Researchers have turned to a second meta-analysis of existing clinical trials to address the question of cardiac safety in users of the GlaxoSmithKline diabetes drug Avandia. Their finding: "an unfavorable benefit-to-risk ratio."
The new meta-analysis, conducted by Steven Nissen (the cardiologist who launched the Avandia controversy with the first meta-analysis three years ago) and Kathy Wolski of the Cleveland Clinic, represents the "most robust available approach" for determining the drug's cardiovascular safety, and it provides a means of overcoming limitations in the first study. The current findings are published in a late June online version of the Archives of Internal Medicine, in time for this month's meeting of the FDA advisory committee considering whether to remove rosiglitazone from the market.
The Cleveland Clinic researchers note the absence of any large, definitive rosiglitazone cardiovascular outcomes trials. The 2009 Record study funded by GSK--which evaluated the drug for cardiac outcomes and regulation of glycemia in diabetes--was limited by low event rates, researchers say, and considered inconclusive.
The current study analyzes myocardial infarction and cardiovascular mortality for 56 randomized trials involving 35,500 subjects. Nissen and Wolski used a study-level meta-analysis to find that the odds ratio for myocardial infarction was in fact "significantly increased," but without evidence of an increase in cardiovascular mortality.
The researchers began by considering for the meta-analysis some 200 clinical trials that they found by scouring GSK's Avandia trial registry as well as MEDLINE and FDA listings. The select 56 all include a randomized comparator group, similar treatment duration, and more than 24 weeks of drug exposure. Of the 56, 15 reported no myocardial infarctions; 30 reported no cardiovascular mortality.
The trials without events were excluded in the primary prespecified analysis. But they were included in an alternative analysis, which yielded a similar hazard. The findings are consistent with prior meta-analyses conducted by GSK, the FDA and most independent investigators, the researchers say.