In the wake of late-October reports of adverse events with Cordis' (Miami Lakes, Florida) Cypher drug-eluting stent, the Johnson & Johnson (New Brunswick, New Jersey) unit sponsored a webcast in early December that included prominent interventional cardiologists as well as a top executive from the company. The group was assembled to discuss the recent reports of sub-acute thrombosis (SAT) and hypersensitivity associated with the Cypher stent, and surgeons discussed personal patient experiences at their respective centers. Cordis also presented clinical findings on the issue and addressed the latest FDA clarification that was posted online Nov. 25, 2003.

In October, the FDA issued a public health notification reporting on a variety of adverse events associated with use of the Cypher, the first drug-eluting stent approved for marketing in the U.S. These adverse events include more than 60 deaths associated with thrombosis following stent placement, the agency said at the time. The FDA noted that reports were first received by its Medical Device Reporting (MDR) system shortly after approval of the stent in April. It added that as of Oct. 20, it had received more than 290 reports involving SAT associated with use of the stent. The term "sub-acute" was defined as an occurrence of thrombosis between 24 hours and 30 days, post-procedure.

Dennis Donohoe, MD, vice president of clinical and regulatory affairs for Cordis, discussing the clinical and preclincal experience with the Cypher as well as the real-world thrombosis rates in everyday practice, said that the all the available data suggest that the rate and timing of stent thrombosis is not significantly different between the Cypher and bare-metal stents, although he acknowledged that a small number of institutions in the U.S. reported a higher-than-expected SAT rate with the Cypher. All the data, Donohoe said, "does not show a difference in rate of sub-acute stent thrombosis between a Cypher stent and that expected for bare-metal stents. Nor does it show a difference in terms of risk factors or the timing of the stent thrombosis." He said that conclusion is based on the company's 10,000-patient clinical data set, plus data collected from independent institutions using the Cypher stent.

If that is the conclusion, the obvious question is why then did the FDA issue its public health notification back in July and why did Cordis issue a "Dear Colleague" letter to physicians warning them about a possible association between SATs and the use of the Cypher stent? Donohoe's answer: "Since this was a brand-new technology seeing very rapid adoption, it was in the best interests of physicians and patients to inform them of this with three specific instructions." These, he said, were "proper use of stent in terms of deployment, proper use of antiplatelet therapy as well as proper patient selection."

The FDA appears to agree with Donohoe's assessment for now. In a web notification update on Nov. 25, the agency said it wants to be sure physicians and their patients understand that, based on current information, it considers the Cypher a "safe and effective product when used according to the labeling, particularly concerning patient selection and appropriate peri-procedural medications." The agency noted that the rate of sub-acute thrombosis associated with any stent is highly dependent on the population in which they are used. Reports received through the MDR system, which the FDA noted is subject to "significant underreporting," reflect use of the Cypher stent in a diverse population.

Between Oct. 20 and Nov. 22, the FDA said it received 75 additional MDR reports (for a total of more than 360 to date) of SAT associated with the stent. In that same time period, Cordis distributed about 125,000 Cypher stents (for a total of more than 575,000 to date). Based on its review of data supporting the Cypher stent from clinical trials (some of which included treating more complex lesions), the FDA said it appears that the rate of SATs is within the expected rate for any stent. As to the issue of hypersensitivity reactions, in most cases reported to the FDA, hypersensitivity seen with implantation of the stent was minor (e.g., skin rashes and itching that cleared up within a few days of onset), but there were some severe reactions (including anaphylaxis). "Although some of the reactions we have observed so far remain unexplained, many of the reactions are believed to be events related to standard drug therapy associated with the procedure," the agency said.

Donohoe said that the instructions that the FDA and Cordis supplied to physicians to ensure proper deployment of the Cypher and proper use of anti-platelet therapy with on-label use of the stent "is still an important message for physicians to realize." He also added that the company believes that the relatively limited availability of the Cypher during its initial U.S. release may have contributed to the risk of thrombosis "in that not all sizes were available." He said that he believes that the release of the 3.5 mm diameter Cypher has helped to decrease the overall rate of SAT with the device since July. As an added precaution, the company is instituting another registry of about 1,500 patients based on angiograms performed so if a thrombotic episode occurs the company will be able to conduct a detailed analysis and possibly identify other procedural items that may help physicians reduce their chance of thrombosis.

Eric Topol, MD, chairman of the department of cardiovascular medicine at the Cleveland Clinic (Cleveland, Ohio) noted that the overall incidence of SATs is very low, less than .05%, or about one in 2,000 patients. While he said this is good news, he believes that doctors in the U.S. are entering a "zone of uncertainty." He noted that "we don't know for sure whether there's any difference of the instances of thrombosis, whether it be in the first 30 days or even late, with bare or with coated stents of any kind." While he acknowledged that there is still a bit of uncertainty, he praised the company for taking the initiative with the device. "Cordis should be commended because they have been all over this," Topol said.

SCAI program to use Simsuite System

The Society for Cardiovascular Angiography and Interventions (SCAI; Bethesda, Maryland) said that it will provide a training program for its 3,000 invasive and interventional cardiologist members using the SimSuite System developed by Medical Simulation (MSC; Denver, Colorado). The program, it said, supports SCAI's commitment "to offering advanced training methods focused on the benchmarking of interventional skills that can familiarize physicians with new procedures and help them maintain standards of quality, including those measured by periodic board exams."

John Hodgson, MD, SCAI president and director of the Invasive Cardiology Section at MetroHealth Medical Center (Cleveland, Ohio), said, "The Society has been following the development of the SimSuite Education System and is convinced that this training method is on the cutting edge. With the SimSuite System, we are leading the way in continuing medical education offering our members a practical and innovative means to improve the quality of care they provide."

David Holmes, MD, a past president of SCAI and Scripps professor of cardiovascular medicine and interventional cardiologist at the Mayo School of Medicine (Rochester, Minnesota), said, "The SimSuite learning experience enhances traditional training methods, such as lectures, animal labs and cases proctored by an experienced user." He added that with the SimSuite System, "our members can practice and perform coronary interventions and get immediate, guideline-driven feedback." Holmes said that his program represents the first time the SCAI has made available to its members a formalized procedures training program. "We believe simulation training is one of the best ways to keep members prepared for their next milestone."

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