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Luisa Ibáñez, MD; Xavier Vidal, MD; Elena Ballarín, RN; Joan-Ramon Laporte, MD

Arch Intern Med. 2005;165:869-874.

Background  Since the publication of a major international case-control study on the risk of agranulocytosis associated with the use of medicines in the 1980s, many new drugs have been introduced in therapeutics.

Methods  Seventeen units of hematology contribute to the case-control surveillance of agranulocytosis and aplastic anemia in Barcelona, Spain. After a follow-up of 78.73 million person-years, 177 community cases of agranulocytosis were compared with 586 sex-, age, and hospital-matched control subjects with regard to previous use of medicines.

Results  The annual incidence of community-acquired agranulocytosis was 3.46:1 million, and it increased with age. The fatality rate was 7.0%, and the mortality rate was 0.24:1 million. The drug most strongly associated with a risk of agranulocytosis was ticlopidine hydrochloride with an odds ratio (OR) of 103.23 (95% confidence interval [CI], 12.73-837.44), followed by calcium dobesilate (OR, 77.84 [95% CI, 4.50-1346.20]), antithyroid drugs (OR, 52.75 [95% CI, 5.82-478.03]), dipyrone (metamizole sodium and metamizole magnesium) (OR, 25.76 [95% CI, 8.39-179.12]), and spironolactone (OR, 19.97 [95% CI, 2.27-175.89]). Other drugs associated with a significant risk were pyrithyldione, cinepazide, aprindine hydrochloride, carbamazepine, sulfonamides, phenytoin and phenytoin sodium, -lactam antibiotics, erythromycin stearate and erythromycin ethylsuccinate, and diclofenac sodium. Individual attributable incidences for all these drugs, which collectively accounted for 68.6% of cases, were less than 1:1 million per year.

Conclusions  Agranulocytosis is rare but serious. A few drugs account for two thirds of the cases. Our results also provide reassurance regarding the risk associated with a number of newly marketed drugs.

Author Affiliation: Fundació Institut Català de Farmacologia, World Health Organization Collaborating Centre for Research and Training in Pharmacoepidemiology (Drs Ibáñez, Vidal, and Laporte and Ms Ballarín), and Department of Pharmacology, Therapeutics, and Toxicology, Universitat Autònoma de Barcelona (Drs Ibáñez, Vidal, and Laporte), Clinical Pharmacology Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain.

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