International Agranulocytosis and Aplastic Anemia Study (IAAAS)

Objectives

To evaluate the hypothesis that dipyrone use increases the risk of agranulocytosis.

To evaluate the relationship of drug use in general (other than immunosuppressive and chemotherapeutic agents) to the risk of agranulocytosis and aplastic anemia.

Methods

The study was an international collaborative effort with participating centers in Israel, West Germany, Italy, Spain, Hungary, Bulgaria, and Sweden; the total population base was approximately 22 million people. New cases were identified by weekly telephone calls to collaborating hematologists in each region. A nurse or physician interviewed each case along with control subjects. Diagnostic criteria for the eligibility of the cases is determined by an international group of hematologists who also reviewed the clinical and pathological material, without knowledge of the drug history. The primary focus of the data collection was on a detailed history of medication use in the six months before hospital admission; information was also obtained on demographic factors, relevant medical history, and some environmental exposures. The study was conducted in consultation with an Advisory Committee consisting of Sir Richard Doll, Oxford (Chairman), Prof. Sven Moeschlin, Solothurn, and Prof. Per Knut Lunde, Oslo. A total of 325 cases of agranulocytosis and 185 cases of aplastic anemia were enrolled, along with 2,500 controls.

Results

Numerous associations between drugs and both dyscrasias were quantified, and the study has proven to be a landmark investigation of these rare diseases. Agranulocytosis has been shown to be primarily a drug-induced disease, with approximately two-thirds of the cases accounted for by associated drugs identified in the study. By contrast, only about 25% of cases of aplastic anemia were accounted for by associated drugs, and the majority remain unexplained. Because of the rarity of the diseases, absolute risks for individual drugs were low.