Risk of drug-induced agranulocytosis: the case of calcium dobesilate.

BACKGROUND

In the last 20 years, some cases of agranulocytosis associated with calcium dobesilate consumption in Spain have been reported. A high risk of dobesilate-associated agranulocytosis (121 cases per million per year) calculated using both a case-control and a case-population strategy has been published. However few spontaneous reports have been noted in the same period of time. No explanation exists for this disagreement.

METHODS

Estimated incidence rates of agranulocytosis in the IAAAS study and the calculated risk of dobesilate-associated agranulocytosis were used as background risks in a Poisson-based methodology, to calculate the number of coincidental reports of agranulocytosis among patients treated with dobesilate. The influence of treatment duration, notification rate and population characteristics were calculated.

RESULTS

During the period 1978-2000, a total of 23 cases would have taken place if the background risk of agranulocytosis were 4.7 per million per year (IAAAS's risk); however, only 9 spontaneous cases of agranulocytosis associated to dobesilate were noted. A simulation showed that with notification rates equal to or higher than 17%, it was not possible to exclude that the 9 cases were false-positives. With notification rates equal or inferior to 16%, it would be unlikely that cases of agranulocytosis were noted in this population with a risk of 4.7 per million per year; therefore, it is necessary to assume a higher agranulocytosis risk. More than 1 case per year could be a false-positive if the background risk of agranulocytosis is 9.5 per million per year, this being the appropriate risk for a population of patients older than 60 years. The duration of treatment beyond 30 days increases the probability of a random coincidence of the intake of drug and an agranulocytosis event.

CONCLUSIONS

The disagreement between calculated dobesilate-associated agranulocytosis risk and the number of noted spontaneous reports may be explained by at least three different factors: under-reporting, duration of treatment and age of patients. It is possible, with the methodology presented, to estimate the influence of these factors to avoid confusion with possible false-positive cases and then to design the correct prospective trial that can provide the true agranulocytosis risk.