title: Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease. Treatment Effect of Clopidogrel Plus Aspirin Within 12 Hours of Acute Minor Stroke or Transient Ischemic Attack Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) Trial: One-Year Outcomes Impact of Clopidogrel Plus Aspirin Versus Aspirin Alone on the Progression of Native Coronary Artery Disease After Bypass Surgery: Analysis From the Clopidogrel After Surgery for Coronary Artery DiseasE (CASCADE) Randomized Trial Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding Preliminary Evidence of a High Risk of Bleeding on Aspirin plus Clopidogrel in Aspirin-Naïve Patients in the Acute Phase after TIA or Minor Ischaemic Stroke Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study Twelve-Month Results of a Randomized Trial Comparing Mono With Dual Antiplatelet Therapy in Endovascularly Treated Patients With Peripheral Artery Disease Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease: a randomised cross-over study Long-term versus short-term clopidogrel therapy in patients undergoing coronary stenting (from the Randomized Argentine Clopidogrel Stent [RACS] trial). The effectiveness and safety of dual antiplatelet therapy in ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis in Chinese patients Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial Dual Antiplatelets Reduce Microembolic Signals in Patients with Transient Ischemic Attack and Minor Stroke: Subgroup Analysis of CLAIR Study Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter Trial Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection: The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial Six-Month Versus 12-Month Dual Antiplatelet Therapy After Implantation of Drug-Eluting Stents: The Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) Randomized, Multicenter Study 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 Benefits and Risks of the Combination of Clopidogrel and Aspirin in Patients Undergoing Surgical Revascularization for Non–ST-Elevation Acute Coronary Syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial The effect of long-term clopidogrel use on neointimal formation after percutaneous coronary intervention The influence of body mass index on outcomes and the benefit of antiplatelet therapy following percutaneous coronary intervention. A new strategy for discontinuation of dual antiplatelet therapy: the RESET Trial (REal Safety and Efficacy of 3-month dual antiplatelet Therapy following Endeavor zotarolimus-eluting stent implantation). Comparison of antiplatelet effect and tolerability of clopidogrel resinate with clopidogrel bisulfate in patients with coronary heart disease (CHD) or CHD-equivalent risks: a phase IV, prospective, double-dummy, parallel-group, 4-week noninferiority trial. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. Aspirin Plus Clopidogrel Versus Aspirin Alone After Coronary Artery Bypass Grafting: The Clopidogrel After Surgery for Coronary Artery Disease (CASCADE) Trial A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. The role of clopidogrel and acetylsalicylic acid in the prevention of early-phase graft occlusion due to reactive thrombocytosis after coronary artery bypass operation. Effects of Aspirin Dose When Used Alone or in Combination With Clopidogrel in Patients With Acute Coronary Syndromes: Observations From the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. Transfusion strategies for acute upper gastrointestinal bleeding. Early and Late Effects of Clopidogrel in Patients With Acute Coronary Syndromes Benefit of Clopidogrel in Patients With Acute Coronary Syndromes Without ST-Segment Elevation in Various Risk Groups Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. Aspirin plus clopidogrel therapy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. The Effect of Combined Clopidogrel and Aspirin Therapy after Off-Pump Coronary Surgery Randomized clinical trial of the antiplatelet effects of aspirin–clopidogrel combination versus aspirin alone after lower limb angioplasty Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Effect of Clopidogrel plus ASA vs. ASA Early after TIA and Ischaemic Stroke: A Substudy of the CHARISMA Trial Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial. Effects of clopidogrel on soluble CD40 ligand and on high-sensitivity C-reactive protein in patients with stable coronary artery disease. Thrombin formation and platelet activation at the site of vascular injury in patients with coronary artery disease treated with clopidogrel combined with aspirin. Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. A comparison of 1-month and 6-month clopidogrel therapy on clinical and angiographic outcome after stent implantation Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. Impact of clopidogrel and aspirin treatment on the expression of proteins in platelets from type-2 diabetic patients with stable coronary ischemia. Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding Academic Research Consortium Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study The curative effect comparison of two kinds of therapeutic regimens on decreasing the relative intensity of microembolic signal in CLAIR trial Long-term cost-effectiveness of early and sustained clopidogrel therapy for up to 1 year in patients undergoing percutaneous coronary intervention after presenting with acute coronary syndromes without ST-segment elevation. The Effectiveness of Dual Antiplatelet Treatment in Acute Ischemic Stroke Patients with Intracranial Arterial Stenosis: A Subgroup Analysis of CLAIR Study Randomized controlled trial of aspirin and clopidogrel versus aspirin and placebo on markers of smooth muscle proliferation before and after peripheral angioplasty. Randomized comparison of the effects of ASA plus clopidogrel versus ASA alone on early platelet activation in acute coronary syndromes with elevated high-sensitivity C-reactive protein and soluble CD40 ligand levels. Combined clopidogrel–aspirin treatment for high risk TIA or minor stroke does not increase cerebral microbleeds The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease Extracardiac vascular disease and effectiveness of sustained clopidogrel treatment Clopidogrel Plus Aspirin Prevents Early Neurologic Deterioration and Improves 6-Month Outcome in Patients With Acute Large Artery Atherosclerosis Stroke Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting. Thrombelastographic hypercoagulability and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): a randomized controlled trial Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease: Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial
abstract: BACKGROUND Patients with transient ischaemic attack ( TIA ) or minor stroke are at high immediate risk of stroke . The optimum early treatment options for these patients are not known . METHODS Within 24 h of symptom onset , we r and omly assigned , in a factorial design , 392 patients with TIA or minor stroke to clopidogrel  ( 300 mg loading dose then 75 mg daily ; 198 patients ) or placebo ( 194 patients ) , and simvastatin ( 40 mg daily ; 199 patients ) or placebo ( 193 patients ) . All patients were also given aspirin and were followed for 90 days . Descriptive analyses were done by intention to treat . The primary outcome was total stroke ( ischaemic and haemorrhagic ) within 90 days . Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin . This study is registered as an International St and ard R and omised Controlled Trial ( number 35624812 ) and with Clinical Trials.gov ( NCT00109382 ) . FINDINGS The median time to stroke outcome was 1 day ( range 0 - 62 days ) . The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins . 14 ( 7.1 % ) patients on clopidogrel had a stroke within 90 days compared with 21 ( 10.8 % ) patients on placebo ( risk ratio 0.7 [ 95 % CI 0.3 - 1.2 ] ; absolute risk reduction -3.8 % [ 95 % CI -9.4 to 1.9 ] ; p=0.19 ) . 21 ( 10.6 % ) patients on simvastatin had a stroke within 90 days compared with 14 ( 7.3 % ) patients on placebo ( risk ratio 1.3 [ 0.7 - 2.4 ] ; absolute risk increase 3.3 % [ -2.3 to 8.9 ] ; p=0.25 ) . The interaction between clopidogrel and simvastatin was not significant ( p=0.64 ) . Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo ( absolute risk increase 1.0 % [ -0.4 to 2.4 ] ; p=0.5 ) . There was no difference between groups for the simvastatin safety outcomes . INTERPRETATION Immediately after TIA or minor stroke , patients are at high risk of stroke , which might be reduced by using clopidogrel in addition to aspirin . The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit . We were unable to provide evidence of benefit of simvastatin in this setting . This aggressive prevention approach merits further study BACKGROUND Clopidogrel therapy has recently been shown to reduce cardiovascular events in patients with stable vascular disease . This benefit may be due to effects not exclusively related to platelet aggregation . The aim of this study was to evaluate the effect of clopidogrel therapy on microvascular endothelial function in subjects with stable coronary artery disease ( CAD ) . METHODS AND RESULTS Forty subjects with stable CAD were r and omised to clopidogrel therapy ( 75mg/day ) or control . Blood and endothelial function testing occurred at baseline , one week and three months following r and omisation . Microvascular endothelial function was assessed via reactive hyperaemic index ( RHI ) . Platelet function was assessed by adenosine diphosphate (ADP)-induced whole blood aggregation and the VerifyNow ™ system . Plasma markers of endothelial function ( asymmetric dimethylarginine , ADMA ) and oxidative stress ( myeloperoxidase , MPO ) were also tested . The primary endpoint was endothelial function assessment ( RHI ) at three months . At one week RHI increased by 20±10 % in the clopidogrel group ; this effect was maintained at three months ( 21±9 % increase from baseline ; P<0.01 ) . A significant decrease in ADP-induced platelet aggregation and P2Y12 reaction units was observed in the clopidogrel therapy group ( P<0.01 ) . There was no correlation between endothelial function and platelet function testing in the clopidogrel therapy group . CONCLUSION Clopidogrel therapy is associated with improved microvascular endothelial function in patients with stable CAD . This effect is independent of its effects on ADP-induced platelet reactivity Background The aim of this study was to analyze the benefits and safety associated with the combination therapy of clopidogrel and aspirin among minor stroke or transient ischemic attack patients treated within 12 hours . Methods and Results This was a sub analysis of the CHANCE ( Clopidogrel in High‐Risk Patients with Acute Nondisabling Cerebrovascular Events ) trial , mainly limited to the prespecified group of patients r and omized within 12 hours to either the combination of clopidogrel plus aspirin or aspirin alone .  The primary outcome was ischemic stroke during 90‐day follow‐up . Recurrent ischemic stroke and progressive ischemic stroke were analyzed . Multivariable Cox modeling showed that r and omization within 12 hours was an independent predictor of ischemic stroke events ( hazard ratio [ 95 % CI ] 1.25 [ 1.04–1.49 ] , P=0.02 ) . Among 2573 patients r and omized within 12 hours , 282 ( 10.96 % ) patients had ischemic stroke events  . Among them , 158 ( 12.34 % ) of 1280 patients taking aspirin  experienced ischemic stroke compared with 124 ( 9.59 % ) of 1293 patients taking clopidogrel – aspirin ( P=0.02 ) . The dual antiplatelet was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke ( 6.57 % versus 8.91 % , P=0.03 ) but not progressive ischemic stroke ( 3.02 % versus 3.43 % , P=0.28 ) . There was no significant difference in hemorrhagic events ( P=0.39 ) . Conclusions Among patients treated within 12 hours , the combination of clopidogrel and aspirin was more effective  than aspirin alone in reducing the risk of recurrent ischemic stroke during the 90‐day follow‐up and did not increase the hemorrhagic risk . Clinical Trial Registration URL : https://www . clinical trials.gov/. Unique identifier : NCT00979589 OBJECTIVES We prospect ively assessed cardiac and pulmonary function in patients with stable coronary artery disease ( CAD ) treated with ticagrelor , clopidogrel , or placebo  in the ONSET/OFFSET ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease ) study . BACKGROUND Ticagrelor reduces cardiovascular events more effectively than clopidogrel in patients with acute coronary syndromes . Dyspnea develops in some patients treated with ticagrelor , and it is not known whether this is associated with changes in cardiac or pulmonary function . METHODS In all , 123 stable aspirin-treated CAD patients r and omly received either ticagrelor ( 180 mg load , then 90 mg twice daily ; n=57 ) , clopidogrel ( 600 mg load , then 75 mg daily ; n=54 ) , or placebo ( n=12 ) for 6 weeks in a double-blind , double-dummy design . Electrocardiography , echocardiography , serum N-terminal pro-brain natriuretic peptide , and pulmonary function tests were performed before ( baseline ) and 6 weeks after drug administration and /or after development of dyspnea . RESULTS After drug administration , dyspnea was reported by 38.6 % , 9.3 % , and 8.3 % of patients in the ticagrelor , clopidogrel , and placebo groups , respectively ( p<0.001 ) . Most instances were mild and /or lasted<24 h , although 3 patients discontinued ticagrelor because of dyspnea . Eight of 22 and 17 of 22 ticagrelor-treated patients experiencing dyspnea did so within 24 h and 1 week , respectively , after drug administration . In all treatment groups , and in ticagrelor-treated patients with dyspnea , there were no significant changes between baseline and 6 weeks in any of the cardiac or pulmonary function parameters . CONCLUSIONS Dyspnea is commonly associated with ticagrelor therapy , but was not associated in this study with any adverse change in cardiac or pulmonary function . ( A Multi-Centre R and omised , Double-Blind , Double-Dummy Parallel Group Study of the Onset and Offset of Antiplatelet Effects of AZD6140 Compared With Clopidogrel and Placebo With Aspirin as Background Therapy in Patients With Stable Coronary Artery Disease [ ONSET/OFFSET ] ; NCT00528411 ) Background — The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events ( CHANCE ) trial showed that the combined treatment of clopidogrel and aspirin decreases the 90-day risk of stroke without increasing hemorrhage in comparison with aspirin alone , but provided insufficient data to establish whether the benefit persisted over a longer period of time beyond the trial termination . We report the 1-year follow-up outcomes of this trial . Methods and Results — The trial was a r and omized , double-blind ,  placebo-controlled trial conducted at 114 centers in China . We r and omly assigned 5170 patients within 24 hours after onset of minor stroke or high-risk transient ischemic attack to clopidogrel-aspirin therapy ( loading dose of 300 mg of clopidogrel on day 1 , followed by 75 mg of clopidogrel per day for 90 days , plus 75 mg of aspirin per day for the first 21 days ) or to the aspirin-alone group ( 75 mg/d for 90 days ) . The primary outcome was stroke event ( ischemic or hemorrhagic ) during 1-year follow-up . Differences in outcomes between groups were assessed by using the Cox proportional hazards model . Stroke occurred in 275 ( 10.6 % ) patients in the clopidogrel-aspirin group , in comparison with 362 ( 14.0 % ) patients in the aspirin group ( hazard ratio , 0.78 ; 95 % confidence interval , 0.65–0.93 ; P=0.006 ) . Moderate or severe hemorrhage occurred in 7 ( 0.3 % ) patients in the clopidogrel-aspirin group and in 9 ( 0.4 % ) patients in the aspirin group ( P=0.44 ) . Conclusions — The early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke persisted for the duration of 1-year of follow-up . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00979589 Background — The effects of dual antiplatelet therapy with aspirin and clopidogrel on the progression of native coronary artery disease after coronary artery bypass grafting are unknown . Methods and Results — In the Clopidogrel After Surgery for Coronary Artery DiseasE ( CASCADE ) trial , a total of 113 patients were r and omized to receive aspirin plus clopidogrel or aspirin plus placebo for 1 year after coronary artery bypass grafting . In this secondary analysis , the 92 patients who underwent preoperative and 1-year postoperative angiograms at 2 centers had each of their coronary stenoses grade d serially by using 6 thresholds ( grade 0 [ 0%–24 % ] , grade 1 [ 25%–37 % ] , grade 2 [ 38%–62 % ] , grade 3 [ 63%–82 % ] , grade 4 [ 83%–98 % ] , and grade 5 [ 99%–100 % ] ) . We compared the incidence and degree of evolving coronary artery disease between the 2 treatment groups . A total of 543 preoperative stenoses and occlusions were quantified and followed . At 1-year postoperatively , there were 103 evolving ( 94 worsened , 9 improved ) and 22 new lesions . The right coronary artery territory and sites proximal to a graft were more commonly associated with worsening coronary artery disease ( P⩽0.02 ) . There were no differences in clinical events between treatment groups , and the proportion of patients with evolving or new lesions was also similar ( 70 % versus 74 % , aspirin – clopidogrel versus aspirin – placebo , respectively ; P=0.8 ) . However , in evolving or new lesions , the mean grade change ( 1.1±1.0 versus 1.6±1.1 , respectively ; P=0.01 ) and the proportion of new occlusions ( 7 % versus 22 % ; P=0.02 ) were lower in the aspirin – clopidogrel group . Conclusions — The addition of clopidogrel to aspirin correlates with less worsening of native coronary artery disease 1 year after coronary artery bypass grafting . These findings may help guide post – coronary artery bypass grafting antiplatelet therapy . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00228423 Context The optimal aspirin dose for prevention of cardiovascular events is unknown . Contribution This post hoc analysis of CHARISMA trial data suggests no overall differences in efficacy or safety by aspirin dose . However , in the subgroup of patients r and omly assigned to clopidogrel , there was a hint of reduced efficacy and increased harm with higher doses . Caution Patients were not r and omly assigned to aspirin dose . Implication Lower aspirin doses ( 75 to 81 mg/d ) may optimize efficacy and safety for patients requiring aspirin for long-term prevention , especially those taking clopidogrel .  The Editors Aspirin is the most widely used drug worldwide for the prevention of thrombotic cardiovascular events . Of note , the doses of aspirin used most often clinical ly or recommended in guidelines are based not on the results of trials design ed to identify the most efficacious or safest dose , but on a combination of historical precedents and trials in which specific doses of aspirin were m and ated by protocol . This practice has led to a wide range in aspirin doses ( 75 to 325 mg/d ) recommended by the U.S. Food and Drug Administration ( 1 ) for the management of cardiovascular disease in various population s. Although as little as 30 mg of aspirin daily is needed to fully inhibit platelet thromboxane production ( 2 ) , doses more than 10 times higher than this are routinely used in long-term prevention of cardiovascular disease . Because aspirin has been used clinical ly for more than a century and is a mainstay of therapy for patients who have or are at risk for atherosclerotic disease and other common ailments , its risks are often underappreciated . However , given that more than one third of U.S. adults are estimated to take aspirin daily for cardiovascular disease ( 3 ) , even a very small incidence of hemorrhagic complications places a large number of people at risk . Consistent with this is a recent analysis of hospitalizations for adverse drug effects that found aspirin to be one of the most common causal agents ( 4 ) . The gastrointestinal tract is the leading source of bleeding events in  aspirin-treated  patients because of inhibition of gastroprotective prostacyclins , with an excess risk for upper gastrointestinal complications of 5 cases per 1000 aspirin users per year ( 5 ) . Prospect i ve evaluation of  aspirin-treated patients with coronary artery disease identified an incidence of upper gastrointestinal bleeding of 1.5 % per year , with substantial associated morbidity ( 6 ) . Because inhibition of gastric prostacyclin is dose-dependent and not maximal until a daily dose of about 1300 mg is reached ( 4 ) , minimizing the dose of aspirin to that needed to fully inhibit platelet thromboxane production would probably offer the greatest potential benefit with the lowest possible risk . In several observational studies of large prospect i ve trials , lower doses of aspirin ( < 162 mg/d ) have been associated with the lowest incidence of thrombotic events ( 7 , 8) and a trend toward fewer bleeding events ( 8) . These favorable trends in efficacy and safety were confirmed in the CURE ( Clopidogrel in Unstable angina to prevent Recurrent Events ) trial ( 9 ) of dual antiplatelet therapy with clopidogrel plus aspirin versus placebo plus aspirin . On the basis of these results , the design of the CHARISMA ( Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ) trial ( 10 ) , which r and omly assigned 15603 patients at high risk for atherothrombotic events to clopidogrel or placebo in conjunction with aspirin , m and ated a daily aspirin dose of 75 to 162 mg . We performed a post hoc analysis of associations between investigator-determined daily aspirin dose and thrombotic and hemorrhagic outcomes in the prospect i ve CHARISMA trial . Methods The design , methods , and primary results of the CHARISMA study are reported elsewhere ( 10 ) . In brief , CHARISMA was a multicenter , double-blind , r and omized , placebo-controlled trial of long-term clopidogrel ( 75 mg/d ) treatment versus placebo in patients 45 years or older who had established atherosclerotic disease or were asymptomatic but at high risk because of a combination of risk factors . All patients also received low-dose aspirin therapy , which was limited by protocol to between 75 and 162 mg/d . Patients were excluded if they had an established indication for clopidogrel therapy , such as a recent acute coronary syndrome or stent implantation . Clinical follow-up was done at 1 , 3 , and 6 months and every 6 months thereafter until the end of the trial . The actual dose of aspirin being taken was confirmed at each evaluation . The ethics committee at each of the 768 participating hospitals worldwide , as well as the appropriate national ethics committee for each of the 32 participating countries , review ed and approved the study protocol . All patients provided written informed consent before enrollment . The primary efficacy end point was the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . The primary safety end point was severe or life-threatening bleeding according to the GUSTO-I ( Global Utilization of Streptokinase and TPA for Occluded coronary arteries ) criteria ( 11 ) : intracerebral bleeding or bleeding result ing in substantial hemodynamic compromise requiring treatment . A secondary safety end point was the combined incidence of severe or life-threatening bleeding or moderate bleeding by the GUSTO-I criteria , with moderate defined as bleeding requiring transfusion but not result ing in hemodynamic compromise ( 11 ) . Of note , patients believed to be at high risk for bleeding were excluded from enrollment .  Aspirin dose was not r and omized ; rather , it was selected at the discretion of the treating physician . We prospect ively divided patients into 3 major groups according to clear demarcations in aspirin dose at baseline : less than 100 mg/d , represented almost entirely by doses of either 75 or 81 mg/d ; 100 mg/d ; and greater than 100 mg/d , represented by either 150 or 162 mg/d . We evaluated the relative efficacy and safety of the different doses of aspirin among all patients , and we evaluated the efficacy and safety end points between the treatment ( clopidogrel ) versus placebo groups by aspirin dose category . Statistical Analysis We performed all data analyses on the intention-to-treat population . We performed hypothesis tests by using 2-sided tests at the 5 % significance level . Baseline characteristics were compared by using chi-square tests for discrete variables and t tests for continuous variables . We calculated cumulative KaplanMeier estimates of the event rates and assessed differences in the unadjusted rates of primary efficacy and safety end points across the aspirin groups by using a 2-sided log-rank test . We used log-rank weights to compute a test for trend across aspirin dose categories . We estimated the treatment effect , measured by the hazard ratio and its 95 % CI , by using the Cox proportional hazards model . Multivariable modeling was performed to determine whether aspirin dose was independently associated with the primary efficacy and safety outcomes after controlling for potentially confounding factors . Because patients could have had more than 1 efficacy or safety event , we defined the time to the primary efficacy end point as the first occurrence of myocardial infa rct ion , stroke , or cardiovascular death . We defined the time to the primary safety end point as the first occurrence of severe or life-threatening bleeding according to the GUSTO-I criteria ( 11 ) . We selected variables for inclusion in the models on the basis of differences in baseline characteristics among patients in the 3 aspirin dose categories or their clinical relevance to the outcomes . Covariates included in the multivariable model for the primary efficacy end point were the continuous variables of age , weight , and systolic blood pressure and the categorical variables of sex ; race or ethnicity ( white or Hispanic vs. other ) ; hypertension ; hypercholesterolemia ; history of congestive heart failure ; previous myocardial infa rct ion ; previous stroke ; previous transient ischemic attack ; diabetes mellitus ; atrial fibrillation ; peripheral arterial disease ; diabetic nephropathy ; current smoking ; primary ( vs. secondary ) prevention and past use of statins , nitrates , and antiplatelet agents other than aspirin . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by aspirin dose category . Adjustment variables in the multivariable model for the primary safety end point ( GUSTO-I severe or life-threatening bleeding ) included age and weight as continuous variables and the categorical variables of stable angina with multivessel disease , sex , race or ethnicity ( white or Hispanic vs. other ) , history of congestive heart failure , previous myocardial infa rct ion , previous stroke , previous transient ischemic attack , diabetes mellitus , atrial fibrillation , peripheral arterial disease , diabetic nephropathy , hypertension , hypercholesterolemia , primary prevention ( vs. secondary ) , and current smoking . We developed models with and without inclusion of interaction terms for r and omized treatment assignment by daily aspirin dose category . To adjust for geographical region without estimating its effect , we used region ( categorized as United States , Canada , Western Europe , Eastern Europe , Latin America , Asia and Australia , or Africa ) as a stratification variable in models for both end points . We assessed the interaction of  aspirin dose and r and omized treatment in both models . We calculated and tested the difference between the maximum likelihood ratios with and without 2 interaction terms ( r and omized treatment assignment by daily aspirin dose of 100 mg and greater than 100 mg ) . We assessed proportional hazards by multiplying each covariate by the log of the time to the event . A Wald test was performed to test the linear hypotheses of the regression coefficients . The proportional Background : Aspirin plus clopidogrel ( A+C ) may be more effective than aspirin only ( AO ) acutely after TIA and minor stroke , but the risk of bleeding in the acute phase is uncertain . We determined this risk , focusing particularly on  aspirin-naïve patients . Methods : We studied consecutive referrals to the EXPRESS study clinic from 1/4/02 to 31/3/08 . A 30- to 90-day course of A+C was given to patients presenting acutely .  Bleeding events were identified by face-to-face follow-up , diagnostic coding , and blood transfusion data . Unpublished data from the FASTER pilot trial were also studied . Results : Among 633 EXPRESS patients treated with aspirin ( + /– clopidogrel )  , there were 12 spontaneous bleeds ( 6 minor , 6 major/life-threatening ) within 90 days after assessment , with a higher risk for A+C vs. AO ( 8/247 vs. 4/386 , p = 0.047 overall ; 5/247 vs. 1/386 , p = 0.03 for major/life-threatening bleeds ) . The excess of major/life-threatening bleeds on A+C vs. AO was seen in aspirin-naïve patients , ( 4/137 vs. 0/273 , p = 0.01 ) , but not in prior-aspirin patients ( 1/110 vs. 1/113 , p = 0.98 ) . All symptomatic bleeds in the FASTER pilot also occurred in aspirin-naïve patients r and omized to A+C ( 6/104 vs. 0/94 , p = 0.03 ) . In a pooled analysis , major/life-threatening bleeding on A+C occurred in 9/241 aspirin-naïve patients ( 90-day risk = 4.8 % , 1.6–8.0 ) versus 1/204 prior-aspirin patients ( p = 0.009 ) . Conclusion : Although based on relatively few outcomes , the high risk of major bleeding on A+C acutely after TIA or minor stroke in aspirin-naïve patients is a cause for concern . The potential risk to patients is sufficient to m and ate detailed monitoring of bleeding risk in ongoing trials and stratify results by whether patients were aspirin-naïve BACKGROUND Despite the use of aspirin , there is still a risk of ischaemic events after percutaneous coronary intervention ( PCI ) . We aim ed to find out whether , in addition to aspirin , pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI . METHODS 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been r and omly assigned double-blind treatment with clopidogrel ( n=1313 ) or placebo ( n=1345 ) . Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission , and for a median of 10 days overall . After PCI , most patients ( > 80 % ) in both groups received open-label thienopyridine for about 4 weeks , after which study drug was restarted for a mean of 8 months . The primary endpoint was a composite of cardiovascular death , myocardial infa rct ion , or urgent target-vessel revascularisation within 30 days of PCI . The main analysis was by intention to treat . FINDINGS There were no drop-outs . 59 ( 4.5 % ) patients in the clopidogrel group had the primary endpoint , compared with 86 ( 6.4 % ) in the placebo group ( relative risk 0.70 [ 95 % CI 0.50 - 0.97 ] , p=0.03 ) . Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death , myocardial infa rct ion , or any revascularisation ( p=0.03 ) , and of cardiovascular death or myocardial infa rct ion ( p=0.047 ) . Overall ( including events before and after PCI ) there was a 31 % reduction cardiovascular death or myocardial infa rct ion ( p=0.002 ) . There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group ( p=0.001 ) . At follow-up , there was no significant difference in major bleeding between the groups ( p=0.64 ) . INTERPRETATION In patients with acute coronary syndrome receiving aspirin  , a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events , compared with placebo Purpose To present the 12-month results of a trial investigating the effects of dual antiplatelet therapy on  target lesion revascularization ( TLR ) after balloon angioplasty ± stenting in the femoropopliteal segment . Methods A prospect i ve , r and omized , single-center , double-blinded and placebo-controlled clinical trial r and omly assigned 40 patients to receive pre- and postinterventional therapy with aspirin and clopidogrel . Another 40 patients received the same doses of aspirin and placebo instead of clopidogrel . Clopidogrel and placebo were stopped after 6 months , and patients remained on aspirin only . At 12 months after the intervention , 36 clopidogrel patients and 37 placebo patients were reevaluated . Results At 6 months , clopidogrel patients had significantly lower rates of TLR compared to placebo patients [ 2 ( 5 % ) vs. 8 ( 20 % ) , p=0.04 ] . After stopping clopidogrel/placebo after 6 months , there was no significant difference in TLR at 12 months after treatment [ 9 ( 25 % ) clopidogrel vs. 12 ( 32.4 % ) placebo , p=0.35 ] . Mortality was 0 vs. 1 in the placebo group at 6 months ( p=0.32 ) and 0 vs. 3 at 12 months ( p=0.08 ) . Conclusion In contrast to the first report of a reduction in the TLR at 6 months , this advantage of dual antiplatelet therapy does not persist after stopping clopidogrel . Prolonged dual therapy ( > 6 months ) should be considered in patients who are at high risk for restenosis Background Despite the use of anti-platelet agents such as acetylsalicylic acid ( ASA ) and clopidogrel in coronary heart disease , some patients continue to suffer from atherothrombosis . This has stimulated development of platelet function assays to monitor treatment effects . However , it is still not recommended to change treatment based on results from platelet function assays . This study aim ed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel . The adhesion assay measures several aspects of platelet adhesion simultaneously , which increases the probability of finding conditions sensitive for anti-platelet treatment . Methods With a r and omised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome . Also , 29 matched healthy controls were included to evaluate intra-individual variability over time . Platelet function was measured by flow cytometry , serum thromboxane B2 (TXB2)-levels and by static platelet adhesion to different protein surfaces . The results were subjected to Principal Component Analysis followed by ANOVA , t-tests and linear regression analysis . Results The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity . Adenosine 5'-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA .  Flow cytometric measurements showed the same pattern ( r2 = 0.49 ) . In opposite , TXB2-levels decreased with ASA compared to clopidogrel . Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively . Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA . Furthermore , adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone . Conclusion The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB2 for evaluation of anti-platelet treatment . This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment The optimal duration of treatment with clopidogrel after percutaneous coronary intervention ( PCI ) with stent placement remains controversial . The R and omized Argentine Clopidogrel Stent ( RACS ) trial was a prospect i ve , r and omized , nonblinded study of 1,004 patients undergoing PCI who were r and omized after successful bare metal stent placement to 30 versus 180 days of clopidogrel ; all patients also received aspirin . Patients were eligible regardless of whether they had presented with ST-elevation myocardial infa rct ion ( MI ) , acute coronary syndrome , or stable angina . The primary end point was a composite of death , MI , and stroke at 180 days . Baseline clinical characteristics showed no differences between groups in terms of age , gender , history , risk factors , or incidence of diabetes ; 72 % presented with an acute coronary syndrome and 15 % had MI as the indication for PCI . At hospital discharge and 30 days , when the 2 groups received the same treatment , there were no significant differences between groups in frequency of death , MI , or stroke . However , from 30 days to 6 months , patients assigned to 6 months of clopidogrel reached the primary end point of death , MI , and stroke less frequently ( 4.99 % vs 1.74 % , p = 0.010 , relative risk decrease 65 % ) . No significant between-group differences were found in frequency of total bleeding ( 0.64 % vs 1.52 % , p = 0.34 ) for the control and study groups . In conclusion , after successful placement of a bare metal stent in a coronary artery , patients treated with 6 months of clopidogrel showed a trend toward fewer adverse events compared with those treated for 30 days Background : There are limited data on the effect of dual antiplatelet treatment with clopidogrel plus aspirin in patients with ischemic cerebrovascular disease and intracranial and extracranial arteriostenosis . The aim of our study was to evaluate the efficacy and safety of aspirin plus clopidogrel in the treatment of ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis . Methods : Patients with clinical ly evident acute cerebral infa rct ion or transient ischemic attack combined with intracranial and extracranial arteriostenosis ( greater than 50 % ) who were unsuitable or reluctance to perform stent implantation were enrolled in this study . We r and omly assigned these patients to receive clopidogrel ( 75 or 50 mg ) plus aspirin ( 100 mg ) or aspirin ( 100 mg ) once daily through 90 days , and followed them for 90 days . We examined the main endpoints including the recurrence of stroke , death from cardiovascular causes , and bleeding events . Results : In all , 200 patients were recruited and followed for 90 days . Ischemic stroke occurred in 6 patients ( 9.1 % ) treated with 50 mg clopidogrel and aspirin , 6 patients ( 9.1 % ) receiving 75 mg clopidogrel and aspirin , whereas 19 patients ( 27.9 % ) in the aspirin group ( aspirin alone vs copidogrel 50 mg plus aspirin ; 95 % confidence intervals 1.704–23.779 , P < 0.05 ; aspirin alone vs copidogrel 75 mg plus aspirin ; 95 % confidence intervals 1.190–13.240 , P < 0.05 ) . There were more hemorrhagic events among recipients ( 3 patients [ 2.3 % ] ) in the copidogrel plus aspirin group than aspirin recipients ( 0 patient [ 0 % ] ) , including 1 subcutaneous hemorrhage in the group of 50 mg clopidogrel and aspirin , doubling the number of nasal and gum bleeding in the group of 75 mg clopidogrel and aspirin ( P > 0.05 ) . No intracranial hemorrhage and gastro-intestinal hemorrhage occurred in these 3 groups . Conclusion : Accordingly , 50 mg clopidogrel plus aspirin , and 75 mg clopidogrel plus aspirin were all superior to aspirin alone as stroke prevention in patients with cerebral infa rct ion or transient ischemic attack combined with intracranial and extracranial arteriostenosis . The effect of secondary stroke prevention was similar between 50 mg clopidogrel plus aspirin and 75 mg clopidogrel plus aspirin . The therapy of 75 mg clopidogrel plus aspirin result ed in a worrisome tread in bleeding events BACKGROUND Few r and omised clinical trials have investigated the use of antithrombotic drugs for early secondary prevention of stroke or transient ischaemic attack in patients with intracranial atherosclerotic stenosis . Microembolic signals , detected by transcranial doppler , are a surrogate marker of future stroke risk and have been used to show treatment efficacy in patients with extracranial carotid stenosis . We aim ed to investigate whether treatment with clopidogrel plus aspirin reduced the number of microembolic signals detected with transcranial doppler ultrasound compared with aspirin alone in patients with recent stroke . METHODS The clopidogrel plus aspirin for infa rct ion reduction in acute stroke or transient ischaemic attack patients with large artery stenosis and microembolic signals ( CLAIR ) trial was a r and omised , open-label , blinded-endpoint trial . Between Oct 28 , 2003 , and Nov 19 , 2008 , patients with acute ischaemic stroke or transient ischaemic attack who had symptomatic large artery stenosis in the cerebral or carotid arteries and in whom microembolic signals were present on transcranial doppler were r and omly assigned within 7 days of symptom onset to receive clopidogrel ( 300 mg for the first day , then 75 mg daily ) plus aspirin ( 75 - 160 mg daily ) or aspirin alone ( 75 - 160 mg daily ) for 7 days . Patients were r and omly assigned in blocks of four or six by use of a r and omisation website . Monitoring of microembolic signals on transcranial doppler was done on days 2 and 7 . The primary endpoint was the proportion of patients who had microembolic signals on day 2 . Analysis was by modified intention to treat . All analyses were done by an investigator masked to both patient identity and the day the recording was taken . This trial is registered with the Centre for Clinical Trials , Chinese University of Hong Kong , number CUHK_CCT00164 . FINDINGS 100 patients were r and omly assigned to clopidogrel plus aspirin ( n=47 ) or aspirin monotherapy ( n=53 ) . 93 of 100 patients had symptomatic intracranial stenosis in either the intracranial internal carotid artery or the middle cerebral artery : 45 of 46 in the dual therapy group and 48 of 52 in the monotherapy group . At day 2 , 14 of 45 patients in the dual therapy group and 27 of 50 patients in the monotherapy group for whom data were available had at least one microembolic signal on transcranial doppler ( relative risk reduction 42.4 % , 95 % CI 4.6 - 65.2 ; p=0.025 ) . Adverse events were similar in the two groups . No patients had intracranial or severe systemic haemorrhage , but two patients in the dual therapy group had minor haemorrhages . INTERPRETATION Combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing microembolic signals in patients with predominantly intracranial symptomatic stenosis . Clinical trials are now warranted to investigate whether this combination treatment also results in a reduction in stroke incidence Background Short course of dual antiplatelet therapy for early secondary prevention is a promising treatment for patients with minor stroke or transient ischemic attack at high risk of recurrence . Methods We examined the efficacy and safety of dual antiplatelets in patients with transient ischemic attack or minor stroke , defined as National Institute of Health Stroke Scale scores 0–3 , in a subgroup analysis of Clopidogrel plus aspirin versus Aspirin alone for Reducing embolization in patients with acute symptomatic cerebral or carotid artery stenosis ( CLAIR ) study .  Microembolic signals on transcranial Doppler monitoring was used as surrogate marker for recurrent stroke risk . Patients with ≥1 microembolic signals at baseline were r and omized to receive dual therapy ( aspirin 75–160 mg daily and clopidogrel 300 mg day 1 then 75 mg daily ) or monotherapy ( aspirin 75–160 mg daily ) for seven-days . Results Sixty-five of 100 patients recruited had transient ischemic attack or minor stroke : 30 received dual therapy and 35 received  monotherapy . Mean onset-to-r and omization was 2·3 days in dual therapy group and 3·2 days in monotherapy group ( P = 0·03 ) . At day 7 , the proportion of patients with ≥1 microembolic signals was 9 of 29 patients in dual therapy group and 18 of 34 patients in monotherapy group ( adjusted relative risk reduction 41·4 % , 95 % CI 29·8–51·1 , P < 0·001 ) . The median number of microembolic signals on day 7 was 0 in dual therapy group and 1·0 in monotherapy group ( P = 0·046 ) . No patients had intracranial or severe systemic hemorrhage . Conclusions Early dual therapy with clopidogrel and aspirin  reduces microembolic signals in patients with minor ischemic stroke or transient ischemic attack , without causing significant bleeding complications Background — The optimal duration of dual-antiplatelet therapy and the risk-benefit ratio for long-term dual-antiplatelet therapy after coronary stenting remain poorly defined . We evaluated the impact of up to 6 versus 24 months of dual-antiplatelet therapy in a broad all-comers patient population receiving a balanced proportion of Food and Drug Administration – approved drug-eluting or bare-metal stents . Methods and Results — We r and omly assigned 2013 patients to receive bare-metal , zotarolimus-eluting , paclitaxel-eluting , or everolimus-eluting stent implantation . At 30 days , patients in each stent group were r and omly allocated to receive up to 6 or 24 months of clopidogrel therapy in addition to aspirin . The primary end point was a composite of death of any cause , myocardial infa rct ion , or cerebrovascular accident . The cumulative risk of the primary outcome at 2 years was 10.1 % with 24-month dual-antiplatelet therapy compared with 10.0 % with 6-month dual-antiplatelet therapy ( hazard ratio , 0.98 ; 95 % confidence interval , 0.74–1.29 ; P=0.91 ) . The individual risks of death , myocardial infa rct ion , cerebrovascular accident , or stent thrombosis did not differ between the study groups ; however , there was a consistently greater risk of hemorrhage in the 24-month clopidogrel group according to all prespecified bleeding definitions , including the recently proposed Bleeding Academic Research Consortium classification . Conclusions — A regimen of 24 months of clopidogrel therapy in patients who had received a balanced mixture of drug-eluting or bare-metal stents was not significantly more effective than a 6-month clopidogrel regimen in reducing the composite of death due to any cause , myocardial infa rct ion , or cerebrovascular accident . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00611286 Background — Evidence for efficacy of dual antiplatelet therapy in stroke is limited . Symptomatic carotid stenosis patients are at high risk of early recurrent stroke . In this group , asymptomatic microembolic signals ( MES ) , detected by transcranial Doppler ultrasound ( TCD ) , are markers of future stroke and transient ischemic attack ( TIA ) risk . They offer a surrogate marker to evaluate antiplatelet therapy , but no multicenter study has evaluated the feasibility of this approach . Methods and Results —Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis ( CARESS ) is a r and omized , double-blind study in subjects with recently symptomatic ≥50 % carotid stenosis . Patients were screened with TCD , and if MES were detected , they were r and omized to clopidogrel and aspirin or aspirin monotherapy . Repeated TCD recordings were made on days 2 and 7 . MES were detected in 110 of 230 patients by online analysis at baseline , of whom 107 were r and omized . Intention-to-treat analysis revealed a significant reduction in the primary end point : 43.8 % of dual-therapy patients were MES positive on day 7 , as compared with 72.7 % of monotherapy patients ( relative risk reduction 39.8 % ; 95 % CI , 13.8 to 58.0 ; P=0.0046 ) . The secondary end point of MES frequency per hour was reduced ( compared with baseline ) by 61.4 % ( 95 % CI , 31.6 to 78.2 ; P=0.0013 ) in the dual-therapy group at day 7 and by 61.6 % ( 95 % CI , 34.9 to 77.4 ; P=0.0005 ) on day 2 . There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis ; 2 additional ipsilateral TIAs occurred before treatment started . MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without ( mean±SD : 24.4±27.7 versus 8.9±11.5 per hour ; P=0.0003 ) . Conclusions —In patients with recently symptomatic carotid stenosis , combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization . Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies Background — The optimal duration of dual antiplatelet therapy ( DAPT ) after implantation of drug-eluting coronary stents remains undetermined . We aim ed to test whether 6-month DAPT would be noninferior to 12-month DAPT after implantation of drug-eluting stents . Methods and Results — We r and omly assigned 1443 patients undergoing implantation of drug-eluting stents  to receive 6- or 12-month DAPT ( in a 1:1 ratio ) . The primary end point was a target vessel failure , defined as the composite of cardiac death , myocardial infa rct ion , or ischemia-driven target vessel revascularization at 12 months . Rates of target vessel failure at 12 months were 4.8 % in the 6-month DAPT group and 4.3 % in the 12-month DAPT group ( the upper limit of 1-sided 95 % confidence interval , 2.4 % ; P=0.001 for noninferiority with a predefined noninferiority margin of 4.0 % ) . Although stent thrombosis tended to occur more frequently in the 6-month DAPT group than in the 12-month group ( 0.9 % versus 0.1 % ; hazard ratio , 6.02 ; 95 % confidence interval , 0.72–49.96 ; P=0.10 ) , the risk of death or myocardial infa rct ion did not differ in the 2 groups ( 2.4 % versus 1.9 % ; hazard ratio , 1.21 ; 95 % confidence interval , 0.60–2.47 ; P=0.58 ) . In the prespecified subgroup analysis , target vessel failure occurred more frequently in the 6-month DAPT group than in the 12-month group ( hazard ratio , 3.16 ; 95 % confidence interval , 1.42–7.03 ; P=0.005 ) among diabetic patients . Conclusions — Six-month DAPT did not increase the risk of target vessel failure at 12 months after implantation of drug-eluting stents compared with 12-month DAPT . However , the noninferiority margin was wide , and the study was underpowered for death or myocardial infa rct ion . Our results need to be confirmed in larger trials . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00698607 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 —Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome , yet all effective therapies also increase the risk of bleeding . Methods and Results —In the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events ( CURE ) trial , 12 562 patients were r and omized to clopidogrel or placebo  in addition to  aspirin  , and the primary outcome was cardiovascular ( CV ) death , myocardial infa rct ion ( MI ) , or stroke . The benefits were consistent among those undergoing percutaneous coronary intervention ( PCI ) [ 9.6 % for clopidogrel , 13.2 % for placebo ; relative risk ( RR ) , 0.72 ; 95 % CI , 0.57 to 0.90 ] , coronary artery bypass grafting ( CABG ) surgery ( 14.5 % for clopidogrel 16.2 % for placebo ; RR , 0.89 ; 95 % CI , 0.71 to 1.11 ) , and medical therapy only ( 8.1 % for clopidogrel , 10.0 % for placebo ; RR , 0.80 ; 95 % CI , 0.69 to 0.92 ; test for interaction among strata , 0.53 ) . For CABG during the initial hospitalization ( 530 for placebo , 485 for clopidogrel ) , the frequency of CV death , MI or stroke before CABG was 4.7 % for placebo and 2.9 % for clopidogrel ( RR , 0.56 ; 95 % CI , 0.29 to 1.08 ) . For the entire study , there was a 1 % excess of major bleeding but no significant excess of life-threatening bleeding . Among patients undergoing CABG , the rates of life-threatening bleeding were 5.6 % for clopidogrel and 4.2 % for placebo ( RR , 1.30 ; 95 % CI , 0.91 to 1.95 ; both nonsignificant ) . Conclusions —The benefits versus risks of early and long-term clopidogrel therapy ( freedom from CV death , MI , stroke , or life-threatening bleeding ) are similar in those undergoing revascularization ( CABG or PCI ) and in the study population as a whole . Overall , the benefits of starting clopidogrel on admission appear to outweigh the risks , even among those who proceed to CABG during the initial hospitalization Objective The purpose of this study was to evaluate the long term effect of clopidogrel-based antiplatelet therapy  on neointimal formation . Methods This study comprised 78 patients with typical stable angina pectoris or documented myocardial ischaemia , and with only one angiographic lesion in one native coronary artery undergoing successful stent implantation without predilatation with C-reactive protein levels ≤5 mg/l at 72 h after the procedure . All patients received dual antiplatelet therapy with 75 mg/day clopidogrel and 300 mg/day aspirin for four weeks . Clopidogrel was switched to isochronous placebo in half of the patients ( n=39 ) at the end of the fourth week . This allocation was maintained for 20 weeks , and at week 24 of the study , coronary angiography and intravascular ultrasound imaging were performed again in all cases in order to evaluate the changes that had occurred in the in-stent neointimal formation ; rates of restenosis were also recorded Results At the end of the follow-up period , angiographic stenosis diameter and restenosis rates were smaller in the clopidogrel group than in the placebo group ( 23.3 % versus 35.6 % , p=0.05 and 5.12 % versus 10.25 % ; p=0.03 respectively ) ; the intravascular ultrasonographic neointimal cross sectional area was also smaller in the clopidogrel group ( 3.6±2.7 mm2 versus 5.2±2.5 mm2 , p=0.03 ) . Conclusions Long-term clopidogrel administration significantly reduced neointimal formation at the stent site as well as reducing major clinical events in patients who did not develop high-risk systemic inflammatory response after percutaneous coronary intervention UNLABELLED In general , obesity is associated with better outcome in patients undergoing percutaneous coronary interventions ( PCI ) . One small study has suggested that these patients do not achieve adequate platelet inhibition with clopidogrel and that this may shape clinical outcomes . We evaluated the relationship between body mass index ( BMI ) and clinical outcomes at 1 year following PCI in patients r and omized to clopidogrel or placebo in the CREDO trial . METHODS AND RESULTS BMI , baseline clinical characteristics and clopidogrel regimen were assessed in 2,116 patients . The primary study endpoint was the 1-year composite of death , MI or stroke . A total of 342 patients had low or normal BMI ( < 25 kg per m2 ) , 847 were overweight ( 25 - 29.9 kg per m2 ) , 810 were obese ( 30 - 39.9 kg per m2 ) and 113 were very obese ( greater than or equal to 40 kg per m2 ) . Obese patients were more likely to be young males with diabetes , hypertension and hyperlipidemia ( p < 0.01 ) . Bleeding complications occurred in 38 % of low BMI , 32 % of overweight/obese , and 25 % of very obese patients ( p = 0.03 ) . R and omization to clopidogrel was associated with a 25 % risk reduction in 1-year death , MI or stroke events , as BMI increased by every 5 kg per m2 ( p = 0.009 ) . CONCLUSION In general , increasing BMI was associated with better efficacy and bleeding outcomes at 1 year in this nonurgent PCI population . R and omization to early- and long-term clopidogrel was associated with even further improvements in those with increasing BMI OBJECTIVES The goal of this study was to evaluate shorter duration ( 3 months ) dual antiplatelet therapy ( DAPT ) after  drug-eluting stent ( DES ) implantation .  BACKGROUND There have been few published reports of prospect i ve r and omized clinical studies comparing the safety and efficacy of shorter duration DAPT after DES implantation . METHODS We r and omly assigned 2,117 patients with coronary artery stenosis into 2 groups according to DAPT duration and stent type : 3-month DAPT following Endeavor zotarolimus-eluting stent ( E-ZES ) implantation ( E-ZES+3-month DAPT , n=1,059 ) versus 12-month DAPT following the other DES implantation ( st and ard therapy , n=1,058 ) . We hypothesized that the E-ZES+3-month DAPT would be noninferior to the st and ard therapy for the primary composite endpoint ( cardiovascular death , myocardial infa rct ion , stent thrombosis , target\vessel revascularization , or bleeding ) at 1 year . RESULTS The primary endpoint occurred in 40 ( 4.7 % ) patients assigned to E-ZES+3-month DAPT compared with 41 ( 4.7 % ) patients assigned to the st and ard therapy ( difference : 0.0 % ; 95 % confidence interval [ CI ] : -2.5 to 2.5 ; p=0.84 ; p<0.001 for noninferiority ) . The composite rates of any death , myocardial infa rct ion , or stent thrombosis were 0.8 % and 1.3 % , respectively ( difference : -0.5 % ; 95 % CI : -1.5 to 0.5 ; p=0.48 ) . The rates of stent thrombosis were 0.2 % and 0.3 % , respectively ( difference : -0.1 % ; 95 % CI : -0.5 to 0.3 ; p=0.65 ) without its further occurrence after cessation of clopidogrel in the E-ZES+3-month DAPT group . The rates of target vessel revascularization were 3.9 % and 3.7 % , respectively ( difference : 0.2 % ; 95 % CI : -2.3 to 2.6 ; p=0.70 ) . CONCLUSIONS E-ZES+3-month DAPT was noninferior to the st and ard therapy with respect to the occurrence of the primary endpoint . ( REal Safety and Efficacy of a 3-month dual antiplatelet Therapy following E-ZES implantation [ RESET ] ; NCT01145079 ) BACKGROUND Clopidogrel resinate is a resinate complex of (+)-clopidogrel optical isomer , wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups . It was approved by the Korean Food and Drug Administration on the basis of a Phase I study that demonstrated the bioequivalence of clopidogrel resinate and clopidogrel bisulfate . However , there are no available data regarding efficacy and tolerability in patients with vascular disease . OBJECTIVE The goal of this study was to investigate the antiplatelet efficacy and tolerability of clopidogrel resinate in patients with coronary heart disease ( CHD ) or CHD-equivalent risks . METHODS This study was a Phase IV , r and omized , double-blind , double-dummy , parallel-group , noninferiority trial . We prospect ively recruited patients in 10 centers between March 2008 and July 2008 . Patients who had documented CHD or CHD-equivalent risks were r and omly assigned to 1 of 3 groups : group A , aspirin ( 100 mg ) + clopidogrel bisulfate placebo + clopidogrel resinate placebo ; group B , aspirin ( 100 mg ) + clopidogrel bisulfate placebo + clopidogrel resinate ( 75 mg ) ; or group C , aspirin ( 100 mg ) + clopidogrel bisulfate ( 75 mg ) + clopidogrel resinate placebo . The primary outcome was the percent P2Y(12 ) inhibition after medication , assessed by using a point-of-care assay . If the 1-sided 90 % upper confidence limit for the difference was less than the prespecified delta value ( -5.7 ) , clopidogrel resinate would be considered noninferior to clopidogrel bisulfate . The secondary outcome , the prevalence of adverse events ( AEs ) associated with study medications , was assessed at each visit by direct interview . RESULTS A total of 314 patients ( mean [ SD ] age , 62.2 [ 9.0 ] years ; male 63.7 % ; weight , 67.3 [ 13.6 ] kg [ range , 45 - 102 kg ] ; all Asian ) were enrolled , and 287 patients finished the study ( group A , n = 97 ; group B , n = 90 ; and group C , n = 100 ) . Eight patients took no study medications and were excluded from the tolerability and efficacy analyses . Nineteen patients discontinued the study because of protocol violation ( n = 15 ) , adverse events ( n = 3 ) , or voluntary withdrawal ( n = 1 ) and were excluded from the efficacy analysis . There were no significant differences in baseline clinical characteristics among the groups except for the frequency of a history of CHD ( group A , 85.4 % ; group B , 73.0 % ; and group C , 88.3 % ; P = 0.01 ) . Patients treated with either type of clopidogrel showed significant inhibition ( mean [ SD ] ) of P2Y(12 ) ( group A , -5.9 % [ 15.1 % ] ; group B , 23.4 % [ 21.9 % ] ; and group C , 19.5 % [ 23.8 % ] ; P < 0.001 ) . Differences between clopidogrel resinate and clopidogrel bisulfate in the inhibition of P2Y(12 ) did not exceed the predetermined value for inferiority ( P for noninferiority , 0.02 ; 90 % CI , -0.9 to 10.3 ) . In the tolerability analysis , there was no mortality during the study period and no significant differences between groups in the frequency of AEs and serious AEs ( AEs : group A , 33.0 % ; group B , 26.0 % ; and group C , 23.3 % [ P = 0.27 ] ; serious AEs : group A , 1.0 % ; group B , 3.0 % ; and group C , 1.0 % [ P = 0.42 ] ) . One patient in group B underwent coronary stent implantation for treatment of stable angina . CONCLUSIONS In this small , selected Asian patient population , differences in the platelet inhibition efficacies of clopidogrel resinate and clopidogrel bisulfate did not exceed the predetermined limits for noninferiority . The differences in tolerability between the 2 drugs did not reach statistical significance 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 A substantial proportion of patients receiving fibrinolytic therapy for myocardial infa rct ion with ST-segment elevation have inadequate reperfusion or reocclusion of the infa rct -related artery , leading to an increased risk of complications and death . METHODS We enrolled 3491 patients , 18 to 75 years of age , who presented within 12 hours after the onset of an ST-elevation myocardial infa rct ion and r and omly assigned them to receive clopidogrel ( 300-mg loading dose , followed by 75 mg once daily ) or placebo . Patients received a fibrinolytic agent , aspirin , and when appropriate , heparin ( dispensed according to body weight ) and were scheduled to undergo angiography 48 to 192 hours after the start of study medication . The primary efficacy end point was a composite of an occluded infa rct -related artery ( defined by a Thrombolysis in Myocardial Infa rct ion flow grade of 0 or 1 ) on angiography or death or recurrent myocardial infa rct ion before angiography . RESULTS The rates of the primary efficacy end point were 21.7 percent in the placebo group and 15.0 percent in the clopidogrel group , representing an absolute reduction of 6.7 percentage points in the rate and a 36 percent reduction in the odds of the end point with clopidogrel therapy ( 95 percent confidence interval , 24 to 47 percent ; P<0.001 ) . By 30 days , clopidogrel therapy reduced the odds of the composite end point of death from cardiovascular causes , recurrent myocardial infa rct ion , or recurrent ischemia leading to the need for urgent revascularization by 20 percent ( from 14.1 to 11.6 percent , P=0.03 ) . The rates of major bleeding and intracranial hemorrhage were similar in the two groups . CONCLUSIONS In patients 75 years of age or younger who have myocardial infa rct ion with ST-segment elevation and who receive aspirin and a st and ard fibrinolytic regimen , the addition of clopidogrel improves the patency rate of the infa rct -related artery and reduces ischemic complications BACKGROUND The potential benefits and risks of the use of dual antiplatelet therapy beyond a 12-month period in patients receiving drug-eluting stents have not been clearly established . METHODS In two trials , we r and omly assigned a total of 2701 patients who had received drug-eluting stents and had been free of major adverse cardiac or cerebrovascular events and major bleeding for a period of at least 12 months to receive clopidogrel plus aspirin or aspirin alone .  The primary end point was a composite of myocardial infa rct ion or death from cardiac causes . Data from the two trials were merged for analysis . RESULTS The median duration of follow-up was 19.2 months . The cumulative risk of the primary outcome at 2 years was 1.8 % with dual antiplatelet therapy , as compared with 1.2 % with aspirin monotherapy ( hazard ratio , 1.65 ; 95 % confidence interval [ CI ] , 0.80 to 3.36 ; P=0.17 ) . The individual risks of myocardial infa rct ion , stroke , stent thrombosis , need for repeat revascularization , major bleeding , and death from any cause did not differ significantly between the two groups . However , in the dual-therapy group as compared with the aspirin-alone group , there was a nonsignificant increase in the composite risk of myocardial infa rct ion , stroke , or death from any cause ( hazard ratio , 1.73 ; 95 % CI , 0.99 to 3.00 ; P=0.051 ) and in the composite risk of myocardial infa rct ion , stroke , or death from cardiac causes ( hazard ratio , 1.84 ; 95 % CI , 0.99 to 3.45 ; P=0.06 ) . CONCLUSIONS The use of dual antiplatelet therapy for a period longer than 12 months in patients who had received drug-eluting stents was not significantly more effective than aspirin monotherapy in reducing the rate of myocardial infa rct ion or death from cardiac causes . These findings should be confirmed or refuted through larger , r and omized clinical trials with longer-term follow-up . ( Clinical Trials.gov numbers , NCT00484926 and NCT00590174 . Background — Clopidogrel inhibits intimal hyperplasia in animal studies and therefore may reduce saphenous vein graft ( SVG ) intimal hyperplasia after coronary artery bypass grafting . The Clopidogrel After Surgery for Coronary Artery DiseasE ( CASCADE ) study was undertaken to evaluate whether the addition of clopidogrel to aspirin inhibits SVG disease after coronary artery bypass grafting , as assessed at 1 year by intravascular ultrasound . Methods and Results — In this double-blind phase II trial , 113 patients undergoing coronary artery bypass grafting with SVGs were r and omized to receive aspirin 162 mg plus clopidogrel 75 mg daily or aspirin 162 mg plus placebo daily for 1 year . The primary outcome was SVG intimal hyperplasia ( mean intimal area ) as determined by intravascular ultrasound at 1 year . Secondary outcomes were graft patency , major adverse cardiovascular events , and major bleeding . One-year intravascular ultrasound and coronary angiography were performed in 92 patients ( 81.4 % ) . At 1 year , SVG intimal area did not differ significantly between the 2 groups ( 4.1±2.0 versus 4.5±2.1 mm2 , aspirin-clopidogrel versus aspirin-placebo , P=0.44 ) . Overall 1-year graft patency was 95.2 % in the aspirin-clopidogrel group compared with 95.5 % in the aspirin-placebo group ( P=0.90 ) , and SVG patency was 94.3 % in the aspirin-clopidogrel group versus 93.2 % in the aspirin-placebo group ( P=0.69 ) . Freedom from major adverse cardiovascular events at 1 year was 92.9±3.4 % in the aspirin-clopidogrel group and 91.1±3.8 % in the aspirin-placebo group ( P=0.76 ) . The incidence of major bleeding at 1 year was similar for the 2 groups ( 1.8 % versus 0 % , aspirin-clopidogrel versus aspirin-placebo , P=0.50 ) . Conclusions — Compared with aspirin monotherapy , the combination of aspirin plus clopidogrel did not significantly reduce the process of SVG intimal hyperplasia 1 year after coronary artery bypass grafting . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00228423 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 BACKGROUND Reactive thrombocytosis has been reported in 20 % of patients after coronary artery bypass grafting ( CABG ) , a frequency that might be related to the high incidence of thrombotic complications . The present study was planned to investigate the effect of combined treatment with clopidogrel and acetylsalicylic acid ( ASA ) on post-CABG reactive thrombocytosis . METHODS Included in this prospect i ve , r and omized study were 60 patients who underwent CABG operation with a 6-month follow-up . Three study groups were defined : group 1 ( n = 20 ) , a control group of patients who have not developed reactive thrombocytosis after CABG surgery ; group 2 ( n = 20 ) , patients who have developed reactive thrombocytosis and continue taking ASA ( 300 mg/day ) ; and group 3 ( n = 20 ) , patients who have developed reactive thrombocytosis and continue taking ASA ( 300 mg/day ) with the addition of clopidogrel ( 75 mg/day ) . RESULTS The mean ages and sex distributions of the patient groups were similar . There were no significant differences between the groups regarding cardiovascular risk factors , baseline laboratory findings , or intraoperative characteristics . Thrombocytosis disappeared within the first month after the operation in both treatment groups . An evaluation of graft patency in the sixth postoperative month revealed that group 2 had significantly more patients with a " positive " result in the exercise test than group 3 and that group 3 had a lower incidence of graft occlusion than group 2 ( P < .01 ) . CONCLUSIONS Combination antiplatelet therapy with ASA and clopidogrel seems to be more effective than ASA alone for maintaining graft patency in patients with reactive thrombocytosis Background —We studied the benefits and risks of adding clopidogrel to different doses of aspirin in the treatment of patients with acute coronary syndrome ( ACS ) . Methods and Results —In the Clopidogrel in Unstable angina to prevent Recurrent Events ( CURE ) trial , 12 562 patients with ACS using aspirin , 75 to 325 mg daily , were r and omized to clopidogrel or placebo for up to 1 year . In this analysis , patients were divided into the following 3 aspirin dose groups : ≤100 mg , 101 through 199 mg , and ≥200 mg . The combined incidence of cardiovascular death , myocardial infa rct ion , or stroke was reduced by clopidogrel regardless of aspirin dose , as follows : ≤100 mg , 10.5 % versus 8.6 % ( relative risk [ RR ] , 0.81 [ 95 % CI , 0.68 to 0.97 ] ) ; 101 to 199 mg , 9.8 % versus 9.5 % ( RR , 0.97 [ 95 % CI 0.77 to 1.22 ] ) ; and ≥200 mg , 13.6 % versus 9.8 % ( RR , 0.71 [ 95 % CI , 0.59 to 0.85 ] ) . The incidence of major bleeding increased with increasing aspirin dose both in the placebo group ( 1.9 % , 2.8 % , and 3.7 % , respectively ; P = 0.0001 ) and the clopidogrel group ( 3.0 % , 3.4 % , and 4.9 % , respectively ; P = 0.0009 ) ; thus , the excess risk with clopidogrel was 1.1 % , 1.2 % , and 1.2 % , respectively . The adjusted hazard ratio for major bleeding for the highest versus the lowest dose of aspirin was 1.9 ( 95 % CI 1.29 to 2.72 ) in the placebo group , 1.6 ( 95 % CI 1.19 to 2.23 ) in the clopidogrel group , and 1.7 ( 95 % CI 1.36 to 2.20 ) in the combined group . Conclusions —In patients with ACS , adding clopidogrel to aspirin is beneficial regardless of aspirin dose . Bleeding risks increase with increasing aspirin dose , with or without clopidogrel , without any increase in efficacy . Our findings suggest that the optimal daily dose of aspirin may be between 75 and 100 mg , with or without clopidogrel BACKGROUND Despite current treatments , patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events . We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients . METHODS We r and omly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel ( 300 mg immediately , followed by 75 mg once daily ) ( 6259 patients ) or placebo ( 6303 patients ) in addition  to aspirin for 3 to 12 months . RESULTS The first primary outcome --a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , or stroke -- occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group ( relative risk with clopidogrel as compared with placebo , 0.80 ; 95 percent confidence interval , 0.72 to 0.90 ; P<0.001 ) . The second primary outcome --the first primary outcome or refractory ischemia -- occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group ( relative risk , 0.86 ; 95 percent confidence interval , 0.79 to 0.94 ; P<0.001 ) . The percentages of patients with in-hospital refractory or severe ischemia , heart failure , and revascularization procedures were also significantly lower with clopidogrel . There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group ( 3.7 percent vs. 2.7 percent ; relative risk , 1.38 ; P=0.001 ) , but there were not significantly more patients with episodes of life-threatening bleeding ( 2.2 percent [ corrected ] vs. 1.8 percent ; P=0.13 ) or hemorrhagic strokes ( 0.1 percent vs. 0.1 percent ) . CONCLUSIONS The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation . However , the risk of major bleeding is increased among patients treated with clopidogrel BACKGROUND The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial . We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy . METHODS We enrolled 921 patients with severe acute upper gastrointestinal bleeding and r and omly assigned 461 of them to a restrictive strategy ( transfusion when the hemoglobin level fell below 7 g per deciliter ) and 460 to a liberal strategy ( transfusion when the hemoglobin fell below 9 g per deciliter ) . R and omization was stratified according to the presence or absence of liver cirrhosis . RESULTS A total of 225 patients assigned to the restrictive strategy ( 51 % ) , as compared with 61 assigned to the liberal strategy ( 14 % ) , did not receive transfusions ( P<0.001 ) [corrected].The probability of survival at 6 weeks was higher in the restrictive- strategy group than in the liberal- strategy group ( 95 % vs. 91 % ; hazard ratio for death with restrictive strategy , 0.55 ; 95 % confidence interval [ CI ] , 0.33 to 0.92 ; P=0.02 ) . Further bleeding occurred in 10 % of the patients in the restrictive- strategy group as compared with 16 % of the patients in the liberal- strategy group ( P=0.01 ) , and adverse events occurred in 40 % as compared with 48 % ( P=0.02 ) . The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer ( hazard ratio , 0.70 ; 95 % CI , 0.26 to 1.25 ) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease ( hazard ratio , 0.30 ; 95 % CI , 0.11 to 0.85 ) , but not in those with cirrhosis and Child-Pugh class C disease ( hazard ratio , 1.04 ; 95 % CI , 0.45 to 2.37 ) . Within the first 5 days , the portal-pressure gradient increased significantly in patients assigned to the liberal strategy ( P=0.03 ) but not in those assigned to the restrictive strategy . CONCLUSIONS As compared with a liberal transfusion strategy , a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding . ( Funded by Fundació Investigació Sant Pau ; Clinical Trials.gov number , NCT00414713 . ) Background —The risk of ischemic events is high , both early and late after acute coronary syndromes ( ACS ) . We examine the benefits and risks associated with the use of adding clopidogrel to aspirin within the first 30 days and later ( 31 days to 12 months ) in 12 562 patients with ACS . Methods and Results —A total of 12 562 ACS patients were r and omized to receive clopidogrel ( 300 mg initially followed by 75 mg/d ) or placebo for 3 to 12 months . The proportion of patients experiencing cardiovascular death , myocardial infa rct ion , or strokes ( primary outcome ) at 30 days was 5.4 % in the placebo group and 4.3 % in the active group ( relative risk 0.79 , 95 % CI 0.67 to 0.92 ) . Beyond 30 days , the corresponding rates were 6.3 % versus 5.2 % ( relative risk 0.82 , 95 % CI 0.70 to 0.95 ) . There was no significant excess in life-threatening bleeds in each period ( 0.97 % versus 1.28 % , relative risk 1.32 , 95 % CI 0.95 to 1.84 for 0 to 30 days ; 0.83 % versus 0.91 % , relative risk 1.09 , 95 % CI 0.75 to 1.59 for 31 days to 12 months ) . Further subdivision of the early data indicates benefits within 24 hours with consistently lower rates of the primary outcome in combination with refractory or severe ischemia . Conclusions —Clopidogrel reduces the risk of ischemic vascular events , with the benefits emerging within 24 hours of initiation of treatment and continuing throughout the 12 months ( mean 9 months ) of the study Background —The Clopidogrel in Unstable angina to prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel , given early and continued long term , was superior to placebo in patients with non-ST – elevation acute coronary syndromes receiving aspirin . The purpose of the present analysis was to estimate the treatment effect Zof clopidogrel in patients who were stratified according to their risk of future cardiovascular events . Methods and Results — Patients ( n=12 562 ) who presented within 24 hours after the onset of symptoms were r and omized to receive clopidogrel ( 300 mg followed by 75 mg daily ) or placebo in addition to aspirin for 3 to 12 months . Treatment effect was analyzed in various risk groups according to the Thrombolysis in Myocardial Infa rct ion ( TIMI ) risk score . The TIMI risk model was vali date d in the CURE population ( C statistic , 0.634 ) . The primary composite outcome of cardiovascular death , myocardial infa rct ion , or stroke increased proportionally with increasing risk according to the TIMI risk score . The impact of clopidogrel versus placebo on the rate of the primary outcome was as follows : low-risk group ( TIMI score 0 to 2 ) , 4.1 % versus 5.7 % ( relative risk [ RR ] , 0.71 ; 95 % confidence interval [ CI ] , 0.52 to 0.97;P < 0.04 ) , intermediate-risk group ( TIMI score 3 to 4 ) , 9.8 % versus 11.4 % ( RR , 0.85 ; 95 % CI , 0.74 to 0.98;P < 0.03 ) , and high-risk group ( TIMI score 5 to 7 ) , 15.9 % versus 20.7 % ( RR , 0.73 ; 95 % CI , 0.60 to 0.90;P < 0.004 ) . There was no evidence of statistical heterogeneity among the groups . Conclusions —The benefit of clopidogrel demonstrated in the CURE trial is consistent in low- , intermediate- , and high-risk patients with acute coronary syndromes ( as stratified by TIMI risk score ) , thus supporting its use in all patients with documented non – ST elevation acute coronary syndromes OBJECTIVES This study sought to determine the optimal timing of a 300-mg clopidogrel loading dose before percutaneous coronary intervention ( PCI ) in patients enrolled in the Clopidogrel for the Reduction of Events During Observation ( CREDO ) trial . BACKGROUND A loading dose of clopidogrel before a PCI has become relatively commonplace , although the data supporting this practice are limited and sometimes conflicting . METHODS Patients were r and omized to receive either  300 mg clopidogrel or a matching placebo administered a minimum of 3 h and a maximum of 24 h before PCI . The primary 28-day combined end point was death , myocardial infa rct ion , or urgent target vessel revascularization . Linear splines were used to summarize the effect of the time of pre-treatment as a continuous variable . RESULTS A total of 1,762 patients were evaluated . For patients r and omized to placebo , there was no relationship between the duration of pre-treatment and the occurrence of the primary end point , whereas longer duration s of pre-treatment in patients r and omized to clopidogrel were associated with improved outcomes . The event rates diverged maximally at 24 h. The difference in outcomes between placebo and clopidogrel pre-treated patients was not significant until > or = 15 h pre-treatment , with a 58.8 % ( p = 0.028 ) reduction in the primary end point in patients pre-treated with clopidogrel > or = 15 h compared with placebo . CONCLUSIONS When a 300-mg loading dose of clopidogrel is used , little benefit is obtained compared with just 75 mg at the time of the PCI when the treatment duration is < 12 h. In patients pre-treated for longer duration s , the optimal duration seems to approach 24 OBJECTIVES We sought to evaluate the effect of aspirin plus clopidogrel versus aspirin alone on saphenous vein graft occlusion at 3 months after coronary artery bypass grafting ( CABG ) . BACKGROUND Prevalence of graft occlusion is high after CABG . Aggressive antiplatelet therapy is expected to improve early post-operative graft patency . METHODS From December 2007 through December 2008 , 249 consecutive patients undergoing elective CABG at Fuwai Hospital were r and omly assigned to 2 groups : 124 received aspirin ( 100 mg ) plus clopidogrel ( 75 mg ) daily ( AC group ) , and 125 received aspirin ( 100 mg ) alone daily ( A group ) . Antiplatelet therapies were initiated when post-operative chest tube drainage was ≤ 30 cc/h for 2 h. All participants were invited for clinical follow-up and 64-slice multislice computed tomography angiography ( MSCTA ) analysis at 3 months post-operatively . Generalized estimating equations analysis was used to determine predictors of graft patency . RESULTS One participant , from group A , died before 3-month follow-up . Of the remaining 248 patients , 224 ( 90.3 % ) underwent MSCTA . Participants had similar pre-operative and intraoperative characteristics at baseline . No significant differences were observed in intraoperative transit-time flow measurement findings or major adverse cardiac-related events . Three-month MSCTA follow-up revealed that saphenous vein graft patency was 91.6 % ( 219 of 239 ) in the AC group versus 85.7 % ( 198 of 231 ) in the A group ( p = 0.043 ) . In multivariate analysis , combined antiplatelet therapy independently increased venous graft patency ( p = 0.045 ) . CONCLUSIONS Aspirin plus clopidogrel is more effective in venous graft patency than aspirin alone in the short term after CABG , but further , long-term study is needed . ( The Clopidogrel and Aspirin After Surgery for Coronary Artery Disease ; NCT00776477 ) BACKGROUND The relative efficacy of streptokinase and tissue plasminogen activator and the roles of intravenous as compared with subcutaneous heparin as adjunctive therapy in acute myocardial infa rct ion are unresolved questions . The current trial was design ed to compare new , aggressive thrombolytic strategies with st and ard thrombolytic regimens in the treatment of acute myocardial infa rct ion . Our hypothesis was that newer thrombolytic strategies that produce earlier and sustained reperfusion would improve survival . METHODS In 15 countries and 1081 hospitals , 41,021 patients with evolving myocardial infa rct ion were r and omly assigned to four different thrombolytic strategies , consisting of the use of streptokinase and subcutaneous heparin , streptokinase and intravenous heparin , accelerated tissue plasminogen activator ( t-PA ) and intravenous heparin , or a combination of streptokinase plus t-PA with intravenous heparin . ( " Accelerated " refers to the administration of t-PA over a period of 1 1/2 hours -- with two thirds of the dose given in the first 30 minutes -- rather than the conventional period of 3 hours . ) The primary end point was 30-day mortality . RESULTS The mortality rates in the four treatment groups were as follows : streptokinase and subcutaneous heparin , 7.2 percent ; streptokinase and intravenous heparin , 7.4 percent ; accelerated t-PA and intravenous heparin , 6.3 percent , and the combination of both thrombolytic agents with intravenous heparin , 7.0 percent . This represented a 14 percent reduction ( 95 percent confidence interval , 5.9 to 21.3 percent ) in mortality for accelerated t-PA as compared with the two streptokinase-only strategies ( P = 0.001 ) . The rates of hemorrhagic stroke were 0.49 percent , 0.54 percent , 0.72 percent , and 0.94 percent in the four groups , respectively , which represented a significant excess of hemorrhagic strokes for accelerated t-PA ( P = 0.03 ) and for the combination strategy ( P < 0.001 ) , as compared with streptokinase only . A combined end point of death or disabling stroke was significantly lower in the accelerated-tPA group than in the streptokinase-only groups ( 6.9 percent vs. 7.8 percent , P = 0.006 ) . CONCLUSIONS The findings of this large-scale trial indicate that accelerated t-PA given with intravenous heparin provides a survival benefit over previous st and ard thrombolytic regimens BACKGROUND Lacunar infa rcts are a frequent type of stroke caused mainly by cerebral small-vessel disease . The effectiveness of antiplatelet therapy for secondary prevention has not been defined . METHODS We conducted a double-blind , multicenter trial involving 3020 patients with recent symptomatic lacunar infa rcts identified by magnetic resonance imaging . Patients were r and omly assigned to receive 75 mg of clopidogrel or placebo daily ; patients in both groups received 325 mg of aspirin daily . The primary outcome was any recurrent stroke , including ischemic stroke and intracranial hemorrhage . RESULTS The participants had a mean age of 63 years , and 63 % were men . After a mean follow-up of 3.4 years , the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel ( dual antiplatelet therapy ) ( 125 strokes ; rate , 2.5 % per year ) as compared with aspirin alone ( 138 strokes , 2.7 % per year ) ( hazard ratio , 0.92 ; 95 % confidence interval [ CI ] , 0.72 to 1.16 ) , nor was the risk of recurrent ischemic stroke ( hazard ratio , 0.82 ; 95 % CI , 0.63 to 1.09 ) or disabling or fatal stroke ( hazard ratio , 1.06 ; 95 % CI , 0.69 to 1.64 ) . The risk of major hemorrhage was almost doubled with dual antiplatelet therapy ( 105 hemorrhages , 2.1 % per year ) as compared with aspirin alone ( 56 , 1.1 % per year ) ( hazard ratio , 1.97 ; 95 % CI , 1.41 to 2.71 ; P<0.001 ) . Among classifiable recurrent ischemic strokes , 71 % ( 133 of 187 ) were lacunar strokes . All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy ( 77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy ) ( hazard ratio , 1.52 ; 95 % CI , 1.14 to 2.04 ; P=0.004 ) ; this difference was not accounted for by fatal hemorrhages ( 9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone ) . CONCLUSIONS Among patients with recent lacunar strokes , the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death . ( Funded by the National Institute of Neurological Disorders and Stroke and others ; SPS3 Clinical Trials.gov number , NCT00059306 . ) Objective The purpose of this r and omized study was to evaluate the effect on graft patency by adding clopidogrel to aspirin in off-pump coronary artery bypass ( OPCAB ) grafting and the possible side effects of such therapy . Methods Twenty patients who underwent st and ard OPCAB through median sternotomy were r and omized immediately after surgery in two groups . Patients in group A ( n = 10 ) received 100 mg of aspirin starting preoperatively , continuing indefinitely . Patients in group B received 100 mg of aspirin and , in addition , 75 mg of clopidogrel starting immediately after the operation and for 3 months . Postoperative bleeding and other perioperative parameters were compared . Angiography was repeated 3 months after surgery to determine the patency and quality of grafts . Results Preoperative risk factors were similar in the two groups . There was no significant difference in average number of distal anastomosis ( P = 0.572 ) , operation time ( P = 0.686 ) , postoperative bleeding ( P = 0.256 ) , ventilation time ( P = 0.635 ) , and intensive care unit stay ( P = 0.065 ) . Length of stay was shorter in group B ( P = 0.024 ) . There was no postoperative complication in either groups . Eight of 27 grafts in group A and 2 of 29 grafts in group B ( P = 0.037 ) were occluded at the time of control angiography . Conclusions Early administration of a combined regimen of clopidogrel and aspirin after OPCAB grafting is not associated with increased postoperative bleeding or other major complications . Despite the small number of patients in this study and small number of examined grafts , the results suggest that the addition of clopidogrel may increase graft patency after OPCAB grafting There is a high risk of reocclusion after successful lower limb angioplasty . Platelets play a central role in this process . The aim of this study was to investigate the antiplatelet effect of a combination of aspirin and clopidogrel compared with aspirin alone in patients with claudication undergoing endovascular revascularization Dual antiplatelet therapy ( DAPT ) with clopidogrel and aspirin is a widely accepted strategy in patients undergoing transcatheter aortic valve implantation ( TAVI ) , but this approach is not evidence based . The goal of the present study was to determine whether DAPT in patients undergoing TAVI is associated with improved outcomes compared to aspirin alone . From May 2009 to August 2010 , consecutive patients were r and omized to receive a 300-mg loading dose of clopidogrel on the day before TAVI followed by a 3-month maintenance daily dose of 75 mg plus aspirin 100 mg lifelong ( DAPT group ) or aspirin 100 mg alone ( ASA group ) . The primary end point was the composite of major adverse cardiac and cerebrovascular events , defined as death from any cause , myocardial infa rct ion , major stroke , urgent or emergency conversion to surgery , or life-threatening bleeding . The cumulative incidence of major adverse cardiac and cerebrovascular events at 30 days and 6 months was 14 % and 16 % , respectively . No significant differences between the DAPT and ASA groups were noted at both 30 days ( 13 % vs 15 % , p = 0.71 ) and 6 months ( 18 % vs 15 % ; p = 0.85 ) . In conclusion , the strategy of adding clopidogrel to aspirin for 3 months after TAVI was not found to be superior to aspirin alone . These results must be confirmed in a larger r and omized trial Background The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation , Management and Avoidance ( CHARISMA ) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease . However , a sub analysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke , myocardial infa rct ion of symptomatic peripheral arterial disease . We aim ed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be ‘ front-loaded ’ , and maximal within the first 30-days of r and omisation , without being unduly hazardous . Methods This was a sub analysis of a r and omised , double-blind , placebo-controlled trial of clopidogrel vs. placebo , in addition to background therapy with low-dose acetylsalicylic acid ( CHARISMA trial ) , restricted to all patients with transient ischaemic attack or ischaemic stroke . The primary efficacy outcome was stroke , and safety outcome severe bleeding , during the follow-up period . Results Among all transient ischaemic attack and ischaemic stroke patients r and omised to placebo ( n=2163 ) , 131 ( 6·1 % ) experienced a stroke during follow-up compared with 105 ( 4·9 % ) of 2157 patients assigned clopidogrel ( hazard ratio : 0·80 , 95 % confidence intervals : 0·62–1·03 ) . There was no significant difference in severe bleeding ( 1·7 % placebo vs. 1·9 % clopidogrel , hazard ratio : 1·11 , 95 % confidence intervals : 0·71–1·73 ) . Among all patients r and omised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo ( n=667 ) , 46 ( 6·9 % ) experienced a stroke compared with 34 ( 5·1 % ) of 664 patients assigned clopidogrel ( hazard ratio : 0·74 , 0·46–1·16 ) . There was no significant difference in severe bleeding ( 1·6 % placebo vs. 1·4 % clopidogrel , hazard ratio : 0·83 , 95 % confidence intervals : 0·34–2·01 ) . Conclusion The data are consistent with , but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone . Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed OBJECTIVE Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid ( ASA ) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention . We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting . METHODS Patients undergoing unilateral , below-knee bypass graft for atherosclerotic peripheral arterial disease ( PAD ) were enrolled 2 to 4 days after surgery and were r and omly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months . The primary efficacy endpoint was a composite of index-graft occlusion or revascularization , above-ankle amputation of the affected limb , or death . The primary safety endpoint was severe bleeding ( Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [ GUSTO ] classification ) . RESULTS In the overall population , the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo ( plus ASA ) group ( hazard ratio [ HR ] , 0.98 ; 95 % confidence interval [ CI ] , 0.78 - 1.23 ) . In a prespecified subgroup analysis , the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients ( HR , 0.65 ; 95 % CI , 0.45 - 0.95 ; P = .025 ) but not in venous graft patients ( HR , 1.25 ; 95 % CI , 0.94 - 1.67 , not significant [ NS ] ) . A significant statistical interaction between treatment effect and graft type was observed ( P(interaction ) = .008 ) . Although total bleeds were more frequent with clopidogrel , there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo ( plus ASA ) groups ( 2.1 % vs 1.2 % ) . CONCLUSION The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting . Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk BACKGROUND Antiplatelet therapy with clopidogrel decreases ischemic complication especially in patients with acute coronary syndromes or after percutaneous coronary interventions . Our study was design ed to test the effects of clopidogrel on soluble CD40 lig and ( sCD40l ) and on high-sensitivity C-reactive protein ( hs-CRP ) in patients with stable coronary artery disease ( CAD ) . METHODS This is a r and omized , double-blind , placebo-controlled study . A total of 73 patients with stable CAD for > 6 months were r and omized to receive either clopidogrel ( loading dose 300 mg followed by 75 mg/d ) for 8 weeks or placebo . Soluble CD40 lig and and hs-CRP were measured at baseline and at completion of the study . RESULTS All patients were on aspirin therapy , and 74 % were on statins .  Median and interquartile ranges ( IQR ) of sCD40l decreased from 64 pg/mL ( 43 - 99 ) at baseline to 53 pg/mL ( 35 - 77 ) at 8 weeks ( P = .03 ) in the clopidogrel group and remained unchanged in the placebo group ( 59 pg/mL , IQR 35 - 77 vs 55 pg/mL , IQR 35 - 78 ) ( P = non significant ) . Levels of hs-CRP were not affected by therapy and remained unchanged in both groups . CONCLUSIONS In patients with stable CAD , clopidogrel inhibits the release of sCD40l by platelets , which may contribute to the clinical benefit provided by this drug . This , however , does not translate in a reduction of sub clinical inflammation , as measured by hs-CRP BACKGROUND Data on the effects of oral antiplatelet agents on blood coagulation in vivo are conflicting . The platelet glycoprotein ( GP ) IIIa PlA2 allele has been suggested to modulate antithrombotic actions of clopidogrel . AIM We investigated whether clopidogrel combined with aspirin affects local thrombin formation and platelet activation triggered by vascular injury . METHOD We studied patients with stable coronary artery disease on chronic aspirin therapy r and omised to addition of clopidogrel 75 mg/d ( n = 30 ) or continuation of aspirin 100 mg/d ( n = 30 ) for 4 weeks .  Markers of thrombin generation [ thrombin-antithrombin complexes ( TAT ) and prothrombin 1.2 fragments ( F1.2 ) ] and markers of platelet activation [ soluble CD40 lig and ( sCD40L ) and P-selectin ] were determined in the supernatant of blood sample s obtained from a microvascular injury site . RESULTS Total amounts of thrombin markers produced at the site of injury were similar before and after addition of clopidogrel , whereas platelet release of sCD40L and P-selectin was lower during treatment with aspirin + clopidogrel by 33.8 % and 27.8 % ( p < 0.001 ) , respectively . Patients in the highest tertile of reduction in platelet activation had previous myocardial infa rct ion and peripheral arterial disease and released the highest amounts of sCD40L and P-selectin at baseline . TAT and F1.2 generation as well as sCD40L or P-selectin release were not influenced by the presence of the PlA2 allele . CONCLUSION Our study shows that clopidogrel combined with aspirin does not reduce thrombin formation following vascular injury , but attenuates platelet sCD40L and P-selectin release BACKGROUND The CURE study demonstrated the benefit of clopidogrel in patients with non-ST elevation ( NSTE ) acute coronary syndromes ( ACSs ) , including those undergoing percutaneous coronary intervention ( PCI ) . It did not report the relation between clopidogrel and timing of PCI or , more specifically , the role of clopidogrel in patients managed with an early interventional strategy , the current preferred treatment option for patients with NSTE ACSs . In the present study , we examined the relation between  clopidogrel therapy , timing of PCI , and cardiovascular ( CV ) events in patients participating in the CURE study . METHODS A total of 12562 patients with NSTE ACSs was r and omized in double-blind fashion to clopidogrel or placebo ( 300 mg loading dose , then 75 mg/d ) in addition to aspirin for up to 1 year . We analyzed the data of the 2658 CURE patients undergoing PCI and related the incidence of outcome events ( CV death/myocardial infa rct ion [ MI ] )  to timing of PCI after r and omization : early ( < 48 hours , median 1.0 day , n = 370 ) , intermediate ( > or = 48 hours to initial hospital discharge , median 6.8 days , n = 1360 ) , and late ( after initial hospital discharge , median 47.6 days , n = 928 ) . RESULTS Clopidogrel showed consistent treatment benefit over the 12-month ( mean 9 months ) follow-up period irrespective of timing of PCI ( relative risk [ RR ] 0.53 for the early group , RR 0.72 for the intermediate group , RR 0.70 for the late group ) . After adjustment for propensity to undergo PCI , the greatest treatment benefit of clopidogrel was observed in patients undergoing PCI < 48 hours after r and omization ( RR 0.45 , 95 % CI 0.21 - 0.96 , P = .038 ) , although with overlap between groups . The lowest absolute event rate ( 6.7 % CV death/MI ) was observed in patients treated with clopidogrel and undergoing PCI within 48 hours . There was no increased risk of major bleeding in the early PCI group . CONCLUSIONS The benefit of therapy with clopidogrel in addition to aspirin in patients presenting with NSTE ACSs was significant irrespective of the timing of PCI . The combination of clopidogrel and an early ( < 48 hours ) interventional strategy was associated with low absolute event rates for CV death/nonfatal MI In this study , we aim ed to disclose the net effect of long-term ( 6-month ) clopidogrel treatment as compared to that of short-term ( 1-month ) treatment in the poststenting period . A total of 278 patients with successful stent implantation were involved in the study . After preloading with 300 mg of clopidogrel orally ( p.o . ) 24 h prior to the procedure , r and omly selected patients were given either 75 mg p.o . for 1 month ( group A ) or 75 mg p.o . for 6 months ( group B ) . The patients were followed up clinical ly and underwent control angiography at 6 months regardless of their clinical status to delineate the coronary anatomy and assess quantitative computer-assisted ( QCA ) analysis . In 140 ( 50.4 % ) patients ( group A ) , 244 ( 50.6 % ) stents were used to treat 237 coronary lesions , and in 138 patients ( group B ) , 238 ( 49.4 % ) stents were used to treat 238 coronary lesions . There was no difference between the groups with respect to any of the clinical characteristics , intracoronary thrombus , antiaggregant therapy , the type of lesion , vessel score index , and baseline QCA parameters . In 62 patients binary in-stent restenosis ( ISR ) was determined with no statistical difference between the groups ( group A : 20.7 % vs group B : 23.9 % , P = not significance ) . There was also no difference between the two groups at 6 months regarding QCA parameters . Thirty-seven of the 62 patients with restenosis have developed major adverse coronary events such as death , myocardial infa rct ion , and target vessel revascularization ( group A : 12.9 % vs group B : 13.8 % , P = not significant ) . In patients with chronic coronary syndrome , in the poststenting period , 6-month clopidogrel use as an adjunct to aspirin has shown no benefit over 1 month use with respect to clinical outcome and angiographic outcome , such as restenosis rate , follow-up , minimal luminal diameter , late loss , lost index , and net gain BACKGROUND Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studied in a broad population of patients at high risk for atherothrombotic events . METHODS We r and omly assigned 15,603 patients with either clinical ly evident cardiovascular disease or multiple risk factors to receive clopidogrel ( 75 mg per day ) plus low-dose aspirin ( 75 to 162 mg per day ) or placebo plus low-dose aspirin and followed them for a median of 28 months . The primary efficacy end point was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . RESULTS The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirin and 7.3 percent with placebo plus aspirin ( relative risk , 0.93 ; 95 percent confidence interval , 0.83 to 1.05 ; P=0.22 ) . The respective rate of the principal secondary efficacy end point , which included hospitalizations for ischemic events , was 16.7 percent and 17.9 percent ( relative risk , 0.92 ; 95 percent confidence interval , 0.86 to 0.995 ; P=0.04 ) , and the rate of severe bleeding was 1.7 percent and 1.3 percent ( relative risk , 1.25 ; 95 percent confidence interval , 0.97 to 1.61 percent ; P=0.09 ) . The rate of the primary end point among patients with multiple risk factors was 6.6 percent with clopidogrel and 5.5 percent with placebo ( relative risk , 1.2 ; 95 percent confidence interval , 0.91 to 1.59 ; P=0.20 ) and the rate of death from cardiovascular causes also was higher with clopidogrel ( 3.9 percent vs. 2.2 percent , P=0.01 ) . In the subgroup with clinical ly evident atherothrombosis , the rate was 6.9 percent with clopidogrel and 7.9 percent with placebo ( relative risk , 0.88 ; 95 percent confidence interval , 0.77 to 0.998 ; P=0.046 ) . CONCLUSIONS In this trial , there was a suggestion of benefit with clopidogrel treatment in patients with symptomatic atherothrombosis and a suggestion of harm in patients with multiple risk factors . Overall , clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of myocardial infa rct ion , stroke , or death from cardiovascular causes . ( Clinical Trials.gov number , NCT00050817 . ) BACKGROUND Stroke is common during the first few weeks after a transient ischemic attack ( TIA ) or minor ischemic stroke .  Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone . METHODS In a r and omized , double-blind , placebo-controlled trial conducted at 114 centers in China , we r and omly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin ( clopidogrel at an initial dose of 300 mg , followed by 75 mg per day for 90 days , plus aspirin at a dose of 75 mg per day for the first 21 days ) or to placebo plus aspirin ( 75 mg per day for 90 days ) . All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1 . The primary outcome was stroke ( ischemic or hemorrhagic ) during 90 days of follow-up in an intention-to-treat analysis . Treatment differences were assessed with the use of a Cox proportional-hazards model , with study center as a r and om effect . RESULTS Stroke occurred in 8.2 % of patients in the clopidogrel-aspirin group , as compared with 11.7 % of those in the aspirin group ( hazard ratio , 0.68 ; 95 % confidence interval , 0.57 to 0.81 ; P<0.001 ) . Moderate or severe hemorrhage occurred in seven patients ( 0.3 % ) in the clopidogrel-aspirin group and in eight ( 0.3 % ) in the aspirin group ( P=0.73 ) ; the rate of hemorrhagic stroke was 0.3 % in each group . CONCLUSIONS Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms , the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage . ( Funded by the Ministry of Science and Technology of the People 's Republic of China ; CHANCE Clinical Trials.gov number , NCT00979589 . ) The purpose of this study was to compare the effect of dual antiplatelet therapy [ clopidogrel + aspirin ( ASA ) ] with respect to ASA on the protein expression of platelets from controlled type-2 diabetic patients with stable coronary ischemia . Patients had been taking ASA ( 100 mg day ) and they were r and omized to receive ( n = 29 ) or not ( n = 28 ) 75 mg day clopidogrel for 12 ± 2 weeks in a blind form . Protein expression was analyzed by two-dimensional electrophoresis and mass spectrometry . The protein expression of a limited number of proteins such as actin-binding protein isotypes 2 and 5 , lactate dehydrogenase , serotransferrin isotype 4 , protein disulfide isomerase-A3 isotype 1 , fibrinogen beta chain isotype 5 , Ras-related protein Rab-7b isotypes 1 and 6 , and immunoglobulin heavy chain was changed after dual antiplatelet therapy . Plasma level of platelet factor 4 ( PF4 ) , an in vivo marker of platelet activity , was not different between both groups . These changes suggest lower platelet reactivity after dual antiplatelet therapy in the studied patients . However , the variation in platelet proteome was lower than it would be initially expected , taking into account the apparent clinical beneficial effects of dual antiplatelet therapy . PF4 plasma level was not further decreased in the platelets treated for a longer time than 9 - 12 months with ASA + clopidogrel , as compared with ASA alone Advances in antithrombotic therapy , along with an early invasive strategy , have reduced the incidence of recurrent ischemic events and death in patients with acute coronary syndromes ( ACS ; unstable angina , non – ST-segment – elevation myocardial infa rct ion [ MI ] , and ST-segment – elevation MI).1,–,4 However , the combination of multiple pharmacotherapies , including aspirin , platelet P2Y12 inhibitors , heparin plus glycoprotein IIb/IIIa inhibitors , direct thrombin inhibitors , and the increasing use of invasive procedures , has also been associated with an increased risk of bleeding . Editorial see p 2664 Bleeding complications have been associated with an increased risk of subsequent adverse outcomes , including MI , stroke , stent thrombosis , and death , in patients with ACS and in those undergoing percutaneous coronary intervention (PCI),5,–,10 as well as in the long-term antithrombotic setting .11,12 Thus , balancing the anti-ischemic benefits against the bleeding risk of antithrombotic agents and interventions is of paramount importance in assessing new therapies and in managing patients . Prior r and omized trials comparing antithrombotic agents suggest that a reduction in bleeding events is associated with improved survival.13,14 Because prevention of major bleeding may represent an important step in improving outcomes by balancing safety and efficacy in the contemporary treatment of ACS , bleeding events have been systematic ally identified as a crucial end point for the assessment of the safety of drugs during the course of r and omized clinical trials , and are an important aspect of the evaluation of new devices and interventional therapies.15 Unlike ischemic clinical events ( eg , cardiac death , MI , stent thrombosis ) , for which there is now general consensus on end-point definitions,16,17 there is substantial heterogeneity among the many bleeding definitions currently in use . Lack of st and ardization makes it difficult to optimally organize key clinical trial processes such as adjudication , and even more difficult to interpret relative Objective To determine the individual variability in the response to aspirin and /or clopidogrel and its impact on graft patency after off-pump coronary artery bypass grafting . Design A single-centre prospect i ve r and omised controlled study design ed according to the Consoli date d St and ards of Reporting Trials statement . R and omisation was obtained by a computer-generated algorithm . Setting University medical school in Italy . Patients 300 patients who underwent off-pump coronary artery bypass grafting were r and omised to receive aspirin ( n=150 ) or aspirin plus clopidogrel ( n=150 ) . Intervention Aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily was initiated when postoperative chest tube drainage was ≤50 ml/h for 2 h and patients were followed up for 12 months . Main outcome measures Qualitative and quantitative assessment of platelet function , angiographic evaluation of coronary revascularisation by 64-slice CT and clinical outcome . Results In the aspirin group , 49 patients ( 32.6 % ) were aspirin resistant and , in the aspirin-clopidogrel group , 19 patients ( 12.6 % ) were aspirin and clopidogrel resistant . The platelet response to aspirin  was similar in all aspirin responders despite the study arm ( Aspirin Reaction Units 313.2±44.8 vs 323.6±53.6 ; p=0.07 ) . The platelet response to clopidogrel  was enhanced by aspirin in patients responsive to both aspirin and clopidogrel ( synergistic effect ) compared with responders to clopidogrel only ( P2Y12 Reaction Units 139.9±15.5 vs 179.4±18.5 ; p<0.001 ) . Combined therapy was associated with a reduced vein graft occlusion rate ( 7.4 % vs 13.1 % ; p=0.04 ) . Antiplatelet resistance was a predictor of graft occlusion ( RR 3.6 , 95 % CI 2.5 to 6.9 ; p<0.001 ) . Synergistic aspirin and clopidogrel activity was a strong predictor of vein graft patency ( RR 5.1 , 95 % CI 1.4 to 16.3 ; p<0.01 ) . Conclusions Combined clopidogrel and aspirin overcome single drug resistances , are safe for bleeding and improve venous graft patency BACKGROUND Microembolic signals ( MESs ) are direct markers of unstable large artery atherosclerotic plaques . In a previous study , we found that the number of MESs is associated with stroke recurrence and that clopidogrel plus aspirin more effectively reduce the number of MESs than does aspirin alone . Stroke recurrence is associated with not only the number of MESs but also the size of the MES , which can theoretically be estimated by monitoring the MES intensity via transcranial doppler ( TCD ) . Thus , we compared the effects of clopidogrel and aspirin with aspirin alone on MES intensity using TCD . METHODS We recruited 100 patients who experienced acute ischemic stroke or transient ischemic attack ( TIA ) within 7days of symptom onset . All patients also had large artery stenosis in the cerebral or carotid arteries and the presence of MES as revealed by TCD . The patients were r and omized to receive either aspirin or clopidogrel and aspirin for 7days . MES monitoring was performed on days 2 and 7 . RESULTS Intent-to-treat ( ITT ) analysis ( 46 patients in the dual therapy group , 52 patients in the monotherapy group ) and per- protocol ( PP ) analysis ( 25 patients in the dual therapy group , 31 patients in the monotherapy group ) were performed on 98 patients . The primary finding was that the MES intensity was dramatically reduced in the dual therapy group . ITT analysis of the dual therapy group revealed that the MES intensity was 8.04 ( 0 - 16 ) dB before treatment , 0.00 ( 0 - 17 ) dB on day 2 , and 0.00 ( 0 - 12 ) dB on day 7 ( P=0.000 ) . In the monotherapy group , the MES intensity was 9.00 ( 0 - 20 ) dB before treatment , 8.25 ( 0 - 17 ) dB on day 2 , and 7.0 ( 0 - 18 ) dB on day 7 ( P=0.577 ) . PP analysis revealed similar results . No severe hemorrhagic complications were detected . The two patients in this study who experienced stroke recurrence were in the monotherapy group . CONCLUSIONS Clopidogrel and aspirin more effectively decrease the MES intensity than aspirin alone in patients with large artery stenotic minor stroke or TIA BACKGROUND The superiority of clopidogrel and aspirin versus aspirin alone for up to 1 year in patients who undergo percutaneous coronary intervention ( PCI ) after presenting with acute coronary syndromes without ST-segment elevation was demonstrated in the PCI-CURE study . We evaluated the long-term cost-effectiveness of clopidogrel use for up to 1 year using patient-level outcomes and re source use from PCI-CURE , and estimates of life expectancy gains based on external sources . METHODS PCI-CURE involved 2658 patients who underwent PCI between 1998 and 2000 after being r and omized in the CURE trial to clopidogrel ( n = 1313 ) or placebo ( n = 1345 ) . Roughly two thirds ( clopidogrel n = 821 , placebo n = 909 ) underwent PCI during the initial hospitalization ( early PCI ) . Costs were applied to hospitalizations according to diagnosis-related group . Clopidogrel was assigned the average wholesale price of 3.22 dollars per day . Life expectancy gains result ing from the prevention of major clinical events were estimated using external sources . RESULTS Average total costs were higher with clopidogrel ( difference [ based on costing method ] 253 dollars-423 dollars ) . For patients who underwent PCI during the initial hospitalization , the difference ranged from 155 dollars lower to 90 dollars higher with clopidogrel . The estimated life expectancy gain with clopidogrel was 0.0885 years , whereas it was 0.0962 years for the early PCI subgroup . Incremental cost per year of life gained with clopidogrel ranges from 2856 dollars to 4775 dollars overall and from dominant ( life expectancy benefit with cost savings ) to 935 dollars for the early PCI subgroup . CONCLUSIONS Clopidogrel given for up to 1 year in patients undergoing PCI after presentation with acute coronary syndromes is a highly cost-effective treatment strategy Background Dual antiplatelet therapy with clopidogrel and aspirin reduces the presence and number of microembolic signals in patients with large artery disease . However , whether it is effective in patients with intracranial disease alone remains uncertain . We performed a subgroup analysis of the The CLopidogrel plus Aspirin for Infa rct ion Reduction ( CLAIR in acute stroke or transient ischemic attack patients with large artery stenosis and microembolic signals ) study of only patients with intracranial occlusive disease , excluding those with extra cranial disease . Methods CLAIR was a r and omized-controlled , open-label , multicenter clinical trial with blinded outcome evaluation , which recruited patients with symptoms of ischemic stroke or transient ischemic attack within seven-days of onset , with large artery stenosis verified by transcranial Doppler and carotid ultrasound , and with microembolic signals detected by transcranial Doppler recording . All patients were r and omized to receive clopidogrel plus aspirin daily for seven-days ( dual treatment ) , or aspirin alone for seven-days ( monotherapy ) . Repeated transcranial Doppler recordings for microembolic signals were made on day one , two , and seven . This subgroup study only analyzed the patients with purely intracranial large artery disease and excluded those with extra cranial stenosis . Results There were 70 patients recruited with purely intracranial stenosis , 34 in the dual treatment group and 36 in the monotherapy group . The proportion of the patients with positive emboli at day seven in the dual treatment group was significantly lower than that in the monotherapy group ( relative risk reduction 56·5 % , 95 % confidence interval 2·5–80·6 ; P = 0·029 ) . The number of emboli in the dual treatment group decreased significantly at day two ( P = 0·043 ) and day seven ( P = 0·018 ) compared with the monotherapy group . After adjustment for the number of emboli at day one , the effect of dual treatment was still significant for the reduction of presence ( relative risk reduction 56·0 % ; 95 % confidence interval 5·4–79·6 ; P = 0·036 ) and number ( adjusted mean difference −0·9 ; 95 % confidence interval −1·5 to −0·3 ; P = 0·004 ) of positive emboli at day seven . Conclusions Dual treatment with clopidogrel and aspirin for seven-days is more effective than aspirin alone to reduce microembolic signals in patients with intracranial arterial stenosis OBJECTIVE In peripheral arterial disease ( PAD ) patients , a limiting factor in the success of percutaneous transluminal angioplasty ( PTA ) is the development of restenosis secondary to vascular smooth muscle cell ( SMC ) proliferation . Following endothelial damage and platelet activation , there is release of factors and adhesion molecules which affect SMC proliferation . The aim of this study was to determine the effect of combination antiplatelet therapy ( clopidogrel and aspirin compared with aspirin and placebo ) on the ability of plasma from PAD patients undergoing PTA to stimulate SMCs in vitro . We further aim ed to investigate the effect of combination treatment on the levels of circulating adhesion molecules and factors , which are known to mediate SMC proliferation in experimental models . METHODS Fifty patients were r and omized to receive blinded clopidogrel or placebo , for thirty days , in addition to their daily 75 mg  aspirin .  To measure proliferative capacity , diluted plasma was incubated for 15 minutes with 24 hour-growth-arrested rat vascular smooth muscle cells , and extracellular regulated kinase (ERK)1/2 activation was analyzed by Western blotting at baseline , one hour pre-PTA , one hour , 24 hours and 30 days post-PTA . Plasma platelet-derived growth factor ( PDGF ) , sE-selectin , intracellular adhesion molecule-1 ( sICAM-1 ) , and von Willebr and factor ( vWF ) were measured by ELISA , at the same five timepoints . Platelet activation was measured by flow cytometry of ADP-stimulated platelet fibrinogen binding at baseline and one hour post-PTA . RESULTS ADP-stimulated platelet fibrinogen binding was significantly inhibited by clopidogrel before and after PTA . ERK 1/2 activation was significantly increased post-PTA in both the aspirin/clopidogrel and aspirin/placebo groups ( P < .001 ) . There was a statistically significant decrease in PDGF ( P = .004 ) , and increase in vWF ( P = .026 ) , following loading with clopidogrel . sICAM-1 levels significantly decreased ( P = .016 ) in the aspirin/placebo group following PTA . There were no other significant changes and also there was no statistically significant difference between the two treatment groups for each of ERK 1/2 , sICAM-1 , sE-selectin , or vWF . CONCLUSIONS This is the first study to show in-vitro ERK 1/2 activation ( a surrogate marker of SMC proliferation ) increases post-PTA . Combination antiplatelet therapy had no significant effect on this , although it did reduce PDGF . Further work is required to evaluate potential therapeutic treatments , which may reduce peripheral PTA-induced smooth muscle cell activation . CLINICAL RELEVANCE High rates of restenosis remain the major limitation of peripheral arterial angioplasty and stenting . The restenotic lesion occurs secondary to platelet activation , released circulating factors , and subsequent smooth musclecell proliferation and migration into the intima . Methods to limit the restenotic lesion are poorly understood . This paperinvestigates the effect of PTA on smooth muscle cell activation and the release of factors in plasma which mediate SMCproliferation . It also examines the effect of combination antiplatelet therapy as a potential therapeutic strategy BACKGROUND High-sensitivity C-reactive protein ( hsCRP ) and soluble cluster of differentiation 40 lig and ( sCD40L ) have been established as effective markers of inflammation in predicting the risk for adverse outcomes in patients with acute coronary syndromes ( ACSs ) . Activated platelets secrete certain inflammatory mediators such as P-selectin and sCD40L , which play a role in the pathogenesis of ACSs . Although acetylsalicylic acid ( ASA ) has been found to be an effective treatment of ACSs , the addition of clopidogrel bisulfate has been found tofurther improve clinical outcomes as a result of additional antiplatelet and anti-inflammatory action . Few data exist concerning the effects of dual antiplatelet therapy on these markers in patients with ACSs . OBJECTIVE The aim of this study was to assess the effectiveness and clinical significance of  clopidogrel  administration in patients with ACSs without ST segment elevation treated with ASA .  METHODS This r and omized , single-blind , controlled trial was conducted at the First Department of Cardiology , Hippokration Hospital , Athens , Greece . In patients aged > or=21 years with ACSs without ST segment elevation were r and omly assigned to 1 of 2 groups : ASA 325 mg/d for 1 week , followed by ASA ( 100 mg/d ) plus clopidogrel ( 300-mg loading dose followed by 100 mg/d ) for 36 weeks ( ASA+Clop group ) or ASA alone ( 325 mg/d for 1 week , followed by 75 mg/d for 36 weeks ) ( ASA group ) . Levels of serum sCD40L , hsCRP , and P-selectin were determined on admission and at 8 hours , 48 hours , and 6 days of treatment . By means of clinical follow-up , Kaplan-Meier free-of-major adverse cardiovascular events ( MACES ) plots were used to assess the prevalence of MACES , including cardiovascular-related death , in patients with and without high levels of hsCRP ( > or=3 mg/L ) and sCD40L ( > or=5 microg/L ) for 52 weeks . RESULTS A total of 86 patients were enrolled ( 71 men , 15 women ; mean [ SD ] age , 68 [ 3 ] years ; mean [ SD ] weight , 86 [ 18 ] kg ; white race , 86 [ 100 % ] ; 43 patients per group ) . Both groups had similar initial clinical characteristics and P-selectin levels . Baseline hsCRP and sCD40L levels were correlated with baseline P-selectin levels ( hsCRP , r2=0.099 CONCLUSIONS The results of this small study suggest that early activation of platelets , as measured using P-selectin levels , was effectively inhibited by the addition of clopidogrel to a regimen of ASA in the subgroup of patients with ACSs and intense activation of platelets ( defined as high hsCRP and sCD40L levels ) . In patients without high hsCRP and sCD40L levels , the addition of clopidogrel did not have a significant effect on P-selectin levels Abstract Objectives : To study whether Clopidogrel – Aspirin combined treatment for high risk transient ischaemic attack ( TIA ) or minor stroke results in increased number of lesions associated with anti-thrombotic cerebral haemorrhage or cerebral micro-bleeds ( CMB ) than aspirin alone treatment . Methods : The patients recruited in CHANCE test in our hospital participated in this study . We made a comparison between treatments Aspirin – Clopidogrel combined group and the Aspirin alone group in the numbers of CMB and subsequent cerebral haemorrhages . In addition , we analysed the association between the increased numbers of CMB and subsequent intracerebral haemorrhages .  All 129 patients with high risk TIA with microbleeds or minor stroke within 24 hours after the onset ( average age 65.9 ± 9.3 , 48.7 % were male patients ) were divided r and omly into two groups : ( 1 ) 67 patients were given combination therapy with clopidogrel and aspirin ( clopidogrel at an initial dose of 300 mg , then 75 mg per day for 90 days , plus aspirin at a dose of 75 mg per day for the first 21 days);(2 ) the rest patients were given aspirin treatment ( 75 mg per day for 90 days ) . All participants received open-label aspirin at a clinician-determined dose of 75–300 mg on the first day . Results : The CMB were found in 52.7 % of all patients in both groups . There was no siginificant difference between the Aspirin group and the Aspirin – clopidogrel treated group , though the latter showed some slight increase in CMB ( Odds ratios ( OR ) = 1.16 , 95 % confidence intervals ( CI ) = 0.54–2.47 , P = 0.71 ) . But the numbers of CMB were remarkably associated with the number of primary existing CMB ( OR = 6.46 , 95%CI 2.57–16.23 , P < 0.001 ) , especially that of primary existing CMB ≥ 3.In addition , the increasing numbers of CMB associated with primary CMB lesions , which located in corticosubcortical area ( CSC ) ( OR = 4.69 , 95%CI 1.51–14.53 , P = 0.007 ) . Conclusions : For the treatment of high-risk TIA or minor stroke patients , the clopidogrel – aspirin treatment did not increase the number of CMB  than Aspirin alone . It appears that the extent of CMB was associated with the extent of existing CMB occurred in previous stroke , which was mostly located in cortical , subcortical zone Peripheral arterial disease ( PAD ) is associated with platelet hyperactivity . Aspirin and clopidogrel , two platelet inhibitors , act by different mechanisms . Aspirin inhibits thromboxane A2 synthesis and clopidogrel acts on the P2Y12 platelet ADP receptor . We evaluated the effect of clopidogrel ( 75 mg/day ) , aspirin ( 75 mg/day ) and then both drugs on several platelet function indices in patients with PAD ( n = 20 ) . There was a significant ( P = 0.0001 ) decrease in ADP-induced aggregation , after clopidogrel but not after taking aspirin . Clopidogrel plus aspirin significantly decreased spontaneous platelet aggregation ( SPA ) ( P = 0.01 to P = 0.002 ) but SPA was not significantly altered by either aspirin or clopidogrel monotherapy . Similarly , monotherapy did not inhibit serotonin (5HT)-induced aggregation but there was a significant inhibition ( P = 0.03 to P<0.02 ) after combination therapy . ADP ( 0.8 μM)-induced platelet shape change ( PSC ) was significantly inhibited by clopidogrel ( P = 0.004 ) or aspirin ( P = 0.01 ) . This was also true for 5HT-induced PSC  ( clopidogrel , P = 0.01 ; aspirin , P = 0.03 ) . Soluble P-selectin decreased significantly ( from 32 ± 24 to 25 ± 17 ng/ml , P = 0.04 ) with combination therapy . Plasma platelet-derived growth factor and intraplatelet 5HT levels were not altered by combination therapy . In PAD , clopidogrel is a more potent inhibitor of ADP-induced platelet activation than aspirin ; combination therapy is more effective than clopidogrel or aspirin monotherapy . These potentially clinical ly relevant findings should be evaluated in appropriately design ed trials Objective : To assess the effectiveness of long term treatment with clopidogrel of patients with extracardiac vascular disease ( ECVD ) ( a history of either peripheral arterial disease or cerebrovascular disease ) . Design : Subgroup analysis of a prospect i ve r and omised clinical trial . Setting : The CREDO ( clopidogrel for the reduction of events during observation ) trial was a r and omised , double blind , placebo controlled trial conducted at 99 centres in North America from June 1999 through April 2001 . Patients : 2116 patients who were to undergo elective coronary intervention or were deemed at high likelihood of undergoing percutaneous coronary intervention were enrolled in the CREDO trial . The current study sample consisted of 272 patients with ECVD . Main outcome measure : One year incidence of the composite of death , myocardial infa rct ion , or stroke in the intent to treat population . Results : Patients with ECVD had a more than twofold greater relative risk reduction  with clopidogrel for the primary end point compared with patients without ECVD ( 47.9 % , 95 % confidence interval ( CI ) −4.2 % to 73.9 % , v 18.2 % , 95 % CI −10.5 % to 39.5 % , respectively ) . Conclusions : Longer term clopidogrel treatment provides added protection against thrombotic events throughout the arterial vasculature , not limited to the coronary arteries , and may be especially effective for patients with more diffuse atherosclerosis such as ECVD Aims : To evaluate the effects of treatments with clopidogrel plus aspirin ( dual therapy ) on early neurological deterioration ( END ) and outcomes at 6 months in patients with acute large artery atherosclerosis ( LAA ) stroke . Methods : A total of 574 patients with LAA stroke were r and omly assigned to receive either dual therapy or aspirin alone ( monotherapy ) . The primary outcome was END . Secondary outcomes included recurrent ischemic stroke ( RIS ) and outcomes at 6 months . Results : The prevalence of END and RIS was lower in patients on dual therapy than in those on monotherapy during the 30 days . At 6 months , dual therapy improved outcomes among older patients and those with symptomatic stenosis in the posterior circulation and basilar artery . Conclusion : Clopidogrel plus aspirin is superior to aspirin alone for reducing END and RIS within 30 days and improves outcomes in certain subgroups at 6 months Coronary artery bypass grafting is pivotal in the contemporary management of complex coronary artery disease . Interpatient variability to antiplatelet agents , however , harbors the potential to compromise the revascularization benefit by increasing the incidence of adverse events . This study was design ed to define the impact of dual antiplatelet therapy ( dAPT ) on clinical outcomes among aspirin-resistant patients who underwent coronary artery surgery .  We r and omly assigned 219 aspirin-resistant patients according to multiple electrode aggregometry to receive clopidogrel ( 75 mg ) plus aspirin ( 300 mg ) or aspirin-monotherapy ( 300 mg ) . The primary end point was a composite outcome of all-cause death , nonfatal myocardial infa rct ion , stroke , or cardiovascular hospitalization assessed at 6 months postoperatively . The primary end point occurred in 6 % of patients assigned to dAPT and 10 % of patients r and omized to aspirin-monotherapy ( relative risk 0.61 , 95 % confidence interval 0.25 to 1.51 , p = 0.33 ) . No significant treatment effect was noted in the occurrence of the safety end point . The total incidence of bleeding events was 25 % and 19 % in the dAPT and aspirin-monotherapy groups , respectively ( relative risk 1.34 , 95 % confidence interval 0.80 to 2.23 , p = 0.33 ) . In the subgroup analysis , dAPT led to lower rates of adverse events in patients with a body mass index > 30 kg/m(2 ) ( 0 % vs 18 % , p < 0.01 ) and those < 65 years ( 0 % vs 10 % , p = 0.02 ) . In conclusion , the addition of clopidogrel in patients found to be aspirin resistant after coronary artery bypass grafting did not reduce the incidence of adverse events , nor did it increase the number of recorded bleeding events . dAPT did , however , lower the incidence of the primary end point in obese patients and those < 65 years Abstract A hypercoagulable state has , in observational studies , been associated with increased risk of thromboembolic events . The aim of this trial was to study whether dual antiplatelet therapy ( DAPT ) with clopidogrel in addition to aspirin could reduce the rate of graft occlusions , thromboembolic events , and death compared to aspirin monotherapy in hypercoagulable patients undergoing coronary artery bypass surgery . A total of 1683 patients were screened for eligibility , among which 165 patients were r and omized and 133 patients underwent multislice computed tomography scan to evaluate their grafts .  Thrombelastography ( TEG ) and multiplate aggregometry  were performed before and after surgery , and again at three months follow up . TEG hypercoagulability was defined as the maximum amplitude above 69 mm . At three months follow up , 17 out of 66 ( 25.7 % ) DAPT patients and 15 of 67 ( 22.4 % ) aspirin patients had significant graft stenosis or occlusions ( p = 0.839 ) . Saphenous vein grafts ( SVGs ) were stenosed or occluded in 15 ( 22.7 % ) patients in the DAPT group and 7 ( 10.4 % ) in the aspirin group ( p = 0.167 ) . Thromboembolic events and death after the second postoperative day ( when clopidogrel was started ) were numerically , but not statistically , lower in the DAPT group , 3 ( 3.8 % ) vs. 8 ( 9.9 % ) , p = 0.211 . In univariate logistic regression analysis , only postoperative day 4 platelet response to aspirin measured with multiplate was correlated with graft occlusion , OR 1.020 [ 1.002–1.039 ] , p = 0.033 . This is the first trial to test the hypothesis of intensified antiplatelet therapy in hypercoagulable patients . Due to the low enrollment and high loss to follow up , our results can only be viewed as hypothesis generating . We found a high rate of graft occlusions in this patient population . Our results were not suggestive of that DAPT improved saphenous vein graft patency . A trend was observed in patients on DAPT toward fewer MI and deaths . Postoperative response to aspirin therapy was found to be associated with early SVG occlusion 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 Background — Uncertainty exists about the frequency , correlates , and clinical significance of bleeding with dual antiplatelet therapy ( DAPT ) , particularly over an extended period in a stable population . We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only ; identify correlates of bleeding ; and determine whether bleeding is associated with mortality . Methods and Results — We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management , and Avoidance ( CHARISMA ) trial , a double-blind , placebo-controlled , r and omized trial comparing long-term clopidogrel 75 mg/d versus placebo ;  all patients received aspirin ( 75 to 162 mg ) daily . Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease . Median follow-up was 28 months . Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries ( GUSTO ) criteria . Severe bleeding occurred in 1.7 % of the clopidogrel group versus 1.3 % on placebo ( P=0.087 ) ; moderate bleeding occurred in 2.1 % versus 1.3 % , respectively ( P<0.001 ) . The risk of bleeding was greatest the first year . Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter . The frequency of bleeding was similar in patients with established disease and risk factors only . In multivariable analysis , the relationship between moderate bleeding and all-cause mortality was strong ( hazard ratio , 2.55 ; 95 % confidence interval , 1.71 to 3.80 ; P<0.0001 ) , along with myocardial infa rct ion ( hazard ratio , 2.92 ; 95 % confidence interval , 2.04 to 4.18 ; P<0.0001 ) and stroke ( hazard ratio , 4.20 ; 95 % confidence interval , 3.05 to 5.77 ; P<0.0001 ) . Conclusions — In CHARISMA , there was an increased risk of bleeding with long-term clopidogrel . The incremental risk of bleeding was greatest in the first year and similar thereafter . Moderate bleeding was strongly associated with mortality . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00050817
target: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infa rct ion and ischaemic stroke , and an increased risk of major and minor bleeding compared with aspirin alone .
  According to GRADE criteria , the quality of evidence was moderate for all outcomes except all-cause mortality ( low quality evidence ) and adverse events ( very low quality evidence )
background: BACKGROUND Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease .
  Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease .
  This is an up date to a previously published review from 2011 .
  OBJECTIVES To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease , ischaemic cerebrovascular disease , peripheral arterial disease , or were at high risk of atherothrombotic disease , but did not have a coronary stent .