Published: November 2000

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Ticlopidine, Clopidogrel and Thrombotic Thrombocytopenic Purpura

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Prescriber Update 20: 19-21
November 2000

Dr Michael Tatley, Medical Assessor
Centre for Adverse Reactions Monitoring
P O Box 913, Dunedin

Ticlopidine (Ticlid™), a thienopyridine antiplatelet agent, has been shown to be associated with potentially fatal thrombotic thrombocytopenic purpura (TTP). A similar agent which is now largely replacing ticlopidine for safety reasons, clopidogrel (Plavix™), has also been associated with this adverse event, though possibly at a lower rate than ticlopidine. Because of the risk of agranulocytosis, thrombocytopenia and TTP, patients taking ticlopidine should have baseline full blood counts followed by monitoring at 2-weekly intervals. Tests should continue for at least 2 weeks after completion of therapy. Early signs of TTP may be a skin reaction and neurological changes.  Patients taking either agent should be advised of the risk of haematological reactions and advised to report any early signs. Early referral for intervention, including plasmapheresis, reduces the risk of mortality substantially.

TTP which may be fatal may occur with ticlopidine

An article published in Prescriber Update in February 1997¹ advised of the possibility of life threatening haematological reactions with ticlopidine (Ticlid™) that were usually reversible, although reports of some fatalities were noted. Recent evidence^2,3 indicates that thrombotic thrombocytopenic purpura (TTP) and death from this adverse reaction may occur more frequently than previously expected.

Unlike some types of thrombocytopenia, TTP is a life threatening, multi-system disease characterised by thrombocytopenia, microangiopathic haemolytic anaemia, neurological changes, renal failure and fever.⁴ Idiopathic cases occur at a rate of 3.7 per year per million persons with a mortality rate for promptly treated cases ranging from 10 to 20%.⁵ Its cause appears to be related to auto-antibodies against a metalloprotease that degrades von Willebrand factor.⁵

Fatality rate is reduced by plasmapheresis

Whilst no cases of TTP were reported in 4 published phase III clinical trials, a review by Bennett et al³ of TTP with ticlopidine revealed 98 evaluable cases captured through post-marketing surveillance. Forty out of the total 259 reported deaths with ticlopidine were caused by TTP and 50 by thrombocytopenia. A total of 85.6% of the deaths were associated with haematological reactions. The estimated incidence of TTP with ticlopidine is 1 case per 1600 to 5000 patients treated.⁵

In the review by Bennett et al,³ TTP had been associated with ticlopidine used following coronary artery stenting (56) and for stroke prevention (42), and 95% of cases occurred after more than 2 weeks of therapy. The overall TTP mortality was substantial in both groups, being greater in the stroke prevention than in the coronary artery setting (37.5% vs 28.6%). Death occurred in 57.9% of those patients who did not undergo plasmapheresis compared to 18.3% of those who underwent plasmapheresis.

In the CARM database, there are no reports of TTP with ticlopidine, although there are 2 reports of agranulocytosis and 2 of granulocytopenia. However, the Australian Adverse Drug Reactions Advisory Committee reported its first case of TTP⁶ in December 1999.

TTP has also been associated with clopidogrel

Clopidogrel (Plavix™), another thienopyridine antiplatelet agent, was given marketing consent in New Zealand in December 1999. It is not yet on the Pharmaceutical Schedule, but it has largely replaced ticlopidine as an alternative antiplatelet agent to aspirin in patients with vascular disease. The main reason for the change is that the incidence of some major (neutropenia) and minor (nausea, skin rash) adverse reactions is lower with clopidogrel than with ticlopidine.⁷

Although TTP was not reported in any randomised clinical trials evaluating clopidogrel (around 20,000 patients), Bennett et al recently identified 11 cases during a 2-year period of active surveillance,⁵ and have subsequently reported identification of 9 further cases.⁸ Bennett et al estimated an incidence of 1 case per 15,000 clopidogrel-treated patients.⁸

In all except 1 case of the initial series of TTP with clopidogrel, the adverse event occurred after a treatment duration of 2 weeks or less.⁵ All patients underwent plasmapheresis, and all except 1 responded.  In this group more plasma exchanges (median 8) were required than in the case series of TTP with ticlopidine, and 2 patients relapsed more than once without re-exposure to clopidogrel and required further episodes of plasma exchange.

Advise patients of the risk of TTP and early signs

Based on this evidence practitioners need to be aware of the potential for serious life threatening haematological reactions, particularly TTP, associated with ticlopidine and possibly also clopidogrel. In the case of ticlopidine consideration should be given to limiting treatment to 2 weeks, whilst with clopidogrel vigilance for TTP within the first 2 weeks needs to be exercised.

Because of the risk of agranulocytosis, thrombocytopenia and TTP, patients taking ticlopidine should have a baseline full blood count with white cell differential and platelet counts performed prior to the start of treatment and then every 2 weeks during the first 4 months.⁹ Because ticlopidine has a long plasma half-life, haematological monitoring should continue for at least 2 weeks after the cessation of therapy. There are no formal monitoring requirements associated with clopidogrel, but based on its recently reported potential for TTP, similar vigilance may be beneficial. However, those taking either agent should be warned of the risk of TTP and advised of the symptoms. Early signs of TTP may be a skin reaction, which may precede the onset of TTP or it may be an indication of purpura, and neurological changes.  Complete blood count and creatinine level determination assist in the diagnosis.

The likelihood of the death of patients on these medications can be reduced by up to 60% if cases with a high index of suspicion are referred to a haematologist for early intervention including plasmapheresis.

References

1. Pillans PI. Ticlopidine-induced blood dyscrasias. Prescriber Update No. 14, p.22-3, Feb 1997.
2. Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine. Ann Intern Med 1998;128:541-4.
3. Bennett CL, Davidson CJ, Raisch DW, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999;159:2524-8.
4. Rock G, Porta C, Bobbio-Pallavicini E. Thrombotic thrombocytopenic purpura treatment in year 2000. Haematologica 2000;85:410-19.
5. Bennett CL, Connors JM, Carwile JM, et al. Thrombocytopenic purpura associated with clopidogrel. NEJM 2000;352:1773-6.
6. TTP with ticlopidine. Aust Adv Drug Reactions Bull 1999;18(4):15.
7. Hankey GJ, Sudlow CLM, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vacular events in high vascular risk patients. Cochrane Database of Systematic Reviews: CD001246, 2000.
8. Bennett CL, Connors JM, Moake JL. Clopidogrel and thrombotic thrombocytopenic purpura. NEJM 2000;343:1193-4.
9. Ticlid data sheet 25 February 2000.