Synopsis Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peri-pheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience. Pharmacological Properties Ticlopidine is a thienopyridine derivative which has a broad spectrum antiaggregating activity. In ex vivo studies of platelets obtained from healthy volunteers and patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease, or other conditions associated with platelet hyperaggregation, ticlopidine inhibits ADP-induced platelet aggregation. A maximal effect was seen 3 to 5 days after repeated administration in healthy volunteers and this can be seen for up to 10 days after withdrawal of drug treatment. Inhibition of ex vivo platelet aggregation induced by other platelet agonists such as arachidonic acid, collagen, thrombin and platelet activating factor (PAF)-acether has also been reported, although this may not be a direct effect but rather a result of the inhibitory effect of ticlopidine on aggregation produced by ADP released by low concentrations of these agonists. Other ticlopidine-induced effects resulting from its interaction with ADP and platelets include a decrease in platelet deposition on atheromatous plaque in patients with cerebrovascular disease, reduced fibrinogen levels and blood viscosity in patients with peripheral arterial disease, and normalised platelet adhesiveness, erythrocyte deformability and β-thromboglobulin release in diabetic patients. Ticlopidine also prolongs bleeding time, with a maximal effect seen after 5 to 6 days in volunteers. The influence of ticlopidine on a variety of platelet agonists suggests a common site of action at an early stage of the platelet activating process. No comprehensive mechanism of action has been proposed, but inhibition of the ADP-induced exposure of the fibrinogen-binding site of the glycoprotein IIb-IIIa complex has been demonstrated. About 80 to 90% of an oral ticlopidine dose is absorbed, with plasma concentrations peaking at 1 to 3 hours. Steady-state peak and trough plasma concentrations of 0.9 mg/ L and 0.2 mg/L, respectively, have been achieved after ticlopidine 250mg twice daily for 14 days. Ticlopidine is rapidly and extensively metabolised, with 1 metabolite more active than the parent drug. A terminal elimination half-life of 96h at steady-state has been reported in healthy volunteers. In the elderly the AUC and half-life of ticlopidine are significantly prolonged compared with younger volunteers after a single dose but this was not significant at steady-state. No studies evaluating the pharmacokinetics of ticlopidine in patients with major organ dysfunction have been published. Therapeutic Trials Since the initial review of ticlopidine appeared in the Journal, attention has focused on the effectiveness of the drug in patients at high risk of thromboembolic events, i.e. those with transient ischaemic attacks and stroke, peripheral arterial disease or ischaemic heart disease. A large multicentre trial, the Canadian-American Ticlopidine Study (CATS) completed since the first review, has demonstrated that ticlopidine administered as a 250mg dose twice daily in patients who had had a recent stroke reduced the incidence of stroke, myocardial infarction or vascular death by 30.2% compared with placebo. Another large trial in more than 3000 patients [the Ticlopidine Aspirin Stroke Study (TASS)] has shown that ticlopidine has a more pronounced preventative effect on death from all causes or nonfatal stroke compared with aspirin. This was statistically significant within 1 year and was maintained over a 5-year period. Ticlopidine appears to be equally effective in women and men. Major clinical trials in patients with intermittent claudication resulting from peripheral arterial disease demonstrate that ticlopidine 250mg twice daily improves walking ability during treatment periods of 6 to 21 months. A reduction in the total mortality rate (by 29.1% compared with placebo), mainly because of its marked effect on ischaemic heart disease mortality, was seen in the Swedish Ticlopidine Multicentre Study (STIMS). In the same trial, the incidence of acute myocardial infarction, stroke, or transient ischaemic attack was significantly lowered by ticlopidine during an average period of 5.6 years. Results of another multicentre study show that ticlopidine 500 mg/day begun within 48 hours of admission reduces the risk of acute myocardial infarction, myocardial infarction and sudden death, and vascular mortality in patients with unstable angina. Ticlopidine also appears to reduce anginal pain to a similar extent to aspirin if administered within 24 hours of acute myocardial infarction. Other indications in which ticlopidine shows some benefit include the following: prevention of thrombotic events in patients undergoing haemodialysis, coronary artery bypass surgery, carotid endarterectomy or extracorporeal circulation; prevention of nonproliferative diabetic retinopathy; and prevention of cerebral vasospasm following subarachnoid haemorrhage. The effectiveness of the drug in Raynaud’s phenomenon, sickle cell disease, ocular vein occlusion, glomerulonephritis and the prevention of postoperative thrombosis and bleeding remains uncertain. Adverse Effects The findings of a large placebo-controlled study in 1053 patients with a recent thromboembolic stroke show a higher incidence of adverse effects associated with ticlopidine compared with placebo: 54% of ticlopidine recipients and 34% of placebo recipients experienced an adverse symptom over a 3-year period. Of these patients, 12 and 3%, respectively, required withdrawal of treatment. The incidence of adverse effects was roughly similar in patients treated with ticlopidine or aspirin over a 2-to 6-year period, although ticlopidine recipients had almost twice the incidence of diarrhoea and skin rash whereas more peptic ulcers were reported in the aspirin group. The most common adverse effects associated with ticlopidine are gastrointestinal symptoms: diarrhoea is the most frequently reported, affecting about 20% of treated patients. Other effects are skin reactions (urticaria, pruritus, erythema), haemorrhagic disorders (epistaxis, ecchymoses, menorrhagia), and haematological disorders (leucopenia, thrombocytopenia, pancytopenia). These effects are generally not severe and resolve on discontinuation of ticlopidine treatment. The most potentially serious symptoms are haematological disturbances and close monitoring is therefore essential for at least the first 12 weeks of ticlopidine therapy. Abnormal liver function is rare with ticlopidine therapy but in instances where a definite causal relationship was determined, abnormal effects disappeared on withdrawal of treatment. Ticlopidine has also been associated with an increase in total cholesterol levels. Dosage and Administration A daily dosage of ticlopidine 500mg, administered orally as two 250mg tablets with food, is recommended. Up to 4 tablets (daily dosage 1000mg) can be administered for short term treatment but patients require careful monitoring. All patients receiving ticlopidine should be monitored during at least the first 12 weeks because of the risk of haematological disturbances. Ticlopidine is contraindicated in patients receiving high dose heparin, those with a history of bleeding disorders, gastroduodenal ulcer or those in the acute phase of haemorrhagic cerebral vascular accident. © 1990, Adis International Limited. All rights reserved.
