Multicenter double-blind study of ticlopidine in the treatment of intermittent claudication and the prevention of its complications. Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication. Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo. Clinical efficacy of picotamide in long-term treatment of intermittent claudication. Effect of picotamide on the clinical progression of peripheral vascular disease. A double-blind placebo-controlled study. The ADEP Group. Double-blind, controlled, multicenter study of indobufen versus placebo in patients with intermittent claudication. Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. Efficacy of indobufen in the treatment of intermittent claudication. Results of EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease.
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. Fifty-one men with atherosclerotic intermittent claudication and haemorheological abnormalities completed a double-blind, one-year randomised trial of Ticlopidine (500 mg/day), a new antiplatelet agent. Ticlopidine caused significant inhibition of platelet aggregation but did not fully correct abnormalities of coagulation, viscosity, and fibrinolysis. There was no significant improvement in walking ability, Doppler ankle-pressure indices, or calf blood flow. Sustained platelet inhibition for 12 months was insufficient to correct the prothrombotic abnormality of extensive atherosclerosis. Many clinical trials have shown the effectiveness of platelet-antiaggregant drugs in the treatment of obliterative peripheral arteriopathy, both locally and in the system, by improving the claudication symptoms and by preventing major cardiovascular events. In this study we evaluated the effectiveness of a 24-week treatment with triflusal, a comparatively new inhibitor of platelet aggregation, in patients affected by chronic peripheral arteriopathy, comparing twice-daily oral doses of 300 mg triflusal with twice-daily placebo doses. The percentages of successes (defined as a 40% increase of total walking distance over the basal control) were 63.6% in the triflusal group (35/55 patients) and 22.5% in the placebo group (14/62 patients). Patients treated with triflusal showed a more important increase in total walking distance and in pain-free walking distance over the basal values than those treated with placebo, together with an improvement of the symptomatology correlated with claudication. Moreover, in the triflusal group there was an increase in the peak-flow recorded through strain-gauge plethysmography. In conclusion, triflusal significantly increased both the distance which could be walked and the clinical symptoms, presumably by improving microperfusion. The clinical efficacy of picotamide was investigated in a randomized, double-blind, placebo-controlled study in patients with peripheral occlusive arterial disease of the lower limbs at functional stage II of the Fontaine classification. Forty patients with a history of claudication for at least six months were admitted to the study and were given either 3 x 300 mg tablets of picotamide (20 subjects) or three identical placebo tablets (20 subjects) for six months. The two groups of patients were similar in regard to clinical features and potential risk factors. At the end of treatment painfree walking distance and systolic ankle-arm pressure ratio improved more in the picotamide than in the placebo group (p = 0.05). Systolic ankle pressure curves, determined before and after the six-month treatment, showed a positive trend to a higher postexercise ankle pressure and a faster return to the preexercise levels in the picotamide group; however, the difference was not statistically significant. Laboratory monitoring revealed a slight prolongation of bleeding time, a significant decrease in arachidonic acid-induced platelet aggregation, and an enhanced fibrinolysis with absence of interference with hemostasis in the picotamide group. One patient in the placebo group developed a major cardiovascular event (angina pectoris) during the study. These results indicate that picotamide is an effective drug that may modify the natural course of intermittent claudication and associated vascular problems. Patients with peripheral vascular disease (PVD) undergo a clinical course that can be complicated by cardiovascular events occurring in several areas of the circulation.
                In the present study we investigated the ability of picotamide, a substance that inhibits platelet thromboxane A2 (TxA2) synthase and antagonizes TxA2 receptors, to reduce cardiovascular complications in PVD patients. The study was double blind and placebo controlled. After a 1-month run-in period, 2,304 patients were randomly allocated to either placebo or picotamide (300 mg t.i.d.) and followed for 18 months. Major and minor events were analyzed. Results of an "intention-to-treat analysis" were that patients on picotamide suffered 45 major events (3.9%) and 77 minor events (6.7%), whereas those taking placebo suffered 52 major (4.5%) and 99 minor events (8.6%). There was borderline statistical difference between the two groups with respect to the sum of the major and minor events (risk reduction, 18.9%; p = 0.056, log-rank test). Results of an "on-treatment" analysis were that patients on picotamide suffered 40 major (3.8%) and 66 minor events (6.3%), whereas those taking placebo suffered 45 major (4.2%) and 95 minor events (8.9%). The sum of both major and minor events was 106 (10.1%) in the picotamide group and 140 (13.1%) in the placebo group. This difference was significant (risk reduction, 23%; p = 0.029, log-rank test).
                The results of this study indicate that picotamide reduces cardiovascular complications in PVD patients. The apparently low effect of this drug in reducing major events suggests that further studies be made with picotamide in PVD patients who are at high risk of cardiovascular complications so as to further assess its clinical efficacy. The objective of the study was to evaluate the efficacy and safety of indobufen compared with placebo in the treatment of moderately severe intermittent claudication. The study consisted of a four-week single-blind, placebo-controlled run-in phase, followed by a six-month double-blind randomized treatment period. A total of 302 patients were allocated to treatment with either placebo (154 patients) or indobufen (148) 200 mg twice daily. The results of the overall intention-to-treat analysis of the study population showed statistically significant superiority of indobufen over placebo after six months for both the initial (ICD) and absolute claudication distances (ACD). The ICD before treatment with indobufen or placebo averaged 137.9 +/- 68.2 and 136.6 +/- 63.2 m (mean +/- SD), respectively. After six months' treatment with active drug or placebo, this parameter reached 227.9 +/- 174.4 and 153.1 +/- 86.8 m (mean +/- SD), respectively (p < 0.01). Similar results were obtained on ACD. The reduction of lower limb symptoms also suggested a greater clinical benefit in the indobufen-treated patients. There was no significant change in either group in the ankle/arm pressure ratio at the end of treatment. Adverse events of any type were reported by 18 patients (12.2%) in the indobufen group and by 11 patients (7.2%) in the placebo group. The mechanism whereby the drug is effective in this clinical condition could be related to both its antiplatelet and hemorheologic effects. After a 3-month, single-blind, run-in period, 151 patients with intermittent claudication were randomly allocated to receive the antiplatelet agent ticlopidine (250 mg twice per day) or an identical placebo. One hundred and twenty patients completed the double-blind phase of the trial, which lasted 21 months. The primary analysis was performed according to the "intention-to-treat principle" in all 151 enrolled patients. There was, continuing on from the third month after randomization, a progressive and sustained improvement of the pain-free and maximum walking distances in the two treatment groups that was significantly greater in the ticlopidine group. The ankle-arm systolic blood pressure ratio at rest and after exercise increased in a significant manner in the ticlopidine group only. In a secondary analysis, with exclusion of 25 patients because of protocol violations at selection, consistently significant differences in favor of the ticlopidine group were still observed for maximum walking distance and systolic ankle-arm blood pressure ratio, both at rest and after exercise. No major side effects were reported in the treated group. It is concluded that long-term treatment with ticlopidine improves walking ability and ankle systolic blood pressure in patients with claudication. Patients with diabetes are at excessive risk of mortality and cardiovascular morbidity. Previous studies suggest that aspirin may be less effective in diabetic patients. In this multi-centre, randomized, double blind trial picotamide, a dual inhibitor of thromboxane A2 synthase and receptor, was compared with aspirin for the prevention of mortality and major cardiovascular events in diabetics with peripheral arterial disease (PAD).
                A total of 1209 adults aged 40-75 years with type 2 diabetes and PAD were randomized to receive picotamide (600 mg bid) or aspirin (320 mg od) for 24 months. The cumulative incidence of the 2 years overall mortality was significantly lower amongst patients who received picotamide (3.0%) than in those who received aspirin (5.5%) with a relative risk ratio for picotamide versus aspirin of 0.55 (95% CI: 0.31-0.98%). Events were reported in 43 patients (7.1%) on picotamide and 53 (8.7%) on aspirin. The combined endpoint of mortality and morbidity had a slightly lower incidence in the picotamide group but this difference did not reach statistical significance.
                Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD. The Swedish Ticlopidine Multicentre Study (STIMS) was a double-blind placebo-controlled trial designed to determine whether ticlopidine, a platelet antiaggregatory agent, reduces the incidence of myocardial infarction, stroke and transitory ischaemic attacks in patients with intermittent claudication. A total of 687 patients was monitored for a minimum of 5 years or until an end-point was reached. The number of end points (99 vs. 89), analysed according to the intention-to-treat principle, was 11.4% lower in the ticlopidine group (P = 0.24). The mortality rate was 29.1% lower in the ticlopidine group (64 vs. 89, P = 0.015); this observation could be accounted for by a reduced mortality from ischaemic heart disease. On-treatment analysis showed there to be significantly fewer end points in the ticlopidine group (47 vs. 76, P = 0.017). Diarrhoea was the most common side-effect. Reversible leucopenia or thrombocytopenia was reported in seven patients on ticlopidine. It is concluded that the high morbidity and mortality from cardio- and cerebrovascular disease in patients with intermittent claudication can be reduced by long-term treatment with ticlopidine. The aim of this trial was to assess the activity of indobufen compared with placebo in peripheral occlusive arterial disease of the lower limbs of atherosclerotic or diabetic origin. Fifty-two outpatients were admitted to the randomized, double-blind study and were given either an indobufen 200-mg tablet (28 subjects) or placebo (24) for six months. Painfree walking distance on a treadmill at a constant speed (4 km/h) and slope (10 degrees) was assessed before and after three and six months' treatment. The painfree walking distance before treatment with indobufen or placebo averaged 153 +/- 23.02 (mean +/- SE) and 199 +/- 30.58 (mean +/- SE) meters respectively. After six months' treatment with active drug or placebo, this parameter reached 610 +/- 115.36 (p less than 0.01) and 243 +/- 32.49 (p greater than 0.05) meters respectively. The difference between the two treatments was statistically significant in favor of indobufen (p less than 0.01 Dunn's test). EMATAP, a randomized stratified, placebo-controlled double-blind multicentre trial was performed in Argentina in order to confirm the effect of ticlopidine in the prevention of thrombotic events in patients with intermittent claudication. Twenty-one clinical centres enrolled 615 patients, 304 (88 diabetic and 216 non diabetic) were assigned to the ticlopidine group and 311 (95 diabetic and 216 non diabetic) to the placebo group. Treatments were given for 24 weeks. The baseline characteristics were identical in both groups. The compliance was good and only 34 patients (17 in each group) did not reach the last visit. Their status however was checked and known at that time and according to the protocol, there was no patient lost to follow-up. Twenty-five patients experienced a first event during the follow-up period and the results show a very dramatic reduction of events in the ticlopidine group (5 vs 20), the difference being highly significant (p = 0.002) in intention-to-treat analysis. If we consider the subgrouping of outcome events: sudden deaths, myocardial infarctions and strokes on the one hand, vascular surgery on the other hand, a significant reduction is found in the ticlopidine group. Taking into account the total deaths plus non-fatal events (9 vs 21), the results were also significant (p = 0.027). These above results therefore demonstrate a consistent reduction in all outcome events. As regard side effects there were fewer gastro-intestinal disturbances and skin reactions than seen in North American trials.(ABSTRACT TRUNCATED AT 250 WORDS)
Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC. Treatment with antiplatelet agents in this patient group however is associated with an increase in adverse effects, including GI symptoms, and healthcare professionals and patients need to be aware of the potential harm as well as the benefit of therapy; more data are required on the effect of antiplatelets on major bleeding. Evidence on the effectiveness of aspirin versus either placebo or an alternative antiplatelet agent is lacking. Evidence for thienopyridine antiplatelet agents was particularly compelling and there is an urgent need for multicentre trials to compare the effects of aspirin against thienopyridines.