A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. Secondary prevention of vascular disease by prolonged antiplatelet treatment Superiority of Clopidogrel Versus Aspirin in Patients With Prior Cardiac Surgery Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trial: Rationale and design Serial Urinary 11-Dehydrothromboxane B2, Aspirin Dose, and Vascular Events in Blacks After Recent Cerebral Infarction Protocol for Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com): a randomized, open-label, parallel-group trial The secondary prevention of stroke according to cytochrome P450 2C19 genotype in patients with acute large-artery atherosclerosis stroke Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). 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 and Aspirin in Acute Ischemic Stroke and High‐Risk TIA A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. 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. Long term prognosis in patients with peripheral arterial disease treated with antiplatelet agents. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. Terutroban versus aspirin in patients with cerebral ischaemic events (PERFORM): a randomised, double-blind, parallel-group trial Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. The Warfarin-Aspirin Symptomatic Intracranial Disease Study Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Reduction in the need for hospitalization for recurrent ischemic events and bleeding with clopidogrel instead of aspirin. CAPRIE investigators. A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent  Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Generalizing the results of clinical trials to actual practice: the example of clopidogrel therapy for the prevention of vascular events. CAPRA (CAPRIE Actual Practice Rates Analysis) Study Group. Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events.
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 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 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 Background After coronary artery bypass surgery , patients have a high cumulative rate of graft closure and recurrent ischemic events . We sought to determine whether antiplatelet therapy with clopidogrel would be more effective than aspirin , the accepted st and ard , in these patients . Methods and Results The event rates for all-cause mortality , vascular death , myocardial infa rct ion , stroke , and rehospitalization were determined for the 1480 patients with a history of cardiac surgery r and omized to either clopidogrel or aspirin in a trial of 19 185 patients . The event rate per year of vascular death , myocardial infa rct ion , stroke , or rehospitalization was 22.3 % in the 705 patients r and omized to aspirin and 15.9 % in the 775 patients r and omized to clopidogrel ( P = 0.001 ) . A risk reduction was also seen in each of the individual end points examined , including a 42.8 % relative risk reduction in vascular death in patients on clopidogrel versus aspirin ( P = 0.030 ) . In a multivariate model incorporating baseline clinical characteristics , clopidogrel therapy was independently associated with a decrease in vascular death , myocardial infa rct ion , stroke , or rehospitalization in patients with a history of cardiac surgery , with a 31.2 % relative risk reduction ( 95 % CI , 15.8 to 43.8;P = 0.0003 ) . Although clopidogrel therapy was efficacious in the entire Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events ( CAPRIE ) population , multivariate analysis demonstrated that patients with previous cardiac surgery derived particular benefit ( P = 0.015 ) . Conclusion Compared with aspirin , clopidogrel therapy results in a striking reduction in the elevated risk for recurrent ischemic events seen in patients with a history of prior cardiac surgery , along with a decreased risk of bleeding Background Ischemic stroke and other vascular outcomes occur in 10–20 % of patients in the three-months following a transient ischemic attack or minor ischemic stroke , and many are disabling . The highest risk period for these outcomes is the early hours and days immediately following the ischemic event . Aspirin is the most common antithrombotic treatment used for these patients . Aim The aim of POINT is to determine whether clopidogrel plus aspirin taken < 12 h after transient ischemic attack or minor ischemic stroke symptom onset is more effective in preventing major ischemic vascular events at 90 days in the high-risk , and acceptably safe , compared with aspirin alone . Design POINT is a prospect i ve , r and omized , double-blind , multicenter trial in patients with transient ischemic attack or minor ischemic stroke . Subjects are r and omized to clopidogrel  ( 600 mg loading dose followed by 75 mg/day )  or matching placebo  , and all will receive  open-label aspirin 50–325 mg/day , with a dose of 162 mg daily for five-days followed by 81 mg daily strongly recommended . Study Outcomes The primary efficacy outcome is the composite of new ischemic vascular events — ischemic stroke , myocardial infa rct ion , or ischemic vascular death — by 90 days . The primary safety outcome is major hemorrhage , which includes symptomatic intracranial hemorrhage . Discussion Aspirin is the most common antithrombotic given to patients with a stroke or transient ischemic attack , as it reduces the risk of subsequent stroke . This trial expects to determine whether more aggressive antithrombotic therapy with clopidogrel plus aspirin , initiated acutely , is more effective than aspirin alone Background and Purpose — Incomplete platelet inhibition by aspirin ( aspirin resistance ) may be a reason for stroke recurrence in some patients . 11-Dehydrothromboxane B2 ( 11-DTB2 ) is a stable thromboxane A2 metabolite that reflects in vivo platelet activation . This pilot study was intended to evaluate the reproducibility of urinary 11-DTB2 over time and to look for evidence of aspirin resistance . Methods — All subjects were screened for the African American Antiplatelet Stroke Prevention Study ( AAASPS ) 7 to 90 days after noncardioembolic cerebral infa rct ion . Of 83 subjects with at least 1 urine sample , 52 were enrolled in AAASPS ( r and omized to blinded treatment with aspirin 650 mg/d or ticlopidine 500 mg/d ) , and 31 were enrolled in an open-label antiplatelet therapy cohort .  Subjects were followed up for 2 years , with 11-DTB2 measurements scheduled at baseline and 6 , 12 , and 24 months . Vascular events were cerebral infa rct ion , myocardial infa rct ion , or vascular death . Results — Despite considerable individual up or down fluctuations , the median 11-DTB2 change did not significantly differ from zero in any of the subgroups . However , in 6 subjects with a 4-fold decrease in aspirin dose from 1300 to 325 or 81 mg/d , the 11-DTB2 level increased from 611 to 1881 pg/mg creatinine ( P = 0.06 ) . Vascular events occurred in 7 of 61 aspirin-treated subjects , and 11-DTB2 levels did not correlate with the events . Conclusions — Fluctuations in urinary 11-DTB2 after cerebral infa rct ion in blacks do not correlate with changes in aspirin doses , except perhaps when the dose changes by a factor of 4 or more . A larger study is needed to look further for aspirin resistance Rationale and aims Monotherapy with antiplatelet agents is only modestly effective in secondary prevention of ischemic stroke ( IS ) , particularly in patients with multiple risk factors such as cervicocephalic arterial stenosis , diabetes , and hypertension . While dual antiplatelet therapy ( DAPT ) with aspirin and clopidogrel reduced IS recurrence , particularly in the early stages after IS , it increased the risk of bleeding . Compared with aspirin , cilostazol prevented IS recurrence without increasing the incidence of serious bleeds . In patients with intracranial arterial stenosis , no significant increase in bleeding events was observed for DAPT with cilostazol and aspirin , compared to that for aspirin monotherapy . DAPT involving cilostazol may therefore be safer than conventional DAPT . These findings prompted us to conduct the Cilostazol Stroke Prevention Study for Antiplatelet Combination ( CSPS.com ; Clinical Trials.gov identifier : NCT01995370 ) to evaluate the safety and efficacy of DAPT involving cilostazol for secondary IS prevention , in comparison with that of antiplatelet monotherapy . Design The CSPS.com is a multicenter , r and omized , open-label , parallel-group trial . A total of 4000 high-risk patients with noncardioembolic IS will be r and omized 8–180 days after onset to receive aspirin or clopidogrel monotherapy , or DAPT with cilostazol and aspirin or clopidogrel for at least one-year . Study outcomes The primary outcome is IS recurrence . Secondary outcomes are composite occurrences of any stroke , death from any cause , myocardial infa rct ion , vascular death , and other vascular events . Discussion The CSPS.com is expected to provide evidence indicating whether secondary IS prevention in high-risk patients can be improved by using DAPT involving cilostazol Purpose To investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke ( IS ) . Methods Between August 2009 and December 2011 , 570 acute IS patients with acute large-artery atherosclerosis were r and omly assigned to receive either combined clopidogrel and aspirin for the first 30 day , and clopidogrel thereafter ( clopidogrel group , n=284 ) or aspirin monotherapy ( aspirin group , n=286 ) . CYP2C19 genotypes were measured and masked until the end-of- study . The primary outcome was a composite of IS , transient ischemic attack ( TIA ) , myocardial infa rct ion ( MI ) , and death . Results During the 5 years follow-up , the primary outcome occurred in 105 patients ( 18.4 % ) ( 71 had IS , 10 had TIA , 12 had MI , and 12 died ) . There were no significant differences in the primary outcome between clopidogrel group and aspirin group ( 16.5 % vs. 20.3 % ) or between carriers of the CYP2C19 reduced-function alleles and noncarriers ( 21.8 % vs.15.7 % ) . In patients with aspirin therapy , CYP2C19 polymorphism was not associated with the primary outcome . However , in patients treated with clopidogrel , carriers of at least one CYP2C19 reduced-function allele had a 3-fold higher adjusted risk for primary outcome compared with noncarriers ( 95 % confidence interval , 1.23 to 8.74 ) . Conclusions Among IS patients treated with clopidogrel  , carriers of a reduced-function CYP2C19 allele had a significantly higher rate of adverse vascular events than did noncarriers . It should avoid prescribing clopidogrel to these patients with known CYP2C19 polymorphisms BACKGROUND Dual antiplatelet therapy with aspirin and clopidogrel is st and ard for prevention of thrombotic complications of percutaneous coronary intervention ( PCI ) . Prasugrel is a thienopyridine that is more potent , more rapid in onset , and more consistent in inhibition of platelets than clopidogrel . TRITON-TIMI 38 is design ed to compare prasugrel with clopidogrel in moderate to high-risk patients with acute coronary syndrome ( ACS ) . STUDY DESIGN TRITON-TIMI 38 is a phase 3 , r and omized , double-blind , parallel-group , multinational , clinical trial . Approximately 13,000 patients with moderate to high-risk ACS undergoing PCI ( 9500 unstable angina/non-ST-segment elevation myocardial infa rct ion [ MI ] , 3500 ST-segment elevation MI ) will be r and omized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months . The primary end point is the time of the first event of cardiovascular death , MI , or stroke . Analyses will be performed first in the unstable angina/non-ST-segment elevation MI cohort and , conditionally , on the whole ACS population . Major safety end points include TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery . CONCLUSIONS TRITON-TIMI 38 is a phase 3 comparison of prasugrel versus clopidogrel in patients with moderate to high-risk ACS undergoing PCI . In addition , it is the first large-scale clinical events trial to assess whether a thienopyridine regimen that achieves a higher level of inhibition of platelet aggregation than the st and ard therapy results in an improvement in clinical outcomes 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 Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack ( TIA ) . A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke . We tested this combination in an international population . METHODS In a r and omized trial , we assigned patients with minor ischemic stroke or high‐risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1 , followed by 75 mg per day , plus aspirin ( at a dose of 50 to 325 mg per day ) or the same range of doses of aspirin alone . The dose of aspirin in each group was selected by the site investigator . The primary efficacy outcome in a time‐to‐event analysis was the risk of a composite of major ischemic events , which was defined as ischemic stroke , myocardial infa rct ion , or death from an ischemic vascular event , at 90 days . RESULTS A total of 4881 patients were enrolled at 269 international sites . The trial was halted after 84 % of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days . Major ischemic events occurred in 121 of 2432 patients ( 5.0 % ) receiving clopidogrel plus aspirin and in 160 of 2449 patients ( 6.5 % ) receiving aspirin plus placebo ( hazard ratio , 0.75 ; 95 % confidence interval [ CI ] , 0.59 to 0.95 ; P=0.02 ) , with most events occurring during the first week after the initial event . Major hemorrhage occurred in 23 patients ( 0.9 % ) receiving clopidogrel plus aspirin and in 10 patients ( 0.4 % ) receiving aspirin plus placebo ( hazard ratio , 2.32 ; 95 % CI , 1.10 to 4.87 ; P=0.02 ) . CONCLUSIONS In patients with minor ischemic stroke or high‐risk TIA , those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone . ( Funded by the National Institute of Neurological Disorders and Stroke ; POINT Clinical Trials.gov number , NCT00991029 . 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 From 1979 - 85 , 2435 patients with a transient ischaemic attack or minor ischaemic stroke were r and omly allocated to receive long term " blind " treatment with aspirin 600 mg twice daily ( n = 815 ) , aspirin 300 mg once daily ( n = 806 ) or placebo ( n = 814 ) . No patient was lost to follow up . The " intention to treat " comparison included all the serious vascular events and deaths which occurred before the end of the follow up period on 30 September 1986 . There was no difference in efficacy between the 300 mg and 1200 mg daily doses of aspirin , but the lower dose was undoubtedly less gastrotoxic . Also , there was no definite difference in the response of  males and females to aspirin . The odds of suffering a major stroke , myocardial infa rct ion or vascular death were 15 % less in the combined aspirin groups compared with the placebo group ( 95 % confidence interval 29 % reduction to 3 % increase in odds ) which is compatible with the continuing overview of all the similar trials of antiplatelet drugs where the relative reduction in odds was 25 % . There was no statistically significant reduction in the likelihood of either disabling major stroke and vascular death or vascular death occurring 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 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 Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications , yet the benefits and risks of treatment beyond 1 year are uncertain . METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed . After 12 months of treatment with a thienopyridine drug ( clopidogrel or prasugrel ) and aspirin , patients were r and omly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months ; all patients continued receiving aspirin . The co primary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events ( a composite of death , myocardial infa rct ion , or stroke ) during the period from 12 to 30 months . The primary safety end point was moderate or severe bleeding . RESULTS A total of 9961 patients were r and omly assigned to continue thienopyridine treatment or to receive placebo . Continued treatment with thienopyridine , as compared with placebo , reduced the rates of stent thrombosis ( 0.4 % vs. 1.4 % ; hazard ratio , 0.29 [ 95 % confidence interval { CI } , 0.17 to 0.48 ] ; P<0.001 ) and major adverse cardiovascular and cerebrovascular events ( 4.3 % vs. 5.9 % ; hazard ratio , 0.71 [ 95 % CI , 0.59 to 0.85 ] ; P<0.001 ) . The rate of myocardial infa rct ion was lower with thienopyridine treatment than with placebo ( 2.1 % vs. 4.1 % ; hazard ratio , 0.47 ; P<0.001 ) . The rate of death from any cause was 2.0 % in the group that continued thienopyridine therapy and 1.5 % in the placebo group ( hazard ratio , 1.36 [ 95 % CI , 1.00 to 1.85 ] ; P=0.05 ) . The rate of moderate or severe bleeding was increased with continued thienopyridine treatment ( 2.5 % vs. 1.6 % , P=0.001 ) . An elevated risk of stent thrombosis and myocardial infa rct ion was observed in both groups during the 3 months after discontinuation of thienopyridine treatment . CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent , as compared with aspirin therapy alone , significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding . ( Funded by a consortium of eight device and drug manufacturers and others ; DAPT Clinical Trials.gov number , NCT00977938 . ) BACKGROUND Patients with ischaemic stroke or transient ischaemic attack ( TIA ) are at high risk of recurrent stroke or other cardiovascular events . We compared the selective thromboxane-prostagl and in receptor antagonist terutroban with aspirin in the prevention of cerebral and cardiovascular ischaemic events in patients with a recent non-cardioembolic cerebral ischaemic event . METHODS This r and omised , double-blind , parallel-group trial was undertaken in 802 centres in 46 countries . Patients who had an ischaemic stroke in the previous 3 months or a TIA in the previous 8 days were r and omly allocated with a central interactive response system to 30 mg per day terutroban or 100 mg per day aspirin . Patients and investigators were masked to treatment allocation . The primary efficacy endpoint was a composite of fatal or non-fatal ischaemic stroke , fatal or non-fatal myocardial infa rct ion , or other vascular death ( excluding haemorrhagic death ) . We planned a sequential statistical analysis of non-inferiority ( margin 1·05 ) followed by analysis of superiority . Analysis was by intention to treat . The study was stopped prematurely for futility on the basis of the recommendation of the Data Monitoring Committee . This study is registered , number IS RCT N66157730 . FINDINGS 9562 patients were assigned to terutroban ( 9556 analysed ) and 9558 to aspirin ( 9544 analysed ) ; mean follow-up was 28·3 months ( SD 7·7 ) . The primary endpoint occurred in 1091 ( 11 % ) patients receiving terutroban and 1062 ( 11 % ) receiving aspirin ( hazard ratio [ HR ] 1·02 , 95 % CI 0·94 - 1·12 ) . There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints . We recorded some increase in minor bleedings  with terutroban compared with aspirin ( 1147 [ 12 % ] vs 1045 [ 11 % ] ; HR 1·11 , 95 % CI 1·02 - 1·21 ) , but no significant differences in other safety endpoints . INTERPRETATION The trial did not meet the predefined criteria for non-inferiority , but showed similar rates of the primary endpoint with terutroban and aspirin , without safety advantages for terutroban . In a worldwide perspective , aspirin remains the gold st and ard antiplatelet drug for secondary stroke prevention in view of its efficacy , tolerance , and cost . FUNDING Servier , France Several studies have established the value of anticoagulation for primary prevention of thromboembolic events in patients with non-rheumatic atrial fibrillation ( NRAF ) . However , in patients with a recent transient ischaemic attack ( TIA ) or minor ischaemic stroke the preventive benefit of anticoagulation or aspirin remains unclear . Physicians in 108 centres from 13 countries collaborated to study this question . 1007 NRAF patients with a recent TIA or minor ischaemic stroke were r and omised to open anticoagulation or double-blind treatment with either 300 mg aspirin per day or placebo ( group 1 , 669 ) . Patients with contraindications to anticoagulation were r and omised to receive aspirin or placebo ( group 2,338 ) . The measure of outcome was death from vascular disease , any stroke , myocardial infa rct ion , or systemic embolism . During mean follow-up of 2.3 years , the annual rate of outcome events was 8 % in patients assigned to anticoagulants vs 17 % in placebo-treated patients in group 1 ( hazard ratio [ HR ] 0.53 ; 95 % confidence interval [ CI ] 0.36 - 0.79 ) . The risk of stroke alone was reduced from 12 % to 4 % per year ( HR 0.34 ; 95 % CI 0.20 - 0.57 ) . Among all patients assigned to aspirin ( groups 1 and 2 ) , the annual incidence of outcome events was 15 % , against 19 % in those on placebo ( HR 0.83 ; 95 % CI 0.65 - 1.05 ) . Anticoagulation was significantly more effective than aspirin ( HR 0.60 ; 95 % CI 0.41 - 0.87 ) . The incidence of major bleeding events was low , both on anticoagulation ( 2.8 % per year ) and on aspirin ( 0.9 % per year ) . No intracranial bleeds were identified in patients assigned to anticoagulation . We conclude that anticoagulation is effective in reducing the risk of recurrent vascular events in NRAF patients with a recent TIA or minor ischaemic stroke . In absolute terms : 90 vascular events ( mainly strokes ) are prevented if 1000 patients are treated with anticoagulation for one year . Aspirin is a safe , though less effective , alternative when anticoagulation is contraindicated ; it prevents 40 vascular events each year for every 1000 treated patients BACKGROUND Despite improvements in the emergency treatment of myocardial infa rct ion ( MI ) , early mortality and morbidity remain high . The antiplatelet agent clopidogrel adds to the benefit of aspirin in acute coronary syndromes without ST-segment elevation , but its effects in patients with ST-elevation MI were unclear . METHODS 45,852 patients admitted to 1250 hospitals within 24 h of suspected acute MI onset were r and omly allocated clopidogrel 75 mg daily ( n=22,961 ) or matching placebo ( n=22,891 ) in addition to aspirin 162 mg daily . 93 % had ST-segment elevation or bundle branch block , and 7 % had ST-segment depression . Treatment was to continue until discharge or up to 4 weeks in hospital ( mean 15 days in survivors ) and 93 % of patients completed it . The two prespecified co- primary outcomes were : ( 1 ) the composite of death , reinfa rct ion , or stroke ; and ( 2 ) death from any cause during the scheduled treatment period . Comparisons were by intention to treat , and used the log-rank method . This trial is registered with Clinical Trials.gov , number NCT00222573 . FINDINGS Allocation to clopidogrel produced a highly significant 9 % ( 95 % CI 3 - 14 ) proportional reduction in death , reinfa rct ion , or stroke ( 2121 [ 9.2 % ] clopidogrel vs 2310 [ 10.1 % ] placebo ; p=0.002 ) , corresponding to nine ( SE 3 ) fewer events per 1000 patients treated for about 2 weeks . There was also a significant 7 % ( 1 - 13 ) proportional reduction in any death ( 1726 [ 7.5 % ] vs 1845 [ 8.1 % ] ; p=0.03 ) . These effects on death , reinfa rct ion , and stroke seemed consistent across a wide range of patients and independent of other treatments being used . Considering all fatal , transfused , or cerebral bleeds together , no significant excess risk was noted with clopidogrel , either overall ( 134 [ 0.58 % ] vs 125 [ 0.55 % ] ; p=0.59 ) , or in patients aged older than 70 years or in those given fibrinolytic therapy . INTERPRETATION In a wide range of patients with acute MI , adding clopidogrel 75 mg daily to aspirin and other st and ard treatments ( such as fibrinolytic therapy ) safely reduces mortality and major vascular events in hospital , and should be considered routinely BACKGROUND Antiplatelet drugs are recommended for patients with acute noncardioembolic stroke . However , few r and omized clinical trials have investigated the safety and efficacy of dual antiplatelet therapy for these patients . The aim of this study was to evaluate the effects of treatment with clopidogrel and aspirin ( combination therapy ) and aspirin alone ( monotherapy ) on neurologic deterioration , platelet activation , and other short-term outcomes in patients with acute large-artery atherosclerosis stroke . MATERIAL S AND METHODS Altogether 574 patients with acute ( ≤2 days ) large-artery atherosclerosis stroke were r and omly assigned to receive either combined clopidogrel and aspirin or aspirin alone . Platelet aggregation and platelet-leukocyte aggregation studies were performed at days 1 and 30 . Primary outcomes including recurrent ischemic stroke , neurologic deterioration , periphery vascular events , and myocardial infa rct ion were monitored . Safety endpoints were hemorrhagic episodes and death . RESULTS The prevalence of neurologic deterioration and recurrent ischemic stroke were lower in patients in the combination therapy group than in those of the monotherapy group ( 3.52 % versus 9.78 % and 1.76 % versus 6.29 % , respectively ) . At day 30 of treatment , the platelet aggregations and platelet-leukocyte aggregates were lower in patients who were treated with clopidogrel and aspirin than in patients given aspirin alone ( P < .001 ) . CONCLUSIONS For patients with acute large-artery atherosclerosis stroke , treatment with clopidogrel and aspirin for 1 month provided significantly greater inhibition of platelet activity  than aspirin alone . Thus , dual therapy can be safer and more effective in reducing ischemic stroke recurrence and neurologic deterioration We conducted a retrospective , multicenter study to compare the efficacy of warfarin with aspirin for the prevention of major vascular events ( ischemic stroke , myocardial infa rct ion , or sudden death ) in patients with symptomatic stenosis of a major intracranial artery . Patients with 50 to 99 % stenosis of an intracranial artery ( carotid ; anterior , middle , or posterior cerebral ; vertebral ; or basilar ) were identified by review ing the results of consecutive angiograms performed at participating centers between 1985 and 1991 . Only patients with TIA or stroke in the territory of the stenotic artery qualified for inclusion in the study . Patients were prescribed warfarin or aspirin according to local physician preference and were followed by chart review and personal or telephone interview . Seven centers enrolled 151 patients ; 88 were treated with warfarin and 63 were treated with aspirin .  Median follow-up was 14.7 months ( warfarin group ) and 19.3 months ( aspirin group ) . Vascular risk factors and mean percent stenosis of the symptomatic artery were similar in the two groups , yet the rates of major vascular events were 18.1 per 100 patient-years of follow-up in the aspirin group ( stroke rate , 10.4/100 patient-years ; myocardial infa rct ion or sudden death rate , 7.7/100 patient-years ) compared with 8.4 per 100 patient-years of follow-up in the warfarin group ( stroke rate , 3.6/100 patient-years ; myocardial infa rct ion or sudden death rate , 4.8/100 patient-years ) . Kaplan-Meier analysis showed a significantly higher percentage of patients free of major vascular events among patients treated with warfarin ( p equals 0.01 ) . The relative risk of a major vascular event in those treated with warfarin was 0.46 ( 95 % CI , 0.23 to 0.86 ) compared with patients treated with aspirin .  Major hemorrhagic complications occurred in three patients on warfarin ( including two deaths ) during 166 patient-years of follow-up and in none of the patients on aspirin during 143 patient-years of follow-up . This study suggests a favorable risk/benefit ratio for warfarin compared with aspirin for the prevention of major vascular events in patients with symptomatic intracranial large-artery stenosis . A prospect i ve , r and omized study is needed to confirm these findings . NEUROLOGY 1995;45 : 1488 - BACKGROUND Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation . However , long-term monitoring is necessary and many patients can not achieve optimum anticoagulation . We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events . METHODS Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke , and were r and omly allocated to receive  oral anticoagulation therapy ( target international normalised ratio of 2.0 - 3.0 ; n=3371 ) or clopidogrel ( 75 mg per day ) plus aspirin ( 75 - 100 mg per day recommended ; n=3335 ) . Outcome events were adjudicated by a blinded committee . Primary outcome was first occurrence of stroke , non-CNS systemic embolus , myocardial infa rct ion , or vascular death . Analyses were by intention-to-treat . This study is registered with Clinical Trials.gov , number NCT00243178 . RESULTS The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy . There were 165 primary events in patients on oral anticoagulation therapy  ( annual risk 3.93 % ) and 234 in those on clopidogrel plus aspirin ( annual risk 5.60 % ; relative risk 1.44 ( 1.18 - 1.76 ; p=0.0003 ) . Patients on oral anticoagulation therapy  who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events ( relative risk 1.50 , 95 % CI 1.19 - 1.89 ) and a significantly ( p=0.03 for interaction ) lower risk of major bleeding with oral anticoagulation therapy ( 1.30 ; 0.94 - 1.79 ) than patients not on this treatment at study entry ( 1.27 , 0.85 - 1.89 and 0.59 , 0.32 - 1.08 , respectively ) . CONCLUSION Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke , especially in those already taking oral anticoagulation therapy 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 Context In patients with unstable angina , combination therapy with clopidogrel plus aspirin has been shown to be more effective than aspirin alone in preventing myocardial infa rct ion , stroke , or cardiovascular death , but the cost-effectiveness of such therapy has yet to be determined . Contribution When the authors used a societal perspective and lifetime time horizon , combination therapy increased quality -adjusted life span at a cost that was within the traditionally accepted limits of cost-effectiveness . Caution s Data are not yet available to determine whether combination therapy for longer than 1 year remains cost-effective , due to the uncertainty of the relationship between long-term efficacy and risk for hemorrhage . The Editors The Clopidogrel  in Unstable Angina to Prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel plus aspirin was superior to aspirin alone in preventing the composite outcome of myocardial infa rct ion , stroke , or cardiovascular death in the year following an acute coronary syndrome or nonQ-wave myocardial infa rct ion ( 1 ) . Although combination therapy is recommended for such patients for at least 1 month , the optimal duration is less clear ( 2 ) . In addition , the cost of clopidogrel complicates the decision to combine it with aspirin . Adding clopidogrel to aspirin is financially unattractive if done in all patients with coronary disease ( 3 ) but may be cost-effective in high-risk patients , for whom clopidogrel offers more substantial absolute risk reduction . To assess the cost-effectiveness of clopidogrel plus aspirin relative to aspirin alone in high-risk patients with coronary artery disease and to explore the optimal duration of therapy , we constructed a decision analytic Markov model comparing these treatment strategies after an acute coronary syndrome as defined in CURE . Methods We performed a cost-effectiveness analysis using a Markov model ( 4 ) ( DATA 4.0 , TreeAge Software , Inc. , Williamstown , Massachusetts ) . We analyzed a reference case assuming a societal perspective ( 5 ) and a lifetime time horizon ( 6 ) . Our analysis was based on the CURE trial , a r and omized comparison of 3 to 12 months of therapy with clopidogrel plus aspirin or aspirin alone to prevent cardiovascular death , myocardial infa rct ion , or stroke in 12562 patients with an acute coronary syndrome ( 1 ) . We discounted costs and utilities at 3 % annually and determined lifetime costs , quality -adjusted life expectancy , and the incremental cost-effectiveness ratio . Sensitivity analyses included 1-way analyses on all data inputs ; probabilistic sensitivity analysis ; evaluation of varying duration of combination therapy , including potential loss of efficacy over time ; and consideration of population s with varying risk . Target Population The target population was analogous to that of the CURE trial ( 1 ) : patients with an acute coronary syndrome characterized by electrocardiographic changes or elevated serum cardiac markers in association with chest pain . Patients who had prolonged ST-segment elevation , who had undergone revascularization in the previous 3 months , who were at risk for severe bleeding or heart failure , or who had been treated with oral anticoagulants or glycoprotein IIb/IIIa inhibitors in the preceding 3 days were excluded . On the basis of the average age of CURE patients , we considered a 64-year-old as our base case and explored other ages in sensitivity analysis . We compared treatment costs and clinical outcomes for 2 types of antiplatelet therapy : 1 ) aspirin alone , 325 mg/d , and 2 ) clopidogrel , 75 mg/d , plus aspirin , 325 mg/d , for 1 year , followed by aspirin monotherapy . Model Structure In our model , we included vascular events : myocardial infa rct ion , stroke , vascular death and revascularization , intracerebral and gastrointestinal hemorrhagic events , and clopidogrel-associated thrombotic thrombocytopenic purpura . We included age-related mortality , correcting for events explicitly included in the model . We did not directly include procedures or outcomes , such as congestive heart failure , that CURE did not specifically address ( 1 ) . We indirectly accounted for the cost of such events by using age-adjusted annual health care costs ( 7 ) . This assumes equal probability of such events in each arm of the analysis . We allowed for multiple events , including multiple events of a particular type , within a given monthly cycle . We created Markov states for conditions that changed quality of life , annual cost , or probability of future events . For events with temporary decrements in quality of life , we assessed a utility toll proportional to the duration of hospitalization required ( 8) . We also modeled each combination of 2 events . When more than 2 events occurred , we used the Markov state that combined the 2 events with the lowest utility ( Figure 1 ) . Figure 1 . Schematic representation of the decision model . Model Inputs Probabilities We derived probabilities for vascular and hemorrhagic events over the first year of our analysis from the CURE trial ( 1 ) . Rates of cardiovascular outcomes were highest in the month immediately following the acute coronary syndrome ( 1 ) . To account for temporal variation in risk , we calculated probabilities for the first month separately from those for subsequent months . Beyond the time frame of the CURE trial , we empirically calculated declining probability functions for myocardial infa rct ion , cardiovascular death , and revascularization on the basis of proportional decline in risk over time in survivors of nonQ-wave myocardial infa rct ion ( 9 ) . We assumed that all bleeding events , other than intracerebral hemorrhage , were gastrointestinal . Because intracerebral hemorrhage was equally likely for the 2 treatment strategies ( 1 ) , all of the excess bleeding in the clopidogrel plus aspirin arm was attributed to gastrointestinal causes . The rate of thrombotic thrombocytopenic purpura associated with clopidogrel was derived from an observational study ( 10 , 11 ) . We represented uncertainty in event rates through distributions based on the number of events that occurred and the number of patient-years at risk . We obtained age-specific mortality from life tables ( 12 ) and corrected for death rates of events explicitly included in our model ( Table ) . Table . Model Inputs Efficacy of Combination Therapy Despite the variation in risk , the relative efficacy of clopidogrel plus aspirin did not vary between the first and subsequent months ( 1 ) . In modeling beyond the time frame of the CURE trial , we assumed in our base case that efficacy remained constant , on the basis of data for clopidogrel monotherapy ( 13 ) . We explored waning efficacy over time in sensitivity analysis . We used 3 variables to describe loss of efficacy , duration of constant efficacy ( 1 year to lifetime ) , duration of efficacy deterioration ( 1 to 10 years ) , and the extent of efficacy decline relative to  aspirin monotherapy ( none to complete loss ) . Costs We derived costs for each event and for chronic care of disabled patients from the literature . For medications , we used the average wholesale price in the United States as our base value ( 35 ) and considered prices negotiated by a large-volume purchaser in constructing the price range . Acute care costs for clinical events represent the direct costs of all medical care incurred during hospitalization . Chronic care costs represent direct expenditures for medications , procedures , and nursing care specific to the condition in question and were assessed for each month in the Markov state . For Markov states representing survival after either severe stroke or intracerebral hemorrhage and another event , we assumed 20 % of the long-term cost of the additional condition to account for overlapping therapy . We accounted for other health care costs by using age-adjusted annual health expenditures ( 7 ) . We up date d costs to 2002 U.S. dollars with a gross domestic product deflator ( 44 ) and generated log-normal distributions for each estimate for use in sensitivity analyses ( Table ) . Utilities We used published population -based utilities , representing either time-tradeoff or st and ard-gamble techniques . For Markov states representing 2 events , we combined utilities with multiplication ( 8) . For events and procedures that did not result in durable changes in the health state of the individual , we used disutility tolls based on the average duration of hospitalization ( 8) . We modeled uncertainty in utility estimates by calculating distributions based on the range of utility estimates in the literature ( Table ) . Sensitivity Analyses To assess the degree to which variation in any variable altered our results , we performed 1-way sensitivity analyses for each model input by analyzing the results at both extremes of its 95 % CI . In evaluating patients of different ages , we adjusted both age-related mortality and estimates of annual health care cost accordingly . To better underst and the distribution of the cost-effectiveness ratio for clopidogrel plus aspirin and the potential value of further research , we performed probabilistic sensitivity analysis using Monte Carlo simulation ( 45 , 46 ) . In each of 1000 simulations , the value for each model input was r and omly selected from its distribution . We constructed a cost-effectiveness acceptability curve by calculating the average net monetary benefit for each strategy in each simulation over cost-effectiveness thresholds ranging from no additional expenditure for the least expensive therapy to $ 100000 for each quality -adjusted life-year ( QALY ) gained . We then determined the proportion of simulations for which clopidogrel plus aspirin result ed in the greater net monetary benefit at each cost-effectiveness threshold . We also assessed varying the duration of  clopidogrel therapy from 1 month to 1 year in monthly increments . We considered prolonged therapy , up to patient lifetime , in yearly increments , simultaneously assessing potential decline in the efficacy of clopidogrel . To better BACKGROUND Dual antiplatelet therapy with aspirin and thienopyridines ( clopidogrel or prasugrel ) is required after placement of coronary stents to prevent thrombotic complications . Although current clinical practice guidelines recommend 12-month treatment after drug-eluting stent placement , even longer duration s may prevent thrombotic events . STUDY DESIGN The Dual Antiplatelet Therapy ( DAPT ) Study is comparing the benefits and risks of 12 versus 30 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention ( PCI ) for the treatment of coronary artery obstructive lesions . The DAPT Study is a multicenter , international , r and omized , double-blind , placebo-controlled trial that will enroll 15,245 subjects treated with drug-eluting stent ( DES ) and 5,400 subjects treated with bare-metal stents ( BMS ) .  All subjects will receive 12 months of open-label thienopyridine treatment in addition to aspirin . After 12 months , subjects who are free from death , myocardial infa rct ion , or stroke ( MACCE ) , repeat revascularization , and GUSTO ( Global Use of Strategies to Open Occluded Coronary Arteries ) moderate or severe bleeding events will be r and omized to receive either 18 additional months of thienopyridine ( clopidogrel or prasugrel ) ( 30 month DAPT arm ) or placebo ( 12 month DAPT arm ) plus aspirin . Co primary end points are MACCE and stent thrombosis . The primary safety end point is GUSTO moderate or severe bleeding . CONCLUSIONS This r and omized trial is design ed to define the relative safety and effectiveness of 12 versus 30 months of dual antiplatelet therapy across the broad spectrum of patients receiving coronary stents The American Heart Association/American Stroke Association ( AHA/ASA ) Writing Committee for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack ( TIA ) has review ed the results of recent trials that were published after our previous recommendations were issued.1 Our intention in the present statement is to provide a brief review of the new data , to up date specific recommendations , and to provide the reasons for any modifications . The 2 areas in which major new clinical trials have been published are ( 1 ) the use of specific antiplatelet agents for stroke prevention in patients with a history of noncardioembolic ischemic stroke or TIA and ( 2 ) the use of statins in the prevention of recurrent stroke . Recently published trials have added to the evidence of the benefit of the use of specific antiplatelet agents for stroke prevention in patients with a history of noncardioembolic ischemic stroke or TIA . The secondary prevention guidelines 1 have been up date d to reflect this new evidence . # # # Addition of Clopidogrel to Aspirin for Prevention of Vascular Events The Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events ( CHARISMA ) trial2 was a double-blinded study that r and omized 15 603 subjects with cardiovascular disease or multiple risk factors for cardiovascular disease to either clopidogrel 75 mg plus low-dose aspirin ( 75 to 162 mg ) or placebo plus aspirin ( 75 to 162 mg ) . Roughly 35 % of subjects ( n=4320 ) qualified on the basis of the presence of cerebrovascular disease within 5 years of enrollment ; approximately a third experienced TIA . The median follow-up was 28 months . No significant differences were seen in the rates of nonfatal ischemic stroke between the 2 groups ( 1.7 % versus 2.1 % , P = 0.07 ) . The placebo plus aspirin group showed a higher rate of nonfatal stroke than did the clopidogrel group ( 1.9 % versus 2.4 % , P = 0.03 ) . The 2 groups experienced no differences in the rate of intracerebral hemorrhage 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 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 PURPOSE An important element in translating the results obtained in clinical trials of a new treatment to clinical practice is the estimated event rate in patients who would be eligible to receive that treatment . We estimated the effect of clopidogrel , compared with aspirin , in actual practice using the relative risk reduction observed in the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events ( CAPRIE ) trial . SUBJECTS AND METHODS Ischemic event rates were estimated for 12,931 aspirin users drawn from the Saskatchewan Health population between 1990 and 1995 who had an index diagnosis of myocardial infa rct ion , ischemic stroke , or peripheral arterial disease . To estimate the absolute risk reduction , the 8.7 % relative risk reduction from clopidogrel compared with aspirin that was observed in CAPRIE was applied to these rates . RESULTS The rates of ischemic events were greater in actual practice than among the control patients in the CAPRIE trial . In the Saskatchewan population , patients experienced an outcome event ( myocardial infa rct ion , stroke including intracranial hemorrhage , or death ) at a rate of 15.9 per 100 patient-years , compared with only 6.9 per 100 patient-years in CAPRIE . If the same 8.7 % relative risk reduction seen in the CAPRIE trial is also true for patients seen in routine clinical practice , the greater absolute risk in actual practice would reduce the number needed to treat to prevent one event from 200 patients to 70 patients . CONCLUSION Absolute risk rates may be substantially greater in clinical practice than in the selected patients enrolled in r and omized trials . As a result , similar reductions in relative risk , if true for clinical practice , may yield substantially more benefit in clinical practice than in r and omized trials
Compared with aspirin , thienopyridines significantly reduced gastrointestinal adverse effects .
However , thienopyridines increased the odds of skin rash and diarrhoea , ticlopidine more than clopidogrel .
Allocation to ticlopidine , but not clopidogrel , significantly increased the odds of neutropenia .
The thienopyridine derivatives are at least as effective as aspirin in preventing serious vascular events in patients at high risk , and possibly somewhat more so .
However , the size of any additional benefit is uncertain and could be negligible .
Clopidogrel has a more favourable adverse effects profile than ticlopidine and so is the thienopyridine of choice .
BACKGROUND Aspirin is the most widely studied and prescribed antiplatelet agent for preventing serious vascular events , reducing the odds of such events among high vascular risk patients by about a quarter .
Thienopyridine derivatives inhibit platelet activation by a different mechanism and so may be more effective .
OBJECTIVES To determine the effectiveness and safety of thienopyridine derivatives ( ticlopidine and clopidogrel ) versus aspirin for preventing serious vascular events ( stroke , myocardial infa rct ion ( MI ) or vascular death ) in patients at high risk , and specifically in patients with a previous TIA or ischaemic stroke .