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Ticlopidine

A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Prevention of Cerebral Ischaemia and Stroke

  • Drug Evaluation
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An Erratum to this article was published on 01 June 1996

Summary

Synopsis

Ticlopidine is a thienopyridine derivative which reduces the risk of reversible ischaemia and stroke in patients who have previously experienced a cerebral ischaemic episode. In comparison with aspirin, ticlopidine produced a significant reduction in the risk of stroke in a multicentre clinical trial involving more than 3000 patients with previous transient or persistent minor ischaemia, and was superior to placebo for the prevention of stroke recurrence in more than 1000 patients who had experienced a major thrombotic stroke. The costutility ratio for ticlopidine in comparison with aspirin was estimated to be $US31 200 to 55 000 per quality-adjusted life-year gained.

Diarrhoea is the most common adverse event in ticlopidine recipients (20 to 22% incidence versus about 10% with placebo), although skin rash, nausea, dyspepsia, bleeding events, abnormal liver function and haematological disturbances were also observed in clinical trials. Severe neutropenia is the most serious event: this developed in 0.85% of patients receiving ticlopidine in 2 large clinical studies (n = 4098) but resolved after treatment withdrawal. Fatal neutropenia, although rare, has been reported in some patients receiving ticlopidine.

Thus, ticlopidine is effective in reducing the risk of recurrent cerebral ischaemia and stroke. It appears to provide a gain over aspirin for the prevention of stroke after reversible ischaemia, particularly during the first year of treatment (when the risk of stroke is greatest), although further data on its absolute relative benefit would be useful. The extent to which ticlopidine is prescribed will probably depend on individual clinicians’ perception of its risk/benefit and costeffectiveness profiles. Ticlopidine is likely to be particularly useful for stroke prophylaxis in patients who do not tolerate aspirin or who have an ischaemic episode during aspirin treatment, and for the prevention of stroke recurrence in patients who have previously experienced a major stroke.

Overview of Pharmacodynamic Properties

Ticlopidine is a thienopyridine derivative which is structurally and functionally unrelated to other platelet aggregation inhibitors. The drug has little or no antiplatelet activity in vitro and the precise source of its antiaggregatory effects in vivo remains unclear. Ex vivo inhibition of adenosine diphosphate (ADP)-induced platelet aggregation is evident 24 to 48 hours after starting multiple-dose ticlopidine treatment, reaches a peak after about 3 days to 1 week, is maintained during long term therapy and persists for several days after treatment withdrawal. Ticlopidine has a less extensive, and generally more variable, inhibitory effect against platelet aggregation induced by collagen, platelet activating factor, epinephrine (adrenaline), thrombin or arachidonic acid than against ADP-induced aggregation. Other pharmacodynamic effects of ticlopidine include a marked prolongation of bleeding time and a modest reduction in levels of plasma fibrinogen.

Ticlopidine inhibits ADP-induced platelet aggregation by a mechanism which appears to involve effects on the 2-methylthio-ADP-binding receptor and the exposure of the fibrinogen binding site of the glycoprotein Ilb/IIIa complex in the platelet membrane.

Pharmacokinetic Properties

About 80 to 90% of an oral ticlopidine dose is absorbed, with peak plasma concentrations (Cmax0.31 to 0.70 mg/L) recorded 1.7 to 2 hours after administration of a single 250mg dose to healthy volunteers. Multiple-dose administration of ticlopidine resulted in Cmax values of 0.89 to 1.42 mg/L and steady-state concendrawal trations of ticlopidine were achieved after 5 to 14 days. In elderly volunteers (mean age ≈70 years), single or multiple doses of ticlopidine 250mg produced significant increases in the area under the plasma concentration-time curve and Cmax in comparison with a control group of younger volunteers (mean age ≈29 years). Food intake increases the rate and extent of ticlopidine absorption.

Ticlopidine is extensively metabolised in the liver, with less than 1% of an oral dose being detected in urine as the unmodified parent molecule in humans. The elimination half-life (t½β) of ticlopidine ranged from about 7 to 19 hours after single-dose administration and from about 29 to 98 hours after repeated administration to healthy volunteers. The value for t½β was increased after single but not multiple doses in elderly compared with younger individuals. Approximately 60% of a radiolabelled single dose of oral ticlopidine was detected in urine, with about 25% of the label excreted in faeces, in healthy volunteers.

Clinical Efficacy

Ticlopidine in a regimen of 250mg twice daily reduces the risk of recurrent cerebral ischaemia and stroke in at-risk patients. In 1053 patients who had experienced a major thromboembolic stroke [the Canadian American Ticlopidine Study (CATS)], ticlopidine decreased risk by 30.2% relative to placebo for the composite end-point of stroke, myocardial infarction or vascular death and by 33.5% for fatal or nonfatal stroke. A similar risk reduction (38.4%) was evident according to an on-treatment (but not intent-to-treat) analysis of composite cardiovascular and cerebrovascular outcome in 687 patients with intermittent claudication resulting from occlusive artery disease.

Ticlopidine was more effective than twice-daily aspirin 650mg in preventing cerebrovascular events when given for up to 6 years in more than 3000 patients who had experienced reversible cerebral ischaemia [the Ticlopidine Aspirin Stroke Study (TASS)]. The benefit of ticlopidine compared with aspirin was most evident during the first year of treatment, with an on-treatment risk reduction for fatal or nonfatal stroke of about 48%. Approximate 3-year risk reductions for ticlopidine compared with aspirin were 12% for death and nonfatal stroke, 21% for fatal or nonfatal stroke and 15.8% for recurrent cerebral ischaemia. Ticlopidine reduced the risk of stroke-related outcomes by up to 19% in males and up to 27% in females in comparison with aspirin.

In a subgroup of 927 patients from TASS who had experienced a minor stroke prior to entry, ticlopidine recipients had risk reductions of 42% (death or nonfatal stroke) and 36% (fatal or nonfatal stroke) during the first year of treatment.

Decision-analysis modelling indicates that 5-year treatment with ticlopidine would reduce the number of lifetime strokes in 100 high-risk patients by 2 at a cost-utility ratio compared with aspirin of $US31 200 to 55 500 (1991 US dollars) per quality-adjusted life-year gained.

Tolerability

Diarrhoea was the most common adverse event (incidence of about 20 to 22%; n = 4785) in patients with previous cerebral ischaemia or intermittent claudication who were treated with ticlopidine 250mg twice daily in large, double-blind clinical trials; about 10% of placebo recipients experienced diarrhoea in comparative studies of ticlopidine. 12.5% of patients in CATS and TASS experienced diarrhoea considered to be probably related to ticlopidine treatment. Other adverse events observed in ticlopidine recipients include skin rash or other dermatological conditions, nausea, dyspepsia, bleeding events, abnormal liver function and haematological disorders. Severe neutropenia developed in 0.85% of patients treated with ticlopidine in CATS and TASS, but resolved after treatment within all individuals. Several cases of fatal neutropenia have been reported in patients receiving ticlopidine.

The total incidence of adverse events in ticlopidine recipients was 54% in CATS (compared with 34% for placebo) and 62% in TASS (compared with 53% for aspirin). For ticlopidine, rates of treatment withdrawal because of adverse events were 1.5-fold higher than for aspirin and 3 to 4 times higher than for placebo.

Dosage and Administration

The recommended dosage of ticlopidine is 250mg twice daily with food. Detailed haematological monitoring (complete blood cell count and white blood cell differential at baseline and every 2 weeks) is essential during the first 3 months of ticlopidine treatment because of the risk of neutropenia; more regular monitoring is appropriate in patients who show signs of neutropenia. Ticlopidine should be used with caution in patients with an increased risk for haemorrhagic events. Dosage reduction or discontinuation may be necessary in patients with renal impairment although data are lacking in this respect. Ticlopidine is contraindicated in patients with severe liver failure, haematopoietic or haemostatic disorders or active pathological bleeding.

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    Stuart Noble & Karen L. Goa

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Various sections of the manuscript reviewed by: G.W. Albers, Stanford Stroke Center, Stanford University Medical Center, Palo Alto, California, USA; N. Anderson, Neurophysiology Department, Auckland Hospital, Auckland, New Zealand; M. Cattaneo, Hemophilia and Thrombosis Centre, Milan, Italy; T. Di Perri, Istituto di Clinica Medica Generale e Terapia Medica, Università degli Studi di Siena, Siena, Italy; M. Gent, Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada; J.C. Grotta, Department of Neurology, University of Texas Medical School, Houston, Texas, USA; G.J. Hankey, Department of Neurology, Royal Perth Hospital, Perth, Western Australia, Australia; J.W. Harbison, Department of Neurology and Ophthalmology, Medical College of Virginia, Richmond, Virginia, USA; A. Harley, The Cardiothoracic Centre — Liverpool, N.H.S. Trust, Liverpool, England; R.H. Raasch, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; J.F. Rothrock, Department of Neurology, University of South Alabama, Mobile, Alabama, USA; K. Schrör, Institutes für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; H. Tohgi, Department of Neurology, Iwate Medical University, Morioka, Japan; S. Uchiyama, Department of Neurology, Tokyo Women’s Medical College, Tokyo, Japan; M. Verstraete, Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259714.

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Noble, S., Goa, K.L. Ticlopidine. Drugs & Aging 8, 214–232 (1996). https://doi.org/10.2165/00002512-199608030-00006

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