The antiplatelet drug clopidogrel is a new thienopyridine derivative with a mechanism of action and chemical structure similar to ticlopidine. The estimated incidence of ticlopidine-associated thrombotic thrombocytopenic purpura is 1 per 1600 to 5000 patients treated (1-4). Thrombotic thrombocytopenic purpura is a life-threatening, multisystem disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia, fever, neurologic changes and renal abnormalities. It can result in multiorgan dysfunction or death (5, 6).
During phase III clinical trials of clopidogrel carried out in 20 000 subjects, no cases of thrombotic thrombocytopenic purpura, neutropenia, adverse skin or gastrointestinal effects were observed. As a result, this more favourable safety profile led to clopidogrel replacing ticlopidine in clinical practice for the prevention of stroke and thrombosis in patients who have received coronary-artery stents and in patients with peripheral vascular disease or acute cardiac ischaemia (7, 8). However, two postmarketing reports of cases of thrombotic thrombocytopenic purpura have been received by the Food and Drug Administration (FDA). A recent report has now been published which has set out to determine the clinical characteristics, interval between treatment and onset of disease, response to treatment, outcomes and laboratory findings related to these cases (9).
Between 1998 and 2000, through active surveillance, eleven cases of thrombotic thrombocytopenic purpura were identified in patients treated with clopidogrel. The 11 patients ranged in age from 35 to 70 years and 6 patients were women. Platelet counts were less than 20 000 per cubic millimetre in 10 patients and haematocrit values were less than 27% in 8 patients. Seven patients had neurological changes, including disorientation, slurred speech, confusion, aphasia, and coma. Four patients had renal insufficiency and two patients had evidence of acute liver injury. All patients underwent plasma exchange, with resolution of symptoms and laboratory abnormalities occurring after a median of 8 plasma exchanges. One patient died.
The features of thrombotic thrombocytopenic purpura in patients who had received ticlopidine can be contrasted with those who had received clopidogrel, despite marked differences in the methods used to ascertain cases. For example, 95% of cases reported among ticlopidine-treated patients occurred after 2 to 12 weeks of treatment, whereas all but one of the cases among clopidogrel-treated patients occurred within 2 weeks of initiation. Although the study was unable to ascertain the frequency of thrombotic thrombocytopenic purpura in patients receiving clopidogrel, physicians should be made aware of the possibility of this syndrome when initiating treatment. The possibility that cholesterol-lowering drugs, which were taken concomitantly by 5 patients, may have adverse pharmacological interactions in some patients deserves further study.
For all new drugs, a comprehensive assessment of safety requires postmarketing surveillance. Ticlopidine-associated thrombotic thrombocytopenic purpura was not widely recognized until 7 years after the drug was approved by the FDA despite its use in several million patients (1-4). In the United States, the occurrence of adverse effects is monitored by the FDA. However, only 1 to 10% of all adverse effects are reported, and the majority of these come from drug companies.
A more aggressive approach is called for in post marketing surveillance of new drugs, particularly if there is a reason - as in the similarity between ticlopidine and clopidogrel - to suspect that there may be adverse effects. A means of funding an evaluation of a drug's safety after it is approved and marketed needs to be developed that is independent of the FDA and drug manufacturers (10).
1. Bennett, C.L, Weinberg, P.D., Rozendberg-Ben-Dror, K. et al. Thrombotic thrombocytopenic purpura associated with ticlopidine: a review of 60 cases. Annals of Internal Medicine, 128: 541-544 (1998).
2. Steinhubl, S.R., Tan, W.A., Foody, J.M. et al. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. Journal of the American Medical Association, 281: 806-810(1999).
3. Bennett, C.L., Kiss, J.E., Weinberg, P.D. et al. Thrombotic thrombocytopenic purpura after stenting and ticlopidine. Lancet, 348: 1329-1339 (1996).
4. Bennett, C.L., Davidson, C.J., Raisch, D.W. et al. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Archives of Internal Medicine, 159: 2524-2528(1999).
5. Amorosi, E., Ultmann, J. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore), 45: 139-159 (1996).
6. Ticlopidine and haematological reactions. WHO Drug Information, 13: 174 (1999).
7. Klein, L.W., Calvin, J.E. Use of clopidogrel in coronary stenting; what was the question? Journal of American College of Cardiology, 34: 1895-1898 (1999).
8. Moussa, I., Oetgen, M., Roubin, G. et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent. Circulation, 99: 2364-2366 (1999).
9. Bennett, C.L., Connors, J.M., Carwile, J.M. et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. New England Journal of Medicine, 342: 1773-1777(2000).
10. Wood, A. Thrombotic thrombocytopenic purpura and clopidogrel - a need for new approaches to drug safety. New England Journal of Medicine, 342: 1824 (2000).