AUC values of ticlopidine increased by 28% and 60% in mild and moderately impaired patients, respectively, and plasma clearance decreased by 37% and 52%, respectively, but there were no statistically significant differences in ADP-induced platelet aggregation. In this small study (26 patients), bleeding times showed significant prolongation only in the moderately impaired patients.

Pharmacodynamics: In healthy volunteers over the age of 50, substantial inhibition (over 50%) of ADP-induced platelet aggregation is detected within 4 days after administration of ticlopidine hydrochloride 250 mg bid, and maximum platelet aggregation inhibition (60% to 70%) is achieved after 8 to 11 days. Lower doses cause less, and more delayed, platelet aggregation inhibition, while doses above 250 mg bid give little additional effect on platelet aggregation but an increased rate of adverse effects. The dose of 250 mg bid is the only dose that has been evaluated in controlled clinical trials.

After discontinuation of ticlopidine hydrochloride, bleeding time and other platelet function tests return to normal within 2 weeks, in the majority of patients.

At the recommended therapeutic dose (250 mg bid), ticlopidine hydrochloride has no known significant pharmacological actions in man other than inhibition of platelet function and prolongation of the bleeding time.

Clinical Trials

Stroke Patients: The effect of ticlopidine on the risk of stroke and cardiovascular events was studied in two multicenter, randomized, double-blind trials.

1. Study in Patients Experiencing Stroke Precursors: In a trial comparing ticlopidine and aspirin (The Ticlopidine Aspirin Stroke Study or TASS), 3069 patients (1987 men, 1082 women) who had experienced such stroke precursors as transient ischemic attack (TIA), transient monocular blindness (amaurosis fugax), reversible ischemic neurological deficit or minor stroke, were randomized to ticlopidine 250 mg bid or aspirin 650 mg bid. The study was designed to follow patients for at least 2 years and up to 5 years.

Over the duration of the study, TICLID significantly reduced the risk of fatal and nonfatal stroke by 24% (p = .011) from 18.1 to 13.8 per 100 patients followed for 5 years, compared to aspirin. During the first year, when the risk of stroke is greatest, the reduction in risk of stroke (fatal and nonfatal) compared to aspirin was 48%; the reduction was similar in men and women.

2. Study in Patients Who Had a Completed Atherothrombotic Stroke: In a trial comparing ticlopidine with placebo (The Canadian American Ticlopidine Study or CATS) 1073 patients who had experienced a previous atherothrombotic stroke were treated with TICLID 250 mg bid or placebo for up to 3 years.

TICLID significantly reduced the overall risk of stroke by 24% (p = .017) from 24.6 to 18.6 per 100 patients followed for 3 years, compared to placebo. During the first year the reduction in risk of fatal and nonfatal stroke over placebo was 33%.

Stent Patients: The ability of TICLID to reduce the rate of thrombotic events after the placement of coronary artery stents has been studied in five randomized trials, one of substantial size (Stent Anticoagulation Restenosis Study or STARS) described below, and four smaller studies. In these trials, ticlopidine 250 mg bid with ASA (dose range from 100 mg bid to 325 mg qd) was compared to aspirin alone or to anticoagulant therapy plus aspirin. The trials enrolled patients undergoing both planned (elective) and unplanned coronary stent placement. The types of stents used, the use of intravascular ultrasound, and the use of high-pressure stent deployment varied among the trials, although all patients in STARS received a Palmaz-Schatz stent. The primary efficacy endpoints of the trials were similar, and included death, myocardial infarction and the need for repeat coronary angioplasty or CABG. All trials followed patients for at least 30 days.

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