title: The Effects of Cilostazol on Peripheral Neuropathy in Diabetic Patients With Peripheral Arterial Disease Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Results of EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease. Effects of captopril and ticlopidine, alone or in combination, in hypertensive patients with intermittent claudication. Effect of cilostazol treatment on adiponectin and soluble CD40 ligand levels in diabetic patients with peripheral arterial occlusion disease. A double‐blind trial of suloctidil v. Placebo in intermittent claudication One-year cardiovascular event rates in outpatients with atherothrombosis. Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Bezafibrate in men with lower extremity arterial disease: randomised controlled trial Peripheral artery occlusion: treatment with abciximab plus urokinase versus with urokinase alone--a randomized pilot trial (the PROMPT Study). Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Blood Viscosity During Long-Term Treatment with Ticlopidine in Patients with Intermittent Claudication. A Double-Blind Study Comparison of beraprost and ticlopidine in Chinese patients with chronic peripheral arterial occlusion: a multicenter, single-blind, randomized, controlled study. Effects of ticlopidine on blood fibrinogen and blood viscosity in peripheral atherosclerotic disease. Therapeutic Effect of Ticlopidine, a New Inhibitor of Platelet Aggregation, on Chronic Arterial Occlusive Diseases, a Double-blind Study versus Placebo Effects of Policosanol and Ticlopidine in Patients with Intermittent Claudication: A Double-Blinded Pilot Comparative Study Comparative Safety and Tolerability of Clopidogrel and Aspirin Treatment of Intermittent Claudication with Antiplatelet Agents The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease Treatment of claudication with dipyridamole and aspirin. A Comparison Between Aspirin and Pentoxifylline in Relieving Claudication Due to Peripheral Vascular Disease in the Elderly Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients. Long-Term Evaluation of Indobufen in Peripheral Vascular Disease A dose-effect study of beraprost sodium in intermittent claudication. Three-Month Therapy with Calcium-Heparin in Comparison with Ticlopidine in Patients with Peripheral Arterial Occlusive Disease at Leriche-Fontaine IIb Class Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Prevention of myocardial infarction and stroke in patients with intermittent claudication; effects of ticlopidine. Results from STIMS, the Swedish Ticlopidine Multicentre Study. The effect of hydroxyethylrutoside and its combination with acetylsalicylic acid in patients with obliterative atherosclerosis. Thrombin and platelet inhibition with low-dose calcium-heparin in comparison with ASA in patients with peripheral arterial occlusive disease at Leriche-Fontaine IIb class. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. Randomized clinical trial of the antiplatelet effects of aspirin–clopidogrel combination versus aspirin alone after lower limb angioplasty Effect of cloricromene on intermittent claudication. A randomized, double-blind, placebo-controlled trial in patients treated with aspirin: effect on claudication distance and quality of life Indobufen versus dipyridamole plus aspirin in the treatment of patients with peripheral atherosclerotic disease. Platelet inhibition with Ticlopidine in atherosclerotic intermittent claudication. [Dose-dependent side effects of acetylsalicylic acid therapy. Results of a prospective randomized clinical study in patients with peripheral arterial occlusive disease]. [The effects of ticlopidine and nifedipine on platelet aggregation in patients with obliterating arteriopathy of the lower limbs]. Reliability of treadmill testing in peripheral arterial disease: a comparison of a constant load with a graded load treadmill protocol Effects of Policosanol and Lovastatin in Patients with Intermittent Claudication: A Double-Blind Comparative Pilot Study [The clinico-instrumental evaluation of the efficacy of picotamide in treating chronic obstructive arteriopathies of the lower extremities]. Triflusal in the treatment of patients with chronic peripheral arteriopathy: multicentre double-blind clinical study vs placebo. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time. Multicenter Double-Blind Study of Ticlopidine in the Treatment of Intermittent Claudication and the Prevention of its Complications Controlled trial of high-versus low-dose aspirin treatment after percutaneous transluminal angioplasty in patients with peripheral vascular disease [Platelet aggregation inhibitory therapy in chronic arterial occlusive disease of the lower limbs: results of short-term clinico-instrumental study with indobufen]. Inhibition of spontaneous platelet aggregation and adhesion by indobufen (K 3920). A randomized, double-blind crossover study on platelet, coagulation and fibrinolysis function tests. Double-blind, controlled, multicenter study of indobufen versus placebo in patients with intermittent claudication. Long term prognosis in patients with peripheral arterial disease treated with antiplatelet agents. A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Mortality over a period of 10 years in patients with peripheral arterial disease. Impact of a 4-Week Treatment with Prostaglandin E1 on Health-Related Quality of Life of Patients with Intermittent Claudication Clinical Efficacy of Picotamide in Long-Term Treatment of Intermittent Claudication Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease. Results from the A.D.E.P. study. A human model of platelet–leucocyte adhesive interactions during controlled ischaemia in patients with peripheral vascular disease DRUG-INDUCED INHIBITION OF PLATELET FUNCTION DELAYS PROGRESSION OF PERIPHERAL OCCLUSIVE ARTERIAL DISEASE: A Prospective Double-Blind Arteriographically Controlled Trial A Double-Blind, Placebo-Controlled Study of the Effects of Policosanol in Patients with Intermittent Claudication Use of Abciximab and Tirofiban in Patients with Peripheral Arterial Occlusive Disease and Arterial Thrombosis Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. Decrease of fibrinogen in patients with peripheral atherosclerotic disease by ticlopidine. [The effect of oral trapidil therapy on clinical and hemorheological parameters in arteriosclerosis obliterans in comparison to pentoxifylline--a pilot study]. Aspirin in peripheral arterial disease: breakthrough or pitfall? Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS). Sarpogrelate, a 5-HT2A receptor antagonist in intermittent claudication. A Phase II European study The STIMS Trial: The Ticlopidine Experience and its Clinical Applications Effect of Picotamide on the Clinical Progression of Peripheral Vascular Disease A Double‐Blind Placebo‐Controlled Study Physical Training and Antiplatelet Treatment in Stage II Peripheral Arterial Occlusive Disease: Alone or Combined? Picotamide, a combined inhibitor of thromboxane A2 synthase and receptor, reduces 2-year mortality in diabetics with peripheral arterial disease: the DAVID study. Effect of acetylsalicylic acid and dipyridamole on platelet survival and aggregation in patients with atherosclerosis obliterans. Inhibition of spontaneous platelet aggregation by sulfinpyrazone. Role of systolic blood pressure and plasma triglycerides in diabetic peripheral arterial disease. The Edinburgh Artery Study. Hemodynamic, Hemorheologic, and Hemocoagulative Changes After Treatment With Picotamide in Patients Affected by Peripheral Arterial Disease (PAD) of the Lower Limbs A Long-Term Study of Policosanol in the Treatment of Intermittent Claudication Variability in responsiveness to clopidogrel in patients with intermittent claudication. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. Clopidogrel has no effect on D-dimer and thrombin-antithrombin III levels in patients with peripheral arterial disease undergoing peripheral percutaneous transluminal angioplasty. Treatment of intermittent claudication with beraprost sodium, an orally active prostaglandin I2 analogue: a double-blinded, randomized, controlled trial. The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease. Medical treatment of intermittent claudication: a comparative double-blind study of suloctidil, dihydroergotoxine and placebo. [Heparan sulphate in association with indobufen in the treatment of chronic peripheral obliterative arteriopathy of the lower extremities. Controlled clinical trial]. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. Platelet survival, atherosclerotic intermittent claudication and ticlopidine. Effects of Indobufen and Pentoxifylline on Walking Capacity and Hemostasis in Patients with Intermittent Claudication: Results of Six Months of Treatment [Effect of ticlopidine on peripheral obliterating arteriopathy]. Efficacy of Indobufen in the Treatment of Intermittent Claudication The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease Ticlopidine in the treatment of intermittent claudication: a 21-month double-blind trial. [Double-blind study of the effect of dipyridamole in patients with intermittent claudication]. The Vascular and Biochemical Effects of Cilostazol in Diabetic Patients With Peripheral Arterial Disease
abstract: Background Evidence from diabetic animal models suggests that cilostazol , a cyclic AMP phosphodiesterase inhibitor used in the treatment of claudication , is efficacious in the treatment of peripheral neuropathy , although this is unproven in humans . The main aim of this study was to assess the effects of cilostazol on neuropathic symptomatology in diabetic patients with peripheral arterial disease ( PAD ) . Methods Diabetic patients with PAD were prospect ively recruited to a r and omized double-blinded placebo-controlled trial . Baseline clinical data were recorded prior to trial commencement following medical optimization . Neurological assessment included the Toronto Clinical Neuropathy Scoring system ( TCNS ) and vibration perception thresholds ( VPT ) with a neurothesiometer  at baseline , 6 weeks , and 24 weeks . Results Twenty-six patients were recruited from December 2004 to January 2006 , which included 20 males . Baseline patient allocation to treatment arms was matched for age , sex , and medical comorbidities . There was no significant difference in neurological assessment between the treatment groups using the TCNS and VPT at 6 and 24 weeks . Conclusions Despite extensive animal-based evidence that cilostazol attenuates neuropathic symptomatology , our results do not support this effect in human diabetic PAD patients Cilostazol is an antiplatelet agent and vasodilator marketed in Japan for treatment of ischemic symptoms of peripheral vascular disease . It is currently being evaluated in the United States for treatment of symptomatic intermittent claudication ( IC ) .  Cilostazol has been shown to improve walking distance in patients with IC . In addition to its reported vasodilator and antiplatelet effects , cilostazol has been proposed to have beneficial effects on plasma lipoproteins . We examined the effect of cilostazol versus placebo on plasma lipoproteins in 189 patients with IC . After 12 weeks of therapy with 100 mg cilostazol BID , plasma triglycerides decreased 15 % ( P<0.001 ) . Cilostazol also increased plasma high density lipoprotein cholesterol ( HDL-C ) ( 10 % ) and apolipoprotein ( apo ) A1 ( 5.7 % ) significantly ( P<0.001 and P<0.01 , respectively ) . Both HDL3 and HDL2 subfractions were increased by cilostazol ; however , the greatest percentage increase was observed in HDL2 . Individuals with baseline hypertriglyceridemia ( > 140 mg/dL ) experienced the greatest changes in both HDL-C and triglycerides with cilostazol treatment . In that subset of patients , HDL-C was increased 12.2 % and triglycerides were decreased 23 % . With cilostazol , there was a trend ( 3 % ) toward decreased apoB as well as increased apoA1 , result ing in a significant ( 9.8 % , P<0.002 ) increase in the apoA1 to apoB ratio . Low density lipoprotein cholesterol and lipoprotein(a ) concentrations were unaffected . Cilostazol treatment result ed in a 35 % increase in treadmill walking time ( P=0.0015 ) and a 9.03 % increase in ankle-brachial index ( P<0.001 ) . These results indicate that in addition to improving the symptoms of IC , cilostazol also favorably modifies plasma lipoproteins in patients with peripheral arterial disease . The mechanism of this effect is currently unknown EMATAP , a r and omized 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 infa rct ions and strokes on the one h and , vascular surgery on the other h and , 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 Twenty four male hypertensive patients suffering also from peripheral obstructive arterial disease were r and omly subdivided in two groups and after a period of farmacological wash-out of one month Group I was treated with Captopril ( C 50 mg bid ) or Ticlopidine ( T 250 mg bid ) for three months and then with the association C plus T for three months again . After placebo administration for one month , patients were further treated with C plus T at low doses ( 25 mg bid and respectively 250 mg daily ) . In the first part of the study , patients of Group II received an inverse sequence of the drugs ( before Ticlopidine 250 mg bid and then Captopril 50 bid ) . In both groups of patients C induced a significant decrease of blood pressure and an increase of PFWD , TWD , and WI . T did not modify blood pressure but slightly increased PFWD , TWD , and WI . The improvement was more evident during administration of C plus T , whereas placebo administration induced a trend toward baseline values . Finally , the chronic administration of C plus T for twelve months induced a further improvement of all considered parameters . In conclusion , chronic administration of C plus T may be useful in the treatment of hypertensive patients suffering from intermittent claudication  , improving significantly PFWD and TWD BACKGROUND Peripheral arterial occlusion disease ( PAOD ) is caused mainly by chronic inflammation and endothelium dysfunction , and is often treated with cilostazol . However , because this drug 's influence on atherogenic cytokines is still not well known , this study examined the effect of cilostazol on the serum levels of soluble CD40 lig and ( sCD40L ) , adiponectin and high-sensitivity C-reactive protein ( hs-CRP ) in patients with type 2 diabetes and PAOD . METHODS AND RESULTS The 92 type 2 diabetics with PAOD and 100 non-PAOD diabetics were enrolled and r and omly assigned to a group receiving either cilostazol or placebo for 6 months . The atherogenic cytokines were measured at the beginning and completion of the study . In the PAOD groups , those in the cilostazol group had significant changes in the levels of hs-CRP , sCD40L and adiponectin ( P=0.001 , P=0.05 , P=0.004 , respectively ) . Changes in the levels of adiponectin and sCD40L were more significant in the PAOD group treated with cilostazol than in the non-PAOD group also treated with the drug ( P=0.01 and P=0.008 , respectively ) . CONCLUSIONS Cilostazol can decrease hs-CPR and sCD40L levels and increase that of adiponectin , and then delay the progression of atherogenesis and chronic inflammation in type 2 diabetics , especially those with PAOD In a recent double‐blind trial lasting over 6 months , 40 patients suffering from intermittent claudication were r and omly allocated to receive 300 mg of suloctidil per day or exactly matching placebo capsules . In addition to treadmill walking distance , other objective criteria including ankle blood pressure response and muscle blood flow measured by 133Xe clearance were used to assess the effectiveness of therapy CONTEXT Few data document current cardiovascular ( CV ) event rates in stable patients with atherothrombosis in a community setting . Differential event rates for patients with documented coronary artery disease ( CAD ) , cerebrovascular disease ( CVD ) , or peripheral arterial disease ( PAD ) or those at risk of these diseases have not been previously evaluated in a single international cohort . OBJECTIVE To establish contemporary , international , 1-year CV event rates in out patients with established arterial disease or with multiple risk factors for atherothrombosis . DESIGN , SETTING , AND PARTICIPANTS The Reduction of Atherothrombosis for Continued Health ( REACH ) Registry is an international , prospect i ve cohort of 68 236 patients with either established atherosclerotic arterial disease ( CAD , PAD , CVD ; n = 55 814 ) or at least 3 risk factors for atherothrombosis ( n = 12 422 ) , who were enrolled from 5587 physician practice s in 44 countries in 2003 - 2004 . MAIN OUTCOME MEASURES Rates of CV death , myocardial infa rct ion ( MI ) , and stroke . RESULTS As of July 2006 , 1-year outcomes were available for 95.22 % ( n = 64 977 ) of participants . Cardiovascular death , MI , or stroke rates were 4.24 % overall : 4.69 % for those with established atherosclerotic arterial disease vs 2.15 % for patients with multiple risk factors only . Among patients with established disease , CV death , MI , or stroke rates were 4.52 % for patients with CAD , 6.47 % for patients with CVD , and 5.35 % for patients with PAD . The incidences of the end point of CV death , MI , or stroke or of hospitalization for atherothrombotic event(s ) were 15.20 % for CAD , 14.53 % for CVD , and 21.14 % for PAD patients with established disease . These event rates increased with the number of symptomatic arterial disease locations , ranging from 5.31 % for patients with risk factors only to 12.58 % for patients with 1 , 21.14 % for patients with 2 , and 26.27 % for patients with 3 symptomatic arterial disease locations ( P<.001 for trend ) . CONCLUSIONS In this large , contemporary , international study , out patients with established atherosclerotic arterial disease , or at risk of atherothrombosis , experienced relatively high annual CV event rates . Multiple disease locations increased the 1-year risk of CV events BACKGROUND Clopidogrel is a more potent antiplatelet agent than aspirin , result ing in greater clinical efficacy in patients with atherothrombotic disease . Furthermore , the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting . Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown . METHODS AND RESULTS The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management , and Avoidance ( CHARISMA ) study was design ed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary , cerebral , or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event . This r and omized , international , multicenter , double-blinded , placebo-controlled study has finished enrolling patients worldwide . A total of 15,603 patients will be followed long term . The primary end point will be the composite of vascular death , myocardial infa rct ion , or stroke . Rates of severe bleeding will also be compared between the two arms of the study . CONCLUSIONS This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current st and ard of care , including low-dose aspirin , for a wide spectrum of patients with atherothrombosis Objective : To assess the effect of bezafibrate on the risk of coronary heart disease and stroke in men with lower extremity arterial disease . Design : Double blind placebo controlled r and omised trial . Setting : 85 general practice s and nine hospital vascular clinics . Participants : 1568 men , mean age 68.2 years ( range 35 to 92 ) at recruitment . Interventions : Bezafibrate 400 mg daily ( 783 men ) or placebo ( 785 men ) . Main outcome measures : Combination of coronary heart disease and of stroke . All coronary events , fatal and non-fatal coronary events separately , and strokes alone ( secondary end points ) . Results : Bezafibrate did not reduce the incidence of coronary heart disease and stroke . There were 150 and 160 events in the active and placebo groups respectively ( relative risk 0.96 , 95 % confidence interval 0.76 to 1.21 ) . There were 90 and 111 major coronary events in the active and placebo groups respectively ( 0.81 , 0.60 to 1.08 ) , of which 64 and 65 were fatal ( 0.95 , 0.66 to 1.37 ) and 26 and 46 non-fatal ( 0.60 , 0.36 to 0.99 ) . Beneficial effects on non-fatal events were greatest in men aged < 65 years at entry , in whom benefit was also seen for all coronary events ( 0.38 , 0.20 to 0.72 ) . There were no significant effects in older men . There were 60 strokes in those on active treatment and 49 in those on placebo ( 1.34 , 0.80 to 2.01 ) . There were 204 and 195 deaths from all causes in the two groups respectively ( 1.03 , 0.83 to 1.26 ) . Bezafibrate reduced the severity of intermittent claudication for up to three years . Conclusions : Bezafibrate has no effect on the incidence of coronary heart disease and of stroke combined but may reduce the incidence of non-fatal coronary events , particularly in those aged < 65 years at entry , in whom all coronary events may also be reduced PURPOSE To evaluate the combination of a platelet glycoprotein IIb/IIIa complex receptor inhibitor and urokinase for treatment of recent ( < or=6 weeks ) arterial occlusion of the legs . MATERIAL S AND METHODS Seventy patients with lower extremity arterial occlusion of less than 6 weeks duration were r and omly separated into two treatment groups : urokinase plus abciximab or urokinase plus placebo . Primary end points were the rate of major complications at 30 days after r and omization and the rates of amputation-free survival and survival without open surgery or major amputation at follow-up of 90 days . Two readers unaware of the patients ' treatment group assignments analyzed digital subtraction angiograms as they related to the study end points , with a final consensus reading . RESULTS Thrombolysis relative to clot length was faster in the urokinase-plus-abciximab group ( odds ratio , 0.52 ; 95 % CI : 0.35 , 0.76 ; P < .001 ) . There were no procedure-related deaths or intracranial hemorrhages , but the rate of nonfatal major bleeding was higher with urokinase plus abciximab ( four of 50 patients ) than with urokinase alone ( none of 20 patients ; P = .32 ) . At 90 days , amputation-free survival was 96 % ( 48 of 50 patients ) in the urokinase-plus-abciximab group compared with 80 % ( 16 of 20 patients ) in the urokinase alone group . The hazard ratio for the two Kaplan-Meier curves was 0.42 ( 95 % CI : 0.16 , 0.96 ; P = .04 ) . CONCLUSION In patients with lower extremity arterial occlusion who were undergoing urokinase thrombolysis  , adjunctive abciximab treatment result ed in faster thrombus dissolution and improved amputation-free survival , despite an increase in major bleeding BACKGROUND Intermittent claudication is associated with a poor prognosis , but less is known of the risks associated with asymptomatic peripheral arterial disease . The aims of this study were to determine the incidence and natural history of claudication , and the incidence of cardiovascular events in symptomatic and asymptomatic peripheral arterial disease . METHODS In 1988 , 1592 subjects aged 55 - 74 years were selected r and omly from the age-sex register of 10 general practice s in Edinburgh , Scotl and . The presence of peripheral arterial disease was determined by the World Health Organization question naire on intermittent claudication , the ankle brachial pressure index and a reactive hyperaemia test . This cohort was followed prospect ively over 5 years for subsequent cardiovascular events and death . RESULTS One hundred and sixteen new cases of claudication were identified ( incidence density 15.5 per 1000 person-years ) . Of those with claudication at baseline , 28.8 % and still had pain after 5 years , 8.2 % underwent  vascular surgery or amputation , and 1.4 % developed leg ulceration .  Claudicants had a significantly increased risk of developing angina compared with normals ( RR : 2.31 , 95 % CI : 1.04 - 5.10 ) , and asymptomatic subjects had a slightly increased risk of myocardial infa rct ion and stroke . Deaths from cardiovascular disease were more likely in both claudicants ( RR : 2.67 , 95 % CI : 1.34 - 5.29 ) and subjects with major ( RR : 2.08 , 95 % CI : 1.13 - 3.83 ) or minor asymptomatic disease ( RR : 1.74 , 95 % CI : 1.09 - 2.76 ) . Subjects with major asymptomatic disease also had an increased risk of non-cardiovascular death ( RR : 2.19 , 95 % CI : 1.33 - 3.59 ) , and therefore had the highest overall risk of death ( RR : 2.44 , 95 % CI : 1.59 - 3.74 ) . CONCLUSIONS Subjects with asymptomatic peripheral arterial disease appear to have the same increased risk of cardiovascular events and death found in claudicants The aim was to test within a r and omized , double-blind trial whether the antiaggregant drug ticlopidine might reduce blood viscosity as has been cl aim ed . Sixteen patients with intermittent claudication were studied before and after three years of treatment with ticlopidine , 500 mg/day , or placebo . At base line , the viscosity values were significantly higher as compared with a reference group of healthy subjects . Whole-blood viscosity , measured at four different shear rates at hematocrit adjusted to a st and ard 40 % , decreased significantly at follow-up , with no difference between ticlopidine treatment and placebo .  Hema tocrit showed a slight increase in the placebo group . The viscosity parameters were unrelated to lower limb blood flow variables , ankle/brachial index , and walking distances . The mechanism behind the overall decrease in whole-blood viscosity is obscure but could possibly be explained by lifestyle changes . Smok ing habits were , however , unaltered . Since plasma viscosity remained increased , it might indicate that some erythrocyte factor , notably red cell aggregability and deformability , had improved . It is concluded that ticlopidine had no long-term effect on blood viscosity BACKGROUND Chronic peripheral arterial occlusion ( CPAO ) is a progressive disease that is associated with a variety of symptoms , the 4 most common being a sensation of coolness in the limbs , intermittent claudication ( in which pain occurs on walking ) , limb pain ( which occurs spontaneously at rest ) , and ischemic leg ulcers . Beraprost sodium is an oral prostagl and in I2 analogue that may ameliorate these symptoms . OBJECTIVE The aim of this study was to compare the efficacy and tolerability of beraprost sodium and ticlopidine hydrochloride in the treatment of patients with CPAO in China . METHODS In this multicenter , single-blind , controlled study , patients with CPAO were r and omly assigned to receive beraprost 120-μg tablet TID or ticlopidine 500-mg tablet BID , both administered orally . The clinical efficacy of the drugs was assessed using the 4 main symptoms of CPAO . Ankle-brachial index ( ABI ) also was measured as a clinical pharmacologic procedure . Adverse events were assessed throughout the study . RESULTS A total of 124 patients ( 96 men , 28 women ; mean [ SD ] age , 65 [ 12 ] years ) were enrolled in 3 hospitals . Data from 119 patients ( 93 men , 26 women ; mean [ SD ] age , 65 [ 12 ] years ) were included in the efficacy analysis ( 64 and 55 patients in the beraprost and ticlopidine groups , respectively ) . Although all 4 symptoms of CPAO were ameliorated after 3 and 6 weeks of treatment with both drugs , only the cool sensation was significantly improved with beraprost compared with ticlopidine at 6 weeks ( P<0.05 ) . ABI was significantly increased with both beraprost and ticlopidine at 6 weeks versus baseline ( P<0.001 and P<0.01 , respectively ) , suggesting that this pharmacologic action may have led to their beneficial effect on various symptoms . The tolerability analysis included 123 patients ( 65 and 58 patients in the beraprost and ticlopidine groups , respectively ) . The numbers of patients who ( 1 ) experienced adverse events ( AEs ) , ( 2 ) experienced adverse drug reactions , and ( 3 ) withdrew due to AEs were significantly smaller in the beraprost group than in the ticlopidine group ( P<0.001 , P<0.05 , and P<0.05 , respectively ) . CONCLUSIONS In this study population of patients with CPAO , beraprost ameliorated cool sensation in the limbs , intermittent claudication , limb pain , and ischemic/leg ulcers .  Beraprost was more efficacious in relieving CPAO symptoms and was better tolerated than ticlopidine . Beraprost may be useful for the treatment of patients with CPAO  , but more studies are needed Ten patients with peripheral atherosclerotic disease(PAD ) treated with 750 mg/d of 5-(2-chlorophenylmethyl)-4,5,6,7-tetrahydrothieno ( 3,5-c-pyridine ) hydrochloride ( ticlopidine , Tiklid )  were studied for three months . As control was studied a similar group of patients treated with a traditional vasodilator ( nicotinate ) . The aim of our study was to evaluate the effect of ticlopidine both on the clinical evolution of the disease and on rheologic , coagulative and platelet parameters . A progressive increase of maximal walking distance was noted during the three months of therapy with ticlopidine and limited to the first 30 days of treatment with nicotinate . The fibrinogen levels result ed significantly lowered during 90 days of treatment with ticlopidine , while that was not evident in the nicotinate group . There was also a slight improvement of blood viscosity in the ticlopidine group ( not evident in the nicotinate group ) , but it was not statistically significant . No further modifications of investigated data were found in the two groups of patients . The clinical benefit of ticlopidine in PAD without adverse reactions can be confirmed at least at the dosage of 750 mg/d instead of the usual dose of 500 mg/d . A direct or indirect action of ticlopidine on plasma fibrinogen is suggested . This observation may supply new clues for the underst and ing of the mechanism of action of this drug The clinical efficacy of ticlopidine , a platelet aggregation inhibitor , was evaluated in a double-blind placebo-controlled study on 193 patients with ischemic ulcers due to chronic arterial occlusion . In the group treated with ticlopidine , significantly better efficacy was noted over the placebo group in terms of judgment on overall improvement by doctors in charge as well as by the committee assessing with color slide films . The drug was particularly effective for the treatment of patients with occlusion in the arteries on the distal side and for the ischemic ulcer with relatively small size . In the group with ticlopidine , granulation was significantly improved compared to the placebo group . Those patients who had pain due to arterial occlusion on the distal side were significantly improved by this agent . The mean diameters of ulcers were clearly reduced . Therefore , this agent could possibly be cl aim ed as an effective remedy against the main symptoms of chronic arterial occlu sion . The frequencies of side effects and abnormalities in laboratory tests were comparable in the group treated with ticlopidine to those of the group with placebo . It was , therefore , concluded that this agent has an outst and ing clinical value as a conservative treatment in chronic arterial occlusion Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects . The present study was undertaken to compare the effects of policosanol and ticlopidine in patients with moderately severe intermittent claudication ( IC ) . The study had a 4-week baseline step , followed by a 20-week double-blinded , r and omized treatment period . Twenty-eight eligible patients were r and omized to  policosanol 10 mg  or ticlopidine  250 mg tablets twice daily ( bid ) . Walking distances in a treadmill ( constant speed 3.2 km/hr , slope 10 ° , temperature 25 ° C ) were assessed before and after 20 weeks of treatment . Both groups were similar at baseline . Compared with baseline , policosanol significantly increased ( p<0.01 ) mean values of initial ( ICD ) and absolute ( ACD ) claudication distances from 162.1 to 273.2 m and from 255.8 to 401.0 m , respectively . Ticlopidine also raised significantly ( p<0.01 ) ICD ( 166.2 to 266.3 m ) and ACD ( 252.9 to 386.4 m ) . Comparisons between groups did not show significant differences . Policosanol , but not ticlopidine , significantly ( p<0.05 ) , but modestly , increased the ankle/arm pressure ratio . After 10 weeks , policosanol significantly ( p<0.001 ) lowered low-density lipoprotein-cholesterol ( LDL-C ) , total cholesterol ( TC ) ( p<0.01 ) , and TC/HDL-C and raised ( p<0.05 ) high-density lipoprotein-cholesterol ( HDL-C ) . At study completion , policosanol  lowered ( p<0.001 ) LDL-C ( 30.2 % ) , TC ( 16.9 % ) , and TC/HDL-C ( 33.9 % ) , increased ( p<0.01 ) HDL-C ( + 31.7 % ) , and left triglycerides  unchanged . Ticlopidine did not affect the lipid profile variable . Policosanol induced modest , but significant , reductions ( p<0.01 ) of fibrinogen levels compared with baseline and ticlopidine . Treatments were well tolerated and did not impair safety indicators .  Three ticlopidine patients ( 21.4 % ) withdrew from the trial , only 1 owing to a serious adverse experience ( AE ) ( unstable angina ) . Three other ticlopidine patients experienced mild AE ( headache , diarrhea , and acidity ) . It is concluded that policosanol ( 10 mg bid ) can be as effective as ticlopidine ( 250 mg bid ) for improving walking distances of claudicant patients , and it could be advantageous for the global risk of these individuals owing to its cholesterol-lowering effects . This study is , however , just a pilot comparison , so that further studies in larger sample sizes are needed for definitive conclusions of the comparative effects of both drugs on patients with IC Objective The objective of this study was to provide a comprehensive comparison of the long term safety and tolerability of clopidogrel , a new adenosine diphosphate ( ADP ) receptor antagonist that inhibits platelet activation induced by ADP , and aspirin ( acetylsalicylic acid ) . Patients and Methods The study population comprised 19 185 patients with symptomatic atherosclerosis manifested as recent ischaemic stroke , recent myocardial infa rct ion or symptomatic peripheral arterial disease . Patients were r and omised to receive  clopidogrel 75 mg/day or aspirin 325 mg/day  for a minimum of 1 year and a maximum of 3 years . Results Compared with aspirin , clopidogrel reduced the combined risk of ischaemic stroke , myocardial infa rct ion or vascular death by 8.7 % ( p = 0.043 ) . The incidence of early permanent discontinuations of the study drug due to adverse events was almost identical in both treatment groups ( 11.94 % for clopidogrel vs 11.92 % for aspirin ) . Reported neutropenia was similar in the clopidogrel and aspirin groups ( 0.10 vs 0.17 % , respectively ) with corresponding rates ( 0.05 vs 0.04 % , respectively ) for severe neutropenia . Thrombocytopenia was identical in the clopidogrel and aspirin groups ( 0.26 % ) , with the rates of severe thrombocytopenia being 0.19 vs 0.10 % , respectively . None of these observed differences was statistically significant . The overall incidence of haemorrhagic events did not differ statistically significantly between treatment groups ( 9.27 % for clopidogrel vs 9.28 % for aspirin ; p = 0.98 ) . There was a trend towards a lower incidence of intracranial haemorrhage in the clopidogrel group ( 0.31 % ) compared with the aspirin group ( 0.42 % ) . Any reported gastrointestinal haemorrhage was significantly less frequent with clopidogrel ( 1.99 % ) than with aspirin ( 2.66 % ) [ p < 0.002 ] . The corresponding data for severe gastrointestinal bleeding were 0.49 vs 0.71 % ; p < 0.05 . Overall , there were significantly fewer gastrointestinal adverse events with clopidogrel than with aspirin ( 27.1 vs 29.8 % ; p < 0.001 ) , with less abdominal pain , dyspepsia , constipation , or peptic , gastric , or duodenal ulceration with clopidogrel .  Diarrhoea was significantly more common in the clopidogrel group ( 4.46 vs 3.36 % ; p < 0.001 ) , although the incidence of severe diarrhoea ( 0.23 vs 0.11 % ) was low and was not significantly different between groups . There were significantly more patients with rash in the clopidogrel group ( 6.0 % ) compared with the aspirin group ( 4.6 % ) [ p < 0.001 ] . However , these events were generally mild and transient in nature . Conclusion Given the favourable benefit/risk ratio , clopidogrel represents a clinical ly important advance in the treatment of patients with manifest atherosclerotic disease In a double-blind study , 296 patients with intermittent claudication ( Fontaine stage II ) were treated with 250 mg ticlopidine twice daily , 500 mg aspirin every third day plus 75 mg dipyridamole three times daily , or 300 mg xanthinol nicotinate three times daily for 6 months . Ticlopidine and aspirin/dipyridamole , but not xanthinol nicotinate , improved platelet aggregation , reduced β-thromboglobulin , platelet factor IV and fibrinopeptide A concentrations , and increased antithrombin III concentrations and red blood cell filterability . No changes in lipid profiles , platelet count or fibrinogen were recorded following any treatment . The doppler systolic blood pressure ratio was improved in patients treated with ticlopidine or aspirin/dipyridamole , but not with xanthinol nicotinate . It is concluded that antiplatelet treatment is useful for the treatment of limb arteriopathy Objective To determine whether aspirin and antioxidant therapy , combined or alone , are more effective than placebo in reducing the development of cardiovascular events in patients with diabetes mellitus and asymptomatic peripheral arterial disease . Design Multicentre , r and omised , double blind , 2 × 2 factorial , placebo controlled trial . Setting 16 hospital centres in Scotl and , supported by 188 primary care groups . Participants 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease . Interventions Daily , 100 mg aspirin tablet plus antioxidant capsule ( n=320 ) , aspirin tablet plus placebo capsule ( n=318 ) , placebo tablet plus antioxidant capsule ( n=320 ) , or placebo tablet plus placebo capsule ( n=318 ) . Main outcome measures Two hierarchical composite primary end points of death from coronary heart disease or stroke , non-fatal myocardial infa rct ion or stroke , or amputation above the ankle for critical limb ischaemia ; and death from coronary heart disease or stroke . Results No evidence was found of any interaction between aspirin and antioxidant . Overall , 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups ( 18.2 % v 18.3 % ) : hazard ratio 0.98 ( 95 % confidence interval 0.76 to 1.26 ) . Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups ( 6.7 % v 5.5 % ) : 1.23 ( 0.79 to 1.93 ) . Among the antioxidant groups 117 of 640 ( 18.3 % ) primary events occurred compared with 116 of 636 ( 18.2 % ) in the no antioxidant groups ( 1.03 , 0.79 to 1.33 ) . Forty two ( 6.6 % ) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 ( 5.7 % ) in the no antioxidant groups ( 1.21 , 0.78 to 1.89 ) . Conclusion This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied . Trial registration Current Controlled Trials IS RCT N53295293 The effects of dipyridamole in association with acetylsalicylic acid were compared with the effects of acetylsalicylic acid alone in patients with peripheral vascular disease . The following parameters were studied in each patient : symptoms-free interval on the treadmill , ankle-arm arterial pressure gradient , oscillographic index , venous occlusion plethysmography and any untoward reactions . Changes were observed in the pain-free interval ( p less than 0.005 ) , and in the venous occlusion plethysmography ( p less than 0.001 ) in the patients treated with the two drugs in association Peripheral vascular disease ( PVD ) commonly presents with leg claudication during walking and eventually limits the walking distance and daily activities . Aspirin or pentox ifylline are commonly prescribed to improve blood flow .  Aspirin works through its antiplatelet aggregation mechanism , and pentoxifylline increases the red blood cell flex ibility , which leads to increased tissue perfusion . Data on comparative studies of these drugs for improving claudication in the elderly are limited . The objective of this study was to compare pain relief offered by either aspirin or pentoxifylline for walking leg pain in the elderly with PVD . Patients sixty-five years or older with claudication were r and omly assigned to receive aspirin or pentoxifylline . Their reported level of walking claudication pain with use of the visual analogue scale ( 0 - 5 ) and the distance walked during exercises were recorded . Six weeks later the same parameters were recorded and results were compared with Student 's t test , and a P value less than 0.05 was considered a statistically significant difference . Of the 90 patients who participated , 45 received aspirin ( 325 mg daily ) and 45 were prescribed pentoxifylline ( 400 mg tid ) for six weeks . Both the aspirin and the pentoxifylline groups reported a moderate level of pain ( 2/5 ) and remained about the same ( 2/5 for aspirin and 1/5 for pentoxifylline , P = 0.9 , NS ) after six weeks . However , the pentoxifylline group reported a farther walking distance of 2 miles compared with the aspirin group of 1.2 miles ( P < 0.05 ) . The level of pain did not change significantly with either aspirin or pentoxifylline , but the walking distance was farther with the pentoxi fylline group The anti-aggregating activity of five rising doses of clopidogrel has been compared to that of ticlopidine in atherosclerotic patients . The aim of this study was to determine the dose of clopidogrel which should be tested in a large scale clinical trail of secondary prevention of ischemic events in patients suffering from vascular manifestations of atherosclerosis [ CAPRIE ( Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events ) trial ] . A multicenter study involving 9 haematological laboratories and 29 clinical centers was set up . One hundred and fifty ambulatory patients were r and omized into one of the seven following groups : clopidogrel at doses of 10 , 25 , 50 , 75 or 100 mg OD , ticlopidine 250 mg BID or placebo . ADP and collagen-induced platelet aggregation tests were performed before starting treatment and after 7 and 28 days . Bleeding time was performed on days 0 and 28 . Patients were seen on days 0 , 7 and 28 to check the clinical and biological tolerability of the treatment . Clopidogrel exerted a dose-related inhibition of ADP-induced platelet aggregation and bleeding time prolongation . In the presence of ADP ( 5 microM ) this inhibition ranged between 29 % and 44 % in comparison to pretreatment values . The bleeding times were prolonged by 1.5 to 1.7 times . These effects were non significantly different from those produced by ticlopidine . The clinical tolerability was good or fair in 97.5 % of the patients . No haematological adverse events were recorded . These results allowed the selection of 75 mg once a day to evaluate and compare the antithrombotic activity of clopidogrel to that of aspirin in the CAPRIE trial Indobufen — an inhibitor of platelets aggregation — has been used in 306 pa tients with intermittent claudication due to peripheral vascular disease . Patients were treated and followed up for one year . One patient of every 3 treated with indobufen was treated with ASA , and a control group of patients receiving no treatment was also followed up . The authors studied by means of a treadmill exercise test the  pain-free walking distance ( PFWD ) , the global walking distance ( GWD ) , and the recovery time after exercise . The treatment period was com pleted by 290 patients : 204 claudicants , 51 claudicants with diabetes , and 35 with a short PFWD and GWD ( > 150 m ) .  Indobufen was more effective than ASA in improving the PFWD and GWD in all groups . There were also fewer side effects with indobufen , and cardiac morbidity and mortality was also reduced . In conclusion indobufen showed its activity and safety in chronic treatment of patients with peripheral disease , and we suggest that it may be used for long periods without side effects We compared the efficacy and safety of three doses of beraprost sodium , an epoprostenol analogue , with placebo in the treatment of intermittent claudication ( Fontaine 's stage II ) . One hundred sixty-four patients were r and omized to receive either placebo , 20 micrograms beraprost sodium ( BPS60 group ) , 40 micrograms beraprost sodium ( BPS120 group ) , or 60 micrograms beraprost sodium ( BPS180 group ) three times daily administered orally in a double-blind manner for 12 weeks . Treadmill exercise tests were performed twice during an initial selection phase ( D-28 and D0 ) at week 10 ( at trough beraprost concentration ) and week 12 ( at peak beraprost concentration ) of the treatment phase . At week 10 , all groups showed an increase in pain-free walking distance , and this distance was greatest in the BPS60 and BPS120 groups ( p = 0.055 ) . At week 12 , a similar pattern was observed , and the difference was significant between the groups ( p = 0.023 ) . The most frequent adverse events reported were gastrointestinal disorders , headaches , skin disorders , and flushes . Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance . Further studies are required to investigate why the highest dose used ( 180 micrograms daily ) showed lower efficacy . Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term , beraprost sodium is a promising drug for the treatment of intermittent claudication Forty patients with a mean age of 62.6 ± 6 years , 36 men and 4 women , with peripheral arterial occlusive disease ( PAOD ) at Leriche-Fontaine IIb class , were r and omly allocated to one of two treatment groups , receiving either 12,500 IU/ day of subcutaneous ( sc ) calcium-heparin ( CAE ) or 250 mg/day of oral ticlopi dine , each given for ninety days . The following parameters were evaluated be fore the start of the active treatment period and after thirty and ninety days of treatment : pain-free walking distance ( PWD ) , maximum walking distance ( WDmax ) , systolic and diastolic blood pressure ( BP ) , posterior tibial arterial pressure and Winsor index at rest and after exercise ( treadmill ) , transcutaneous oxygen and carbon dioxide pressures at rest ( TcPO2 and TcPCO2 respectively ) , and time to 50 % TcPo2 recovery after three-minute ischemia . Both treatments induced an improvement in PWD/WDmax , which , at the end of the study , were increased by 50.7/58.7 % and 31.7/36.2 % , respectively , for CAE and ticlopidine treatments , respectively . Statistical analysis did not show any difference between treatments , al though a statistically significant difference was found in comparison with basal measurements for both CAE and ticlopidine treatments ( p < 0.01 ) . Neverthe less , the effects determined by ticlopidine were , on the whole , less impressive than those of CAE . In fact , interestingly , although not in a statistically significant way , the CAE group walked longer in comparison with the ticlopidine group irrespective of the more critical baseline clinical conditions . Moreover , TcPo2 was favorably modified by CAE ( p < 0.01 ) but not by ticlopidine treatment while the other parameters remained unchanged . In conclusion , CAE , given at the daily dose of 12,500 IU in patients with PAOD at the Leriche-Fontaine IIb class , showed beneficial clinical effects , which , in turn , could be due both to the removal of the thrombophilic i m balance and to the restoration of the fibrinolytic-coagulatory hemostasis in the involved microvascular circulation BACKGROUND Platelets play a key role in the pathogenesis of atherosclerosis , thrombosis , and acute coronary and cerebrovascular syndromes . Inhibition of platelet function by acetylsalicylic acid ( aspirin ) has been shown to reduce the incidence atherothrombotic events in patients with coronary , cerebrovascular , or peripheral vascular disease .  Thienopyridine agents , however , including ticlopidine and clopidogrel , inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death , myocardial infa rct ion , and stroke among a broad group of patients with vascular disease . More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events . METHODS Lotrafiban , a selective , nonpeptide antagonist of the human platelet fibrinogen receptor ( glycoprotein [ GP ] IIb/IIIa [ alphaIIb/beta3 integrin ] ) , blocks the binding of fibrinogen to the GP IIb/IIIa receptor , which is the final common pathway of platelet aggregation . Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week , double-blind , placebo-controlled , dose-ranging study in patients with recent myocardial infa rct ion , unstable angina , transient ischemic attack , or stroke when added to aspirin therapy . On the basis of these results , a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion ( BRAVO ) trial based on pharmacodynamics and drug tolerability . In the pivotal BRAVO study , lotrafiban therapy is being evaluated in patients who have had a recent myocardial infa rct ion , unstable angina , transient ischemic attack , or ischemic stroke , or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease . RESULTS The efficacy evaluation will be based on a composite end point of clinical events ( death by any cause , myocardial infa rct ion , stroke , recurrent ischemia requiring hospitalization , or urgent ischemia-driven revascularization ) .  The target enrollment is 9200 patients worldwide . Approximately 700 centers will participate and will be distributed within 30 countries across North America , Europe , Australia , and Asia The Swedish Ticlopidine Multicentre Study ( STIMS ) was a double-blind placebo-controlled trial design ed to determine whether ticlopidine , a platelet antiaggregatory agent , reduces the incidence of myocardial infa rct ion , 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 effect of 7-mono-hydroxyethylrutoside and its combination with acetylsalicylic acid was evaluated in a controlled clinical trial , performed in 105 patients with obliterative atherosclerosis of the lower limbs , and using non-invasive measurement of peripheral haemodynamic parameters -- blood flow during reactive hyperaemia and ankle systolic blood pressure . Patients , r and omized into three groups , received either placebo or 7-mono-hydroxyethylrutoside alone or in combination with acetylsalicylic acid for 12 months . The placebo group showed a decrease in maximum calf blood flow and a decrease in ankle systolic pressure . Administration of 7-mono-hydroxyethylrutoside did not lead to any significant changes in systolic pressure but there was a decrease in the maximum calf blood flow . There were no statistically significant changes in patients receiving the 7-mono-hydroxyethylrutoside and acetylsalicylic acid combination who , by contrast , showed a tendency to increased values of the parameters measured Sixty patients with a mean age of 64 years ( range 57 - 77 years ) , 55 males and 5 females , with peripheral arterial occlusive disease ( PAOD ) at Leriche-Fontaine IIb class were r and omly allocated to receive either subcutaneous calcium-heparin ( 12,500 IU once daily ) or oral acetylsalicylic acid ( ASA ) ( 300 mg twice daily ) , each given for 3 months , followed by a 6-month follow-up period during which no treatment was given . The following parameters were evaluated before r and omization , after 1 and 3 months of therapy and after 1 , 3 and 6 months of follow-up : pain-free walking distance ( PWD ) , maximum walking distance ( WDmax ) , systolic and diastolic blood pressure , posterior tibial arterial pressure and ankle/arm index at rest and after exercise ( treadmill ) , transcutaneous gas analysis at rest ( TcPO2 ) . Under both treatments a statistically significant increase ( p < 0.01 ) in PWD/WDmax was observed after 3 months of therapy . Calcium-heparin was slightly but significantly more effective than ASA in prolonging WDmax ( p < 0.05 ) after 3 months of therapy . Both treatment groups maintained the clinical improvement after 6 months of follow-up without any difference between each-other . Both treatments result ed in a statistically significant increase in TcPO2 and decrease in plasma fibrinogen but under calcium-heparin treatment these modifications were doubled in comparison with ASA ( p < 0.01 and p < 0.05 , respectively for TcPO2 and fibrinogen ) . The sustained effects on these parameters after 6 months of follow-up could suggest a more direct and multifactorial activity of calcium-heparin on microcirculation . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To assess the prophylactic efficacy of aspirin and a high-dose antioxidant vitamin combination in patients with peripheral arterial disease ( PAD ) in terms of reduction of the risk of a first vascular event ( myocardial infa rct ion , stroke , vascular death ) and critical limb ischaemia . DESIGN R and omized , placebo-controlled , double-blind clinical trial with 2 x 2 factorial design . SETTING Thirty-seven European angiology/vascular medicine units . SUBJECTS A total of 366 out patients with stage I-II PAD documented by angiography or ultrasound , with ankle/brachial index < 0.85 or toe index < 0.6 ; 210 patients completed the follow-up . INTERVENTIONS Four treatment groups : ( i ) oral aspirin ( 100 mg daily ) , ( ii ) oral antioxidant vitamins ( 600 mg vitamin E , 250 mg vitamin C and 20 mg beta-carotene daily ) , ( iii ) both or ( iv ) neither , given for 2 years . MAIN OUTCOME MEASURE Major vascular events ( cardiovascular death , myocardial infa rct ion or stroke ) and critical leg ischaemia . RESULTS Seven of 185 patients allocated aspirin and 20 of 181 allocated placebo suffered a major vascular event ( risk reduction 64 % , P = 0.022 ) ; five and eight patients , respectively , suffered critical leg ischaemia ( total 12 vs. 28 , P = 0.014 ) . There was no evidence that antioxidant vitamins were beneficial ( 16/185 vs. 11/181 vascular events ) . Neither treatment was associated with any significant increase in adverse events . Inclusion of this trial in a meta- analysis of other r and omized trials of anti-platelet therapy in PAD makes the overall results highly significant ( P < 0.001 ) and suggests that low-dose aspirin reduces the incidence of vascular events by 26 % . CONCLUSIONS For the first time direct evidence shows that low-dose aspirin should routinely be considered for PAD patients , including those with concomitant type 2 diabetes There is a high risk of reocclusion after successful lower limb angioplasty . Platelets play a central role in this process . The aim of this study was to investigate the antiplatelet effect of a combination of aspirin and clopidogrel compared with aspirin alone in patients with claudication undergoing endovascular revascularization The main aim of medical treatment for intermittent claudication ( IC ) is the reduction of mortality and morbidity from ischemic cardiovascular disease . However , symptomatic treatment with the aim of improving exercise performance and the overall quality of life may also be an important target of the clinical management of patients with intermittent claudication .  Cloricromene , a drug with antithrombotic and anti-ischemic activities , has previously shown some promising results in patients with claudication . We have carried out a clinical trial to assess the effect of cloricromene on the claudication distance and on the quality of life of patients with IC chronically treated with aspirin . A total of 159 patients with IC , Stage II ( Fontaine ) , were enrolled in a double-blind , r and omized , prospect i ve , multicenter study comparing cloricromene ( 100 mg orally b.i.d . ) or an identical placebo for 6 months . All patients received 160 mg/day aspirin . The primary end-point was the improvement of initial claudication distance ( ICD ) at 6 months as measured by a st and ardized treadmill test . The secondary end-points were the absolute claudication distance ( ACD ) at 6 months , the percentage of patients defined as responders to treatment ( improvement of ICD of at least 40 % ) , changes in the ischemic window ( IW ) , quality of life as assessed by the SF-36 question naire , and the occurrence of major cardiovascular events . The ICD increased in both treatment groups , with a non-significant difference at 6 months in favor of cloricromene of + 12.3 m. The ACD , percentage of responders to treatment and ischemic window also improved in both groups with a slight , non-significant trend in favor of cloricromene . Pretreatment quality of life scores showed only a slight worsening compared with an age-matched , healthy population and did not change upon treatment . A post hoc subgroup analysis showed a significant benefit from cloricromene in patients with an ICD at enrollment higher than the median of the patient population . In conclusion , treatment with cloricromene for 6 months does not significantly improve  claudication in patients with Stage II Fontaine peripheral arteriopathy chronically treated with aspirin . An improvement of 40 - 60 m in the ICD on a st and ardized treadmill test does not translate into a self-perceived improvement in the quality of life as assessed by the SF-36 question naire Twenty-seven patients with peripheral atherosclerotic disease were r and omized into two therapy regimens consisting of indobufen ( Indo ) ( 400 mg/day ) and dipyridamole ( Dip ) ( 225 mg/day ) plus acetylsalicylic acid ( ASA ) ( 1 g/day ) , respectively . Maximal walking distance ( MWD ) and ankle-arm systolic pressure ratios were measured before and after three and six months of therapy ; bleeding time , beta-thromboglobulin ( beta-TG ) , platelet factor 4 ( PF4 ) and serum thromboxane B2 ( TXB2 ) were also assessed . The two treatment groups showed a significant and progressive increase in pain-free walking distance at both three and six months of therapy , but patients taking indobufen showed a greater improvement . On the contrary , the pressure doppler ratio at rest was statistically improved only in the ASA plus Dip group . Basal beta-TG and PF4 levels were normal and no changes occurred during the study in either group , while in all patients bleeding times showed a significant increase above basal values and serum TBX2 decreased Fifty-one men with atherosclerotic intermittent claudication and haemorheological abnormalities completed a double-blind , one-year r and omised 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 BACKGROUND AND METHODS In 359 patients with peripheral arterial occlusive disease who had undergone percutaneous transluminal angioplasty ( PTA )  , a r and omized double-blind , controlled clinical study was done to investigate the tolerability of acetyl salicylic acid ( ASA ) given for reocclusion prophylaxis . A comparison was made between a conventional daily dose of 900 mg ASA and a dose of 50 mg ASA . RESULTS Within an observation period of one year following PTA , 35 patients ( 20 % ) in the 900 mg group , and 32 patients ( 17 % ) in the 50 mg group left the trial because of side effects ( p = NS ) . Under the higher dose , however , severe gastrointestinal side effects ( ulcer , haemorrhagic gastritis requiring transfusion ) were significantly more common ( nine patients delta 5.1 % vs two patients delta 1.1 % , respectively ; p = 0.03 ) . Overall , 107 patients ( 30 % ) reported subjective side effects such as upper abdominal pain , a sensation of fullness or nausea during the course of the trial . 62 of these patients were from the 900 mg group ( 35 % ) as compared with 45 patients ( 24 % ) in the 50 mg group ( p = 0.02 ) . Self-scoring of epigastric pain on the basis of a visual analogue scale revealed a score of 1.3 ( 95 % confidence interval 0.9 to 1.6 ) in the 900 mg group and 0.8 ( 95 % confidence interval 0.6 to 1.0 ) in the 50 mg group . The subjective pain intensity showed a uniform time course for all three types of symptom , with a maximum after three months . CONCLUSION Our results confirm the superior tolerability of the lower dose , in particular in elderly patients . For long-term treatment , the smallest possible effective dose should be chosen This paper evaluates the antiaggregant action of ticlopidine and nifedipine in patients with obliterate arteriopathy in inferior limbs of arteriosclerotic etiology ( OAIL ) . They were established 4 study groups : control , with health volunteers without treatment ( N = 10 ) ; patients treated with placebo ( n = 11 ) ; patients treated with 500 mg/day of ticlopidine ( n = 12 ) and treated with 30 mg/day of nifedipine ( n = 12 ) . The last 3 groups the treatment duration was 30 days . It was studied the platelet aggregatory activity against ADP and collagen , before drug administration and at 15 and 30 days post-treatment . Our results suggest that : Platelet aggregation is increased in patients with AOMI compared with that observed in the control group . Ticlopidine inhibits platelet aggregation induced by ADP , but not that induced by collagen . Nifedipine does n't produce any effect on platelet aggregation This study aims to evaluate the reliability of repeated grade d workload treadmill testing ( G-test ; 2 mph ; 0 % grade , increasing 2 % every 2 min ) and to compare the reliability of a constant workload treadmill protocol ( C-test ; 2 mph ; 12 % grade ) versus the grade d workload treadmill protocol in patients with intermittent claudication , studied longitudinally . A clinical trial investigating an orally stable prostacycline derivative that included 330 patients with intermittent claudication was performed . The trial employed three active treatment groups and one placebo group . Because there were no significant inter-group differences at baseline or after treatment , data from all groups were pooled for the evaluation of treadmill test reliability . Treadmill data were obtained from a 2-week run-in phase where three G-tests were performed , as well as from the beginning and the end of a 3-month double-blind phase where a G-test and a C-test were performed in r and om order . Treadmill test reliability was described through test process-related and between-subject variances and also using variance-derived parameters such as the reliability coefficient ( RC ) and the relative precision ( RP ) . A higher value for the RC and a lower value for the RP indicate that the test variability is predominantly due to between-subject variance and not to test process-related variance . Estimates of variance were described for both the maximal or absolute claudication distance ( ACD ) and the initial claudication distance ( ICD ) with each treadmill test . Reliability estimates are reported for the total study sample and for patients with baseline claudication distances < 300 feet and .300 feet ( approximately < 100 m ; .100 m ) , as measured with the C-test . The cut-off value was empirically chosen to separate severely diseased from mild to moderately diseased claudicants . Theoretical considerations suggest that reliability measures may differ in these subgroups . With repeated testing during the run-in phase for the measure of ACD , the G-test had an RC of 0.952 and an RP of 21.9 % . With the comparison of both test protocol s in the entire study population for the measurement of ACD , the G-test had an RC of 0.902 and an RP of 31.3 % , while the C-test had an RC of 0.876 and an RP of 35.2 % . The results for ICD on the G-test were an RC of 0.809 and an RP of 43.7 % , while the C-test had an RC of 0.737 and an RP of 51.3 % . The reliability of the ACD measurement for RC and RP was numerically superior to those for the ICD for both protocol s. In patients with a baseline ACD < 300 feet , the RC for ACD on the G-test was 0.827 and the RP was 41.4 % . In contrast , on the C-test the RC decreased to 0.250 and the RP increased to 86.6 % . These changes in RC and RP were due to a marked decrease in the between-subject variance , demonstrating the inability of the C-test to separate appropriately the different claudication distances in population s with highly limited baseline claudication distances . During a run-in phase , the G-test has excellent test characteristics . During the longitudinal phase of a trial , the reliability of G-tests and C-tests  are comparable in the entire study population . However , in patients with low claudication distances , the G-test should be given preference over the C-test Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects . The present study was undertaken to compare the effects of policosanol and lovastatin on patients with moderately severe intermittent claudication . The study had a 4-week baseline step , followed by a 20-week double blinded , r and omized treatment period . Twenty-eight patients who met study entry criteria were r and omized to policosanol 10 mg or lovastatin 20 mg tablets once daily  . Walking distances in a treadmill ( constant speed 3.2 km/hr , slope 10 ° , temperature 25 ° C ) were assessed before and after 20 weeks of treatment . Both groups were similar at r and om ization . Compared with baseline , policosanol increased significantly ( p<0.01 ) the initial claudi cation distance ( ICD ) from 160.39 ±15.82 m to 211.31 ±21.48 m ( + 33.7 % ) and the absolute claudication distance ( ACD ) ( p<0.001 ) from 236.39 ±25.44 m to 288.09 ±28.47 m ( + 24.3 % ) ; meanwhile both variables remained unchanged after lovastatin  therapy . Changes in ICD and ACD were significantly larger in the policosanol than in the lovastatin group ( p<0.01 ) . Policosanol , but not lovastatin , significantly increased ( p < 0.05 ) the ankle/arm index , although between-group differences were not significant . The frequency of patients reporting improve ment on quality of life domains was greater in the policosanol than in the lovastatin group . Policosanol significantly ( p < 0.00 1 ) lowered total cholesterol ( TC ) and low-density lipoprotein- cholesterol ( LDL-C ) by 17.5 % and 31.0 % , respectively , and meanwhile increased ( p<0.01 ) high- density lipoprotein-cholesterol ( HDL-C ) levels by 31.5 % . Lovastatin  reduced ( p<0.01 ) TC ( 18.0 % ) , LDL-C ( 22.6 % ) , and ( p<0.05 ) triglycerides ( 9.8 % ) . In addition , policosanol , but not lovastatin , moderately , but significantly , reduced ( p < 0.05 ) fibrinogen levels , so that final values and percent changes in both groups were different ( p<0.01 ) . Treatments were well tolerated . Only 1 lovastatin patient withdrew from the study because of a nonfatal myocardial infa rct ion . Five lovastatin patients , but none from the policosanol group , experienced 6 adverse events ( AE ) ( p<0.01 ) . The present results indicate that policosanol , but not lovastatin , is a suitable alternative to manage patients with intermittent claudication  because of pleiotropic properties beyond its cholesterol-lowering effects In 25 patients ( 19 males and 6 females ) suffering from chronic arteriopathy of lower extremities at Fontaine stage II , the clinical efficacy of picotamide was investigated in double blind , cross over placebo-controlled study . Patients were assigned r and omly to the treatment with placebo or picotamide ( 900 mg/die ) for three months and , after 15 days of wash-out , to the treatment with picotamide or placebo for the same period . Painfree walking distance and ankle/arm systolic pressure ratio improved significantly only during picotamide treatment . Laboratory monitoring revealed a significant decrease in platelet aggregation and an increase of fibrinogen degradation products only during picotamide treatment . Three patients during picotamide treatment referred transient gastrointestinal discomfort ( nausea , vomiting and diarrhoea ) ; however in no case the treatment was suspended because of the appearance of these symptoms . These results indicate that picotamide is an effective drug in the management of chronic arteriopathy of lower extremities 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 BACKGROUND Atherosclerotic peripheral arterial disease is associated with an increased risk of myocardial infa rct ion , stroke , and death from cardiovascular causes . Antiplatelet drugs reduce this risk , but the role of oral anticoagulant agents in the prevention of cardiovascular complications in patients with peripheral arterial disease is unclear . METHODS We assigned patients with peripheral arterial disease to combination therapy with an antiplatelet agent and an oral anticoagulant agent ( target international normalized ratio [ INR ] , 2.0 to 3.0 ) or to antiplatelet therapy alone . The first co primary outcome was myocardial infa rct ion , stroke , or death from cardiovascular causes ; the second co primary outcome was myocardial infa rct ion , stroke , severe ischemia of the peripheral or coronary arteries leading to urgent intervention , or death from cardiovascular causes . RESULTS A total of 2161 patients were r and omly assigned to therapy . The mean follow-up time was 35 months . Myocardial infa rct ion , stroke , or death from cardiovascular causes occurred in 132 of 1080 patients receiving combination therapy ( 12.2 % ) and in 144 of 1081 patients receiving antiplatelet therapy alone ( 13.3 % ) ( relative risk , 0.92 ; 95 % confidence interval [ CI ] , 0.73 to 1.16 ; P=0.48 ) . Myocardial infa rct ion , stroke , severe ischemia , or death from cardiovascular causes occurred in 172 patients receiving combination therapy ( 15.9 % ) as compared with 188 patients receiving antiplatelet therapy alone ( 17.4 % ) ( relative risk , 0.91 ; 95 % CI , 0.74 to 1.12 ; P=0.37 ) . Life-threatening bleeding occurred in 43 patients receiving combination therapy ( 4.0 % ) as compared with 13 patients receiving antiplatelet therapy alone ( 1.2 % ) ( relative risk , 3.41 ; 95 % CI , 1.84 to 6.35 ; P<0.001 ) . CONCLUSIONS In patients with peripheral arterial disease , the combination of an oral anticoagulant and antiplatelet therapy was not more effective than antiplatelet therapy alone in preventing major cardiovascular complications and was associated with an increase in life-threatening bleeding . ( Clinical Trials.gov number , NCT00125671 [ Clinical Trials.gov ] . ) PURPOSE Patients with lower-extremity peripheral arterial disease ( PAD ) face a high risk of cardiovascular morbidity and mortality . Platelet inhibition ( PI ) significantly reduces this risk . Combination PI is common and increasingly indicated in patients with PAD ; however , the effect on platelet function has not been objective ly evaluated . Aspirin ( ASA ) , clopidogrel ( Clop ) , and cilostazol ( Cilo ) are the three most commonly used PI drugs in patients with PAD . A prospect i ve , sequential evaluation of platelet function using the template bleeding time ( BT ) was performed for PAD patients taking these medications singly and in combination . METHODS Twenty-one patients with PAD , averaging 65.9 years of age , were studied . Patients were placed on sequential two-week regimens of the following therapies : washout ( no PI ) , ASA ( 325 mg daily ) , ASA + Cilo ( 100 mg twice daily ) , washout , Cilo , Cilo + Clop ( 75 mg each day ) , washout , Clop , Clop + ASA , and Clop + ASA + Cilo . At the end of each phase , trained personnel measured the BT . RESULTS Baseline bleeding time for the group was 4.29 + /- 1.69 minutes . ASA ( BT = 6.64 + /- 3.52 ) and Clop ( BT = 10.17 + /- 5.4 ) significantly prolonged bleeding time ( P < 0.01 ) ; however , no significant effect was observed with Cilo alone ( BT = 5.41 + /- 2.69 ) . Combined treatment with ASA + Clop ( BT = 17.39 + /- 4.59 ) had a more pronounced effect on BT compared with either agent alone ( P < 0.01 ) . The addition of Cilo to either ASA ( BT = 8.3 + /- 4.27 ) or Clop ( BT = 12.7 + /- 7.46 ) or the combination of ASA + Clop ( BT = 17.92 + /- 4.69 ) did not prolong BT . CONCLUSION All patients with PAD require platelet inhibition , and many require pharmacotherapy for intermittent claudication . The platelet inhibitors aspirin and clopidogrel are used for the reduction of ischemic events . They significantly prolong bleeding time individually and to a greater extent in combination . Cilo is used to improve walking distance in patients with intermittent claudication . When Cilo is added to ASA , Clop , or the combination of the two , there is no additional increase in bleeding time . Therefore , Cilo can be used in combination with other platelet inhibitors without an additional effect on platelet function as reflected by the bleeding time In this multicenter trial 169 patients with chronic intermittent claudication due to obstructive peripheral vascular disease were r and omized 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 ticlo pidine 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 complica tions in patients with intermittent claudication Percutaneous transluminal angioplasty of aortoiliac and femoropopliteal atherosclerotic lesions can provide long-lasting hemodynamic improvement . High-dose aspirin is commonly prescribed as reocclusion prophylaxis , but low doses would be preferable because of fewer adverse effects . We performed a double-blind , r and omized , controlled clinical trial in patients with peripheral vascular disease with lesions appropriate for angioplasty . We compared the efficacy and side effects of two doses of aspirin ( 50 mg vs. 900 mg daily ) during a period of 12 months after angioplasty .  A total of 359 patients were evaluated : 175 were r and omly assigned to treatment with 900 mg aspirin daily and 184 to 50 mg aspirin a day . Thirty-nine patients developed restenosis at the angioplasty site ; the cumulative percentage of event-free survival after 1 year ( patency rate ) was 85 % in the 900-mg group and 84 % in the 50-mg group . An equivalence test showed the two groups equivalent with respect to restenosis rates ( P = 0.003 for an equivalence region of < 10 % difference ) . Nine patients ( 5 % ) in the 900-mg group had serious gastrointestinal side effects ( peptic ulcer , eight ; erosive gastritis requiring transfusion , one ) compared to two ( peptic ulcer ) in the 50-mg group ( P = 0.03 ) . The results of our study show that a dose of 50 mg aspirin a day is as effective as one of 900 mg for the prevention of restenoses after lower limb angioplasty , and that severe gastrointestinal side effects are less frequent Aim of our study was to evaluate the effectiveness of indobufen in the treatment of II degree stage lower limb occlusive arterial disease . Forty patients were r and omly assigned to the iIndobufen ( 400 mg/die ) treatment group or the no treatment control group ( 20 patients each ) . Doppler pressure measurement ( Winsor index ) and subjective symptomatology were evaluated at the time of enrollment and after one month . A significant improvement ( p less than 0.01 ) was noted only in the treated group . We conclude that indobufen may be of therapeutic value in the treatment of peripheral occlusive arterial disease In a r and omized double-blind crossover study in 12 patients with atherosclerotic disease , the effect of 2 dosages ( 100 and 200 mg twice daily ) of indobufen , a new synthetic inhibition of platelet aggregation , on some platelet functions , coagulation and fibrinolysis tests was investigated . Regardless of the dosage used , indobufen was shown to induce a prompt normalization of the enhanced platelet aggregation of these patients . The effect lasted for the entire period of drug administration and in 50 % of patients a normal platelet aggregation was maintained until the fourth day after discontinuation of the drug . Indobufen was also able to reduce platelet adhesiveness and to lengthen bleeding time , especially when the higher dosage was used 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 r and omized 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 OBJECTIVE To determine the fatal and non-fatal cardiovascular event rate in patients with intermittent claudication treated with antiplatelet agents .  METHODS AND DESIGN Patients with PAD-II stage Fontaine ( n=223 ) and sex and age matched controls ( n=446 ) were followed up from 1974 to 1998 . All patients were treated with antiplatelet agents ( aspirin , 325 mg once daily or ticlopidine , 250 mg twice daily ) and for risk factors , if present . The end points were death for any cause ( vascular event , cancer , and others ) and non-fatal vascular events ( myocardial infa rct ion , ischemic/hemorrhagic stroke , and leg amputation ) . RESULTS PAD patients had a significantly higher mortality rate than controls ( 3.99 vs. 2.53 deaths for 100 patients per year , respectively ) , cancer ( mostly lung , stomach and colon ) and vascular mortality accounted for such difference . The incidence of non-fatal vascular events was three times higher in patients than in controls ( 1.7 vs. 0.56 , 100 patients per year , respectively , p<0.05 ) even considering amputation separately ( 0.28 vs. 0.00 , 100 patients per year , p<0.05 ) . No difference between patients treated with aspirin or ticlopidine could be found in both end points . CONCLUSIONS Vascular mortality and morbidity , despite the use of antiplatelet agents , are still higher than sex and age matched controls ; however , the commonest cause of death is cancer BACKGROUND The manifestations of atherothrombosis such as myocardial infa rct ion , ischemic stroke , limb ischemia , or cardiovascular death pose a global health care burden . Additional therapies to decrease ischemic events in patients with established vascular disease or at risk for developing vascular disease are necessary . We sought to characterize the risk factors and treatments of a diverse contemporary population of patients with atherothrombosis . METHODS The CHARISMA trial has enrolled 15,603 patients from around the world . Patients with established coronary , cerebrovascular , or peripheral arterial disease , or those at high risk of developing atherothrombosis due to multiple risk factors , have been r and omized to receive either the adenosine diphosphate receptor antagonist clopidogrel or placebo , in addition to background therapy with low- to moderate-dose aspirin . RESULTS A high percentage of enrolled patients are being treated with statins and angiotensin-converting enzyme inhibitors . In the CHARISMA population , a total of 75.6 % of the population had an abnormal body mass index : 42.2 % were overweight and 33.4 % were obese , with particularly high rates in the United States , especially of morbid obesity . Correspondingly , the prevalence of diabetes was 42 % . CONCLUSION The CHARISMA trial will further characterize atherothrombosis and provide insight into the role of dual antiplatelet therapy in improving outcomes in patients with multiple risk factors or established vascular disease . Of note , the rates of obesity and diabetes in patients with atherothrombosis throughout the world are particularly alarming BACKGROUND Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication , and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease , as diagnosed by noninvasive testing . In this study , we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease . METHODS We examined 565 men and women ( average age , 66 years ) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques -- measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound . We identified 67 subjects with the disease ( 11.9 percent ) , whom we followed prospect ively for 10 years . RESULTS Twenty-one of the 34 men ( 61.8 percent ) and 11 of the 33 women ( 33.3 percent ) with large-vessel peripheral arterial disease died during follow-up , as compared with 31 of the 183 men ( 16.9 percent ) and 26 of the 225 women ( 11.6 percent ) without evidence of peripheral arterial disease . After multivariate adjustment for age , sex , and other risk factors for cardiovascular disease , the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 ( 95 percent confidence interval , 1.9 to 4.9 ) for deaths from all causes , 5.9 ( 95 percent confidence interval , 3.0 to 11.4 ) for all deaths from cardiovascular disease , and 6.6 ( 95 percent confidence interval , 2.9 to 14.9 ) for deaths from coronary heart disease . The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease . After the exclusion of subjects who had a history of cardiovascular disease at base line , the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated . Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic . CONCLUSIONS Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes Intermittent claudication impairs functional status and quality of life in many patients by limiting walking capacity . The aim of this study was to evaluate the effects of a 4-week treatment with prostagl and in E1 ( PGE1 ) , a drug inducing vasodilation and inhibiting platelet aggregation , on improving functional status and health-related quality of life in patients with disabling intermittent claudication . Forty-two untrained out patients ( 37 men and five women , mean age 64 ±8 years ) with intermittent claudication , and maximum walking distance ( MWD ) of at least 50 and no more than 200 m on treadmill test ( 5 % slope , 3 km/hr ) were r and omized to 4 weeks of double-blind treatment either with 60 mcg PGE1 daily given IV in 250 mL saline over a period of 2 hours ( 21 patients ) or placebo ( 250 mL saline , 21 patients ) . Treatment-free follow-up was completed 8 weeks after the final infusion . Pain free walking distance ( PFWD ) , MWD , and question naire evaluation were determined at baseline , after the 4-week treatment period , and at the end of the 8 weeks of the treatment-free follow-up period . After 4 weeks of treatment with PGE1 PFWD and MWD increased from 72 ±16 m to 135 ±33 m ( + 87 % , p<0.001 ) and from 140 ±30 m to 266 ±62 m ( + 90 % , p<0.001 ) , respectively . Analysis of the Walking Impairment Question naire responses in the PGE1 group at 4 weeks demonstrated significant improvements in the walking impairment score ( + 19 percentage points , p<0.001 ) , in the distance score ( + 25 percentage points , p<0.001 ) , in the speed score ( + 24 percentage points , p<0.001 ) , in the stair climbing score ( + 20 percentage points , p < 0.001 ) . The R AND survey responses showed improvements in physical function and bodily pain scores ( + 14 percentage points , p<0.001 , and + 15 percentage points , p<0.01 , respectively ) . After the treatment-free follow-up period of 8 weeks , increases in PFWD and MWD were maintained ( 113 ±26 m , + 57 % , p<0.001 , and 229 ±55 m , + 63 % , p<0.001 , respectively ) . Similarly , at the end of the treatment-free follow-up , the walking impairment score ( + 16 percentage points , p<0.001 ) , the distance score ( + 23 percentage points , p<0.001 ) , the speed score ( + 22 percentage points , p<0.001 ) , the stair climbing score ( + 18 percentage points , p<0.001 ) as well as the R AND physical function and bodily pain scores ( + 10 percentage points , p<0.001 , and + 13 percentage points , p<0.01 , respectively ) were still increased compared with baseline . No change from baseline was found in all the target parameters in the placebo group after 4 weeks of treatment and at the end of the treatment-free follow-up period . These data show that a 4-week treatment with PGE1 improves functional status and quality of life as well as treadmill performance in patients with disabling intermittent claudication as compared with placebo-treated patients . The improvements are also maintained for a period of 8 weeks beyond the end of the treatment . Additional studies are needed to determine the duration of functional benefits after the end of treatment The clinical efficacy of picotamide was investigated in a r and omized , 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 admit ted 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 pres sure 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 arachi donic acid-induced platelet aggregation , and an enhanced fibrinolysis with ab sence 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 prob lems The relationship between risk factors and the onset of cardiovascular events was analyzed in patients suffering from peripheral obstructive arterial disease . One thous and and eleven patients were recruited in 120 Italian centers and participated in a clinical trial on picotamide ( A.D.E.P. study ) , whose results have been previously reported . Patients were followed-up for 18 months and cardiovascular events were recorded . Hypertension ( 35 % ) , smoking ( 34 % ) , and diabetes ( 19 % ) were the most common risk factors at baseline . During the follow-up period , 246 patients ( 11.7 % ) had a cardiovascular event , mainly affecting cerebral , cardiac or peripheral circulation . Thirty-five of these events ( 14.2 % ) were fatal . A logistic regression analysis showed in general that hypertension ( odds ratio 1.48 ) , an ankle arm pressure ratio lower than 0.8 ( odds ratio 1.42 ) , smoking ( odds ratio 1.43 ) , previous vascular surgery ( odds ratio 1.35 ) , high white blood cell ( WBC ) count ( odds ratio 1.15 for a difference of 2.0 x 10(9 ) WBC/1 ) and plasma fibrinogen ( odds ratio 1.16 for a difference of 1.05 g/l ) were significantly associated with a higher incidence of cardiovascular events . In particular , deaths of any origin were more frequent in patients with an ankle/arm pressure ratio below 0.8 . High plasma fibrinogen increased the risk of cerebrovascular events , hypertension or coronary heart events and , to a less evident extent , peripheral vascular complications and cerebrovascular events . A history of vascular surgery increased the risk of peripheral vascular complications . Both smoking and a high WBC count showed to be borderline significant risk factors for coronary heart events and the former also for peripheral vascular complications . In male patients ( 84 % ) , ankle/arm pressure ratio lower than 0.8 , high fibrinogen and hypertension were the most important factors for cardiovascular events . This study helps to identify some categories at higher risk of cardiovascular events among patients with peripheral obstructive arterial disease ; this finding is useful to plan future trials to decrease the frequency of such complications Aims : In humans , little is known about the effects of platelet – leucocyte interactions on blood viscosity and microvascular perfusion . This study tested the hypotheses that ( 1 ) activation and interactions between platelets and leucocytes may have an impact on microvascular blood viscosity and perfusion in patients with stage II peripheral arterial occlusive disease , and ( 2 ) a powerful antiplatelet drug such as Clopidogrel might help to improve microvascular perfusion by reducing platelet – leucocyte activation and blood viscosity . Methods : Plasma concentrations of certain markers of leucocyte and platelet activation , in addition to low and high shear rate blood viscosity , were measured before and after a repeated exercise treadmill test . Functional parameters including maximum walking time , transcutaneous oxygen pressure , and half recovery time were also measured . Results : Blocking platelet activation only with a single dose of Clopidogrel ( 300 mg ) did not improve microvascular blood viscosity and perfusion after repeated exercise , but a significant improvement in microvascular perfusion during controlled ischaemia and a lack of post exercise increase in low shear rate blood viscosity was achieved when both platelet and leucocyte activation were suppressed by a relatively longer treatment with Clopidogrel ( four days ) . Conclusions : Clopidogrel , by inhibiting platelet activation and aggregation , might also block the vicious cycle of leucocyte – platelet activation , thus improving the functioning of the microcirculation 240 patients were admitted to a double-blind study to determine the effect of long-term treatment with platelet-function inhibiting agents on occlusive arterial disease in the lower extremities . Patients were r and omised into 1 of 3 treatment groups : aspirin 330 mg ; dipyridamole 75 mg and aspirin 330 mg ; or matching placebo 3 times daily . The duration of treatment was 2 years . Arteriography was carried out at the beginning of the study and 2 years later or before if deterioration was observed . 199 patients completed the study according to the trial protocol . The serial arteriograms were assessed in pairs qualitatively , by means of simple comparative viewing , and semiquantitatively with Bollinger 's score system . Progression of the disease was most pronounced in the placebo-treated group , less so in the aspirin-treated group , and least of all in the dipyridamole- and -aspirin group . Patients who smoke and those with hypertension may benefit most from treatment with the 2 preparations under investigation This study was undertaken to evaluate the efficacy and tolerability of policosanol , a new cholesterol-lowering drug with concomitant antiplatelet effects , in patients with inter mittent claudication . After a baseline period of 6 weeks , 62 patients were r and omized to receive , under double-blind conditions , either placebo ( 31 patients ) or policosanol ( 31 ) , 10 mg twice daily . Walking distances in a treadmill ( constant speed 3.2 km/hr , slope 10 ° ) were assessed before and after 6 months of treatment . Both groups were similar at r and omization . Policosanol increased significantly ( p<0.01 ) the initial claudication distance from 132.5 ±13.5 m ( baseline ) to 205.7 ±36.3 m ( after therapy ) and the absolute claudication distance ( p<0.0001 ) from 229.5 ±22.0 m to 365.4 _ ±46.9 m ; meanwhile both variables remained unchanged in the placebo group ( p<0.05 ) . The reduction of lower limb symptoms showed a greater benefit in the policosanol group . There was no significant change in either group in the ankle/arm pressure ratio . The treatment was well tolerated . There were 10 discontinuations ( seven placebo , three poli- cosanol ) from the study . Six withdrawals occurred because of adverse events ( AE ) ; all were in placebo patients . There were five serious vascular AEs in the placebo group but none in the policosanol group ( p<0.05 ) . Overall , 12/31 ( 38.7 % ) placebo patients and 3/31 ( 9.7 % ) policosanol patients experienced AEs after r and omization , which showed a lesser incidence of AEs in the policosanol group ( p<0.01 ) . The present study demon strates a beneficial effect of policosanol in patients with intermittent claudication Acute peripheral arterial occlusive disease is an important factor affecting the mobility and mortality rate of elderly patients . Catheter-guided arterial thrombolysis in these patients has its limitations : long lysis times , early occlusions , and high restenosis rates . The study investi gated whether the use of tirofiban has the same favorable effect as the glycoprotein ( GP ) IIb/IIIa receptor antagonist abciximab and whether lysis times can be shortened and the disease course positively influenced by these substances . Sixty patients were r and omly assigned to 2 groups . Each group received 5 mg recombinant tissue-type ( rt-PA ) plasminogen activator by slow intra-arterial injection for 10 minutes followed by 5 mg rt-PA per hour and 500 IU heparin per hour IV . After r and omization 1 group received a bolus of 0.25 mg abciximab per kg body weight followed by 10 mg per minute IV for 12 hours ( heparin was reduced to 250 IU/hr ) . The other group received a bolus of 0.4 μg tirofiban per kg body weight as well as postinterventional medication with 0.1 μg tirofiban per minute and kg body weight for 24 hours . During medication with GP IIb/IIIa inhibitor , the patients received a reduced heparin dosage for 24 hours . After 24 hours both groups received 200 mg aspirin orally and full heparinization controlled on the basis of the partial thromboplastin time . The following efficacy criteria were analyzed : rehospitalization events , reintervention events , and amputations within 6 months . Secondary endpoints were changes in the Fontaine stage , the crurobrachial index , the distance to claudication , and the duration of local arterial lysis . No significant differences were found between the abciximab and tirofiban groups in terms of the rehospitalization , rein tervention , or amputation rates , nor were there any group differences in the total number of events . The secondary parameters , such as the crurobrachial index , distance to claudication , and Fontaine stage , also showed no significant differences between the 2 groups within 6 months . The duration of lysis was significantly shorter in the abciximab group . Major bleeding events did not occur in either group . With regard to the adverse effect rate , there were no significant differences between the 2 groups . Both abciximab and tirofiban can be used successfully in patients with peripheral arterial occlusive disease and arterial thrombosis CONTEXT A low ankle brachial index ( ABI ) indicates atherosclerosis and an increased risk of cardiovascular and cerebrovascular events . Screening for a low ABI can identify an asymptomatic higher risk group potentially amenable to preventive treatments . OBJECTIVE To determine the effectiveness of aspirin in preventing events in people with a low ABI identified on screening the general population . DESIGN , SETTING , AND PARTICIPANTS The Aspirin for Asymptomatic Atherosclerosis trial was an intention-to-treat double-blind r and omized controlled trial conducted from April 1998 to October 2008 , involving 28,980 men and women aged 50 to 75 years living in central Scotl and , free of clinical cardiovascular disease , recruited from a community health registry , and had an ABI screening test . Of those , 3350 with a low ABI ( < or = 0.95 ) were entered into the trial , which was powered to detect a 25 % proportional risk reduction in events . INTERVENTIONS Once daily 100 mg aspirin ( enteric coated ) or placebo . MAIN OUTCOME MEASURES The primary end point was a composite of initial fatal or nonfatal coronary event or stroke or revascularization . Two secondary end points were ( 1 ) all initial vascular events defined as a composite of a primary end point event or angina , intermittent claudication , or transient ischemic attack ; and ( 2 ) all-cause mortality . RESULTS After a mean ( SD ) follow-up of 8.2 ( 1.6 ) years , 357 participants had a primary end point event ( 13.5 per 1000 person-years , 95 % confidence interval [ CI ] , 12.2 - 15.0 ) . No statistically significant difference was found between groups ( 13.7 events per 1000 person-years in the aspirin group vs 13.3 in the placebo group ; hazard ratio [ HR ] , 1.03 ; 95 % CI , 0.84 - 1.27 ) . A vascular event comprising the secondary end point occurred in 578 participants ( 22.8 per 1000 person-years ; 95 % CI , 21.0 - 24.8 ) and no statistically significant difference between groups ( 22.8 events per 1000 person-years in the aspirin group vs 22.9 in the placebo group ; HR , 1.00 ; 95 % CI , 0.85 - 1.17 ) . There was no significant difference in all-cause mortality between groups ( 176 vs 186 deaths , respectively ; HR , 0.95 ; 95 % CI , 0.77 - 1.16 ) . An initial event of major hemorrhage requiring admission to hospital occurred in 34 participants ( 2.5 per 1000 person-years ) in the aspirin group and 20 ( 1.5 per 1000 person-years ) in the placebo group ( HR , 1.71 ; 95 % CI , 0.99 - 2.97 ) . CONCLUSION Among participants without clinical cardiovascular disease , identified with a low ABI based on screening a general population , the administration of aspirin compared with placebo did not result in a significant reduction in vascular events . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N66587262 Ticlopidine ( Ticlodone : CAS 55142 - 85 - 3 ) is able to develop a positive effect on  claudication in patients affected by peripheral atherosclerotic disease ( PAD ) . It is also known that ticlopidine decreases fibrinogen levels in plasma . 15 PAD patients treated with ticlopidine for 3 months were studied , evaluating the drug 's effect both on maximum walking distance and on fibrinogen . Plasma fibrinogen as coagulable protein , fibrinogen antigen ( Partigen method ) , 125I-fibrinogen survival , euglobulin lysis time and plasminogen were determined with the aim of clarifying if the decrease of plasma fibrinogen induced by ticlopidine is due to an increased destruction of a decreased production of the molecule . The normal levels of all tests before and after therapy both in ticlopidine treated patients and in the control group ( acetylsalicylic acid + dipyridamol ) indicate that the two hypotheses are not true . It is proposed that ticlopidine developing the known effect in decreasing the binding of fibrinogen to platelets induces a decrease only of activated fibrinogen 20 male patients from 44 to 61 years of age with arteriosclerotic disturbances of the blood supply of the legs ( stage II after Fontaine ) were in the cross-over treated with 3 x 200 mg trapidil or 3 x 200 mg pentoxifylline daily . The duration of the therapy was in each case 6 weeks with a one-week elutriation phase . Statistically ascertained was an increase of the distance of intermittent claudication for the two drugs in patients with initial values lower than 550 m. On the other h and the tibio-brachial Doppler quotient and the submaximal blood supply established by the venous-occlusion plethysmography did not change . The post-ischaemic recovery phase of the transcutaneous oxygen partial pressure at the lower leg shortened in particular under the influence of trapidil . Lipid parameter , haematocrit , fibrinogen and plasma viscosity remained unchanged . The subjective tolerance of the two remedies was good BACKGROUND This paper introduces a proof-of-concept trial in progress , supposedly providing new important information on anti-platelet drugs used in patients with peripheral arterial disease ( PAD ) . The Arteriogenesis Competence Network ( Art . Net . ) of the Universities of Basel , Berlin , and Freiburg could show in animal models that Aspirin ( ASA ) , in contrast to Clopidogrel , inhibits the formation of an appropriate collateral network ( arteriogenesis ) . This trial is supposed to reproduce the animal data in man . MATERIAL S AND METHODS In a prospect i ve , double-blind , parallel-group , bi-national ( D , CH ) , multicentre trial , 250 patients will be r and omised to either 100 mg ASA or 75 mg Clopidogrel once daily . Patients will then enter a three months structured rehabilitation programme with daily physical training supposed to induce arteriogenesis . The claudication distances will be tested as the primary endpoint at baseline , 6 weeks , and at 3 months . Also , the 24h physical activity profile of all patients will be electronically documented . CONCLUSIONS This trial will provide information on potential disadvantages when using ASA in PAD patients . If data emerging from animal pharmacology can be reproduced in man , the present st and ard scheme of anti-aggregant treatment in PAD patients has to be reconsidered OBJECTIVE To study the effect of long-term treatment of the platelet inhibitor ticlopidine as secondary prevention against the need of vascular surgery in patients with intermittent claudication . DESIGN The Swedish Ticlopidine Multicentre Study ( STIMS ) , was conducted in six medical and surgical clinics of university hospitals in Sweden . METHODS 687 claudicants were r and omised to ticlopidine 250 mg bd or placebo and vascular surgery events were recorded prospect ively over a 7-year period . Cox proportional hazards models of risk for leg vascular surgery were constructed using drug treatment and 11 putative risk factors for vascular disease as covariates . Surgical event-free survivals were compared by Kaplan-Meier analysis . RESULTS The overall rate of first operations was 2.4 % per annum . More than half of these operations were in the aortoiliac region . One-quarter of patients operated during the period required further operations but amputation was rare . Ticlopidine treatment reduced the need for vascular reconstructive surgery by about half , both in intention-to-treat and on-treatment analyses ( unadjusted relative risks 0.486 , 95 % CI 0.317 - 0.745 ; p < 0.001 ; 0.493 , 95 % CI 0.290 - 0.841 : p < 0.01 , respectively ) . In Cox model analysis only male sex was confirmed as a risk factor for surgery . Previous peripheral arterial surgery was the strongest predictor of the need for surgery . None of the risk factors examined interacted statistically with the effect of treatment with ticlopidine . CONCLUSION In patients with intermittent claudication it seems possible to prevent the need for future vascular surgery by the use of platelet inhibition with ticlopidine This was a multinational , multicentre , double-blind Phase II study in Europe to evaluate the efficacy and safety of two dose regimens ( 200 mg bid and 200 mg tid ) of sarpogrelate ( MCI-9042 , 5-HT2A receptor antagonist ) compared to placebo in patients with stable , moderately severe intermittent claudication . Following a single-blind placebo run-in period of 6 weeks , 364 ( 309 male and 55 female ) patients ( 59.2 ± 8.4 years , mean SD ) were r and omized to receive sarpogrelate 200 mg bid , 200 mg tid or placebo for 24 weeks with a follow-up of 8 weeks . The primary objective was the increase of absolute claudication distance ( ACD ) at the end of treatment ( week 24 ) compared to placebo . Analysis of covariance ( ANCOVA ) was performed on the log-transformed percentage of baseline ACD : loge ( ACD/baseline ) . A responder analysis ( defined as a 50 % improvement in ACD ) was also performed . There was a marked training/placebo effect on the ACD which persisted up to 16 weeks . At 24 weeks the primary objective did not reach statistical significance ( 200 mg bid vs placebo , p = 0.225 ; 200 mg tid vs placebo , p = 0.580 ) . In the responder analysis , 200 mg bid showed a statistically significant difference vs placebo ( p = 0.035 ) . In the exploratory analysis with completers ( patients completing all treadmill tests ) , there was a statistical difference in ACD/baseline change for 200 mg bid ( p = 0.035 ) and in the responder analysis for 200 mg tid ( p = 0.044 ) at 24 weeks compared to placebo . Both treatments showed a carry-over effect for ACD during the 8-week follow-up ( weeks 28 - 32 ) . The treatment was well tolerated and no clinical ly significant safety concerns were reported . In conclusion , the study results confirm that sarpogrelate is well tolerated and although the primary endpoint failed to reach statistical significance , the responder analysis showed an increased absolute walking distance , which makes a further trial warranted , including a larger population , and possibly also a longer treatment period The mortality in patients with intermittent claudication can be reduced by treatment with ticlopidine . This is the clinical ly most significant result from STIMS , the Swedish Ticlopidine Multicenter Study . During an average treatment period of 5.6 years , 153 of the 687 patients  died , 26.1 % in the placebo group and 18.5 % in the ticlopidine group ( RR0.7 , p=0.015 ) . The incidence of fatal vascular events in the two groups was 12 % and 6 % . In terms of lives saved per years of treatment , STIMS showed that by treating 200 claudicants for 5 years one can save 13 from a cardiovascular death , not merely dying from something else as treatment was associated with a reduced total mortality as well . The interpretation of the on-treatment analysis is that for those who tolerate the drug the combined vascular morbidity and mortality rate is lowered from 24 % to 14 % . The disadvantage is that many patients do not tolerate ticlopidine . In STIMS , 22 % ( 2.5 times as many as in the control group ) had to stop medication because of gastrointestinal side-effects . Although ticlopidine is associated with an increased risk of leukopenia , the risk in absolute numbers is small : according to STIMS , 4 % during 5.6 years . All events were reversible . The 1.4 % incidence of thrombocytopenia did not seem to be associated with ticlopidine treatment Background Patients with peripheral vascular disease ( PVD ) undergo a clinical course that can be complicated by cardiovascular events occurring in several areas of the circulation . Methods and Results 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 r and omly 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 , 18.9o ; 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%o ) . 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 ) . Conclusions 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 efficacy of physical training alone or combined with antiplatelet thera py ( dipyridamole and aspirin ) was studied in 30 patients with stage II peripheral arterial occlusive disease ( PAOD ) . Patients were r and omly allocated to one of the following groups : Group A— dipyridamole 75 mg three times daily and aspirin 330 mg once daily : Group B— physical exercise ; Group C — physical exercise and dipyridamole 75 mg three time daily and aspirin 330 mg once daily . After six months ' treatment the pain-free walking time ( PFWT ) and the max imum walking time ( MWT ) improved significantly ( p < 0.05 ) in all three groups . In group A the PFWT lengthened by 35 % ( from 101.00 ± 34.56 to 137.32 ± 40.50 s ) and the MWT by 38 % ( from 150.34 ± 55.60 to 207.26 ± 60.67 s ) ; in group B the PFWT lengthened by 90 % ( from 90.65 ± 40.54 to 171.45 ± 55.60 s ) and the MWT by 86 % ( from 145.39 ± 60.50 to 270.63 ± 63.61 s ) . When physical exer cise was associated with drugs as in group C , the PFWT lengthened by 120 % ( from 89.51 ± 43.89 to 196.72 ±51.73 s ) and the MWT by 105 % ( from 160.43 ± 59.84 to 329.05 ± 63.96 s ) . No significant variations were observed at any stage of the study in the ankle/arm pressure ratio at rest and after st and ard treadmill exercise , in the plethysmographic rest and peak flows , or in the trans cutaneous oxygen pressure in basal conditions and in its half recovery time after an induced ischemia . The results confirm the benefits of regular exercise in stage II PAOD pa tients but suggest they may be enhanced by antiplatelet therapy AIMS 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 , r and omized , 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 ) . METHODS AND RESULTS A total of 1209 adults aged 40 - 75 years with type 2 diabetes and PAD were r and omized 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 . CONCLUSION Picotamide is significantly more effective than aspirin in reducing overall mortality in type 2 diabetic patients with associated PAD The effect of combined treatment with acetylsalicylic acid and dipyridamole on platelet consumption and aggregation was studied in 9 patients with peripheral atherosclerotic disease . The trial was carried out as a r and omized double-blind , cross-over study . All patients had increased consumption of blood platelets . The treatment produced a marked inhibition of platelet aggregation , increased the bleeding time , but did not reduce the platelet consumption In a r and omized double-blind crossover study in 16 patients with enhanced in vitro spontaneous platelet aggregation , sulfinpyrazone proved to be effective in normalizing platelet aggregability within 4 days after initiation of therapy OBJECTIVE To determine the risk factors for peripheral arterial disease ( PAD ) in a diabetic population and to examine whether different levels of these risk factors might explain why diabetic subjects have an increased risk of PAD compared with normal glucose tolerance subjects . RESEARCH DESIGN AND METHODS There were 1,592 men and women aged 55 - 74 years selected at r and om from the age-sex registers of 11 general practice s in Edinburgh , Scotl and . Subjects underwent a comprehensive medical examination , including assessment for PAD  ( intermittent claudication on World Health Organization question naire or major asymptomatic disease on noninvasive testing ) and a glucose tolerance test . RESULTS Of the subjects , 288 ( 18.7 % ) were found to have diabetes or impaired glucose tolerance ( IGT ) . The prevalence of PAD was greater in those with diabetes/IGT ( 20.6 % ) compared with those with normal glucose tolerance ( 12.5 % ) ( odds ratio [ OR ] 1.64 , 95 % CI 1.17 - 2.31 ) . Among the diabetes/IGT group , mean levels of smoking , systolic blood pressure , and triglycerides were higher in subjects with PAD than in those without PAD ( P < or = 0.05 ) . Mean levels of systolic blood pressure and plasma triglycerides were also higher in diabetic subjects than in nondiabetic subjects with PAD ( P < or = 0.05 ) . In multivariate analysis , those with diabetes/IGT no longer had a significantly higher risk of PAD after adjusting separately for systolic blood pressure ( OR 1.22 , 95 % CI 0.85 - 1.73 ) and plasma triglycerides ( OR 1.26 , 95 % CI 0.89 - 1.79 ) . Simultaneous adjustment for both systolic blood pressure and triglycerides reduced the risk of PAD among diabetic subjects to 1.11 ( 95 % CI 0.78 - 1.58 ) . CONCLUSIONS Increased mean levels of triglycerides and systolic blood pressure may help to explain the higher prevalence of PAD in diabetic subjects compared with that in normal glucose tolerance subjects Effects of picotamide on platelet activity and on some hemorheologic , coagu lative , and hemodynamic parameters were investigated in a r and omized , dou ble-blind , placebo-controlled study for eighteen months . Twenty patients , average age 61.5±9.6 ( SD ) years , with peripheral arterial disease ( PAD ) at functional stage 2 of the Fontaine classification and with intermittent claudica tion for at least six months were studied . Ten patients received tablets of picotamide , 300 mg three times a day , and 10 subjects received three identical placebo tablets each day . Similar atheroscler otic disease risk factors were present in both groups . Picotamide induced a significant decrease of plasma viscosity , fibrinogen , and beta-thromboglobulin and an increase of amplitude of the photoplethysmo graphic wave Policosanol is a cholesterol-lowering drug with concomitant antiplatelet effects . This study was undertaken to investigate the long-term effects of policosanol administered to patients with moderately severe intermittent claudication . The study consisted of a 6-week single-blind , placebo-controlled run in phase , followed by a 2-year double-blind , r and omized treatment step . Fifty-six patients who met study entry criteria were r and omized to receive placebo or poli cosanol 10 mg twice daily . Walking distances on a treadmill ( constant speed 3.2 km/h , slope 10 ° , temperature 25 ° C ) were assessed before and after 6 , 12 , 18 , and 24 months of treatment . Both groups were similar at r and omization . After 6 months of therapy , policosanol significantly increased ( p < 0.0 1 ) the initial claudication distance from 125.9 ±8.7 m to 201.1 ±24.8 m and the absolute claudication distance from 219.5 ± 14.1 m to 380.7 ±50.2 m. Both variables remained unchanged in the placebo group ( p<0.01 ) . These effects did not wear off but improved after long-term therapy , so that final values were 333.5 ±28.6 m ( initial claudication distance ) and 648.9 ±54.1 m ( absolute claudication distance ) ; both significantly greater ( p<0.0001 ) than those obtained in the placebo group , which showed values of 137.9 ±21.8 m ( initial claudication distance ) and 237.7 ±28.1 m ( absolute claudication distance ) , respectively . At study completion , 21 policosanol and 5 placebo patients attained increases in claudication distance values > 50 % ( p < 0.001 ) . Policosanol , but not placebo , significantly increased the ankle/arm pressure index . In addition , from month 6 up to study completion , the frequency of patients reporting improve ment of lower limb symptoms was greater in the policosanol group than in the placebo group . The treatment was tolerated well . There were 16 withdrawals ( 12 placebo , 4 policosanol ) from the study . Eight patients in the placebo group experienced a total of 10 serious adverse events , 8 of which were vascular events , compared with none in the policosanol group ( p<0.01 ) . In addition , 3 patients in the policosanol group and 3 patients in the placebo group reported mild adverse events during the study . The present results demonstrate the long-term usefulness of policosanol therapy to treat patients with intermittent claudication OBJECTIVE The concept of clopidogrel resistance is frequently evoked in the cardiac literature . The variability of antiplatelet response in patients with intermittent claudication has not been investigated . The aim of this study was to describe the effect of the addition of clopidogrel to aspirin using ex vivo measures of platelet activation in patients with life-style limiting intermittent claudication . DESIGN OF STUDY Data from r and omised controlled trial . MATERIAL S Data from 67 patients with intermittent claudication taking part in a r and omised controlled trial and who received clopidogrel in addition to aspirin was analysed . METHODS Platelet activation was measured using whole-blood flow cytometric measurement of ADP-stimulated fibrinogen binding at baseline and 12h after administration of a loading dose of 300 mg clopidogrel . Patients continued to receive 75 mg clopidogrel daily for 30 days and platelet activation was again measured at day 30 . Compliance with treatment was assessed by counting returned tablets  . RESULTS Six patients were excluded from analysis because of incomplete compliance with treatment . Six of the sixty-one patients ( 9.8 % ) showed no reduction in platelet activation 12h after administration of the loading dose of clopidogrel . At 30 days these six patients still showed no response to clopidogrel . Amongst the remaining 55 patients , the mean reduction in fibrinogen binding after clopidogrel administration was 51.5 % ( 95 % CI : 43.8 - 59.2 ) . Amongst responders there was a wide variability in reduction of fibrinogen binding in response to clopidogrel ( range 8.11 - 97.7 % ) . Four of these patients ( 6.6 % ) showed a reduction of more than 95 % in fibrinogen binding . CONCLUSIONS Patients with intermittent claudication show a wide variability in their response to clopidogrel . While a small proportion of these patients shows no response at all , another small group appears to respond excessively to clopidogrel . Clinical studies are required to identify whether hyper-responders are at increased risk of bleeding complications and whether hyporesponders are at a higher risk of thrombotic events OBJECTIVE We aim ed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin ; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin . METHODS We performed a r and omized , double-blind , placebo-controlled , crossover trial , comparing clopidogrel 75 mg day(-1 ) versus placebo , in 36 aspirin-treated patients with symptomatic objective ly confirmed peripheral arterial disease . RESULTS The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid , urinary 11 dehydro thromboxane B2 concentrations , or soluble markers of platelet activation markers ( P-selectin , CD40-lig and ) and inflammation ( high sensitivity serum C-reactive protein , interleukin-6 ) . Clopidogrel significantly inhibited platelet aggregation induced by ADP ( reduction 26.2 % ; 95 % CI : 21.3 - 31.1 % , P < 0.0001 ) and collagen ( reduction 6.2 % ; 95 % CI : 3.2 - 9.3 % , P = 0.0003 ) . The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [ lower tertile of arachidonic acid-induced platelet aggregation : 2.8 % ( 95 % CI : -0.8 to 6.3 % ) reduction in mean collagen-induced aggregation by clopidogrel ; middle tertile : 4.0 % ( 95 % CI : 0.4 - 7.6 % ) ; upper tertile 12.6 % ( 95 % CI : 4.5 - 20.8 % ) ; P-value for interaction 0.01 ] . CONCLUSIONS The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin . This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin . Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor , thereby overcoming the problem of laboratory aspirin resistance OBJECTIVE Coagulation activation markers are significantly elevated in patients with peripheral arterial disease compared with healthy controls . The more severe the disease , the higher the markers . Increased coagulation activation may contribute to the disease process and the risk of complications in patients with peripheral arterial disease , particularly after endovascular intervention . Animal studies have shown that clopidogrel significantly inhibits coagulation activation . The aim of this study was to determine whether combination of aspirin and clopidogrel affects thrombin-antithrombin III and D-dimer in patients with intermittent claudication undergoing angioplasty , compared with aspirin alone . METHODS This was a double blind , r and omized placebo-controlled trial conducted in a vascular unit in a tertiary referral center . One hundred thirty-two patients with intermittent claudication were r and omized to clopidogrel and aspirin or placebo and aspirin , with a loading dose 12 hours before endovascular intervention . D-dimer and thrombin-antithrombin III ( TAT ) levels were measured using enzyme-linked immunosorbent assay at baseline , 1 hour before , and 1 hour , 24 hours , and 30 days after intervention in 103 patients who underwent endovascular intervention . RESULTS There was a significant rise in D-dimer levels at 1 hour and 24 hours after angioplasty in both groups ( placebo group : 63.69 , 141.45 , 122.18 ng/mL ; clopidogrel group : 103.79 , 159.95 , 134.69 ng/mL ) , but no difference between the two groups ( P = .514 ) . Similarly there was a significant rise in TAT levels at 1 hour after angioplasty in both groups ( placebo group : 2.93 , 6.16 microg/L ; clopidogrel group : 3.39 , 5.27 microg/L ) , with no significant difference between the two groups ( P = .746 ) . CONCLUSION Endovascular intervention results in a significant increase in TAT and D-dimer . The addition of clopidogrel to aspirin has no effect on TAT and D-dimer before or after endovascular intervention OBJECTIVES In the current study , we hypothesized that beraprost would : 1 ) improve treadmill exercise performance and quality of life ; and 2 ) decrease rates of ischemic events in patients with intermittent claudication . BACKGROUND Previous trials with beraprost sodium , an orally active prostagl and in I(2 ) analogue , in the treatment of claudication in patients with peripheral arterial disease ( PAD ) have been inconsistent . METHODS Patients with intermittent claudication ( n = 897 ) were r and omized to receive either 40 microg three times a day of beraprost with meals ( n = 385 ) or placebo ( n = 377 ) in a double-blinded manner for one year . The primary efficacy parameter was treadmill-measured maximum walking distance , as assessed at three and six months after r and omization . Secondary efficacy parameters included treadmill-measured pain-free walking distance and change in quality of life . RESULTS There was no significant improvement in maximum walking distance in the beraprost group ( 16.7 % ) as compared with the placebo group ( 14.6 % , p = NS ) . Administration of beraprost did not improve the pain-free walking distance ( p = NS between treatment groups ) , and there was no improvement in the quality -of-life measures between the treatment groups . The incidence of critical cardiovascular events was 7.3 % in the beraprost group and 11.4 % in the placebo group ( p = NS ) . There was a significant reduction in the combination of cardiovascular death and myocardial infa rct ion in the beraprost group ( p = 0.01 ) . CONCLUSIONS Despite previous investigations suggesting efficacy , these results indicate that beraprost is not an effective treatment to improve symptoms of intermittent claudication in patients with PAD . The potential benefit of beraprost on critical cardiovascular events would require confirmation in a larger prospect i ve investigation OBJECTIVES The current study tested the hypothesis that NM-702 improves treadmill exercise performance in peripheral arterial disease patients with claudication-limited exercise performance . BACKGROUND Patients with claudication experience significant disability , owing to their exercise limitation . Therapeutic options to improve exercise performance in these patients are limited . NM-702 is a novel drug that inhibits phosphodiesterase as well as thromboxane A2 synthase . METHODS This study was a r and omized , multi-center , placebo-controlled , double-blind trial . Patients were r and omized to receive 24 weeks of twice-daily treatment with either placebo ( intent to treat population , n = 130 ) , 4 mg NM-702 ( n = 126 ) , or 8 mg NM-702 ( n = 130 ) . RESULTS After 24 weeks of treatment , 8 mg NM-702 was associated with a statistically significant increased peak walking time on a grade d treadmill as compared with placebo ( p = 0.004 ) . Peak walking time after 24 weeks was increased by 17.1 + /- 49.0 % in the placebo arm , 22.1 + /- 60.1 % in the 4-mg NM-702 arm , and 28.1 + /- 50.5 % in the 8-mg NM-702 arm . NM-702 at the 8-mg dose for 24 weeks was associated with statistically significant improvements in the treadmill claudication onset time as compared with placebo . In addition , as compared with placebo , NM-702 improved the physical component and physical functioning scores of the Medical Outcomes Study 36-Item Short Form and the walking distance and stair climbing domains of the Walking Impairment Question naire . NM-702 was generally well tolerated , but adverse events typical of vasodilators were common . CONCLUSIONS NM-702 used for 24 weeks by patients with claudication was associated with improvements in laboratory- and ambulatory-based exercise performance Forty-five patients suffering from intermittent claudication were admitted to a double-blind non-crossover study . Three groups were constituted at r and om and treated for 2 months with either 100 mg suloctidil t.i.d . or 1.5 mg dihydroergotoxine methylate t.i.d . or placebo . From the results of measurements of pain-free walking distance and venous occlusion plethysmography recordings , suloctidil was shown to be active and significantly superior to dehydroergotoxine and placebo : in the two latter groups a decrease in calf blood perfusion after 2 months was also noted . The physician 's overall assessment of response to treatment showed that suloctidil and dihydroergotoxine were significantly superior to placebo , and that suloctidil was significantly better than dihydroergotoxine BACKGROUND The aim of this study has been to assess the efficacy and the safety of heparansulphate administered with indobufen in the treatment of occlusive arterial disease . METHODS In a controlled open study , nineteen out- patients with Fontaine 's stage II occlusive arterial disease since one year were r and omly assigned to treatment with indobufen 200 mg/day or indobufen 200 mg/day and heparansulphate 200 mg/day for 6 months . Efficacy assessment s were based on functional evaluations ( pain-free sub-maximal exercise ergometric test , ankle-arm pressure ratio at rest and after induced ischemia ) , on hemocoagulative parameters and on physical signs and subjective symptoms assessed monthly over the whole period of treatment . All patients but one who was lost to follow-up completed the study treatment period as foreseen by the experimental protocol . RESULTS The results of the study show an improvement of 10.89 % ( day 30 ) , 15.92 % ( day 60 ) , 21.04 % ( day 90 ) , 24.19 % ( day 120 ) , 25.18 ( day 150 ) 28.84 % ( day 180 ) end of study in ergometric test pain-free interval obtained by patients treated with heparansulphate and indobufen with respect to patients receiving indobufen alone . Also hemocoagulative parameters and signs and patients ' subjective symptoms were positively influenced by the association heparansulphate and indobufen . CONCLUSIONS On the whole , the results of the study indicate that heparansulphate in association with antiplatelet therapy with indobufen has a beneficial effect in the treatment of peripheral occlusive arterial disease BACKGROUND Repeat hospitalizations of patients with atherosclerosis represent a considerable burden on the health care system . We sought to determine whether clopidogrel compared with aspirin decreases the need for rehospitalization for ischemia and bleeding . METHODS AND RESULTS The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events ( CAPRIE ) trial was a r and omized , blinded , multicenter , trial of 19,185 patients with atherosclerotic disease manifested as recent ischemic stroke or myocardial infa rct ion or symptomatic peripheral arterial disease . Without any double-counting of events , the number of rehospitalizations for ischemic events ( defined as angina , transient ischemic attack , or limb ischemia ) or bleeding events was determined for the entire cohort . There was a significant reduction in the total number of rehospitalizations for ischemic events or bleeding with clopidogrel use compared with aspirin ( 1502 vs 1673 ; P = .010 ) over an average of 1.6 years of treatment . This reduction in rehospitalization was consistent across individual outcomes of angina , transient ischemic attack , limb ischemia , and bleeding . Compared with aspirin , clopidogrel also result ed in a 7.9 % relative risk reduction in a combined end point of vascular death , stroke , myocardial infa rct ion , or rehospitalization for ischemic events or bleeding ( 15.1 % to 13.7 % at 1 year ; P = .011 ) . Adjusting for baseline prognostic variables , clopidogrel therapy was an independent predictor for reduction of vascular death , stroke , myocardial infa rct ion , or rehospitalization for ischemic events or bleeding ( P = .009 ) . CONCLUSIONS Treatment with clopidogrel results in a significant decrease in the need for rehospitalization for ischemic events or bleeding compared with aspirin . This meaningful end point tracks well with other , more traditional measures of outcome and has incremental value beyond such end points Platelet survival times were measured twice within 6 months using autologous 111-Indium-labelled platelets in 13 male patients diagnosed as stable intermittent claudicants . Linear , exponential , weighted mean and gamma function ( multiple-hit ) analyses were carried out on the data . Of these methods , exact mathematical models such as linear and exponential are unsuitable for the comparison of curves which may alter with treatment or disease progression . Weighted mean platelet survival correlated ( r = 0.96 ) with platelet survival calculated by the precision reference method of analysis , gamma function . Statistics were expressed from gamma function analyses unless otherwise stated . Severity of claudication was measured by doppler ; the ratio of brachial to mean ankle pressures was directly related to platelet survival ( r = 0.84 ) . In 7 patients , where duration of claudication was greater than 5 years , platelet survival was significantly reduced ( P less than 0.02 ) compared with 6 newly diagnosed claudicants of less than 18 months duration . Six r and omly selected patients were treated with 250 mg b.d . ticlopidine during one of the study periods . Ticlopidine significantly increased platelet survival ( P less than 0.02 ) in all patients irrespective of disease duration or severity . The involvement of platelets in atherosclerosis observed in these claudicants , can be reduced by therapy with ticlopidine , however , the lack of clinical improvement following long-term drug treatment only confirms the platelet 's secondary role in this disabling disease Seventy-one patients with peripheral arterial occlusive disease ( PAOD ) were r and om ized into two groups of different treatment modalities . The diagnosis of PAOD was estab lished by history of intermittent claudication , clinical examination , and by Doppler pressure assessment or lower extremity arteriography . After a three-month washout period , 35 patients ( Group 1 ) started treatment with indobufen ( 400 mg per day ) and 36 patients ( Group 2 ) with pentoxifylline ( 600 mg per day ) . Twenty-nine patients from each group completed six months of treatment . Both of the drugs significantly improved maximal and pain-free walking distances , but the effect of indobufen was more pronounced than that of pentoxifylline .  Patients with PAOD exhibited signs of hyperco agulation . Fibrinogen , D-dimer , and b-thromboglobulin concentrations did not change significantly following treatment in both of the groups . The authors observed a decrease of platelet aggregation after treatment with indobufen and a decrease of F1 + 2 fragment and PAI-1 antigen after treatment with pentoxifylline The efficacy of and tolerance to ticlopidine , a platelet inhibitor , in preventing progression of obliterative arterial disease was compared with that of a placebo in a double-blind and r and omized trial in 43 patients ( 22 on placebo , 21 on ticlopidine ) over a period of one year . The course of the disease in both groups was assessed by serial angiography of the lower limbs , both at the beginning and at the end of the study . There was a significantly reduced progression in the ticlopidine group ( P less than 0.01 ) . The results support the hypothesis that platelets are of great importance in the progression of arteriosclerosis and that inhibition of platelet function is an effective principle of prevention . Ticlopidine in this respect is an alternative to the use of acetylsalicylic acid 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 atheroscle rotic or diabetic origin . Fifty-two out patients were admitted to the r and omized , double-blind study and were given either an indobufen 200-mg tablet ( 28 sub jects ) or placebo ( 24 ) for six months . Painfree walking distance on a treadmill at a constant speed ( 4 km/h ) and slope ( 10 ° ) 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 < 0.01 ) and 243 ± 32.49 ( p > 0.05 ) meters respec tively . The difference between the two treatments was statistically significant in favor of indobufen ( p < 0.01 Dunn 's test ) Peripheral arterial disease ( PAD ) is associated with platelet hyperactivity . Aspirin and clopidogrel , two platelet inhibitors , act by different mechanisms . Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor . We evaluated the effect of clopidogrel ( 75 mg/day ) , aspirin ( 75 mg/day ) and then both drugs on several platelet function indices in patients with PAD ( n = 20 ) . There was a significant ( P = 0.0001 ) decrease in ADP-induced aggregation , after clopidogrel but not after taking aspirin . Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation ( SPA ) ( P = 0.01 to P = 0.002 ) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy . Similarly , monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a significant inhibition ( P = 0.03 to P<0.02 ) after combination therapy . ADP ( 0.8 μM)-induced platelet shape change ( PSC ) was significantly inhibited by clopidogrel ( P = 0.004 ) or aspirin ( P = 0.01 ) . This was also true for 5HT-induced PSC  ( clopidogrel , P = 0.01 ; aspirin , P = 0.03 ) . Soluble P-selectin decreased significantly ( from 32 ± 24 to 25 ± 17 ng/ml , P = 0.04 ) with combination therapy . Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy . In PAD , clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin ; combination therapy is more effective than clopidogrel or aspirin monotherapy . These potentially clinical ly relevant findings should be evaluated in appropriately design ed trials After a 3-month , single-blind , run-in period , 151 patients with intermittent claudication were r and omly 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 r and omization , 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 32 patients ( mean age 65 years , range 51 - 75 years ) were included in this controlled , double blind study to evaluate the effect of dipyridamole in patients with intermittent claudication . Following a run-in phase of one month , 15 patients received 400 mg dipyridamole per day and 17 patients placebo . Patient characteristics ( risk factors , age , clinical and apparative tests ) of both groups did not differ significantly before and during the study period . Mean pain free und absolute walking distance on the treadmill ( 3.2 km/h , 12.5 degrees gradient ) increased significantly in both groups during study period ( p < 0.001 and p < 0.01 ) . Explanations are more intensive physical activity and increasing adaptation to treadmill exercise . However , dipyridamole did not induce a significantly longer walking distance in comparison with placebo . The working hypothesis that the drug with inhibiting properties of thrombocyte function prolongs walking distance in intermittent claudication , could not be confirmed Objectives : Cilostazol improves walking in patients with peripheral arterial disease ( PAD ) . We hypothesized that cilostazol reduces diabetic complications in PAD patients . Methods : Diabetic PAD patients were prospect ively recruited to a r and omized double-blinded , placebo-controlled trial , using cilostazol 100 mg twice a day . Clinical assessment included ankle-brachial index , arterial compliance , peripheral transcutaneous oxygenation , treadmill walking distance and vali date d quality of life ( QoL ) question naires . Biochemical analyses included glucose and lipid profiles . All tests were at baseline , 6 , and 24 weeks . Results : 26 diabetic PAD patients ( 20 men ) were recruited .  Cilostazol improved absolute walking distance at 6 and 24 weeks ( 86.4 % vs. 14.1 % , P = .049 ; 143 % vs. 23.2 % , P = .086 ) . Arterial compliance and lipid profiles improved as did some QoL indices for cilostazol at 6 and 24 weeks . Blood indices were similar at baseline and at follow-up points for both treatment groups . Conclusions : Cilostazol is a well-tolerated and efficacious treatment , which improves claudication distances in diabetic PAD patients with further benefits in arterial compliance , lipid profiles , and
target: Antiplatelet agents have a beneficial effect in reducing all cause mortality and fatal cardiovascular events in patients with IC .
background: BACKGROUND Peripheral arterial disease ( PAD ) is common and is a marker of systemic atherosclerosis .
  Patients with symptoms of intermittent claudication ( IC ) are at increased risk of cardiovascular events ( myocardial infa rct ion ( MI ) and stroke ) and of both cardiovascular and all cause mortality .
  OBJECTIVES To determine the effectiveness of antiplatelet agents in reducing mortality ( all cause and cardiovascular ) and cardiovascular events in patients with intermittent claudication .