They were waiting in a long line outside the hall to see Dr Steven Nissen (Cleveland Clinic, OH).
He arrived to a packed auditorium to tell the audience what he knew about rosiglitazone (Avandia, GlaxoSmithKline), when he knew it, and what he believes needs to be done next. Although he has been much in the spotlight in the past month, his audience this time, instead of politicians on Capitol Hill, was a house full of doctors and researchers in a hastily added panel discussion at the American Diabetes Association (ADA) 2007 Scientific Sessions in Chicago, IL.
Discussing the cardiovascular safety of a drug that has shaken up the cardiovascular and diabetic communities, Nissen outlined his rationale for performing and publishing a meta-analysis that linked the popular diabetes drug to increased cardiovascular events. Speaking during the panel discussion, Nissen defended his decision to put the results of his analysis into the scientific realm, despite the expected tumult the findings would generate, as well as the confusion that might ensue among patients taking the drug.
"We didn’t call for the withdrawal of the drug, and we didn’t call for regulatory action," said Nissen. "We simply said that we want you and others who treat these patients to be aware of the findings. There was a lot of criticism–should this have been published or shouldn’t it–but let me say to you the alternative to us was unacceptable. The alternative would be to keep the scientific community in the dark, to not tell you that a pooled analysis of all these data showed a pretty substantial increase in the risk of the most serious complication of diabetes."
Some audience members weren’t having anything of this argument, however, and one in particular said publishing the results was irresponsible, mainly because patient dropouts in ongoing rosiglitazone trials would be a natural consequence. The failure of those trials, he said, would fall squarely on Nissen’s shoulders.
The meta-analysis in question, published in the May 21, 2007 issue of New England Journal of Medicine (Nissen SE and Wolski K. N Engl J Med 2007; 356:2457-71), suggested that rosiglitazone increased the risk of MI 43% and might also increase the risk of cardiovascular death, an end point that met only borderline statistical significance. Nissen noted that GlakoSmithKline, the maker of rosiglitazone, as well as the FDA conducted similar meta-analyses, and both of these showed an increase in ischemic events.
Like all meta-analyses, Nissen said there are weaknesses to his study. He did not have access to patient-level data, and the cardiovascular events, which were not adjudicated, were not the primary end point in any of the 42 trials included in the meta-analysis.
"This is an important weakness," said Nissen. "We’re always on firmer ground when we have prospective, adjudicated, carefully collected end points. These end points were primarily collected as serious adverse events." Despite these limitations, however, "patients and providers should consider the potential for serious cardiovascular effects of treatment with rosiglitazone for type 2 diabetes."
Dr Philip Home (Newcastle University, Newcastle upon Tyne, UK), who spoke during the panel discussion, said he believes the meta-analysis should have been published, as did all panel members, including Drs David Nathan (Harvard University Medical School, Boston, MA), Barry Goldstein (Thomas Jefferson University, Philadelphia, PA), and John Buse (University of North Carolina Medical School, Chapel Hill). However, Home said study was "data snooping on quite a big scale" and that the results should be used only to generate future studies.
Home, who is the lead author of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, pointed out that an interim analysis of this trial, conducted in light of the recent rosiglitazone concerns and published online June 5, 2007 in the New England Journal of Medicine, showed no statistically significant differences in the overall risk of hospitalization or death from cardiovascular causes. The RECORD study, he noted, is specifically designed to examine cardiovascular events, unlike the trials included in the meta-analysis. The results, he said, suggest that rosiglitazone should continue to have a role in glucose-lowering therapy and that studies like Nissen’s meta-analysis, while important for raising awareness, form a "a poor basis for making decisions."
While it is important to wait for cardiovascular-end-point trials before making regulatory decisions, Nissen lamented the fact that in the eight years since the approval of rosiglitazone no definitive end-point trials have been published, despite the signal of increased risk of ischemic events observed in the earliest studies. The RECORD study, said Nissen, is too flawed to answer the question of whether or not rosiglitazone increases cardiovascular risk.
One of the biggest criticisms leveled by Home, as well by other audience members, was aimed squarely at last month’s editorial accompanying Nissen’s meta-analysis. Written by Drs Bruce Psaty (University of Washington, Seattle) and Curt Furberg (Wake Forest University, Winston-Salem, NC), the editorialists shared Nissen’s concerns, but Home called it a "half-baked editorial with an axe to grind."
In a later discussion with Dr Richard Kahn, the chief scientific and medical officer of the ADA, when asked if they would start a patient on rosiglitazone, Nathan, Goldstein, and Buse said they would not, at least not until the cardiovascular issues were settled. They would be reluctant to take a well-controlled patient off the drug, however, but might switch if the patient failed to reach glycemic targets with the drug. Nathan reminded the audience that rosiglitazone, at this time, is intended for glycemic control to prevent microvascular and neurologic complications, not for the prevention of cardiovascular disease.
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