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Rosiglitazone and Cardiovascular Risk
Curt D. Furberg, M.D., Ph.D., Bruce M. Psaty, Ph.D., New England Journal of Medicine, 5-24-07

Psaty and Furberg have written a thoughtful and balanced review of the meta–analysis of Avandia safety data published by Dr. Steve Nissen and his co–authors in the same issue of the New England Journal. It is well worth reading in full.

The meta–analysis has a number of strengths. Among these were the effort to include unpublished studies, the prespecified analysis plan, the use of major cardiovascular events as the primary outcome, and an analysis in which rosiglitazone was compared with placebo. In the latter analysis, the odds ratio for myocardial infarction was 1.80 (95% CI, 0.95 to 3.39; P = 0.07), and the odds ratio for death from cardiovascular causes was 1.22 (0.64 to 2.34; P = 0.55).

The study also has a number of weaknesses. Only summary trial-level data (rather than patientlevel data) were available, so it was not possible to conduct time–to–event analyses or to evaluate the time course of risks. Data were not adequate to conduct dose–response analyses. The eligible trials included both placebo and active–treatment control groups. Across the trials, there was no standard method for identifying or validating outcomes; events in eligible or ineligible trials may have been missed or misclassified.

The total number of events was relatively small, with the result that there was little or no power to detect potential differences among the trials if they were present. Although, in general, these limitations are likely to move estimated odds ratios toward the null, the weaknesses, which are largely related to the quality of the available data, are nonetheless substantial. A few events either way might have changed the findings for myocardial infarction or for death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded. In their discussion, the authors properly emphasize the fragility of their findings.

Project FDA.
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