July Monthly Topic:

FDA’s Forthcoming Guidance for Regulation of Drug Eluting Stents
in Atmosphere of Controversy Over Late Stent Thrombosis

Against the backdrop of impending FDA guidance specifically addressing drug eluting stents (DES), as well as shrinkage in U.S. market penetration of DES from about 90% to 65% over the past year, stent makers, both established and newly arrived, are releasing re-analyses, registry data, and safety data for their marketed products as well as for products under investigation, including next-generation stents.(1)  While FDA signaled its intent, in early 2005, to release a guidance aimed at premarket guidelines,(2) two years later it has previewed, but not yet released the anticipated guidance that is likely to have a broader scope, including changes both in premarket and postmarket policies.  “The guidance has become a vehicle for regulators to respond to elevated concerns about thrombosis.”(3)

Increases in the incidence of stent thrombosis, estimated to be on the order of about 0.5% for DES as compared to bare metal stents (BMS), appear to occur between 12 and 24 months, rather than in the usual, earlier post-operative window for this adverse event in patients implanted with BMS.(4)   Given the nature, delayed onset, and frequency of these events, FDA officials reportedly indicated in the February 12, 2007 issue of the New England Journal of Medicine that larger studies with longer patient follow-up, focusing on clinical safety endpoints such as death and myocardial infarction, will be needed to assess the risks and benefits of DES. (5)

FDA convened an advisory panel meeting in December 2006 to weigh the risks and benefits of DES in light of data then available.  The panel generally concluded that when DES are used for on-label indications, their benefits outweigh their risks, and that there are no increases in incidence of death or heart attack.  The panelists highlighted that DES are accompanied by a 50%-70% reduction in revascularization procedures necessitated by in-stent restenosis in patients treated with Boston Scientific’s paclitaxel-eluting stent and Johnson & Johnson/Cordis’ sirolimus-eluting stent.  Nevertheless, panelists were worried that very long term events, such as thromboses in years 5 and 6 post-operatively, might overwhelm the benefits of restenosis reduction.

At this time, the consensus is that much remains to be learned.(6)(7)  To assist in this effort, studies should be conducted using standardized definitions of outcomes.  Prior study data have already been re-analyzed using a standardized definition of thrombosis proposed by the Academic Research Consortium (ARC), a body of cardiologists, researchers, FDA staffers and stent manufacturers.  Cordis indicated that FDA required the ARC definition to be used for all data to be presented at the December 2006 advisory panel meeting.(8)  FDA officials say that they are working on developing recommendations for clinical trial programs that will help answer some of the important questions.  The consensus is that studies should be conducted to determine optimal duration of antiplatelet therapy and real-world benefits and risks of DES in populations not studied in the randomized pivotal clinical trials – such as diabetics, patients with multivessel disease, and those with other comorbidities.  Estimates for DES use outside of FDA-approved indications range from 50%-80%.  Garnering the needed information might include conducting large trials and setting up registries.  Who would pay for this research activity is an unanswered question.(9)