Correspondence

Correction

Prevention of Ischemic Stroke

N Engl J Med 1995; 333:460August 17, 1995

Article

To the Editor:

Barnett et al. (Jan. 26 issue)1 state that “neutropenia occurs early but is reversible after the cessation of [ticlopidine].” Unfortunately, this is not always true. Six patients who died of irreversible ticlopidine-induced bone marrow failure have been reported to the Canadian Health Protection Branch. In four of the patients (one man and three women; age, 70 to 86 years), agranulocytosis developed (granulocyte count, <500 per cubic millimeter) 15 to 74 days (mean, 38) after ticlopidine was begun. Two women, 72 and 84 years old, had aplastic anemia that first presented as agranulocytosis 27 and 41 days after ticlopidine was begun.

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

3 References

1. 1

   Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995;332:238-248
   Full Text | Web of Science | Medline

2. 2

   Oh PI, Lanctot KL, Naranjo CA, Shear NH. Fatal aplastic anemia associated with ticlopidine therapy -- approaches to an adverse drug reaction. Can J Clin Pharmacol 1995;2:19-22
   

3. 3

   Gardner FH. Ticlopidine-induced neutropenia: recognition and management. Intern Med 1991;12:35-41
   CrossRef

Author/Editor Response

The authors reply:

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

3 References

1. 1

   Hass WK, Easton JD, Adams HP Jr, et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stoke in high-risk patients. N Engl J Med 1989;321:501-507
   Full Text | Web of Science | Medline

2. 2

   Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989;1:1215-1220
   CrossRef | Web of Science | Medline

3. 3

   Barnett HJM, Eliasziw M, Meldrum HE. Drugs and surgery in the prevention of ischemic stroke. N Engl J Med 1995;332:238-248
   Full Text | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   A. Symeonidis, A. Kouraklis-Symeonidis, U. Seimeni, A. Galani, N. Giannakoulas, E. Fragopanagou, M. Tiniakou, P. Matsouka, N. Zoumbos. (2002) Ticlopidine-induced aplastic anemia: Two new case reports, review, and meta-analysis of 55 additional cases. American Journal of Hematology 71:1, 24-32
   CrossRef

2. 2

   DEBORAH SHATIN, STEPHANIE D. SCHECH, ALLEN BRINKER. (2002) Ambulatory Use of Ticlopidine and Clopidogrel in Association with Percutaneous Coronary Revascularization Procedures in a National Managed Care Organization. Journal of Interventional Cardiology 15:3, 181-186
   CrossRef

3. 3

   Bradford B. Worrall, Karen C. Johnston. (2000) Antiplatelet therapy in secondary stroke prevention. Current Atherosclerosis Reports 2:2, 104-109
   CrossRef

4. 4

   Alexander Haushofer, Walter Michael Halbmayer, Herbert Prachar. (1997) Neutropenia with ticlopidine plus aspirin. The Lancet 349:9050, 474-475
   CrossRef

5. 5

   (1996) Antiplatelet and Anticoagulant Therapy after Coronary-Artery Stenting. New England Journal of Medicine 335:15, 1160-1161
   Full Text