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.

Samuel Shapiro, M.B., F.R.C.P.(E)
Micha Levy, M.D., Chairman
David W. Kaufman, Sc.D.
Judith Kelly, M.S.
Prof. Hermann Heimpel
Prof. Helmut Kewitz, M.D.
Joan-Ramon Laporte, M.D.
Gianni Tognoni, M.D.
Prof. Gyorgy Retsagi, M.D.
Prof. Vitan Vlahov, M.D.
Bengt-Erik Wiholm, M.D.

Sources of Funding:

  • Hoechst AG
  • Individual center funding from January 1987

Study Period:

July 1979 to December 1986 (surveillance continued in Sweden, January 1987 to 1992)

  • Kaufman DW, Kelly JP, Issaragrisil S, Laporte JR, Anderson T, Levy M, Shapiro S, Young NS. Relative incidence of agranulocytosis and aplastic anemia. Am J Hematol 2006;81(1):65-7.
  • Siskind V, Kelly JP, Kaufman DW. Estimating risks for matching factors in case-control studies. J Clin Epidemiol 2000;53:251-6.
  • Wiholm BE, Kelly JP, Kaufman DW, Issaragrisil S, Levy M, Anderson T, Shapiro S. Relation of aplastic anaemia to use of chloramphenicol eye drops in two international case-control studies. BMJ 1998;316:666.
  • Kaufman DW, Kelly JP, Jurgelon JM, Anderson T, Issaragrisil S, Wiholm BE, Young NS, Leaverton P, Levy M, Shapiro S. Drugs in the aetiology of agranulocytosis and aplastic anaemia. Eur J Haematol 1996;57(Suppl.):23-30.
  • Kelly JP, Jurgelon JM, Issaragrisil S, Keisu M, Kaufman DW. An epidemiological study of aplastic anaemia: relationship of drug exposures to clinical features and outcome. Eur J Haematol 1996;57(Suppl.):47-52.
  • Shapiro S. L-trytophan and eosinophilia-myalgia syndrome [letter to the editor]. Lancet 1994;343:1035.
  • Kaufman DW. Risk/benefit consideration in the use of analgesics. In: Gerber WD, Nappi G, eds. Update on non-narcotic analgesic research. Fiuggi, Italy. October 2-3, 1992. Basel: Birkhäuser Verlag, 1993:91-100.
  • Kaufman DW, Kelly JP, Levy M, Shapiro S. Risk evaluation of antipyretic analgesics: new results from ongoing studies. In: Brune K, ed. New clinical and epidemiological data on dipyrone. Yokohama, Japan. July 28, 1992. Basel: Birkhäuser Verlag, 1993:39-52.
  • Kaufman DW, Kelly JP, Levy M, Shapiro S. The drug etiology of agranulocytosis: an update of the International Agranulocytosis and Aplastic Anemia Study. Pharmacoepidemiol Drug Saf 1993;2:S25-9.
  • Kelly JP, Kaufman DW, Shapiro S. Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: the International Agranulocytosis and Aplastic Anemia Study. Clin Pharmacol Ther 1991;49:330-41.
  • Kaufman DW, Kelly JP, Levy M, Shapiro S. The drug etiology of agranulocytosis and aplastic anemia: the International Agranulocytosis and Aplastic Anemia Study. New York: Oxford University Press, 1991.
  • Keisu M, Heit W, Lambertenghi-Deliliers G, Parcells-Kelly J, Polliack A, Heimpel H. Transient pancytopenia: a report from the International Agranulocytosis and Aplastic Study. Blut 1990;61:240-4.
  • International Agranulocytosis and Aplastic Anemia Study. Anti-infective drug use in relation to the risk of agranulocytosis and aplastic anemia. Arch Intern Med 1989;149:1036-40.
  • International Agranulocytosis and Aplastic Anemia Study. Risk of agranulocytosis and aplastic anemia in relation to use of antithyroid drugs. BMJ 1988;297:262-5.
  • International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: the relevance of diagnostic criteria. Blood 1987;70:1718-21.
  • International Agranulocytosis and Aplastic Anemia Study. Risks of agranulocytosis and aplastic anemia: a first report of their relation to drug use with special reference to analgesics. J Am Med Assoc 1986;256:1749-57.
  • International Agranulocytosis and Aplastic Anemia Study. The design of a study of the drug etiology of agranulocytosis and aplastic anemia: a report from the International Agranulocytosis and Aplastic Anemia Study. Eur J Clin Pharmacol 1983;24:833-6.