Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology. A critique of the International Agranulocytosis and Aplastic Anemia Study.

The International Agranulocytosis and Aplastic Anemia Study (IAAAS) of analgesic-induced risks of blood dyscrasias represents the current "state of the art" in case-control pharmacoepidemiology. We present a conceptual framework for examining the goal, methods, and analysis of an epidemiologic study of drug risks and review the IAAAS within this framework. In our view, the new risk estimates reported by the IAAAS are not inherently more accurate than existing ones, nor have they been measured in clinically and sociodemographically relevant groups of patients over the anticipated course of therapy. Thus, the reported risks cannot be used to guide clinical or regulatory decisions concerning available treatment options for such patients. Furthermore, we believe that the IAAAS methods for selection of cases and controls, ascertainment of exposure, and data analysis may well have led to invalid estimates even for those risks that are reported. We hope that closer attention to the conceptual framework we suggest and the methodologic issues we raise will enable future case-control pharmacoepidemiologic studies to provide more useful and accurate answers to questions concerning the adverse effects of drugs.