not been defined.  The recommended duration of clopidogrel administration and patient compliance with the prescribed regimen are likely interrelated with patient and anatomical factors that are associated with DES thrombosis.  Additional clinical data are likely needed to reach conclusions regarding the optimal antiplatelet therapy regimen for DES patients.

FDA will convene a public meeting of the Circulatory System Devices Advisory Panel by the end of the year in an effort to improve our knowledge regarding the incidence and timing of stent thrombosis as well as the appropriate duration of clopidogrel use in patients who receive DES. This Panel of outside experts will assist the agency in the review and analysis of the available scientific data and provide recommendations for appropriate actions to address this issue, such as possible changes to device labeling or the need for additional clinical studies. An announcement of this meeting will appear on FDA’s web site, www.fda.gov/cdrh.

At this time, FDA believes that coronary DES 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. The approved indications are:

• The CYPHER Sirolimus-eluting Coronary Stent is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of length = 30 mm in native coronary arteries with reference vessel diameter of =2.5 mm to =3.5 mm.

• The TAXUS Express Paclitaxel-Eluting Coronary Stent System is indicated for improving luminal diameter for the treatment of de novo lesions =28 mm in length in native coronary arteries =2.5 to =3.75 mm in diameter.

For more information, see http://www.fda.gov/cdrh/pdf2/P020026.html and http://www.fda.gov/cdrh/pdf3/P030025.html.

For thousands of patients each year, these devices have resulted in a significant reduction in the need of second procedures to treat restenosis. The FDA will continue to carefully evaluate all DES data in an attempt to maximize the benefits and minimize the risks for patients undergoing this therapy for treatment of their coronary artery disease.

To summarize:

• 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.

• New data were released recently that suggest a small but significant increased risk of 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.

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

• To better understand this issue, FDA met with the two manufacturers of these products in recent months to discuss any information they might have pertaining to this issue and get their perspective. In addition, we plan to convene a public panel meeting of outside scientific experts in the near future to assist us in a thorough review of all the data and make recommendations about what actions may be appropriate, such as possible labeling changes or additional studies.

At this time, FDA believes that coronary drug-eluting stents remain safe and effective when used for the FDA-approved indications. These devices have significantly reduced the need for a second surgery to treat restenosis for thousands of patients each year.

For further information, see Questions and Answers on Coronary Drug-Eluting Stents.

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.

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