Antiplatelet therapy in the prevention of ischaemic stroke.

Prevention of stroke is a crucial health care issue, as stroke is the third cause of death and the first cause of major disability in developed countries. The established role of platelet aggregation in TIA or minor and major ischaemic stroke has provided the rationale for many randomized trials of antiplatelet agents (aspirin, sulfinpyrazone, dipyridamole alone or in combination with aspirin, suloctidil, ticlopidine). The recent Antiplatelet Trialists' Collaboration (APT) meta-analysis (1994) based on 142 trials involving 100,000 vascular patients confirmed the data of the previous overview (1988). Aspirin, the only drug evaluated for primary prevention of ischaemic events, is not indicated for safety reasons in subjects at low risk of occlusive disease. Compared to control, antiplatelet therapy, notably aspirin which is by far the most widely used agent in trials, provides a 27% risk reduction of stroke, myocardial infarction or vascular death in patients suffering from ischaemic vascular events and a 22% risk reduction of these outcomes in patients having experienced a prior TIA/stroke. Aspirin (around 325 mg/day) and ticlopidine (500 mg/day) are currently the reference drugs for secondary prevention in cerebrovascular patients. The long term efficacy of ticlopidine, a specific antiaggregating agent, has been evaluated in two North American trials involving more than 4,000 patients. TASS showed ticlopidine to be significantly more effective in reducing the incidence of fatal or nonfatal stroke and death than aspirin in patients with TIA or minor stroke. The relative risk reductions over aspirin, the first year of greatest risk, were 41% for stroke and death and 46% for fatal or nonfatal stroke. CATS showed that ticlopidine compared with placebo induces a significant 30% relative risk reduction of stroke, myocardial infarction and vascular death over three years in patients who had suffered a recent thromboembolic stroke. The above results elicit two important issues: the optimal dose of aspirin and its tolerability compared to ticlopidine. The three controlled trials (UK-TIA, SALT, Dutch TIA) which have compared high (> or = 1 g/day) and low dose aspirin (< or = 300 mg/day) or various low doses of aspirin did not give a definite answer on the efficacy of low or very low (30 or 75 mg/day) doses of aspirin for reducing the risk of vascular outcomes in patients with stroke precursors. Even with low doses of aspirin there was still a risk of severe gastrointestinal bleeding, although minor side effects were less frequent.(ABSTRACT TRUNCATED AT 400 WORDS)

The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.

The Canadian American Ticlopidine Study (CATS) is a randomised, double-blind, placebo-controlled trial to assess the effect of ticlopidine (250 mg twice daily) in reducing the rate of subsequent occurrence of stroke, myocardial infarction, or vascular death in patients who have had a recent thromboembolic stroke. Twenty-five centres entered 1072 patients into the study between 1 week and 4 months after their qualifying stroke. The patients were treated and followed for up to 3 years (mean 24 months). In the efficacy analysis, the event rate per year for stroke, myocardial infarction or vascular death, considered together, was 15.3% in the placebo group and 10.8% in the ticlopidine group, representing a relative risk reduction with ticlopidine of 30.2% (95% confidence interval 7.5-48.3%; p = 0.006). Ticlopidine was beneficial for both men and women (relative risk reductions 28.1%, p = 0.037, and 34.2%, p = 0.045, respectively). Analysis by intention-to-treat gave a smaller estimate of risk reduction (23.3%, p = 0.020) for stroke, myocardial infarction, or vascular death. Adverse experiences associated with ticlopidine included neutropenia (severe in about 1% of cases) and skin rash and diarrhoea (severe in 2% of cases each); all were reversible. This study provides evidence of a beneficial effect of ticlopidine in both men and women with a recent thromboembolic stroke.

The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Design, organization, and baseline results.

The Canadian American Ticlopidine Study is a randomized, placebo-controlled, double-blind, multicenter study to assess the efficacy and safety of ticlopidine hydrochloride in patients who have suffered a thromboembolic stroke no less than 1 week and no more than 4 months before entry into the study. The primary assessment of efficacy will be based on the cluster of outcome events recurrent stroke, myocardial infarction, or vascular death. Twenty-five clinical centers, 12 in Canada and 13 in the United States, entered a total of 1,072 patients during a 3-year recruitment period; these patients were randomly allocated to receive either 250 mg ticlopidine or identical-appearing placebo tablets twice daily for up to 3 years. Patient recruitment was completed in December 1986. Patients were followed for a maximum of 3 years or until the close of the study in December 1987; at that time an average follow-up of 25 months had been achieved. We summarize the protocol and organization of the study and document the methods of execution and analysis, with corresponding criteria, before disclosure of the treatment code to any of the study investigators. We also provide a clinical description of the patients at entry into the study.

Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications.

In this multicenter trial 169 patients with chronic intermittent claudication due to obstructive peripheral vascular disease were randomized in a double-blind fashion into two parallel groups receiving either 250 mg ticlopidine or placebo, twice daily. At entry, the two groups (83 ticlopidine, 86 placebo) were well matched for the major clinical features apart from an excess of women in the ticlopidine group. At six months, 167 patients were alive, 2 having died of malignant disease (1 from each group). At this stage, 39 patients from the ticlopidine group and 29 from the placebo group (p = 0.04) had increased their walking distance by more than 50% of baseline values. For the groups as a whole pain-free and total walking distance were greater in the ticlopidine group than in the placebo group (194 vs 124 meters, p = 0.03 and 236 vs 170 meters, p = 0.04, respectively). Two patients from the ticlopidine group vs 9 patients from the placebo group (p = 0.03) developed significant cardiovascular events during the study. These results indicate that ticlopidine has a beneficial effect both in the treatment of the symptoms and the prevention of vascular complications in patients with intermittent claudication.

Meta-analysis of clinical trials: summary of an international conference.

An international conference of clinicians, clinical investigators and biostatisticians discussed meta-analysis in relation to clinical trials, i.e. the combination of data from separate studies for the purpose of obtaining information that cannot be derived from the individual studies. Meta-analysis can be a helpful tool for generating hypotheses for future trials, for studying the consistency of trials of the same or similar goals, and for generating more precise estimates of effect. There are still a number of unresolved questions about the methodology and interpretation of meta-analysis. Better and more uniform reporting of primary studies would increase the usefulness of meta-analysis.

A possible method to control prolongations of bleeding time under antiplatelet therapy with ticlopidine.

The interactions of oral and i.v. administrations of corticosteroids with the effects of ticlopidine were studied, in a search for an antidote for possible excessive prolongations of bleeding time induced by antiaggregating agents. Indeed, the results show that an i.v. injection of methylprednisolone or an oral treatment with prednisolone counteract the prolongation of bleeding time but do not interfere with the inhibition of platelet aggregation brought about by ticlopidine. This could be ascribed to a vasoconstrictive effect of corticosteroids, possibly through reduction of vascular prostacyclin release. If this mode of action was confirmed, this useful finding would essentially apply to ticlopidine, but not to cyclooxygenase inhibitors such as aspirin which, by themselves, abolish prostacyclin production.

The interactions of ticlopidine and aspirin in normal subjects.

This trial was performed on 24 health volunteers in order to study the possible interactions between aspirin and ticlopidine. The results confirm the inhibitory activity of aspirin on collagen-induced aggregation and that of ticlopidine on ADP-induced aggregation. If aspirin does not modify the inhibitory effect of ticlopidine on ADP-induced aggregation, ticlopidine on the other hand potentiates the effect of aspirin on collagen-induced aggregation.

Effects of ticlopidine, a new platelet aggregation inhibitor in man.

Ticlopidine is a new platelet aggregation inhibitor. The effect of this drug was studied on 55 subjects, healthy volunteers and hospitalized patients. The action requires 24 to 48 hr to appear, and lasts more than 3 days. A dose-effect relationship was studied with oral daily doses ranging from 250 to 1,000 mg during 1 wk; it showed a 50% inhibition on adenosine diphosphate (ADP)-induced aggregation at 2 muM concentration on an oral daily dose of 450 mg. No action was found on collagen-induced aggregation, and a mild effect was observed on platelet adhesiveness. Clinical tolerance was assessed in patients given ticlopidine in oral doses up to 500 mg/day during several weeks, showing no overt side effects and no change in the safety parameters.