Cimetidine-induced hemolytic anemia: the fallacy of clinical associations

Two patients developed hemolytic anemia while taking cimetidine. Neither patient was taking other drugs known to cause hemolytic anemia. In both, the hemolytic anemia resolved after the drug was stopped. In one patient, the direct antiglobulin (Coombs') test was strongly positive when the hemolytic anemia was recognized and became only weakly positive as the hemolysis subsided. However, serologic studies for antidrug antibodies yielded negative results in both patients; readministration of cimetidine for 55 days in patient 1 and for more than 24 months in patient 2 did not cause recurrence of hemolysis. We conclude that we cannot incriminate cimetidine as the cause of the hemolytic anemia in either of our patients. These findings emphasize that a temporal association of drug administration and hemolytic anemia is not proof of a cause-effect relationship and that reports of drug-related adverse hematologic effects must be interpreted with caution.