• There was a general agreement that DES, when used in accordance to their FDA approved labeled indications, are associated with a clinically important numerical excess of late stent thromboses (1 year post-implantation) compared to BMS; however, the magnitude of this excess is uncertain and additional data are needed.

• Based on the analyses presented by Boston Scientific and Cordis, it was concluded that DES are not associated with an increased risk of death or myocardial infarction (MI) compared to BMS, despite an apparent increase in stent thrombosis rates after 1-year post-DES implantation. This finding may be due to (1) insufficient sample size in currently available studies; or (2) that an increase in death and MI secondary to DES thrombosis might be offset by a reduction in death and MI associated with in-stent restenosis and additional revascularization procedures in DES patients.

• The panel agreed that when compared to BMS, DES are not associated with an increased rate of all-cause mortality. The panel requested longer-term follow-up and an increased number of patients in future trials.

• The panel was in agreement that the safety concerns discussed applied equally to the currently approved DES.

• The panel reached consensus that the DES safety concerns do not outweigh their benefits compared to BMS when used within the limits of the approved labeling.

• The panel discussed different options to modifying the labeling for the approved DES.

• The panel was in consensus that the DES labeling should reference the ACC/AHA/SCAI PCI Practice Guidelines for duration of antiplatelet therapy following DES implantation.
  
• The Panel recognized that with more complex patients, there is an expected increased risk in adverse events in these subsets. The panel generally agreed that off-label use of DES is associated with an increased risk of stent thrombosis, death and MI when compared to on-label use of DES. The Panel did not find sufficient data were available to identify subsets of patients as at a particularly increased risk.

• The panel agreed that at least 12 months of dual antiplatelet therapy should be recommended for off-label uses of DES.

• The panel was unanimous that insufficient available data precluded an opinion regarding whether concerns related to off-label use were similar between the currently approved DES.

• The panel was in agreement that the data on off-label use are limited and recommended that the DES labeling state that results from off-label use of DES should not necessarily be expected to be the same as the results from the clinical trials conducted to support marketing approval.

• The panel called for larger and longer premarket clinical trials and longer follow-up for post-approval studies, with specific definitions related to stent thrombosis events, and more attention paid to patient monitoring and patient compliance with antiplatelet therapy.

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1b) DES and Vessel Healing

Restenosis is Checked - Is Longer Term Vascular Healing at Risk?
DES significantly reduce the possibility of restenosis, but can also lead to delayed or incomplete vascular healing. Dr. William Wijns, MD has presented an overview of current safety concerns with DES, and a timeline and predictive factors for stent thrombosis (discussed below). Dr. Wijns noted that post-implantation delayed healing is observed with DES up to one year, and that up to two years sequential IVUS virtual histology has demonstrated that plaque size can change behind stent struts.

According to Dr. Wijns DES led to inflammation, allergic reactions and lack of endothelialization. He also noted that bare metal stents and DES appear to induce different responses. Functional studies of endothelium-dependent vasomotion show abnormal vasoconstriction with DES, but not BMS. In terms of stent thrombosis, Dr. Wijns described that BMS and DES exhibit similar characteristics during the first month, within which thrombosis generally occurs early and there is no significant difference between the two stent varieties. This trend continues as there is no significant difference in late stent thrombosis up to one year for today's commercially available DES (0.53%) and BMS (0.53%). A head-to-head study between the Cypher and Taxus stents shows no difference in late stent thrombosis rates between the two.

Dr. Wijns suggests that one must look beyond one year to find that "very late" stent thrombosis occurs more frequently in DES vs. BMS, although to better understand this issue more adequate trials are necessary. He suggests a consensus on study endpoints and their definitions, independent data analysis of all patient data, and adequately-sized trials focusing on safety, efficacy and quality of life endpoints.

Planned Studies-
Appropriately, three new studies have been announced to help better characterize the long-term effects of DES. Gregg Stone, MD, Chairman of the Cardiovascular Research Foundation and Professor of Medicine at Columbia University Medical Center in New York, notes that these studies are needed to better understand the risks and benefits of DES treatment. The announced studies include:

• STENT Thrombosis - This study will examine 10,000 consecutive DES patients at 12 centers as compared to 30,000 control patients. A two to five year follow-up period is planned.
• INSIGHT - This 30,000-patient global registry will look at the use of standard versus long-term clopidogrel use in DES patients.
• PROTECT - This study will compare the Endeavor (Medtronic) DES to the Cypher (Cordis / J&J) DES in a randomized, international trial of 8,000 patients with a primary endpoint of in-stent thrombosis.

• Premature discontinuation of antiplatelet therapy
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