Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Secondary prevention of vascular disease by prolonged antiplatelet treatment Clopidogrel added to aspirin adds no benefit but bleeding risk in patients with recent lacunar stroke. A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. Comparison between aspirin combined with dipyridamole versus aspirin alone within 48 hours after ischemic stroke event for prevention of recurrent stroke and improvement of neurological function: a preliminary study. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial 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. Low‐dose acetylsalicylic acid (ASA) plus dipyridamole versus dipyridamole alone in the prevention of stroke in patients with reversible ischemic attacks Low-molecular weight heparin versus aspirin and dipyridamole after femoropopliteal bypass grafting Secondary stroke prevention with low-dose aspirin, sustained release dipyridamole alone and in combination. ESPS Investigators. European Stroke Prevention Study. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone Anti-platelet therapy in graft thrombosis: results of a prospective, randomized, double-blind study. Effect of dipyridamole plus aspirin on hemodialysis graft patency. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. Antiplatelet therapy is effective in primary prevention of myocardial infarction in patients with a previous cerebrovascular ischemic event. "AICLA" controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Effect of preoperative antiplatelet drugs on vascular prostacyclin synthesis. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial
BACKGROUND Results of trials of aspirin and dipyridamole combined versus aspirin alone for the secondary prevention of  vascular events after ischaemic stroke of presumed arterial origin are inconsistent . Our aim was to resolve this uncertainty . METHODS We did a r and omised controlled trial in which we assigned patients to aspirin ( 30 - 325 mg daily ) with ( n=1363 ) or without ( n=1376 ) dipyridamole ( 200 mg twice daily ) within 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin . Our primary outcome event was the composite of death from all vascular causes , non-fatal stroke , non-fatal myocardial infa rct ion , or major bleeding complication , whichever happened first . Treatment was open , but auditing of outcome events was blinded . Primary analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial ( number IS RCT N73824458 ) and with ( NCT00161070 ) . FINDINGS Mean follow-up was 3.5 years ( SD 2.0 ) . Median aspirin dose was 75 mg in both treatment groups ( range 30 - 325 ) ; extended-release dipyridamole was used by 83 % ( n=1131 ) of patients on the combination regimen . Primary outcome events arose in 173 ( 13 % ) patients on aspirin and dipyridamole and in 216 ( 16 % ) on aspirin alone ( hazard ratio 0.80 , 95 % CI 0.66 - 0.98 ; absolute risk reduction 1.0 % per year , 95 % CI 0.1 - 1.8 ) . Addition of the ESPRIT data to the meta- analysis of previous trials result ed in an overall risk ratio for the composite of vascular death , stroke , or myocardial infa rct ion of 0.82 ( 95 % CI 0.74 - 0.91 ) . Patients on aspirin and dipyridamole  discontinued trial medication more often than those on aspirin alone ( 470 vs 184 ) , mainly because of headache . INTERPRETATION The ESPRIT results , combined with the results of previous trials , provide sufficient evidence to prefer the combination regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin Thirty one r and omised trials of antiplatelet treatment for patients with a history of transient ischaemic attack , occlusive stroke , unstable angina , or myocardial infa rct ion were identified . Six were still in progress , and the results of the remaining 25 were review ed . They included a total of some 29 000 patients , 3000 of whom had died . Overall , allocation to antiplatelet treatment had no apparent effect on non-vascular mortality but reduced vascular mortality by 15 % ( SD 4 % ) and non-fatal vascular events ( stroke or myocardial infa rct ion ) by 30 % ( 4 % ) . This suggested that with good compliance these treatments might reduce vascular mortality by about one sixth , other vascular events by about a third , and total vascular events by about a quarter . There was no significant difference between the effects of the different types of  antiplatelet treatment tested ( 300 - 325 mg aspirin daily , higher aspirin doses , sulphinpyrazone , or high dose aspirin with dipyridamole ) , nor between the effects in patients with histories of cerebral or cardiac disease . Thus antiplatelet treatment can reduce the incidence of serious vascular events by about a quarter among a wide range of patients at particular risk of occlusive vascular disease . The balance of risk and benefit , however , might be different for “ primary ” prevention among people at low absolute risk of occlusive disease if antiplatelet treatment produced even a small increase in the incidence of cerebral haemorrhage Patients with transient ischemic attack or ischemic stroke have a high risk of recurrent stroke .  Antiplatelet therapy has shown efficacy in secondary stroke prevention and is recommended by guidelines .1–3 In patients without cardiac source of embolism  aspirin , clopidogrel or the combination of aspirin and dipyridamole is recommended . In cardiology , the combination of aspirin and clopidogrel was superior to aspirin monotherapy in the prevention of vascular events after acute coronary syndrome4 but carried a higher bleeding risk . In patients with atrial fibrillation the combination of aspirin plus clopidogrel was superior to aspirin alone in preventing strokes,5 but was again associated with a significant higher risk of major bleeds . In early secondary stroke prevention after transient ischemic attack or minor stroke combination , antiplatelet therapy seems to be superior to monotherapy , but larger r and omized trials are needed.6,7 Combination antiplatelet therapy carries a consistent higher risk of major bleeding complications than monotherapy . Therefore , the possible benefit of a reduction in vascular events has to be balanced against the bleeding risk , especially in stroke patients . In the Management of Atherothrombosis with Clopidogrel in High-risk patients ( MATCH ) trial , aspirin plus clopidogrel was investigated against aspirin monotherapy in high-risk patients with recent transient ischemic attack or ischemic stroke.8 Similar to the Secondary Prevention of Small Subcortical Strokes ( SPS3 ) trial , patients with a cardiac source of embolism and significant carotid stenosis requiring surgery were excluded . About 50 % of patients were categorized to have small vessel disease with suspected lacunar strokes , but in contrast to the SPS3 trial , Background Aspirin , dipyridamole and clopidogrel are effective in secondary vascular prevention . Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment  in the secondary prevention of ischaemic stroke . Methodology /Principal Findings A r and omised , parallel group , observer-blinded phase II trial compared the combination of aspirin , clopidogrel and dipyridamole with aspirin alone .  Adult patients with ischaemic stroke or transient ischaemic attack ( TIA ) within 5 years were included . The primary outcome was tolerability to treatment assessed as the number of patients completing r and omised treatment . Recruitment was halted prematurely after publication of the ESPRIT trial ( which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone ) . 17 patients were enrolled : male 12 ( 71 % ) , mean age 62 ( SD 13 ) years , lacunar stroke syndrome 12 ( 71 % ) , median stroke/TIA onset to r and omisation 8 months . Treatment was discontinued in 4 of 9 ( 44 % ) patients receiving triple therapy vs. none of 8 taking aspirin ( p = 0.08 ) . One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications . The number of patients with adverse events and bleeding complications , and their severity , were significantly greater in the triple therapy group ( p<0.01 ) . Conclusions / Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates , and their severity , and a trend to increased discontinuations . However , the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy . Trial Registration Controlled-Trials.com IS RCT 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 OBJECTIVES To determine efficacy and tolerability of aspirin plus dipyridamole ( combination ) versus aspirin alone in acute intervention treatment after acute ischemic stoke among Thai patients . MATERIAL AND METHOD This pilot study enrolled ischemic stroke patients within 48 hours and r and omized to aspirin 300 mg/d or combination ( aspirin 300 mg/d+ st and ard release dipyridamole 75 mg thrice a day ) and followed up for 6 months . Endpoints were recurrent ischemic stroke , transient ischemic attack and vascular death . Side effects were recorded . National Institutes of Health Stroke Scale was assessed at entry and at 6 months period for determining neurological functions . RESULTS Of 38 patients , mean age was 64.3 years . Male and female were 52.6 % and 47.4 % respectively . There were 18 patients in the aspirin group and 20 patients in the combination group . No patient developed end point events or no significant adverse event in both groups . The combination group showed more improvement in neurological function than the aspirin group ( p-value 0.009 ) . CONCLUSION This pilot study showed equal efficacy and tolerability of the combination group and aspirin alone in acute intervention treatment for prevention of recurrent stroke or vascular death within 6 months Summary Background Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia . We aim ed to compare the safety and efficacy of intensive antiplatelet therapy ( combined aspirin , clopidogrel , and dipyridamole ) with that of guideline -based antiplatelet therapy . Methods We did an international , prospect i ve , r and omised , open-label , blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack ( TIA ) within 48 h of onset . Participants were assigned in a 1:1 ratio using computer r and omisation to receive loading doses and then 30 days of intensive antiplatelet therapy ( combined aspirin 75 mg , clopidogrel 75 mg , and dipyridamole 200 mg twice daily ) or guideline -based therapy ( comprising either clopidogrel alone or combined aspirin and dipyridamole ) . R and omisation was stratified by country and index event , and minimised with prognostic baseline factors , medication use , time to r and omisation , stroke-related factors , and thrombolysis . The ordinal primary outcome was the combined incidence and severity of any recurrent stroke ( ischaemic or haemorrhagic ; assessed using the modified Rankin Scale ) or TIA within 90 days , as assessed by central telephone follow-up with masking to treatment assignment , and analysed by intention to treat . This trial is registered with the IS RCT N registry , number IS RCT N47823388 . Findings 3096 participants ( 1556 in the intensive antiplatelet therapy group , 1540 in the guideline antiplatelet therapy group ) were recruited from 106 hospitals in four countries between April 7 , 2009 , and March 18 , 2016 . The trial was stopped early on the recommendation of the data monitoring committee . The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy ( 93 [ 6 % ] participants vs 105 [ 7 % ] ; adjusted common odds ratio [ cOR ] 0·90 , 95 % CI 0·67–1·20 , p=0·47 ) . By contrast , intensive antiplatelet therapy was associated with more , and more severe , bleeding ( adjusted cOR 2·54 , 95 % CI 2·05–3·16 , p<0·0001 ) . Interpretation Among patients with recent cerebral ischaemia  , intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA , but did significantly increase the risk of major bleeding . Triple antiplatelet therapy should not be used in routine clinical practice . Funding National Institutes of Health Research Health Technology Assessment Programme , British Heart Foundation BACKGROUND Clopidogrel was superior to aspirin in patients with previous manifestations of atherothrombotic disease in the CAPRIE study and its benefit was amplified in some high-risk subgroups of patients . We aim ed to assess whether addition of aspirin to clopidogrel could have a greater benefit than clopidogrel alone in prevention of vascular events with potentially higher bleeding risk . METHODS We did a r and omised , double-blind , placebo-controlled trial to compare aspirin ( 75 mg/day ) with placebo in 7599 high-risk patients with recent ischaemic stroke or transient ischaemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day . Duration of treatment and follow-up was 18 months . The primary endpoint was a composite of ischaemic stroke , myocardial infa rct ion , vascular death , or rehospitalisation for acute ischaemia ( including rehospitalisation for transient ischaemic attack , angina pectoris , or worsening of peripheral arterial disease ) . Analysis was by intention to treat , using logrank test and a Cox 's proportional-hazards model . FINDINGS 596 ( 15.7 % ) patients reached the primary endpoint in the group receiving aspirin and clopidogrel compared with 636 ( 16.7 % ) in the clopidogrel alone group ( relative risk reduction 6.4 % , [ 95 % CI -4.6 to 16.3 ] ; absolute risk reduction 1 % [ -0.6 to 2.7 ] ) . Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone ( 96 [ 2.6 % ] vs 49 [ 1.3 % ] ; absolute risk increase 1.3 % [ 95 % CI 0.6 to 1.9 ] ) . Major bleedings were also increased in the group receiving aspirin and clopidogrel but no difference was recorded in mortality . INTERPRETATION Adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or transient ischaemic attack is associated with a non-significant difference in reducing major vascular events . However , the risk of life-threatening or major bleeding is increased by the addition of aspirin 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 Abstract A total of 243 patients who had reversible ischemic attacks ( RIA ) were su bmi tted to clinical trial to determine whether dipyridamole ( 400 mg/day ) ( D ) or aspirin ( 100 mg/48 hours ) + dipyridamole ( 300 mg/day ) ( ASA+D ) would produce significant reduction in the subsequent occurrence of RIA and completed stroke .  One hundred and fifteen were selected for Group ASA+D and 71 were treated with dipyridamole only . The treatment groups were similar in relation to age , sex , risk factors , duration and presumed vascular territory of RIA , incidence of alterations of arterial supra‐aortic trunks , cerebral infa rct ( CT scan ) , and platelet function . Patients were followed for a mean time of 21 months Low-molecular weight heparin has theoretical advantages over aspirin and dipyridamole in maintaining vascular-graft patency by virtue of its better antithrombotic effect and antiproliferative activity on vascular , smooth-muscle cells . We tested the hypothesis that low-molecular weight heparin would be more effective than aspirin and dipyridamole in maintaining graft patency in patients undergoing femoropopliteal bypass grafting . Patients were r and omised to receive either a daily injection of 2500 IU low-molecular weight heparin , or 300 mg aspirin with 100 mg dipyridamole 8 hourly for 3 months . 94 patients were r and omised to low-molecular weight heparin and 106 to aspirin and dipyridamole . Patients were stratified according to indication for surgery and were followed up for 1 year . Kaplan-Meier estimate of graft patency showed 87 % graft survival on low-molecular-weight heparin and 72 % on aspirin and dipyridamole at 6 months . At 12 months , the respective figures were 78 % and 64 % . Stratified survival analysis showed that this benefit was confined to those having salvage surgery ( log rank test p = 0.0006 ) ; for those having surgery for claudication there was no significant benefit . No major bleeding events occurred in either group . We conclude that low-molecular weight heparin is better than aspirin and dipyridamole in maintaining femoropopliteal-graft patency in patients with critical limb ischaemia undergoing salvage surgery . This treatment should have considerable cost benefits Patients who had survived a stroke or transient ischaemic attacks ( TIA ) were admitted to a trial of low-dose aspirin ( 50 mg ) alone , sustained release dipyridamole ( 400 mg/day ) alone , or a combination of the two agents , and results compared with a placebo over 24 months . This low-dose aspirin regimen produced in pairwise comparisons a significant risk reduction of 18 % for stroke , 13 % for stroke and /or death but no reduction in all cause mortality . The sustained release dipyridamole produced a significant risk reduction of 16 % for stroke , 15 % for stroke and /or death but no significant reduction of mortality . In combination , aspirin and dipyridamole produced a risk reduction of 37 % in stroke , 24 % in stroke and /or death , and no reduction in mortality . Similar findings were found in TIA , which was a secondary endpoint . These results are highly significant in comparison with placebo . As expected , there were enhanced reports of alimentary side-effects in the aspirin groups and also enhanced bleeding .  Dipyridamole was associated with a slight increase in headache , which resolved in most patients if therapy was continued . The conclusions are that 50 mg/day of aspirin alone or 400 mg/day of sustained release dipyridamole alone are equally effective in stroke and TIA prevention . When used in combination the effects were additive and were significantly more effective than the single agents BACKGROUND Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events .  Aspirin and ticlopidine have been shown to be effective , but both have potentially serious adverse effects .  Clopidogrel , a new thienopyridine derivative similar to ticlopidine , is an inhibitor of platelet aggregation induced by adenosine diphosphate . METHODS CAPRIE was a r and omised , blinded , international trial design ed to assess the relative efficacy of clopidogrel ( 75 mg once daily ) and aspirin ( 325 mg once daily ) in reducing the risk of a composite outcome cluster of ischaemic stroke , myocardial infa rct ion , or vascular death ; their relative safety was also assessed . The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke , recent myocardial infa rct ion , or symptomatic peripheral arterial disease . Patients were followed for 1 to 3 years . FINDINGS 19,185 patients , with more than 6300 in each of the clinical subgroups , were recruited over 3 years , with a mean follow-up of 1.91 years . There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32 % risk of ischaemic stroke , myocardial infa rct ion , or vascular death compared with 5.83 % with aspirin . These rates reflect a statistically significant ( p = 0.043 ) relative-risk reduction of 8.7 % in favour of clopidogrel ( 95 % Cl 0.3 - 16.5 ) . Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4 % . There were no major differences in terms of safety . Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash ( 0.26 % vs 0.10 % ) , diarrhoea ( 0.23 % vs 0.11 % ) , upper gastrointestinal discomfort ( 0.97 % vs 1.22 % ) , intracranial haemorrhage ( 0.33 % vs 0.47 % ) , and gastrointestinal haemorrhage ( 0.52 % vs 0.72 % ) , respectively . There were ten ( 0.10 % ) patients in the clopidogrel group with significant reductions in neutrophils ( < 1.2 x 10(9)/L ) and 16 ( 0.17 % ) in the aspirin group . INTERPRETATION Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke , myocardial infa rct ion , or vascular death . The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin Background and Purpose — In patients with acute ischemic stroke caused by large artery atherosclerosis , clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia . However , there is no clear evidence . Methods — In this multicenter , double-blind , placebo-controlled trial , we r and omized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel ( 75 mg/d without loading dose ) plus aspirin ( 300-mg loading followed by 100 mg/d ) or to aspirin alone ( 300-mg loading followed by 100 mg/d ) for 30 days . The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days . Secondary outcomes were 30-day functional disability , clinical stroke recurrence , and composite of major vascular events . Safety outcome was any bleeding . Results — Of 358 patients enrolled , 334 ( 167 in each group ) completed follow-up magnetic resonance imaging . The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups ( 36.5 % versus 35.9 % ; relative risk , 1.02 ; 95 % confidence interval , 0.77–1.35 ; P=0.91 ) . Of the recurrent ischemic lesions , 94.2 % were clinical ly asymptomatic . There were no differences in secondary outcomes between the 2 groups . Any bleeding were more frequent in the combination group than in the aspirin monotherapy group , but the difference was not significant ( 16.7 % versus 10.7 % ; P=0.11 ) . One hemorrhagic stroke occurred in the clopidogrel plus aspirin group . Conclusions — Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00814268 Hemodialysis ( HD ) vascular access thrombosis remains a major cause of morbidity , accounting for 17.4 % of all HD patient hospital admissions in 1986 . We initiated this prospect i ve , r and omized , double-blind , placebo-controlled , parallel group study to examine if dipyridamole and /or aspirin decreased the rate of thrombosis of exp and ed polytetrafluoroethylene ( ePTFE ) grafts in HD patients . Two patient groups were studied : Type I -- with a new ePTFE graft ; and Type II -- with thrombectomy and /or revision of a previously placed ePTFE graft . One hundred and seven patients were followed for 18 months or until the first thrombotic episode . Actuarial analysis of Type I patients showed cumulative thrombosis rates ( mean + /- SEM ) of 21 + /- 9 % on dipyridamole alone , compared with 25 + /- 11 % on dipyridamole and aspirin combination , 42 + /- 13 % on placebo , and 80 + /- 12 % on aspirin alone . The relative risk of thrombosis with dipyridamole was 0.35 ( P = 0.02 ) and that for aspirin was 1.99 ( P = 0.18 ) . In Type II patients , the rate of thrombosis was high in all study drug and placebo groups ( overall 78 % thrombosis ) and actuarial analysis was not carried out because of the small number of patients enrolled . We conclude that dipyridamole is beneficial in patients with new ePTFE grafts and that aspirin does not improve the risk of thrombosis in ePTFE grafts . Neither dipyridamole nor aspirin has any beneficial effect in patients with prior thrombosis of ePTFE grafts BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis . Procedural interventions may restore patency but are costly . Although there is no proven pharmacologic therapy , dipyridamole may be promising because of its known vascular antiproliferative activity . METHODS We conducted a r and omized , double-blind , placebo-controlled trial of extended-release dipyridamole , at a dose of 200 mg , and aspirin , at a dose of 25 mg , given twice daily after the placement of a new arteriovenous graft until the primary outcome , loss of primary unassisted patency ( i.e. , patency without thrombosis or requirement for intervention ) , was reached . Secondary outcomes were cumulative graft failure and death . Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates . RESULTS At 13 centers in the United States , 649 patients were r and omly assigned to receive dipyridamole plus aspirin ( 321 patients ) or placebo ( 328 patients ) over a period of 4.5 years , with 6 additional months of follow-up . The incidence of primary unassisted patency at 1 year was 23 % ( 95 % confidence interval [ CI ] , 18 to 28 ) in the placebo group and 28 % ( 95 % CI , 23 to 34 ) in the dipyridamole-aspirin group , an absolute difference of 5 percentage points . Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency ( hazard ratio , 0.82 ; 95 % CI , 0.68 to 0.98 ; P=0.03 ) and inhibited stenosis . The incidences of cumulative graft failure , death , the composite of graft failure or death , and serious adverse events ( including bleeding ) did not differ significantly between study groups . CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts . ( Clinical Trials.gov number , NCT00067119 . Aspirin is only modestly effective in the secondary prevention after cerebral ischemia . Studies in other vascular disorders suggest that anticoagulant drugs in patients with cerebral ischemia of presumed arterial ( noncardiac ) origin might be more effective . The aim of the Stroke Prevention in Reversible Ischemia Trial ( SPIRIT ) therefore was to compare the efficacy and safety of 30 mg aspirin daily and oral anticoagulation ( international normalized ratio [ INR ] 3.0–4.5 ) . Patients referred to a neurologist in one of 58 collaborating centers because of a transient ischemic attack or minor ischemic stroke ( Rankin grade $ 3 ) were eligible . R and omization was concealed , treatment assignment was open , and assessment of outcome events was masked . The primary measure of outcome was the composite event “ death from all vascular causes , nonfatal stroke , nonfatal myocardial infa rct ion , or nonfatal major bleeding complication . ” The trial was stopped at the first interim analysis . A total of 1,316 patients participated ; their mean follow‐up was 14 months . There was an excess of the primary outcome event in the anticoagulated group ( 81 of 651 ) versus 36 of 665 in the aspirin group ( hazard ratio , 2.3 ; 95 % confidence interval [ CI ] , 1.6–3.5 ) . This excess could be attributed to 53 major bleeding complications ( 27 intracranial ; 17 fatal ) during anticoagulant therapy versus 6 on aspirin ( 3 intracranial ; 1 fatal ) . The bleeding incidence increased by a factor of 1.43 ( 95 % CI , 0.96–2.13 ) for each 0.5 unit increase of the achieved INR . Anticoagulant therapy with an INR range of 3.0 to 4.5 in patients after cerebral ischemia of presumed arterial origin is not safe . The efficacy of a lower intensity anticoagulation regimen remains to be determined BACKGROUND Recurrent stroke is a frequent , disabling event after ischemic stroke . This study compared the efficacy and safety of two antiplatelet regimens -- aspirin plus extended-release dipyridamole ( ASA-ERDP ) versus clopidogrel . METHODS In this double-blind , 2-by-2 factorial trial , we r and omly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily . The primary outcome was first recurrence of stroke . The secondary outcome was a composite of stroke , myocardial infa rct ion , or death from vascular causes . Sequential statistical testing of noninferiority ( margin of 1.075 ) , followed by superiority testing , was planned . RESULTS A total of 20,332 patients were followed for a mean of 2.5 years .  Recurrent stroke occurred in 916 patients ( 9.0 % ) receiving ASA-ERDP and in 898 patients ( 8.8 % ) receiving clopidogrel ( hazard ratio , 1.01 ; 95 % confidence interval [ CI ] , 0.92 to 1.11 ) . The secondary outcome occurred in 1333 patients ( 13.1 % ) in each group ( hazard ratio for ASA-ERDP , 0.99 ; 95 % CI , 0.92 to 1.07 ) . There were more major hemorrhagic events among ASA-ERDP recipients ( 419 [ 4.1 % ] ) than among clopidogrel recipients ( 365 [ 3.6 % ] ) ( hazard ratio , 1.15 ; 95 % CI , 1.00 to 1.32 ) , including intracranial hemorrhage ( hazard ratio , 1.42 ; 95 % CI , 1.11 to 1.83 ) . The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups ( 1194 ASA-ERDP recipients [ 11.7 % ] , vs. 1156 clopidogrel recipients [ 11.4 % ] ; hazard ratio , 1.03 ; 95 % CI , 0.95 to 1.11 ) . CONCLUSIONS The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel . There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke . ( Clinical Trials.gov number , NCT00153062 . OBJECTIVE A secondary subgroup analysis of the European Stroke Prevention Study of the effect of antiplatelet medication on the risk of  myocardial infa rct ion . DESIGN AND SETTING A r and omized , double-blind placebo-controlled study with two parallel treatment groups ( dipyridamole plus aspirin and placebo ) . Sixteen centers from six countries participated in the study . PATIENTS A total of 2500 patients who had had one or more transient ischemic attacks or cerebral infa rct ions participated . INTERVENTION Combination therapy with dipyridamole ( 75 mg three times a day ) and aspirin ( 330 mg three times a day ) was compared with placebo during 24 months ' follow-up . OUTCOME MEASURES Prevention of fatal and nonfatal myocardial infa rct ion . RESULTS A total of 105 myocardial infa rct ions occurred in the intention-to-treat analysis and 76 occurred in the explanatory analysis . The overall risk reduction of myocardial infa rct ion with the study drugs was approximately 40 % in both statistical analyses , but the result was statistically significant only in the intention-to-treat analysis . Therapeutic efficacy was better among male patients , patients younger than 65 years , and patients with hypertension . CONCLUSION Combination therapy with dipyridamole and aspirin reduces not only the risk of cerebrovascular ischemic events but also the risk of myocardial infa rct ion 604 Patients with atherothrombotic cerebral ischemic events ( transient , 16 % : or completed , 84 % ) referrable either to the carotid or to the vertebral-basilar circulation were entered into a double blind r and omized clinical trial ( AICLA ) to determine whether aspirin ( A ) ( 1 g/day ) or aspirin ( 1 g/day ) + Dipyridamole ( 225 mg/day ) ( AD ) would produce a significant reduction in the subsequent ( 3 years ) occurrence of fatal and nonfatal cerebral infa rct ion . R and omization produced remarkably comparable treatment groups and this good comparability was maintained throughout the study . Adherence to the protocol and drug compliance were excellent . Side effects , particularly symptoms of peptic ulcer and hemorrhagic events were significantly ( p less than 0.03 ) more frequent in the two treatment groups containing aspirin . With the exception of patients who withdrew from the study , each patient was followed for 3 years . At the end of the study , the number of fatal and nonfatal cerebral infa rct ions was 31 in the placebo ( P ) group , 17 in the A group and 18 in the AD group . Taking into account the duration of follow-up for each patient , these figures correspond to cumulative rates of 18 % in the P group and 10.5 % in each of the 2 active treatment groups . Analysis with the Mantel Method showed : 1)--A difference at the 6 % level between the 3 groups and between P and AD ; 2)--A difference at the 5 % level between P and A ; 3)--No difference between ( A and AD ; 4)--A difference at the 2 % level between the P group and the two treated groups taken together ( A + AD ) . Among other diseases occurring during the trial , the only significant difference concerned myocardial infa rct ion , which was less frequent in the 2 treated groups ( P less than 0.05 ) . Subgroup analysis failed to show a significant sex difference in the efficacy of aspirin . It is concluded that , in patients comparable to those defined in the protocol , Aspirin ( 1 g ) has a significantly beneficial effect in the secondary prevention of atherothrombotic cerebral infa rct ion Patients undergoing aortocoronary bypass using autogenous saphenous veins were r and omly divided into three comparable groups . Group 1 ( n = 10 ) acted as a control , Group 2 ( n = 14 ) received 80 mg of aspirin at midnight before the operation , and Group 3 ( n = 12 ) received 80 mg of aspirin and 75 mg of dipyridamole at midnight and an additional 75-mg dose of dipyridamole at 6 AM . The purpose was to determine which regimen would maximally inhibit platelet function without depressing vascular prostacyclin synthesis . Serum thromboxane A2 , saphenous vein wall and aortic wall prostacyclin , platelet aggregation , and bleeding time were measured in all patients . None was restarted on a regimen of aspirin or dipyridamole postoperatively . Aspirin alone and in combination with dipyridamole significantly inhibited thromboxane A2 and platelet aggregation in all treated patients but spared venous prostacyclin synthesis . Aortic prostacyclin synthesis was partially inhibited in both treated groups . Chest tube drainage was comparable in all three groups . These results indicate that the combination of aspirin and dipyridamole offers no measurable advantage over aspirin alone in the perioperative period BACKGROUND Little is known about the best antiplatelet treatment immediately after ischaemic stroke or transient ischaemic attack ( TIA ) . The EARLY trial aim ed to compare outcome in patients given aspirin plus extended-release dipyridamole twice daily either within 24 h of stroke or TIA or after 7 days of aspirin monotherapy . METHODS In 46 stroke units in Germany , patients aged 18 years or more who presented with symptoms of an acute ischaemic stroke that caused a measurable neurological deficit ( National Institutes of Health stroke scale score < or = 20 ) were r and omly assigned to receive 25 mg aspirin plus 200 mg extended-release dipyridamole open-label twice daily or 100 mg aspirin monotherapy open-label once daily for 7 days . Patients were r and omised by use of a pseudor and om number generator . All patients were then given open-label aspirin plus extended-release dipyridamole for up to 90 days . The primary endpoint was modified Rankin scale score as recorded by central ised , blinded assessment by telephone ( tele-mRS ) at 90 days . Vascular adverse events ( non-fatal stroke , TIA , non-fatal myocardial infa rct ion , and major bleeding complications ) and mortality were assessed in a composite safety and efficacy endpoint . Patients were analysed as treated . This trial is registered , number NCT00562588 . FINDINGS Between July , 2007 , and February , 2009 , 543 patients were treated : 283 received early aspirin plus extended-release dipyridamole and 260 received aspirin plus extended-release dipyridamole after 7 days on aspirin . At day 90 , 154 ( 56 % ) patients in the aspirin plus early extended-release dipyridamole group and 133 ( 52 % ) in the aspirin plus later extended-release dipyridamole group had no or mild disability ( tele-mRS 0 or 1 ; difference 4.1 % , 95 % CI -4.5 to 12.6 , p=0.45 ) . 28 patients in the early initiation group and 38 in the late initiation group reached the composite endpoint ( hazard ratio 0.73 , 95 % CI 0.44 - 1.19 p=0.20 ) . INTERPRETATION Early initiation of aspirin plus extended-release dipyridamole within 24 h of stroke onset is likely to be as safe and effective in preventing disability as is later initiation after 7 days . FUNDING Boehringer Ingelheim
This result was not influenced by the dose of dipyridamole or type of presenting vascular disease .
For patients who presented with arterial vascular disease , there was no evidence that dipyridamole , in the presence or absence of another antiplatelet drug reduced the risk of vascular death , though it reduces the risk of further vascular events .
This benefit was found only in patients presenting after cerebral ischaemia .
There was no evidence that dipyridamole alone was more efficacious than aspirin
BACKGROUND Patients with limited cerebral ischaemia of arterial origin are at risk of serious vascular events ( 4 % to 11 % annually ) .
Aspirin reduces that risk by 13 % .
In one trial , adding dipyridamole to aspirin was associated with a 22 % risk reduction compared with aspirin alone .
OBJECTIVES To assess the efficacy and safety of dipyridamole versus control in the secondary prevention of vascular events in patients with vascular disease .