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.

Summary. Background: Idraparinux is an inhibitor of activated factor X (FXa) with a long half-life allowing once-weekly dosing. Idrabiotaparinux is a biotinylated version of idraparinux; its activity can be reversed with avidin. Objective: To investigate the tolerability, safety and pharmacodynamics of avidin in healthy subjects and patients with deep vein thrombosis (DVT) receiving idrabiotaparinux. Patients and Methods: In a placebo-controlled, randomized, double-blind Phase I study, 41 healthy males received subcutaneous idrabiotaparinux before being randomized to a 30-min intravenous avidin infusion or placebo. Idrabiotaparinux plus avidin were re-administered 10-14 months later in eight subjects. In addition, in a prospective substudy of the Phase III EQUINOX trial, 55 patients who received weekly idrabiotaparinux for 6 months were randomized to receive either 100 mg avidin (n = 33) or placebo (n = 22). The primary activity outcome was anti-FXa activity calculated immediately before and after avidin infusion. Adverse events were recorded to assess safety and tolerability. Results: Avidin rapidly reversed the anti-FXa activity of idrabiotaparinux, ranging from 66.1 to 90.3% in healthy subjects and from 67 to 97% (mean 78%) in DVT patients. Avidin was well tolerated, with a similar nature and frequency of adverse events to placebo. No venous thromboembolism recurrence occurred in the 3-month post-avidin infusion. Conclusion: A 30-min intravenous infusion of avidin 100 mg is well tolerated, safe, and offers immediate and specific reversibility both after single and repeated doses of idrabiotaparinux in healthy subjects, and in DVT patients following a 6-month treatment period.

SummaryThis study meta-analysed randomized, double-blind, placebo controlled trials in patients with intermittent claudication of the lower limbs comparing ticlopidine to placebo in order to test the hypothesis that the drug, a pure antiplatelet agent, is able to reduce the incidence of thrombotic cardio-vascular events on atherosclerotic arteries in these patients. A highly significant reduction, from 9% to 3% (p ranging from 0.006 to 0.002), was observed for fatal or non-fatal cardio-vascular events in a total of 611 patients (301 with ticlopidine, 310 with placebo). The duration of follow-up ranged from 6 to 12 months. Side-effects, defined as withdrawal from study medication for any reason but death, cardio-vascular events or cancer, were 2.4 times more frequent in the ticlopidine treated patients as compared to placebo. We concluded that in this high risk population, prevention of cardio-vascular events is likely to be effective.

A cohort of thirty-five patients with angina pectoris were followed-up for six months with placebo as the only anti-anginal treatment apart from short-acting nitroglycerin. Only patients with at least five attacks per week were entered into the study. Prior to the study, their average number of attacks per week was 10.3(+/- 0.9) and their average nitroglycerin tablet consumption per week was 10.6(+/- 1.2). After admission into the study, the individual dosage of placebo could be blindly titrated during the first eight weeks. Once an adequate dosage was found, it was continued for 6 months. The primary end-point was predefined success or failure of the placebo treatment. Failure was assessed on the lack of improvement, occurrence of 'side-effects', or need for other anti-anginal treatment. In 27 patients, the placebo treatment was said to be a success (95% confidence limits of the percentage of success: 60-90%). No severe cardiac event occurred (confidence limits: 0-10%). Six patients developed 'side-effects'. The number of attacks per week decreased by 48% (P less than 0.0001) during the titration period (8 weeks) and by 77% during the whole 6 months. Exercise test improved, however, less markedly.

Idrabiotaparinux is a novel synthetic anticoagulant that links idraparinux, a specific, indirect factor Xa inhibitor, to biotin. The long half-life of idraparinux allows once-weekly (o.w.) subcutaneous (s.c.) injection. Avidin, a hen egg protein, specifically and tightly binds with biotin. When given by intravenous (i.v.) infusion, avidin (half life: 15-minutes) reverses the anti-factor Xa (a-Xa) activity of idrabiotaparinux by forming a complex that is rapidly cleared from the circulation. Idraparinux 2.5 mg s.c. o.w. was effective and safe in the van Gogh DVT trial of 2904 patients with deep vein thrombosis (DVT), when compared with standard anticoagulant therapy 1. Methods: In EQUINOX, patients with symptomatic and confirmed DVT were randomised to receive weekly s.c. injection of equimolar amounts of idrabiotaparinux (3 mg) or idraparinux (2.5 mg) for 6 months. The aims of this multicentre, double-blind, study were to demonstrate, at the end of the 6 months of therapy, bioequipotency of idrabiotaparinux with idraparinux, to measure the effect of i.v. avidin on peak circulating a-Xa activity, and to document efficacy and safety. The main outcome events were clinically relevant bleeding (major or not), death, or symptomatic recurrent venous thromboembolism (VTE) within 6 months of randomisation, assessed by a blinded independent adjudication committee. Reversal of anticoagulant effect by 100 mg i.v. avidin infused over 30 minutes, and its safety, were assessed in a subset of patients re-randomised at 6 months and blindly allocated to receive avidin (idrabiotaparinux arm) or placebo (idrabiotaparinux and idraparinux arms, to preserve blinding). Avidin or placebo was infused 2–5 hours (around tmax) after the last injection of the 6 month treatment period; plasma a-Xa activity was measured just before avidin/placebo infusion, just after, and then for 5 days. Results: Of 757 patients randomised, 385 received idrabiotaparinux and 370 idraparinux. Overall, 22.7% had previous venous thromboembolism (VTE), 5.2% had cancer within the past 6 months, 53.8% had apparently unprovoked thrombosis, and 36.2% were aged >65. There was less clinically relevant bleeding (20 v. 27; 5.2% v. 7.3%) and less major bleeding (3 v. 14; 0.8% v. 3.8%) with idrabiotaparinux than with idraparinux. Rates of recurrent VTE and of fatal or non-fatal pulmonary embolism PE were similar with idrabiotaparinux and idraparinux (VTE: 9 v. 12; 2.3% v. 3.2%. PE: 6 v. 7; 1.6% v. 1.8%). Trough levels of a-Xa activity were identical in the treatment groups throughout 6 months. Of 52 idrabiotaparinux patients re-randomised at 6 months to receive i.v. avidin or placebo, 41 were analysable for reversal of a-Xa activity (23 avidin and 18 placebo). At the end of the 30 minute avidin infusion, mean anti-Xa activity was reduced by 77.8%, sustained for at least 5 days, compared with 2.4% after placebo (p = 3.45 × 10−15). No allergic reactions were observed to avidin. Conclusion: A 6-month treatment period with idrabiotaparinux, compared to idraparinux in patients with DVT, showed a comparable efficacy with a trend to less bleeding. Trough a-Xa activity was identical in the two groups. Avidin infusion at around tmax after the last idrabiotaparinux injection led to rapid and substantial reversal of a-Xa activity, sustained for at least 5 days. Avidin infusion was well-tolerated.