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We used information from the adverse-reaction forms completed by the reporting physicians and two analytic methods to determine the relation between the ticlopidine and the hematologic toxicity. First, evaluation according to the World Health Organization definitions of causality (certain, probable or likely, possible, and likely) suggested there was a "probable or likely" association in each case because the timing was appropriate for drug-induced agranulocytosis and it could not be attributed to another cause. Second, using a computer-based method of probabilistic differential diagnosis to calculate whether the drug was responsible for the agranulocytosis,2,3 we found that the probability that ticlopidine was responsible for the hematologic toxicity was greater than 90 percent in each patient — that is, nine times more likely than any alternative cause.2,3
These case reports indicate that ticlopidine can cause irreversible agranulocytosis and aplastic anemia.
Neil H. Shear, M.D.
University of Toronto Drug Safety Research Group
Toronto, ON M4N 3M5, Canada
Curt Appel, Ph.D.
Health Protection Branch
Ottawa, ON K1A 0L2, Canada
References
To the Editor: Drs. Shear and Appel have drawn attention to previously unpublished information that clearly indicates that bone marrow suppression related to the use of ticlopidine is not always reversible. Using the records of the Canadian Health Protection Branch, they report that six fatalities have occurred in Canadian patients who received this drug. Dr. Robert Pless, head of the Adverse Drug Reaction Evaluation Section, Bureau of Drug Surveillance, has allowed us access to their data on these six patients and on a seventh death possibly associated with ticlopidine therapy. In three of the seven patients there is documentation of adequate monitoring of blood counts. The records of another three make it uncertain whether there was monitoring, and in the last case the record states "blood counts were monitored."
At our request Dr. Peter Glasner, head of Roche Global Pharmacoepidemiology, has done a preliminary search of the records for adverse hematologic events associated with ticlopidine therapy based on worldwide reports through the end of 1994. He writes: "There were a total of 645 cases of aplastic anemia, bone marrow suppression, pancytopenia and agranulocytosis, of which 102 (16%) had been coded as being fatal as a result of the primary reported adverse event term."
These records chronicle an estimated 10 million patient-years of ticlopidine treatment (Dorey G, Sanofi Pharma, Gentilly, France: personal communication). It is not known which patients in this data base were monitored according to the guidelines. Nor is it possible to be certain that none of them had another reason for the agranulocytosis or aplastic anemia. It is also not certain that the voluntary reporting of complications in the post-marketing period is complete. Thus, an exact estimate of these complications is not possible.
Clearly, Shear and Appel are correct: ticlopidine can cause fatal bone marrow suppression. The risk is low. There were no deaths from bone marrow suppression among the approximately 8000 patients who were studied either in the closely monitored studies1,2 or during the post-marketing monitoring surveillance (Glasner P: personal communication). The risk of this complication is probably less than the risk of stroke and fatal stroke in properly selected patients. No one should receive ticlopidine without a proved indication, without an understanding of the potential complications, and without careful drug and hematologic monitoring. The manufacturer recommends blood-count monitoring every other week for the first three months after therapy is instituted.
There was an unrelated error in the article.3 In the entry in Table 1 on the ECST study (European Carotid Artery Surgery Trial), the enrollment criterion for internal-carotid-artery stenosis was given as >82 percent; the correct value is >70 percent.
H.J.M. Barnett, M.D.
Michael Eliasziw, Ph.D.
Heather E. Meldrum, B.A.
John P. Robarts Research Institute
London, ON N6A 5K8, Canada
References
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