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, released online by the New England Journal of Medicine on Feb. 12, were detailed versions of reports presented last December to the Circulatory System Devices Advisory Panel of the Food and Drug Administration. The published reports included no changed or added findings and continued to support the panel's December conclusions, said Dr. William H. Maisel, panel chairman and author of an accompanying perspective article (N. Engl. J. Med 2007;356:981-1039; N. Engl. J. Med. 2007;356:1059-60).
Four of the new papers were reanalyses of data from the previous studies that led to FDA approval of the sirolimus- and paclitaxel-eluting stents (Cypher and Taxus), and in aggregate the results confirmed that drug-eluting stents (DESs) had comparable safety to bare-metal stents (BMSs) with the advantage of a substantial reduction in the need for target lesion revascularization.
“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 myocardial infarctions,” Dr. Maisel said in an interview. One possible explanation is that the reduced restenosis rate with DES leads to fewer complications from restenosis.
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 new data are “reassuring in the sense that there were nearly equal outcomes of patients treated with drug-eluting stents and bare-metal stents. They are less reassuring in that both types of stents are associated with episodes of late thrombosis,” although the rates are low, said Dr. Donald E. Cutlip, a cardiologist at Beth Israel Deaconess Medical Center in Boston and senior author of one of the new studies.
The meta-analyses are limited by relatively small numbers of patients. The largest 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 recommended that all patients who receive DESs should be treated for at least 12 months with a combination of clopidogrel and aspirin. (See box.) None of the new reports dealt specifically with the impact of dual antiplatelet therapy.
The fifth article contrasted with the other four by focusing on data collected in a registry of nearly 20,000 patients, all the patients who received a DES or BMS in Sweden in 2003-2004. This study and others like it are considered critical in the safety debate because they deal with “real-world” use of DESs, including in thousands of patients who had off-label indications. Experts estimate that 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 death and of death or myocardial infarction, 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 important differences. The researchers from Uppsala (Sweden) University who did these analyses used a propensity-score method to account for this so they could focus on differences between the two stent types. But a propensity-score analysis is “not perfect,” said Dr. Cutlip.
Despite the Swedish study's limitations, it prompted Dr. Nissen to recommend that DES use be limited to on-label patients until trials are conducted in other types of patients. “I'm not willing to accept on faith that we know the performance of drug-eluting stents in real-world situations,” said Dr. Nissen in his interview with the journal. “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.” Dr. Nissen is on the FDA panel.
Current data are inadequate to compare the safety and efficacy of DESs, BMSs, and coronary bypass surgery in off-label patients, said Dr. Maisel, also a cardiologist at Beth Israel Deaconess Medical Center. But it is known that DESs reduce the risk of restenosis and need for revascularization, compared with BMSs, in all patients.