Results from five new safety analyses of drug-eluting coronary stents, compared with bare-metal stents, gave added reassurance about using drug-eluting stents for their labeled indications and framed some of the concerns about off-label use of the stents.
The five reports were detailed versions of reports that were presented last December to the Circulatory System Devices Advisory Panel of the Food and Drug Administration (N. Engl. J. Med. 2007;981–1039 and 1059–60). The published form of the reports included no changed or added findings and continued to support the panel's December conclusions, said Dr. William H. Maisel, the panel's chairman and author of a perspective article that ran with the new reports.
Four of the five new papers were reanalyses of data previously collected from the studies that led to FDA approval of the sirolimus- and paclitaxel-eluting stents (Cypher and Taxus), and in aggregate the results confirmed that DESs had comparable safety to bare-metal stents (BMSs) with the advantage of a substantial reduction in the need for target lesion revascularization in the uncomplicated patients who were enrolled in these studies.
“There probably is a true increase in the rate of late stent thrombosis in the on-label group, but importantly and equally convincingly there is no evidence of increased mortality or MIs,” Dr. Maisel said in an interview.
Because of these findings, “I feel comfortable with drug-eluting stents continuing to be used in that group [on-label patients], and it's the stent of choice in that group, because there is a convincingly marked reduction in the need for repeat revascularization,” Dr. Maisel said.
The meta-analyses are limited by dealing with relatively small numbers of patients. The largest of the overviews included fewer than 5,300 patients, which included both those getting BMSs and those getting DESs. “The statistical power to detect a doubling of risk was well under 50% in all of the analyses,” said Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic, in an interview done by the New England Journal of Medicine and released with the papers.
The FDA panel also recommended that all patients who receive DESs should be treated for at least 12 months with a combination of clopidogrel and aspirin. None of the new reports dealt specifically with the impact of dual antiplatelet therapy.
The fifth new article contrasted with the other four by focusing on data collected in a registry of nearly 20,000 patients, all of the patients who received a DES or BMS in Sweden during 2003 and 2004. This study and others like it are considered critical in the safety debate because they deal with “real-world” use of DESs, including thousands of patients who had off-label indications for a DES. Experts estimate that, at least until last summer, about 60% of DES use in the United States was in off-label patients.
The registry analysis showed that during 3 years of follow-up, patients who received DESs had about a 20% increased rate of deaths and of deaths or MIs, compared with patients who received BMSs; both were statistically significant differences.
Experts, including Dr. Maisel, cautioned that in this series the baseline clinical profiles of the patients who received DESs and BMSs had several important differences. The researchers from Uppsala (Sweden) University who did these analyses used a propensity-score method to try to account for this so they could focus entirely on differences between the two stent types. But while a propensity-score analysis is “the best we have” for adjusting a retrospective analysis, “it's not perfect,” said Dr. Donald E. Cutlip, a cardiologist at Beth Israel Deaconess Medical Center in Boston and senior author of one of the new studies, in an interview.
Despite the limitations of the Swedish study, it prompted Dr. Nissen to recommend that DES use be limited to on-label patients until the stents are tested in other types of patients in prospective, controlled trials. “You really need at least an 8,000-patient trial. If there is a hazard and the Swedish study is right, then we might regret putting these devices in patients who have not been adequately studied for safety.” said Dr. Nissen, a member of the FDA panel, in his interview with the journal.
Current data are inadequate to compare the safety and efficacy of DES, BMS, and coronary bypass surgery in off-label patients, and studies are underway to collect these data, said Dr. Maisel, also a cardiologist at Beth Israel Deaconess Medical Center in Boston. However, it is known that DESs reduce the risk of restenosis and need for revascularization, compared with BMSs, in off-label as well as on-label patients.