Clopidogrel added to aspirin versus aspirin alone in secondary prevention and high-risk primary prevention: rationale and design of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and transient ischemic attack. Aspirin to Prevent Cardiovascular Disease: The Association of Aspirin Dose and Clopidogrel With Thrombosis and Bleeding Extended Duration Dual Antiplatelet Therapy After Coronary Stenting Among Patients With Peripheral Arterial Disease: A Subanalysis of the Dual Antiplatelet Therapy Study. Rationale and design of the dual antiplatelet therapy study, a prospective, multicenter, randomized, double-blind trial to assess the effectiveness and safety of 12 versus 30 months of dual antiplatelet therapy in subjects undergoing percutaneous coronary intervention with either drug-eluting stent  Update on dual antiplatelet therapy for percutaneous coronary intervention A global view of atherothrombosis: baseline characteristics in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial. Aspirin resistance and diabetes mellitus Secondary prevention of vascular disease by prolonged antiplatelet treatment Efficacy and safety of 12 versus 48 months of dual antiplatelet therapy after implantation of a drug-eluting stent: the OPTImal DUAL antiplatelet therapy (OPTIDUAL) trial: study protocol for a randomized controlled trial Expert position paper on the management of antiplatelet therapy in patients undergoing coronary artery bypass graft surgery Cost-effectiveness of clopidogrel plus aspirin versus aspirin alone for secondary prevention of cardiovascular events: results from the CHARISMA trial. Enhanced antiplatelet effect of clopidogrel in patients whose platelets are least inhibited by aspirin: a randomized crossover trial. New antiplatelet therapies in development. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial Clopidogrel added to aspirin adds no benefit but bleeding risk in patients with recent lacunar stroke. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Platelet reactivity and cardiovascular events after percutaneous coronary intervention in patients with stable coronary artery disease: the Stent Thrombosis In Belgium (STIB) trial. Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial. Unstable angina, stroke, myocardial infarction and death in aspirin non‐responders. A prospective, randomized trial. The ASCET (ASpirin non‐responsiveness and Clopidogrel Endpoint Trial) design Impact of dual antiplatelet therapy on outcomes among aspirin-resistant patients following coronary artery bypass grafting. Clopidogrel as adjunctive antiplatelet therapy during coronary stenting. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance [CHARISMA] trial). Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial. High on-treatment platelet reactivity to both aspirin and clopidogrel is associated with the highest risk of adverse events following percutaneous coronary intervention Earlier application of loading doses of aspirin and clopidogrel decreases rate of recurrent cardiovascular ischemic events for patients undergoing percutaneous coronary intervention. Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention: Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance  An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial. Comparison of antiplatelet effect of loading dose of clopidogrel versus abciximab during coronary intervention 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. Benefit of switching dual antiplatelet therapy after acute coronary syndrome: the TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study Prophylactic Add-on Antiplatelet Therapy in Chronic Kidney Disease With Type 2 Diabetes Mellitus: Comparison Between Clopidogrel and Low-dose Aspirin The effectiveness and safety of dual antiplatelet therapy in ischemic cerebrovascular disease with intracranial and extracranial arteriostenosis in Chinese patients 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 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Clopidogrel with or without omeprazole in coronary artery disease. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. Short- Versus Long-Term Duration of Dual-Antiplatelet Therapy After Coronary Stenting: A Randomized Multicenter Trial Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study) A Cost-Effectiveness Analysis of Combination Antiplatelet Therapy for High-Risk Acute Coronary Syndromes: Clopidogrel plus Aspirin versus Aspirin Alone Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. Antithrombotic management and 1-year outcome of patients on oral anticoagulation undergoing coronary stent implantation (from the Registro Regionale Angioplastiche Emilia-Romagna Registry). Relation of genetic polymorphisms in the cytochrome P450 gene with clopidogrel resistance after drug-eluting stent implantation in Koreans. Incomplete Inhibition of Thromboxane Biosynthesis by Acetylsalicylic Acid: Determinants and Effect on Cardiovascular Risk Prevention of Bleeding in Patients With Atrial Fibrillation Undergoing PCI (PIONEER): Three May End Up Being a Crowd Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial Net Clinical Benefit of Adding Clopidogrel to Aspirin Therapy in Patients With Atrial Fibrillation for Whom Vitamin K Antagonists Are Unsuitable A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE) Clinical Relevance of Anticoagulation and Dual Antiplatelet Therapy to the Outcomes of Patients With Atrial Fibrillation and Recent Percutaneous Coronary Intervention With Stent Effect of Clopidogrel plus ASA vs. ASA Early after TIA and Ischaemic Stroke: A Substudy of the CHARISMA Trial Aspirin resistance in Indian patients with coronary artery disease and cardiovascular events. Aspirin prescription and outcomes in hemodialysis patients: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Bleeding Increases the Risk of Ischemic Events in Patients With Peripheral Arterial Disease The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events Duration of dual antiplatelet therapy after implantation of drug-eluting stents. Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial Aspirin for primary prevention: yes or no? Thrombin formation and platelet activation at the site of vascular injury in patients with coronary artery disease treated with clopidogrel combined with aspirin. A Randomised Controlled Trial of Triple Antiplatelet Therapy (Aspirin, Clopidogrel and Dipyridamole) in the Secondary Prevention of Stroke: Safety, Tolerability and Feasibility Glycoprotein IIb/IIIa inhibitors improve outcome after coronary stenting in clopidogrel nonresponders: a prospective, randomized study. Outcome of patients on oral anticoagulation undergoing coronary artery stenting: data from discharge to 12 months in the Warfarin and Coronary Stenting (WAR-STENT) Registry.
BACKGROUND Clopidogrel is a more potent antiplatelet agent than aspirin , result ing in greater clinical efficacy in patients with atherothrombotic disease . Furthermore , the combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin alone in the treatment of patients with acute coronary syndromes and after coronary stenting . Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention and secondary prevention is unknown . METHODS AND RESULTS The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management , and Avoidance ( CHARISMA ) study was design ed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established coronary , cerebral , or peripheral arterial disease or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event . This r and omized , international , multicenter , double-blinded , placebo-controlled study has finished enrolling patients worldwide . A total of 15,603 patients will be followed long term . The primary end point will be the composite of vascular death , myocardial infa rct ion , or stroke . Rates of severe bleeding will also be compared between the two arms of the study . CONCLUSIONS This large-scale trial of patients at high risk for atherothrombotic events will allow determination of the value of a strategy of adding clopidogrel to the current st and ard of care , including low-dose aspirin , for a wide spectrum of patients with atherothrombosis The American Heart Association/American Stroke Association ( AHA/ASA ) Writing Committee for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack ( TIA ) has review ed the results of recent trials that were published after our previous recommendations were issued.1 Our intention in the present statement is to provide a brief review of the new data , to up date specific recommendations , and to provide the reasons for any modifications . The 2 areas in which major new clinical trials have been published are ( 1 ) the use of specific antiplatelet agents for stroke prevention in patients with a history of noncardioembolic ischemic stroke or TIA and ( 2 ) the use of statins in the prevention of recurrent stroke . Recently published trials have added to the evidence of the benefit of the use of specific antiplatelet agents for stroke prevention in patients with a history of noncardioembolic ischemic stroke or TIA . The secondary prevention guidelines 1 have been up date d to reflect this new evidence . # # # Addition of Clopidogrel to Aspirin for Prevention of Vascular Events The Clopidogrel and Aspirin Versus Aspirin Alone for the Prevention of Atherothrombotic Events ( CHARISMA ) trial2 was a double-blinded study that r and omized 15 603 subjects with cardiovascular disease or multiple risk factors for cardiovascular disease to either clopidogrel 75 mg plus low-dose aspirin ( 75 to 162 mg ) or placebo plus aspirin ( 75 to 162 mg ) . Roughly 35 % of subjects ( n=4320 ) qualified on the basis of the presence of cerebrovascular disease within 5 years of enrollment ; approximately a third experienced TIA . The median follow-up was 28 months . No significant differences were seen in the rates of nonfatal ischemic stroke between the 2 groups ( 1.7 % versus 2.1 % , P = 0.07 ) . The placebo plus aspirin group showed a higher rate of nonfatal stroke than did the clopidogrel group ( 1.9 % versus 2.4 % , P = 0.03 ) . The 2 groups experienced no differences in the rate of intracerebral hemorrhage 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 OBJECTIVES This study sought to determine whether patients with peripheral arterial disease ( PAD ) experience different reductions in ischemic event and increases in bleeding events with extended duration dual antiplatelet therapy versus those without PAD . BACKGROUND Patients with PAD have increased ischemic and bleeding risks after coronary stenting . METHODS The DAPT ( Dual Antiplatelet Therapy ) study r and omized 11,648 patients free from ischemic and bleeding events 12 months after coronary stenting to continued thienopyridine plus aspirin therapy for an additional 18 months versus aspirin therapy alone . The effects of continued thienopyridine on myocardial infa rct ion ( MI ) or stent thrombosis , major adverse cardiovascular and cerebrovascular events ( death , MI , or stroke ) and bleeding ( GUSTO [ Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries ] moderate or severe ) were assessed among those with versus without PAD . RESULTS Among 11,648 r and omized patients , 649 ( 5.57 % ) had PAD . Between 12 and 30 months , r and omized patients with PAD had higher rates of MI/stent thrombosis ( 6.03 % vs. 2.92 % ; p < 0.001 ) , major adverse cardiovascular and cerebrovascular events ( 11.65 % vs. 4.62 % ; p < 0.001 ) , and bleeding ( 4.86 % vs. 1.74 % ; p < 0.001 ) . Continued thienopyridine versus placebo was associated with consistent treatment effects for MI/stent thrombosis ( with PAD , HR : 0.63 ; 95 % CI : 0.32 to 1.22 ; without PAD , HR : 0.53 ; 95 % CI : 0.42 , 0.66 ; interaction p = 0.631 ) , major adverse cardiovascular and cerebrovascular events ( with PAD , HR : 1.06 ; 95 % CI : 0.67 to 1.67 ; without PAD , HR : 0.70 ; 95 % CI : 0.59 to 0.84 ; interaction p = 0.103 ) , and bleeding ( with PAD , HR , 1.82 ; 95 % CI : 0.87 to 3.83 ; without PAD , HR : 1.66 ; 95 % CI : 1.23 to 2.24 ; interaction p = 0.811 ) . CONCLUSIONS Among patients undergoing coronary stenting , those with PAD have more ischemic and bleeding events versus those without PAD . Extended duration dual antiplatelet therapy is associated with consistent ischemic benefit and bleeding harm among patients with and without PAD BACKGROUND Dual antiplatelet therapy with aspirin and thienopyridines ( clopidogrel or prasugrel ) is required after placement of coronary stents to prevent thrombotic complications . Although current clinical practice guidelines recommend 12-month treatment after drug-eluting stent placement , even longer duration s may prevent thrombotic events . STUDY DESIGN The Dual Antiplatelet Therapy ( DAPT ) Study is comparing the benefits and risks of 12 versus 30 months of dual antiplatelet therapy in preventing stent thrombosis or major adverse cardiovascular and cerebrovascular events in subjects undergoing percutaneous coronary intervention ( PCI ) for the treatment of coronary artery obstructive lesions . The DAPT Study is a multicenter , international , r and omized , double-blind , placebo-controlled trial that will enroll 15,245 subjects treated with drug-eluting stent ( DES ) and 5,400 subjects treated with bare-metal stents ( BMS ) .  All subjects will receive 12 months of open-label thienopyridine treatment in addition to aspirin . After 12 months , subjects who are free from death , myocardial infa rct ion , or stroke ( MACCE ) , repeat revascularization , and GUSTO ( Global Use of Strategies to Open Occluded Coronary Arteries ) moderate or severe bleeding events will be r and omized to receive either 18 additional months of thienopyridine ( clopidogrel or prasugrel ) ( 30 month DAPT arm ) or placebo ( 12 month DAPT arm ) plus aspirin . Co primary end points are MACCE and stent thrombosis . The primary safety end point is GUSTO moderate or severe bleeding . CONCLUSIONS This r and omized trial is design ed to define the relative safety and effectiveness of 12 versus 30 months of dual antiplatelet therapy across the broad spectrum of patients receiving coronary stents Platelet activation is central in the vascular response to percutaneous coronary intervention ( PCI ) . In addition , patients with coronary artery disease ( CAD ) , particularly those with an acute coronary syndrome ( ACS ) , have pre-existing platelet hyper-reactivity . Together , these are among the factors that predispose to stent thrombosis ( ST ) . Thus , dual antiplatelet therapy ( DAT ) , which consists of aspirin and a thienopyridine , forms the cornerstone of pharmacotherapy following PCI with the goal of reducing ST , as well as ischaemic events related to the underlying CAD . Adherence to DAT , and the need for a longer duration of treatment , has become even more important for patients receiving drug-eluting stents ( DES ) , as concerns have been raised regarding the increased risk of very late ST ( > 1 year ) with the current generation of stents.1 Table 1 summarises the most recent guidelines on DAT following PCI which have been jointly published by the American College of Cardiology ( ACC ) , American Heart Association ( AHA ) and Society for Cardiovascular Angiography and Interventions (SCAI).2 3 Despite the routine use of clopidogrel , there is uncertainty about the optimal timing , dose and duration of thienopyridine therapy , and there is a lack of consensus on the management of patients requiring non-cardiac surgery or chronic anticoagulation while being treated with DAT . View this table : Table 1 ACC/AHA/SCAI recommendations for the use of antiplatelet agents in patients requiring PCI2 3 Although current practice in many parts of the world is to administer clopidogrel in the catheterisation laboratory at the time of ad hoc PCI , several clinical trials have evaluated the efficacy of pretreatment ( table 2).4–8 Overall , the data suggest a potential benefit of pretreatment with the 300 mg loading dose , though both PCI-CURE and PCI-CLARITY represent analyses in which the decision to perform PCI was made after r and omisation to the two loading strategies . It appears that a 300 mg clopidogrel loading dose needs to be administered at least 6 h prior to BACKGROUND The manifestations of atherothrombosis such as myocardial infa rct ion , ischemic stroke , limb ischemia , or cardiovascular death pose a global health care burden . Additional therapies to decrease ischemic events in patients with established vascular disease or at risk for developing vascular disease are necessary . We sought to characterize the risk factors and treatments of a diverse contemporary population of patients with atherothrombosis . METHODS The CHARISMA trial has enrolled 15,603 patients from around the world . Patients with established coronary , cerebrovascular , or peripheral arterial disease , or those at high risk of developing atherothrombosis due to multiple risk factors , have been r and omized to receive either the adenosine diphosphate receptor antagonist clopidogrel or placebo , in addition to background therapy with low- to moderate-dose aspirin . RESULTS A high percentage of enrolled patients are being treated with statins and angiotensin-converting enzyme inhibitors . In the CHARISMA population , a total of 75.6 % of the population had an abnormal body mass index : 42.2 % were overweight and 33.4 % were obese , with particularly high rates in the United States , especially of morbid obesity . Correspondingly , the prevalence of diabetes was 42 % . CONCLUSION The CHARISMA trial will further characterize atherothrombosis and provide insight into the role of dual antiplatelet therapy in improving outcomes in patients with multiple risk factors or established vascular disease . Of note , the rates of obesity and diabetes in patients with atherothrombosis throughout the world are particularly alarming Despite multiple interventions to reduce the risk of cardiovascular disease , the majority of people with diabetes develop macrovascular complications , and mortality following myocardial infa rct ion remains unacceptably high [ 1 ] . Antiplatelet agents are used for both the primary and secondary prevention of cardiovascular disease , although current guidelines are not consistent in their recommendation for the use of aspirin in diabetes [ 2 ] . In fact , there is little direct evidence supporting its efficacy in this group of patients . Instead , there is convincing data in the literature to suggest inadequate cardiovascular protection by aspirin in diabetes . In a meta- analysis of 287 r and omised trials , antiplatelet treatment ( aspirin in most studies ) reduced the risk of ischaemic events by 22 % , but the risk reduction in the subgroup with diabetes was only 7 % , which was not statistically significant [ 3 ] . This outcome was mirrored in the Primary Prevention Project trial , which reported that cardiovascular risk reduction with aspirin was marginal and non-significant in the presence of diabetes [ 4 ] . Despite this , there are no published studies specifically design ed to evaluate the clinical efficacy of aspirin in individuals with diabetes , a surprising omission in the era of ‘ evidence based ’ medicine . These findings from clinical trials raise the question as to why there should be a reduction in the clinical efficacy of  aspirin  in patients with diabetes compared with a nondiabetic population . Diabetes is intrinsically associated with particular biochemical abnormalities that may have the capacity to diminish the effects of aspirin on platelet function and cardiovascular risk — a possibility that has led to the hotly debated concept of aspirin resistance [ 5 , 6 ] . Unfortunately , aspirin resistance suffers from a lack of a st and ardised definition , although now generally thought of as either ( 1 ) reflecting clinical aspirin resistance ( or perhaps , more accurately , treatment failure ) , characterised by the occurrence of a thrombotic episode despite treatment with aspirin ; or ( 2 ) biochemical aspirin resistance where platelet responses persist despite platelet exposure to aspirin . Controversy remains as to the cause of biochemical aspirin resistance , its relevance to clinical outcomes , and the place of aspirin treatment in the management of cardiovascular risk in diabetes patients . All of this highlights the urgent need to underst and the mechanisms that underpin the interactions between diabetes and aspirin , to establish the role of aspirin in particular , and antiplatelet therapy in general , in the amelioration of cardiovascular events in individuals with diabetes . Diabetologia ( 2008 ) 51:385–390 DOI 10.1007/s00125 - 007 - 0898 - Thirty one r and omised trials of antiplatelet treatment for patients with a history of transient ischaemic attack , occlusive stroke , unstable angina , or myocardial infa rct ion were identified . Six were still in progress , and the results of the remaining 25 were review ed . They included a total of some 29 000 patients , 3000 of whom had died . Overall , allocation to antiplatelet treatment had no apparent effect on non-vascular mortality but reduced vascular mortality by 15 % ( SD 4 % ) and non-fatal vascular events ( stroke or myocardial infa rct ion ) by 30 % ( 4 % ) . This suggested that with good compliance these treatments might reduce vascular mortality by about one sixth , other vascular events by about a third , and total vascular events by about a quarter . There was no significant difference between the effects of the different types of  antiplatelet treatment tested ( 300 - 325 mg aspirin daily , higher aspirin doses , sulphinpyrazone , or high dose aspirin with dipyridamole ) , nor between the effects in patients with histories of cerebral or cardiac disease . Thus antiplatelet treatment can reduce the incidence of serious vascular events by about a quarter among a wide range of patients at particular risk of occlusive vascular disease . The balance of risk and benefit , however , might be different for “ primary ” prevention among people at low absolute risk of occlusive disease if antiplatelet treatment produced even a small increase in the incidence of cerebral haemorrhage Background Dual antiplatelet therapy with aspirin and thienopyridine is required after placement of coronary drug-eluting stents ( DES ) to prevent thrombotic complications . Current clinical guidelines recommend at least 6 to 12 months of treatment after a DES implantation , but it may be beneficial to apply dual antiplatelet therapy for a longer duration . Methods / design The optimal dual antiplatelet therapy ( OPTIDUAL ) study aims to compare the benefits and risks of dual antiplatelet therapy applied for either 12 or 48 months . We will examine the occurrence of major adverse cardiovascular and cerebrovascular events ( MACCE ) in patients undergoing percutaneous coronary intervention with DES for the treatment of coronary lesions . The OPTIDUAL study is an open-label multicenter , r and omized , national trial that will include 1,966 patients treated with DES . All patients will be treated with dual antiplatelet therapy for 12 months ( + /− 3 ) . Then , patients with no MACCE or major bleeding will be r and omized to receive either 36 additional months of clopidogrel plus aspirin or aspirin only . The primary end-point is the combination of death from all causes , myocardial infa rct ion , stroke and major bleeding . The secondary end points include the individual components of the primary end-point , stent thrombosis , repeat revascularization of the treated vessel and minor bleeding . Discussion This r and omized trial is design ed to assess the benefits and safety of 12 versus 48 months of dual antiplatelet therapy in patients that receive a DES . We aim to determine whether substantial prolongation of clopidogrel ( a thienopyridine ) after DES implantation offers an advantage over its discontinuation . Trial registration Clinical Trials.gov Identifier : Coronary artery bypass grafting (CABG)-related bleeding complications and perioperative coronary events are strongly influenced by the management of antithrombotic therapy before and after CABG . Bleeding but also blood products transfusion increase the risk of death and compromise the long-term benefits of CABG.1 The use of new P2Y12 inhibitors , increasing pre-CABG percutaneous coronary interventions ( PCI ) with drug eluting stents ( DES ) requiring specific antiplatelet regimens , and advances in surgical technique has prompted the ESC Working Group on Cardiovascular Surgery and the ESC Working Group on Thrombosis to review the evidence of peri-CABG recommendations on antithrombotic management . Due to the paucity of r and omized trials , most of the evidence is still derived from observational studies and expert consensus , further reinforcing the importance of a multidisciplinary consultation for optimal decision making . # # # Benefits of preoperative aspirin Aspirin ( acetylsalicylic acid , ASA ) is recommended as secondary prevention therapy for all patients with proven coronary artery disease ( CAD ) and without contraindications . Its indication is even stronger for post-CABG patients ( recommendation IA).2 The general consensus is that ASA treatment withdrawal has ominous prognostic implication s in patients with CAD , especially in those with intracoronary stents , and should be advocated only when the bleeding risk clearly outweighs that of atherothrombotic events.3 The benefits of continuing ASA until the day of CABG ( ‘ preoperative ASA ’ ) are less clear and may explain the wide variability in the management of ASA therapy in the perioperative period and differences between guidelines endorsed by different professional and scientific societies ( Supplementary material online , Table S1 ) . This was based on the demonstration that ASA started the day before surgery was no more effective than ASA started 6 h after surgery at improving early ( 7- to 10-day ) graft patency , but was associated with increased bleeding complications.4 More recent evidence suggests , however , that ASA use within 5–7 days prior to CABG OBJECTIVE To determine the incremental cost-effectiveness of clopidogrel plus aspirin ( C + A ) compared with aspirin ( A ) alone during the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ( CHARISMA ) trial from a US payer perspective . BACKGROUND Although the CHARISMA trial did not find a benefit of adding clopidogrel to aspirin in its overall study cohort , a benefit was suggested in a prespecified subgroup of patients with established cardiovascular ( CV ) disease . The cost-effectiveness of dual antiplatelet therapy in this population is unknown . METHODS Medical re source utilization was assessed prospect ively , and costs for hospitalizations , physician services , outpatient care , and medications were assigned using 2007 US dollars . Life expectancy was estimated contingent on fatal and nonfatal CV events using statistical models of long-term survival from the Saskatchewan Health data base . RESULTS C + A was associated with a 12.5 % relative reduction in CV death , myocardial infa rct ion , or stroke compared with A alone ( 6.9 % vs. 7.9 % , P = 0.048 ) over a median 28 months of follow-up . Severe or moderate bleeding events were higher in patients receiving C + A versus A alone ( 3.6 % vs. 2.5 % , P < 0.001 ) . Mean cost/patient was $ 2607 higher for C + A , while projected life expectancy increased by an average of 0.072 years due to fewer in-trial events . The result ing incremental cost-effectiveness ratio ( ICER ) for C + A was $ 36,343/year of life gained . Findings were insensitive to discount rate , life expectancy projections , post-event costs , and indirect costs from lost productivity ; the ICER was most sensitive to the cost of clopidogrel . Bootstrap analysis demonstrated that the ICER for C + A remained < $ 50,000/life-year gained in 70.6 % of bootstrap replicates and < $ 100,000/life-year gained in 87.4 % . CONCLUSIONS Among patients with established CV disease , adding clopidogrel to aspirin appears to increase life expectancy modestly at a cost generally considered acceptable within the US health-care system OBJECTIVE We aim ed to determine whether adding clopidogrel to aspirin in patients at high risk of future cardiovascular events would suppress laboratory measures of the antiplatelet effects of aspirin ; and have greater platelet inhibitory effects in patients with the least inhibition of platelets by aspirin . METHODS We performed a r and omized , double-blind , placebo-controlled , crossover trial , comparing clopidogrel 75 mg day(-1 ) versus placebo , in 36 aspirin-treated patients with symptomatic objective ly confirmed peripheral arterial disease . RESULTS The addition of clopidogrel to aspirin did not suppress platelet aggregation induced by arachidonic acid , urinary 11 dehydro thromboxane B2 concentrations , or soluble markers of platelet activation markers ( P-selectin , CD40-lig and ) and inflammation ( high sensitivity serum C-reactive protein , interleukin-6 ) . Clopidogrel significantly inhibited platelet aggregation induced by ADP ( reduction 26.2 % ; 95 % CI : 21.3 - 31.1 % , P < 0.0001 ) and collagen ( reduction 6.2 % ; 95 % CI : 3.2 - 9.3 % , P = 0.0003 ) . The greatest inhibition of collagen-induced platelet aggregation by clopidogrel was seen in patients with the least inhibition of arachidonic acid induced aggregation by aspirin [ lower tertile of arachidonic acid-induced platelet aggregation : 2.8 % ( 95 % CI : -0.8 to 6.3 % ) reduction in mean collagen-induced aggregation by clopidogrel ; middle tertile : 4.0 % ( 95 % CI : 0.4 - 7.6 % ) ; upper tertile 12.6 % ( 95 % CI : 4.5 - 20.8 % ) ; P-value for interaction 0.01 ] . CONCLUSIONS The greatest platelet inhibitory effect of clopidogrel occurs in patients with the least inhibition of arachidonic acid-induced platelet aggregation by aspirin . This raises the possibility that the clinical benefits of adding clopidogrel to aspirin may be greatest in patients whose platelets are least inhibited by aspirin . Confirmation in clinical outcome studies may allow these patients to be targeted with antiplatelet drugs that inhibit the ADP receptor , thereby overcoming the problem of laboratory aspirin resistance PURPOSE The efficacy and safety of new antiplatelet therapies , as well as antiplatelet therapies in development , are review ed . SUMMARY Variability in the response to treatment with aspirin has been recognized for more than 40 years . Thienopyridine antiplatelet agents are now a st and ard pharmacologic component in the management of patients undergoing percutaneous coronary intervention ( PCI ) and stent placement . However , investigators have recently described wide inter-individual variability in the level of platelet inhibition following treatment with the thienopyridine clopidogrel , with a small number of patients classified as " non-responders " or " resistant . " Such variability in response is likely to have important clinical implication s , because antiplatelet therapy plays a key role in the prevention and treatment of cardiovascular disease , For example , recent studies have demonstrated that diminished response to clopidogrel may be associated with increased cardiac events after PCI . Even with larger-than-approved loading doses , clopidogrel requires several hours to reach a steady-state effect , and therapy must be discontinued for several days prior to surgery in order to avoid major bleeding events . Clinical trials of prasugrel , a new oral thienopyridine with a more rapid onset of platelet inhibition , have demonstrated significant reductions in adverse cardiovascular outcomes and stent thrombosis ; however , there is an increased risk for major bleeding events with prasugrel in some subgroups of the study population s. These limitations have led to development of agents that may potentially overcome such clinical challenges . AZD6140 , a novel , potent oral P2Y12 antagonist , demonstrated more effective platelet inhibition versus clopidogrel in a large r and omized trial of patients with acute coronary syndrome . However , patients taking AZD6140  reported dyspnea significantly more frequently than those taking clopidogrel . Cangrelor , a novel intravenous P2Y(12 ) receptor antagonist with a rapid onset of action and complete reversibility of platelet inhibition within 20 - 50 minutes of administration , may offer advantages over currently approved antiplatelet therapies . A new oral antiplatelet thrombin-receptor antagonist , TRA-SCH 530348 , is in early clinical trials . Unlike currently available drugs , TRA-SCH 530348 effectively prevents thrombin-induced activation of platelets . CONCLUSION Each new class of antiplatelet therapies has the potential for specific benefits and adverse effects in clinical use BACKGROUND Dual antiplatelet therapy is recommended after coronary stenting to prevent thrombotic complications , yet the benefits and risks of treatment beyond 1 year are uncertain . METHODS Patients were enrolled after they had undergone a coronary stent procedure in which a drug-eluting stent was placed . After 12 months of treatment with a thienopyridine drug ( clopidogrel or prasugrel ) and aspirin , patients were r and omly assigned to continue receiving thienopyridine treatment or to receive placebo for another 18 months ; all patients continued receiving aspirin . The co primary efficacy end points were stent thrombosis and major adverse cardiovascular and cerebrovascular events ( a composite of death , myocardial infa rct ion , or stroke ) during the period from 12 to 30 months . The primary safety end point was moderate or severe bleeding . RESULTS A total of 9961 patients were r and omly assigned to continue thienopyridine treatment or to receive placebo . Continued treatment with thienopyridine , as compared with placebo , reduced the rates of stent thrombosis ( 0.4 % vs. 1.4 % ; hazard ratio , 0.29 [ 95 % confidence interval { CI } , 0.17 to 0.48 ] ; P<0.001 ) and major adverse cardiovascular and cerebrovascular events ( 4.3 % vs. 5.9 % ; hazard ratio , 0.71 [ 95 % CI , 0.59 to 0.85 ] ; P<0.001 ) . The rate of myocardial infa rct ion was lower with thienopyridine treatment than with placebo ( 2.1 % vs. 4.1 % ; hazard ratio , 0.47 ; P<0.001 ) . The rate of death from any cause was 2.0 % in the group that continued thienopyridine therapy and 1.5 % in the placebo group ( hazard ratio , 1.36 [ 95 % CI , 1.00 to 1.85 ] ; P=0.05 ) . The rate of moderate or severe bleeding was increased with continued thienopyridine treatment ( 2.5 % vs. 1.6 % , P=0.001 ) . An elevated risk of stent thrombosis and myocardial infa rct ion was observed in both groups during the 3 months after discontinuation of thienopyridine treatment . CONCLUSIONS Dual antiplatelet therapy beyond 1 year after placement of a drug-eluting stent , as compared with aspirin therapy alone , significantly reduced the risks of stent thrombosis and major adverse cardiovascular and cerebrovascular events but was associated with an increased risk of bleeding . ( Funded by a consortium of eight device and drug manufacturers and others ; DAPT Clinical Trials.gov number , NCT00977938 . ) BACKGROUND 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 Patients with transient ischemic attack or ischemic stroke have a high risk of recurrent stroke .  Antiplatelet therapy has shown efficacy in secondary stroke prevention and is recommended by guidelines .1–3 In patients without cardiac source of embolism  aspirin , clopidogrel or the combination of aspirin and dipyridamole is recommended . In cardiology , the combination of aspirin and clopidogrel was superior to aspirin monotherapy in the prevention of vascular events after acute coronary syndrome4 but carried a higher bleeding risk . In patients with atrial fibrillation the combination of aspirin plus clopidogrel was superior to aspirin alone in preventing strokes,5 but was again associated with a significant higher risk of major bleeds . In early secondary stroke prevention after transient ischemic attack or minor stroke combination , antiplatelet therapy seems to be superior to monotherapy , but larger r and omized trials are needed.6,7 Combination antiplatelet therapy carries a consistent higher risk of major bleeding complications than monotherapy . Therefore , the possible benefit of a reduction in vascular events has to be balanced against the bleeding risk , especially in stroke patients . In the Management of Atherothrombosis with Clopidogrel in High-risk patients ( MATCH ) trial , aspirin plus clopidogrel was investigated against aspirin monotherapy in high-risk patients with recent transient ischemic attack or ischemic stroke.8 Similar to the Secondary Prevention of Small Subcortical Strokes ( SPS3 ) trial , patients with a cardiac source of embolism and significant carotid stenosis requiring surgery were excluded . About 50 % of patients were categorized to have small vessel disease with suspected lacunar strokes , but in contrast to the SPS3 trial , OBJECTIVE We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes . RESEARCH DESIGN AND METHODS The Primary Prevention Project ( PPP ) is a r and omized , open trial with a two-by-two factorial design aim ed to investigate low-dose aspirin ( 100 mg/day ) and vitamin E ( 300 mg/day ) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors . The primary end point was a composite end point of cardiovascular death , stroke , or myocardial infa rct ion . A total of 1,031 people with diabetes in the PPP , aged > /=50 years , without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics . RESULTS The PPP trial was prematurely stopped ( after a median of 3.7 years ) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors . In diabetic patients , aspirin treatment was associated with a nonsignificant reduction in the main end point ( relative risk [ RR ] = 0.90 , 95 % CI 0.50 - 1.62 ) and in total cardiovascular events ( 0.89 , 0.62 - 1.26 ) and with a nonsignificant increase in cardiovascular deaths ( 1.23 , 0.69 - 2.19 ) . In nondiabetic subjects , RRs for the main end point , total cardiovascular events , and cardiovascular deaths were 0.59 ( 0.37 - 0.94 ) , 0.69 ( 0.53 - 0.90 ) , and 0.32 ( 0.14 - 0.72 ) , respectively . No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects . CONCLUSIONS Our data suggest a lower effect of primary prevention of cardiovascular disease ( CVD ) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors . If confirmed , these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation , thus making the balance between benefits and harms of aspirin treatment unfavorable . Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed AIMS The Stent Thrombosis In Belgium ( STIB ) trial aim ed to determine whether assessing platelet reactivity ( PR ) in patients with stable coronary artery disease undergoing elective percutaneous coronary intervention ( PCI ) could predict the risk of ischaemic complications and adverse clinical events up to 30 days post PCI . METHODS AND RESULTS PR before intervention was determined in 891 patients undergoing PCI for stable angina pectoris . Twelve to 24 hours before PCI , all patients received a 600 mg clopidogrel dose followed by 75 mg daily , and 500 mg of aspirin followed by 80 - 100 mg daily . Residual PR was assessed by  VerifyNow point-of-care aspirin and P2Y12 assay before PCI . " Non-responders " to antiplatelet therapy were defined as aspirin reaction unit ( ARU ) > 550 and as P2Y12 reaction unit ( PRU ) > 230 . The endpoint of the study was the composite of periprocedural myonecrosis , stent thrombosis , non-fatal myocardial infa rct ion ( MI ) , stroke and death at 30 days in patients with or without high PR . The endpoint was observed in 180 patients : four deaths , one stroke , 11 Q-wave MI , three non-Q-wave MI and 161 periprocedural myonecroses . At multivariate analysis , the endpoint was predicted by total stent length ( OR : 1.020 ) , GFR < 60 ml/min ( OR : 1.87 ) , history of PCI ( OR : 0.58 ) , white blood cell count ( OR : 1.95 ) and diabetes ( OR : 1.83 ) . No significant association was found between residual PR and the primary endpoint or any of its components . CONCLUSIONS PR measured before PCI in stable patients undergoing elective PCI who are preloaded with 500 mg of aspirin and 600 mg of clopidogrel is not predictive of periprocedural myocardial injury or adverse ischaemic complications up to 30 days BACKGROUND Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke , data in peripheral artery disease ( PAD ) are less compelling . Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD , whereas clopidogrel monotherapy may be more effective in PAD . Ticagrelor , a potent , reversibly binding P2Y12 receptor antagonist , is beneficial in patients with acute coronary syndrome and prior myocardial infa rct ion . The EUCLID trial is design ed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events . STUDY DESIGN EUCLID is a r and omized , double-blind , parallel-group , multinational clinical trial design ed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD . Subjects with established PAD will be r and omized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily . The primary end point is a composite of cardiovascular death , myocardial infa rct ion , or ischemic stroke . Other end points address limb events including acute leg ischemia , need for revascularization , disease progression by ankle-brachial index , and quality of life . The primary safety objective is Thrombolysis in Myocardial Infa rct ion-defined major bleeding .  Recruitment began in December 2012 and was completed in March 2014 ; 13,887 patients were r and omized . The trial will continue until at least 1,364 adjudicated primary end points occur . CONCLUSIONS The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel , given as antiplatelet monotherapy , will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD Background —Aspirin is widely used as an antiplatelet drug in patients with coronary heart disease . Despite documented clinical benefit , many patients on aspirin  still experience severe cardiovascular events . Several laboratory reports have shown lack of platelet inhibition in 5–40 % of aspirin‐treated patients , and the term aspirin resistance has been introduced . The clinical relevance of these laboratory findings is , however , still unknown . New antiplatelet drugs have been developed , and the adenosin diphosphate ( ADP ) receptor inhibitor clopidogrel has at least the same efficacy as aspirin with an acceptable safety profile . Laboratory methods for determination of platelet reactivity and treatment efficacy have been complicated and time consuming . New method ologies , like the PFA‐100 ® system , have made such analyses more suitable for clinical use . Design —In the ASCET study , 1000 patients with documented coronary heart disease will be r and omized to either continued treatment with aspirin 160 mg/d or change to clopidogrel 75 mg/d after initial determination of their platelet reactivity while on aspirin treatment . Clinical endpoints will be recorded for at least 2 years and related to the initial aspirin response 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 OBJECTIVES We examined the procedural and 30-day clinical outcomes among patients receiving aspirin and either ticlopidine or clopidogrel during coronary stenting . BACKGROUND Ticlopidine-plus-aspirin has become st and ard antiplatelet therapy for the prevention of thrombotic complications after coronary stenting . Clopidogrel has a similar mechanism of action as ticlopidine , but both its efficacy and its safety as a pharmacologic adjunct to coronary stenting have not been well described . METHODS This single-center , prospect i ve analysis examined the in-hospital procedural and 30-day clinical outcomes among 875 consecutive patients undergoing coronary stenting who received adjunctive aspirin and either clopidogrel ( n = 514 ; 58.7 % ) or ticlopidine ( n = 361 ; 41.3 % ) therapy . RESULTS Procedural success rates were similar among the clopidogrel- ( 99.6 % ) and ticlopidine-treated patients ( 99.4 % ) . Subacute stent thrombosis ( i.e. , > 24 h < or = 30 days ) occurred in one clopidogrel-treated ( 0.2 % ) and in one ticlopidine-treated ( 0.3 % ) patient ( p = 0.99 ) . By 30 days following the index procedure , the combined rates of death , nonfatal myocardial infa rct ion and need for target vessel revascularization were similar among patients who received either clopidogrel ( 2.1 % ) or ticlopidine ( 1.4 % ; p = 0.57 ) therapy . CONCLUSIONS In this analysis the antiplatelet combination therapy of aspirin-plus-clopidogrel was an effective regimen for preventing thrombotic complications and major adverse cardiovascular events among a broad spectrum of patients undergoing coronary artery stenting 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 . ) No prospect i ve r and omized trial has specifically examined the long-term outcomes of clopidogrel use in patients with chronic kidney disease . This study aim ed to determine the risks and benefits of long-term clopidogrel administration in patients with diabetic nephropathy , the most common form of chronic kidney disease . We performed a post hoc analysis of the CHARISMA trial , which r and omly assigned patients without active acute coronary syndrome , but with established atherosclerotic disease ( symptomatic ) or multiple risk factors for atherosclerotic disease ( asymptomatic ) , to clopidogrel plus aspirin versus placebo plus aspirin .  All CHARISMA patients ( n = 15,603 ) were separated into the 3 groups : nondiabetic patients , diabetic patients without nephropathy , and diabetic patients with nephropathy . Within each group , outcomes of patients r and omly assigned to clopidogrel were compared with those of patients r and omly assigned to placebo . Outcomes in the prespecified CHARISMA subgroups of asymptomatic and symptomatic patients were also compared with respect to study drug assignment and nephropathy status . Patients with nephropathy who received clopidogrel had no difference in bleeding , but experienced significantly increased cardiovascular ( CV ) and overall mortality compared with those r and omly assigned to placebo . There were no differences in bleeding , overall mortality , or CV mortality for nondiabetic or diabetic patients without nephropathy who received clopidogrel versus placebo . In the asymptomatic cohort , patients with nephropathy r and omly assigned to clopidogrel had significantly increased overall and CV mortality compared with placebo , whereas asymptomatic patients without nephropathy r and omly assigned to clopidogrel had no significant mortality difference compared with placebo . In conclusion , this post hoc analysis suggested that clopidogrel may be harmful in patients with diabetic nephropathy . Additional studies are needed to investigate this possible interaction Statin interference has been suggested among the mechanisms of reduction of the antiplatelet effect of clopidogrel . We thus sought to assess the influence of rosuvastatin on clopidogrel antiplatelet action in high-risk ( HR ) cardiovascular patients . To set the level of platelet inhibition by combined antithrombotic treatments we retrospectively studied two population s of HR patients , one under aspirin alone , the other under aspirin plus rosuvastatin , before and after addition of clopidogrel .  The effects of rosuvastatin compared with atorvastatin were then prospect ively investigated in patients who underwent percutaneous coronary intervention ( PCI ) , under clopidogrel  and  aspirin  treatment . Light transmission platelet aggregation ( LTA ) was studied in response to adenosine diphosphate ( ADP ) ( 5 μM ) or arachidonic acid ( 0.5 mM ) . The inhibitory effect of clopidogrel in reducing ADP-induced LTA was similar in the two HR groups of patients . No difference in ADP-induced platelet aggregation was observed in the two PCI groups of patients with either atorvastatin or rosuvastatin . In conclusion , rosuvastatin does not interfere with the antiplatelet effect of clopidogrel in patients with cardiovascular disease BACKGROUND AND OBJECTIVES Low response to antiplatelet therapy may be a risk factor for the development of ischemic complications in patients with non-ST segment elevation acute coronary syndrome ( NSTE ACS ) undergoing coronary stenting . METHODS We prospect ively studied the platelet response to both clopidogrel and aspirin in 106 NSTE ACS consecutive patients undergoing percutaneous coronary intervention ( PCI ) with stenting .  A single post-treatment blood sample was obtained just before PCI and analyzed by platelet aggregometry using both ADP and arachidonic acid ( AA ) as agonists to explore the responses to clopidogrel and aspirin , respectively . Patients were divided into quartiles according to the ADP or AA induced maximal intensity of platelet aggregation . Patients of the highest quartile ( quartile 4 ) were defined as the ' low-responders ' . RESULTS Twelve recurrent cardiovascular ( CV ) events occurred during the 1-month follow-up . Clinical outcome was significantly associated with platelet response to clopidogrel [ Quartile 4 vs. 1 , 2 , 3 : OR ( 95 % CI ) 22.4 ( 4.6 - 109 ) ] . Low platelet response to aspirin  was significantly correlated with clopidogrel low response ( P = 0.003 ) but contributed less to CV events [ OR ( 95%CI ) : 5.76 ( 1.54 - 35.61 ) ] . CONCLUSIONS A post-treatment ADP-induced platelet aggregation performed just before PCI identifies low responders to dual antiplatelet therapy with an increased risk of recurrent CV events BACKGROUND Platelets play a key role in the pathogenesis of atherosclerosis , thrombosis , and acute coronary and cerebrovascular syndromes . Inhibition of platelet function by acetylsalicylic acid ( aspirin ) has been shown to reduce the incidence atherothrombotic events in patients with coronary , cerebrovascular , or peripheral vascular disease .  Thienopyridine agents , however , including ticlopidine and clopidogrel , inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death , myocardial infa rct ion , and stroke among a broad group of patients with vascular disease . More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events . METHODS Lotrafiban , a selective , nonpeptide antagonist of the human platelet fibrinogen receptor ( glycoprotein [ GP ] IIb/IIIa [ alphaIIb/beta3 integrin ] ) , blocks the binding of fibrinogen to the GP IIb/IIIa receptor , which is the final common pathway of platelet aggregation . Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week , double-blind , placebo-controlled , dose-ranging study in patients with recent myocardial infa rct ion , unstable angina , transient ischemic attack , or stroke when added to aspirin therapy . On the basis of these results , a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion ( BRAVO ) trial based on pharmacodynamics and drug tolerability . In the pivotal BRAVO study , lotrafiban therapy is being evaluated in patients who have had a recent myocardial infa rct ion , unstable angina , transient ischemic attack , or ischemic stroke , or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease . RESULTS The efficacy evaluation will be based on a composite end point of clinical events ( death by any cause , myocardial infa rct ion , stroke , recurrent ischemia requiring hospitalization , or urgent ischemia-driven revascularization ) .  The target enrollment is 9200 patients worldwide . Approximately 700 centers will participate and will be distributed within 30 countries across North America , Europe , Australia , and Asia Aim High on-clopidogrel platelet reactivity ( HCPR ) and high on-aspirin platelet reactivity ( HAPR ) are associated with atherothrombotic events following coronary stenting . There are , however , few data concerning high on-treatment platelet reactivity to both aspirin and clopidogrel simultaneously . The aim of the present study was to determine the incidence of dual high on-treatment platelet reactivity ( DAPR ) and its impact on clinical outcome . Methods On-treatment platelet reactivity was measured in parallel by ADP- and arachidonic acid-induced light transmittance aggregometry ( LTA )  ( n=921 ) and the point-of-care VerifyNow system ( P2Y12 and aspirin ) ( n=422 ) in patients on dual antiplatelet therapy undergoing elective stent implantation . HCPR and HAPR were established by receiver-operator characteristic curve analysis . The primary endpoint was a composite of all-cause death , non-fatal acute myocardial infa rct ion , stent thrombosis and ischaemic stroke at 1-year follow-up . Results The incidence of DAPR varied between 14.7 % and 26.9 % depending on the platelet function test used . DAPR , assessed by LTA and the VerifyNow system , was highly associated with an adverse clinical outcome . At 1-year follow-up the primary endpoint occurred more frequently in patients with isolated HCPR ( 11.7 % ) , isolated HAPR ( 9.6 % ) or DAPR ( 10.7 % ) compared with patients without high on-treatment platelet reactivity ( 4.2 % , all p<0.01 ) when platelet function was evaluated with LTA . Using the VerifyNow system , patients exhibiting DAPR had the highest risk for the primary endpoint ( 17.7 % vs 4.1 % in patients without high on-treatment platelet reactivity , p=0.001 ) . Conclusions In patients undergoing elective percutaneous coronary intervention , DAPR to aspirin and clopidogrel is present in one in five patients and is associated with a high risk for atherothrombotic events . DAPR measured by the point-of-care VerifyNow system has a higher predictability for atherothrombotic events than LTA . Clinical Trial Registration Information www . clinical trials.gov : NCT00352014 BACKGROUND Aspirin and clopidogrel resistance plays a significant role in the development of cardiovascular ischemic events for ninety patients undergoing percutaneous coronary intervention . Recent studies have indicated that increasing the dose of antiplatelet drugs maybe a potent method to improve the inhibition of platelet aggregation . METHODS  Thrombelastograph ( TEG ) determinations were used to evaluate the effect of antiplatelet therapy . According to the results , 90 patients were divided into three groups and given different doses of aspirin and clopidogrel . Thirty patients with both an inhibition rate of  aspirin > 50 % and an inhibition rate of clopidogrel > 50 % were defined as the control group . Sixty patients with an inhibition rate for aspirin < 50 % and an inhibition rate for clopidogrel < 50 % were defined as the resistance group . Patients in resistance group were r and omly assigned to be given a routine dose ( 100 mg aspirin plus 75 mg clopidogrel per day , which we called a resistance plus routine dose group , R + R ) and a loading dose ( 200 mg aspirin and 150 mg clopidogrel per day , which we called resistance plus loading dose group , R + L ) of antiplatelet therapy . A 12-month follow-up was observed to examine the change of inhibition rate of antiplatelet therapy and to estimate the relationship between inhibition rate and the occurrence of cardiovascular ischemic events . RESULTS After 6 months of antiplatelet therapy , the inhibition rate of aspirin  in the R + L group increased from ( 31.4 ± 3.7)% to ( 68.6 ± 7.1)% , which was significantly higher than that in R + R group , ( 51.9 ± 8.2)% ( P < 0.01 ) . The inhibition rate of clopidogrel  in the R + L group increased from ( 22.1 ± 3.8)% to ( 60.2 ± 7.4)% , which was significantly higher than in the R + R group , ( 45.9 ± 4.3)% ( P < 0.01 ) . The occurrence rates of cardiovascular ischemic events , stent thrombosis , recurrent unstable angina and myocardial infa rct ion in the R + R group were 20 % , 36 % and 17 % , respectively . Occurrence was significantly increased compared with that in the control group , 3 % , 10 % and 1 % , respectively ( P < 0.01 ) . In contrast , the occurrence rates in the R + L group ( 10 % , 23 % and 6 % , respectively ) were attenuated compared with those in the R + R group ( P < 0.01 ) , although still higher than in the control group ( P < 0.01 ) . CONCLUSIONS Almost all of the cardiovascular ischemic events occurred in the first six months after percutaneous coronary intervention . According to the result of TEG determinations , earlier application of a loading dose of aspirin and clopidogrel can decrease the rate of recurrent cardiovascular ischemic events Background — Inhibition of platelet aggregation after aspirin or clopidogrel intake varies greatly among patients , and previous studies have suggested that poor response to oral antiplatelet agents may increase the risk of thrombotic events , especially after coronary angioplasty . Whether this reflects suboptimal platelet inhibition per se , which might benefit from more potent antiplatelet agents such as tirofiban , is unknown . Methods and Results — We screened 1277 patients to enroll 93 aspirin , 147 clopidogrel , and 23 dual poor responders , based on a point-of-care assay , who underwent elective coronary angioplasty at 10 European sites for stable or low-risk unstable coronary artery disease . Patients were r and omly assigned in a double-blind manner to receive either tirofiban ( n=132 ) or placebo ( n=131 ) on top of st and ard aspirin and clopidogrel therapy . The primary end point , consisting of troponin I/T elevation at least 3 times the upper limit of normal , was attained in 20.4 % ( n=27 ) in the tirofiban group compared with 35.1 % ( n=46 ) in the placebo group ( relative risk , 0.58 ; 95 % confidence interval , 0.39 to 0.88 ; P=0.009 ) . The rate of major adverse cardiovascular events within 30 days in the tirofiban group also was reduced ( 3.8 % versus 10.7 % ; P=0.031 ) . The overall incidence of bleeding was low , likely explained by a substantial use of the transradial approach , and did not differ between the 2 groups . Conclusions — In low-risk patients according to clinical presentation who had poor responsiveness to st and ard oral platelet inhibitors via a point-of-care assay , intensified platelet inhibition with tirofiban lowers the incidence of myocardial infa rct ion after elective coronary intervention AIMS To examine the unanticipated , excess mortality observed in patients r and omized to clopidogrel and aspirin vs. aspirin alone  in the prespecified ' asymptomatic ' subgroup of CHARISMA , we investigated whether dual-antiplatelet therapy may be associated with adverse  cardiovascular ( CV )  events in a primary prevention population . METHODS AND RESULTS Of 15 603 patients enrolled , 3284 were initially categorized as asymptomatic with CV risk factors , but 995 had a prior CV event , leaving 2289 patients to represent the primary prevention cohort . This subset was compared with 13 148 symptomatic patients with established vascular disease and both were evaluated for CV death and bleeding . A multivariate analysis analysed predictors of CV death in this group . No post mortem data were available . Compared with aspirin alone , a significant increase in CV death ( P = 0.01 ) was observed in patients receiving dual-antiplatelet therapy in the asymptomatic population . Within the primary prevention cohort , this excess CV death was not significant ( P = 0.07 ) . Multivariate analysis of the primary prevention group showed a trend towards excess CV death ( P = 0.054 ; HR 1.72 ; CI 0.99 - 2.97 ) with dual-antiplatelet therapy ( aspirin plus clopidogrel ) . Other independent predictors of CV death included increasing age , hypertension , atrial fibrillation , and a history of heart failure . There was a non-significant increase in moderate or severe bleeding ( P = 0.218 ) with dual-antiplatelet therapy ; thus , bleeding was an unlikely explanation for the excess event rate . CONCLUSION These findings do not support the use of dual-antiplatelet therapy with clopidogrel and aspirin in a primary prevention population . In this subgroup analysis , CV death occurred more frequently than anticipated . The cause of this apparent harm is not eluci date d , may represent play of chance , but requires further prospect i ve evaluation R and omized clinical trials have evidently shown that the addition of thienopyridines or abciximab to st and ard aspirin results in a significant reduction of ischaemic complications after coronary stent implantation . A head-to-head comparison of these antithrombotic drug regimens during coronary intervention is , however , lacking , and this was the main aim of the present study . Thirty-nine patients with angina pectoris who were scheduled for coronary stent implantation were assigned to either group 1 ( 160 mg aspirin + 500 mg ticlopidine post-stent ) , group 2 ( 160 mg aspirin + abciximab + 500 mg ticlopidine post-stent ) or group 3 ( 160 mg aspirin + loading dose ( 375/450 mg ) clopidogrel pre-stent and 75 mg clopidogrel post-stent ) . A loading dose of 450 mg clopidogrel was found to be more effective than the st and ard loading dose of 375 mg . Platelet aggregation induced by 4 μmol/l adenosine diphosphate ( ADP ) was assessed in sample s collected before intervention and 10 min , 4 h and 20 h after intervention . Before intervention , a moderate antiplatelet effect because of aspirin intake was observed ( ADP aggregation level , ± 50 % ) in all study groups . After intervention , platelet aggregation tended to be enhanced in group 1 while it was strongly inhibited in the groups pre-treated with clopidogrel or abciximab : ADP induced an aggregation level early after intervention of 60 ± 12 % in group 1 ( ticlopidine post-stenting ) versus 30 ± 10 % in group 3 ( loading dose clopidogrel ) versus 3 ± 6 % in group 2 ( abciximab ) . Abciximab achieved a more complete inhibition of aggregation  than clopidogrel ( P = 0.007 ) . The overall complication rate was low with only one major bleeding and one death due to side-branch occlusion with re-infa rct ion occurring , both in the abciximab  group . Platelet aggregation during coronary intervention is strongly inhibited by both abciximab and by high loading dose of clopidogrel . Although abciximab showed a stronger antiplatelet effect than clopidogrel , it remains to be established whether this ex vivo superiority of abciximab also translates into an overall clinical benefit in patients with elective stent implantation 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 ) Aims Newer P2Y12 blockers ( prasugrel and ticagrelor ) demonstrated significant ischaemic benefit over clopidogrel after acute coronary syndrome ( ACS ) . However , both drugs are associated with an increase in bleeding complications . The objective of the present study was to evaluate the benefit of switching dual antiplatelet therapy ( DAPT ) from aspirin plus a newer P2Y12 blocker to aspirin plus clopidogrel 1 month after ACS . Methods and results We performed an open-label , monocentric , and r and omized trial . From March 2014 to April 2016 , patients admitted with ACS requiring coronary intervention , on aspirin and a newer P2Y12 blocker and without adverse event at 1 month , were assigned to switch to aspirin and clopidogrel ( switched DAPT ) or continuation of their drug regimen ( unchanged DAPT ) . The primary outcome was a composite of cardiovascular death , urgent revascularization , stroke and bleeding as defined by the Bleeding Academic Research Consortium ( BARC ) classification ≥2 at 1 year post ACS . Six hundred and forty six patients were r and omized and 645 analysed , corresponding to 322 patients in the switched DAPT and 323 in the unchanged DAPT group . The primary endpoint occurred in 43 ( 13.4 % ) patients in the switched DAPT group and in 85 ( 26.3 % ) patients in the unchanged DAPT ( HR 95%CI 0.48 ( 0.34 - 0.68 ) , P < 0.01 ) . No significant differences were reported on ischaemic endpoints , while BARC ≥ 2 bleeding occurred in 13 ( 4.0 % ) patients in the switched DAPT and in 48 ( 14.9 % ) in the unchanged DAPT group ( HR 95%CI 0.30 ( 0.18 - 0.50 ) , P < 0.01 ) . Conclusion A switched DAPT is superior to an unchanged DAPT strategy to prevent bleeding complications without increase in ischaemic events following ACS Background : Chronic kidney disease ( CKD ) coexisting with type 2 diabetes mellitus ( DM ) leads to coronary artery disease . The present study compares clopidogrel and low-dose aspirin as prophylactic therapy against coronary events in patients with CKD with diabetes . Methods : Total 80 patients of CKD with type 2 DM were r and omized and allocated to clopidogrel and aspirin groups to receive the drug at a dose of 75 mg and 150 mg once daily respectively for 8 weeks as add-on therapy . Main outcome was change in blood pressure , metabolic parameters , renal function , inflammatory biomarkers , platelet aggregability and ( UKPDS ) United Kingdom Prospect i ve Diabetes Study risk scoring . Results : Significant decrease in blood pressure ( P < 0.01 ) , total cholesterol ( P = 0.02 ) , LDL ( P < 0.01 ) , triglyceride ( P < 0.01 ) and a better glycemic control ( P < 0.01 ) was found in clopidogrel group . Renal markers and electrolytes have been improved in clopidogrel group but in aspirin group there was deterioration ( 2.5 % ) of creatinine clearance . Clopidogrel group has shown a significant decrease in hsCRP ( P < 0.01 ) , UKPDS risk scoring ( P < 0.01 ) and better anti-aggregatory effect . Conclusions : Clopidogrel has prophylactic role in CKD with type 2 DM due to better control of metabolic parameters , renal function and inflammatory burden in comparison to aspirin 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 — 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 99mTc : technetium-99 m 201TI : thallium 201 ABCB1 : ATP-binding cassette sub-family B member 1 ABI : ankle-brachial index ACC : American College of Cardiology ACCF : American College of Cardiology Foundation ACCOMPLISH : Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension ACE : angiotensin converting enzyme ACIP : Asymptomatic Cardiac Ischaemia Pilot ACS : acute coronary syndrome ADA : American Diabetes Association ADP : adenosine diphosphate AHA : American Heart Association ARB : angiotensin II receptor antagonist ART : Arterial Revascularization Trial ASCOT : Anglo-Sc and inavian Cardiac Outcomes Trial ASSERT : Asymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial AV : atrioventricular BARI 2D : Bypass Angioplasty Revascularization Investigation 2 Diabetes BEAUTIFUL : Morbidity-Mortality Evaluation of the If Inhibitor Ivabradine in Patients With Coronary Artery Disease and Left Ventricular Dysfunction BIMA : bilateral internal mammary artery BMI : body mass index BMS : bare metal stent BNP : B-type natriuretic peptide BP : blood pressure b.p.m . : beats per minute CABG : coronary artery bypass graft CAD : coronary artery disease CAPRIE : Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events CASS : Coronary Artery Surgery Study CCB : calcium channel blocker CCS : Canadian Cardiovascular Society CFR : coronary flow reserve CHARISMA : Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization , Management and Avoidance CI : confidence interval CKD : chronic kidney disease CKD-EPI : Chronic Kidney Disease Epidemiology Collaboration CMR : cardiac magnetic resonance CORONARY : The CABG Off or On Pump Revascularization Study COURAGE : Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation COX-1 : cyclooxygenase-1 COX-2 : cyclooxygenase-2 CPG : Committee for Practice Guidelines CT : computed tomography CTA : computed tomography angiography CV : cardiovascular CVD : cardiovascular disease CXR : chest X-ray CYP2C19 * 2 : cytochrome P450 2C19 CYP3A : cytochrome P3A CYP3A4 : cytochrome P450 3A4 CYP450 : cytochrome P450 DANAMI : Danish trial in Acute Myocardial Infa rct ion DAPT : dual antiplatelet therapy DBP : diastolic blood pressure DECOPI : Desobstruction Coronaire en Post-Infa rct us DES : drug-eluting stents DHP : dihydropyridine DSE : dobutamine stress echocardiography EACTS : European Association for Cardiothoracic Surgery EECP : enhanced external counterpulsation EMA : European Medicines Agency EASD : European Association for the Study of Diabetes ECG : electrocardiogram Echo : echocardiogram ED : erectile dysfunction EF : ejection fraction ESC : European Society of Cardiology EXCEL : Evaluation of XIENCE PRIME or XIENCE V vs. Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization FAME : Fractional Flow Reserve vs. Angiography for Multivessel Evaluation FDA : Food & Drug Administration ( USA ) FFR : fractional flow reserve FREEDOM : Design of the Future Revascularization Evaluation in patients with Diabetes mellitus : Optimal management of Multivessel disease GFR : glomerular filtration rate HbA1c : glycated haemoglobin HDL : high density lipoprotein HDL-C : high density lipoprotein cholesterol HR : hazard ratio HRT : hormone replacement therapy hs-CRP : high-sensitivity C-reactive protein HU : Hounsfield units ICA : invasive coronary angiography IMA : internal mammary artery IONA : Impact Of Nicor and il in Angina ISCHEMIA : International Study of Comparative Health Effectiveness with Medical and Invasive Approaches IVUS : intravascular ultrasound JSAP : Japanese Stable Angina Pectoris KATP : ATP-sensitive potassium channels LAD : left anterior descending LBBB : left bundle branch block LIMA : Left internal mammary artery LDL : low density lipoprotein LDL-C : low density lipoprotein cholesterol LM : left main LMS : left main stem LV : left ventricular LVEF : left ventricular ejection fraction LVH : left ventricular hypertrophy MACE : major adverse cardiac events MASS : Medical , Angioplasty , or Surgery Study MDRD : Modification of Diet in Renal Disease MERLIN : Metabolic Efficiency with Ranolazine for Less Ischaemia in Non-ST-Elevation Acute Coronary Syndromes MERLIN-TIMI 36 : Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes : Thrombolysis In Myocardial Infa rct ion MET : metabolic equivalents MI : myocardial infa rct ion MICRO-HOPE : Microalbuminuria , cardiovascular and renal sub- study of the Heart Outcomes Prevention Evaluation study MPI : myocardial perfusion imaging MRI : magnetic resonance imaging NO : nitric oxide NSAIDs : non-steroidal anti-inflammatory drugs NSTE-ACS : non-ST-elevation acute coronary syndrome NYHA : New York Heart Association OAT : Occluded Artery Trial OCT : optical coherence tomography OMT : optimal medical therapy PAR-1 : protease activated receptor type 1 PCI : percutaneous coronary intervention PDE5 : phosphodiesterase type 5 PES : paclitaxel-eluting stents PET : positron emission tomography PRECOMBAT : Premier of R and omized Comparison of Bypass Surgery vs. Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease PTP : pre-test probability PUFA : polyunsaturated fatty acid PVD : peripheral vascular disease QoL : quality of life RBBB : right bundle branch block REACH : Reduction of Atherothrombosis for Continued Health RITA-2 : Second R and omized Intervention Treatment of Angina ROOBY : Veterans Affairs R and omized On/Off Bypass SAPT : single antiplatelet therapy  SBP : systolic blood pressure SCAD : stable coronary artery disease SCORE : Systematic Coronary Risk Evaluation  SCS : spinal cord stimulation SES : sirolimus-eluting stents SIMA : single internal mammary artery SPECT : single photon emission computed tomography STICH : Surgical Treatment for Ischaemic Heart Failure SWISSI II : Swiss Interventional Study on Silent Ischaemia Type II SYNTAX : SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery TC : total cholesterol TENS : transcutaneous electrical neural stimulation TERISA : Type 2 Diabetes Evaluation of Ranolazine  in Subjects With Chronic Stable Angina TIME : Trial of Invasive vs. Medical therapy TIMI : Thrombolysis In Myocardial Infa rct ion TMR : transmyocardial laser revascularization TOAT : The Open Artery Trial WOEST : What is the Optimal antiplatElet and anticoagulant therapy  in patients with oral anticoagulation and coronary StenTing Guidelines summarize and evaluate all evidence available , at the time of the writing process , on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient with a given condition , taking into account the impact on outcome , as well BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy . Proton-pump inhibitors ( PPIs ) are believed to decrease the risk of such complications , though no r and omized trial has proved this in patients receiving dual antiplatelet therapy . Recently , concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel . METHODS We r and omly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo , in addition to aspirin . The primary gastrointestinal end point was a composite of overt or occult bleeding , symptomatic gastroduodenal ulcers or erosions , obstruction , or perforation . The primary cardiovascular end point was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , revascularization , or stroke . The trial was terminated prematurely when the sponsor lost financing . RESULTS We planned to enroll about 5000 patients ; a total of 3873 were r and omly assigned and 3761 were included in analyses . In all , 51 patients had a gastrointestinal event ; the event rate was 1.1 % with omeprazole and 2.9 % with placebo at 180 days ( hazard ratio with omeprazole , 0.34 , 95 % confidence interval [ CI ] , 0.18 to 0.63 ; P<0.001 ) . The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo ( hazard ratio , 0.13 ; 95 % CI , 0.03 to 0.56 ; P = 0.001 ) . A total of 109 patients had a cardiovascular event , with event rates of 4.9 % with omeprazole and 5.7 % with placebo ( hazard ratio with omeprazole , 0.99 ; 95 % CI , 0.68 to 1.44 ; P = 0.96 ) ; high-risk subgroups did not show significant heterogeneity . The two groups did not differ significantly in the rate of serious adverse events , though the risk of diarrhea was increased with omeprazole . CONCLUSIONS Among patients receiving aspirin and clopidogrel , prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding . There was no apparent cardiovascular interaction between clopidogrel and omeprazole , but our results do not rule out a clinical ly meaningful difference in cardiovascular events due to use of a PPI . ( Funded by Cogentus Pharmaceuticals ; Clinical Trials.gov number , NCT00557921 . ) BACKGROUND Patients ' responses to oral antiplatelet therapy  are subject to variation . Bedside monitoring offers the opportunity to improve outcomes after coronary stenting by individualizing therapy . METHODS We r and omly assigned 2440 patients scheduled for coronary stenting at 38 centers to a strategy of platelet-function monitoring  , with drug adjustment in patients who had a poor response to antiplatelet therapy , or to a conventional strategy without monitoring and drug adjustment . The primary end point was the composite of death , myocardial infa rct ion , stent thrombosis , stroke , or urgent revascularization 1 year after stent implantation . For patients in the monitoring group , the  VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2 to 4 weeks later . RESULTS In the monitoring group , high platelet reactivity in patients taking clopidogrel ( 34.5 % of patients ) or aspirin ( 7.6 % ) led to the administration of an additional bolus of clopidogrel , prasugrel , or aspirin along with glycoprotein IIb/IIIa inhibitors during the procedure . The primary end point occurred in 34.6 % of the patients in the monitoring group , as compared with 31.1 % of those in the conventional-treatment group ( hazard ratio , 1.13 ; 95 % confidence interval [ CI ] , 0.98 to 1.29 ; P=0.10 ) . The main secondary end point , stent thrombosis or any urgent revascularization , occurred in 4.9 % of the patients in the monitoring group and 4.6 % of those in the conventional-treatment group ( hazard ratio , 1.06 ; 95 % CI , 0.74 to 1.52 ; P=0.77 ) . The rate of major bleeding events did not differ significantly between groups . CONCLUSIONS This study showed no significant improvements in clinical outcomes with platelet-function monitoring and treatment adjustment for coronary stenting , as compared with st and ard antiplatelet therapy without monitoring . ( Funded by Allies in Cardiovascular Trials Initiatives and Organized Networks and others ; A RCT IC Clinical Trials.gov number , NCT00827411 . ) 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 Patients with chronic kidney disease ( CKD ) are at high risk for developing cardiovascular events . However , limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression . Study Design Prospect i ve , multicenter , open-label r and omized controlled trial . Setting and Participants One hundred eleven patients with estimated glomerular filtration rate ( eGFR ) 15–60 ml/min/1.73 m2 without previous cardiovascular events . InterventionAspirin treatment ( 100 mg/day ) ( n = 50 ) or usual therapy ( n = 61 ) . Mean follow-up time was 64.8 ± 16.4 months . Outcomes The primary endpoint was composed of cardiovascular death , acute coronary syndrome ( nonfatal MI , coronary revascularization , or unstable angina pectoris ) , cerebrovascular disease , heart failure , or nonfatal peripheral arterial disease . Secondary endpoints were fatal and nonfatal coronary events , renal events ( defined as doubling of serum creatinine , ≥ 50 % decrease in eGFR , or renal replacement therapy ) , and bleeding episodes . Results During follow-up , 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups , respectively . Aspirin did not significantly reduce primary composite endpoint ( HR , 0.396 ( 0.146–1.076 ) , p = 0.069 . Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group . Aspirin significantly reduced the risk of coronary events ( log-rank , 5.997 ; p = 0.014 ) . Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group . Aspirin treatment decreased renal disease progression in a model adjusted for age , baseline kidney function , and diabetes mellitus ( HR , 0.272 ; 95 % CI , 0.077–0.955 ; p = 0.043 ) but did not when adjusted for albuminuria . No differences were found in minor bleeding episodes between groups and no major bleeding was registered . Limitations Small sample size and open-label trial . Conclusions Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint ; however , there were reductions in secondary endpoints with fewer coronary events and renal outcomes . Clinical Trials.gov Identifier : NCT01709994 Context In patients with unstable angina , combination therapy with clopidogrel plus aspirin has been shown to be more effective than aspirin alone in preventing myocardial infa rct ion , stroke , or cardiovascular death , but the cost-effectiveness of such therapy has yet to be determined . Contribution When the authors used a societal perspective and lifetime time horizon , combination therapy increased quality -adjusted life span at a cost that was within the traditionally accepted limits of cost-effectiveness . Caution s Data are not yet available to determine whether combination therapy for longer than 1 year remains cost-effective , due to the uncertainty of the relationship between long-term efficacy and risk for hemorrhage . The Editors The Clopidogrel  in Unstable Angina to Prevent Recurrent Events ( CURE ) trial demonstrated that clopidogrel plus aspirin was superior to aspirin alone in preventing the composite outcome of myocardial infa rct ion , stroke , or cardiovascular death in the year following an acute coronary syndrome or nonQ-wave myocardial infa rct ion ( 1 ) . Although combination therapy is recommended for such patients for at least 1 month , the optimal duration is less clear ( 2 ) . In addition , the cost of clopidogrel complicates the decision to combine it with aspirin . Adding clopidogrel to aspirin is financially unattractive if done in all patients with coronary disease ( 3 ) but may be cost-effective in high-risk patients , for whom clopidogrel offers more substantial absolute risk reduction . To assess the cost-effectiveness of clopidogrel plus aspirin relative to aspirin alone in high-risk patients with coronary artery disease and to explore the optimal duration of therapy , we constructed a decision analytic Markov model comparing these treatment strategies after an acute coronary syndrome as defined in CURE . Methods We performed a cost-effectiveness analysis using a Markov model ( 4 ) ( DATA 4.0 , TreeAge Software , Inc. , Williamstown , Massachusetts ) . We analyzed a reference case assuming a societal perspective ( 5 ) and a lifetime time horizon ( 6 ) . Our analysis was based on the CURE trial , a r and omized comparison of 3 to 12 months of therapy with clopidogrel plus aspirin or aspirin alone to prevent cardiovascular death , myocardial infa rct ion , or stroke in 12562 patients with an acute coronary syndrome ( 1 ) . We discounted costs and utilities at 3 % annually and determined lifetime costs , quality -adjusted life expectancy , and the incremental cost-effectiveness ratio . Sensitivity analyses included 1-way analyses on all data inputs ; probabilistic sensitivity analysis ; evaluation of varying duration of combination therapy , including potential loss of efficacy over time ; and consideration of population s with varying risk . Target Population The target population was analogous to that of the CURE trial ( 1 ) : patients with an acute coronary syndrome characterized by electrocardiographic changes or elevated serum cardiac markers in association with chest pain . Patients who had prolonged ST-segment elevation , who had undergone revascularization in the previous 3 months , who were at risk for severe bleeding or heart failure , or who had been treated with oral anticoagulants or glycoprotein IIb/IIIa inhibitors in the preceding 3 days were excluded . On the basis of the average age of CURE patients , we considered a 64-year-old as our base case and explored other ages in sensitivity analysis . We compared treatment costs and clinical outcomes for 2 types of antiplatelet therapy : 1 ) aspirin alone , 325 mg/d , and 2 ) clopidogrel , 75 mg/d , plus aspirin , 325 mg/d , for 1 year , followed by aspirin monotherapy . Model Structure In our model , we included vascular events : myocardial infa rct ion , stroke , vascular death and revascularization , intracerebral and gastrointestinal hemorrhagic events , and clopidogrel-associated thrombotic thrombocytopenic purpura . We included age-related mortality , correcting for events explicitly included in the model . We did not directly include procedures or outcomes , such as congestive heart failure , that CURE did not specifically address ( 1 ) . We indirectly accounted for the cost of such events by using age-adjusted annual health care costs ( 7 ) . This assumes equal probability of such events in each arm of the analysis . We allowed for multiple events , including multiple events of a particular type , within a given monthly cycle . We created Markov states for conditions that changed quality of life , annual cost , or probability of future events . For events with temporary decrements in quality of life , we assessed a utility toll proportional to the duration of hospitalization required ( 8) . We also modeled each combination of 2 events . When more than 2 events occurred , we used the Markov state that combined the 2 events with the lowest utility ( Figure 1 ) . Figure 1 . Schematic representation of the decision model . Model Inputs Probabilities We derived probabilities for vascular and hemorrhagic events over the first year of our analysis from the CURE trial ( 1 ) . Rates of cardiovascular outcomes were highest in the month immediately following the acute coronary syndrome ( 1 ) . To account for temporal variation in risk , we calculated probabilities for the first month separately from those for subsequent months . Beyond the time frame of the CURE trial , we empirically calculated declining probability functions for myocardial infa rct ion , cardiovascular death , and revascularization on the basis of proportional decline in risk over time in survivors of nonQ-wave myocardial infa rct ion ( 9 ) . We assumed that all bleeding events , other than intracerebral hemorrhage , were gastrointestinal . Because intracerebral hemorrhage was equally likely for the 2 treatment strategies ( 1 ) , all of the excess bleeding in the clopidogrel plus aspirin arm was attributed to gastrointestinal causes . The rate of thrombotic thrombocytopenic purpura associated with clopidogrel was derived from an observational study ( 10 , 11 ) . We represented uncertainty in event rates through distributions based on the number of events that occurred and the number of patient-years at risk . We obtained age-specific mortality from life tables ( 12 ) and corrected for death rates of events explicitly included in our model ( Table ) . Table . Model Inputs Efficacy of Combination Therapy Despite the variation in risk , the relative efficacy of clopidogrel plus aspirin did not vary between the first and subsequent months ( 1 ) . In modeling beyond the time frame of the CURE trial , we assumed in our base case that efficacy remained constant , on the basis of data for clopidogrel monotherapy ( 13 ) . We explored waning efficacy over time in sensitivity analysis . We used 3 variables to describe loss of efficacy , duration of constant efficacy ( 1 year to lifetime ) , duration of efficacy deterioration ( 1 to 10 years ) , and the extent of efficacy decline relative to  aspirin monotherapy ( none to complete loss ) . Costs We derived costs for each event and for chronic care of disabled patients from the literature . For medications , we used the average wholesale price in the United States as our base value ( 35 ) and considered prices negotiated by a large-volume purchaser in constructing the price range . Acute care costs for clinical events represent the direct costs of all medical care incurred during hospitalization . Chronic care costs represent direct expenditures for medications , procedures , and nursing care specific to the condition in question and were assessed for each month in the Markov state . For Markov states representing survival after either severe stroke or intracerebral hemorrhage and another event , we assumed 20 % of the long-term cost of the additional condition to account for overlapping therapy . We accounted for other health care costs by using age-adjusted annual health expenditures ( 7 ) . We up date d costs to 2002 U.S. dollars with a gross domestic product deflator ( 44 ) and generated log-normal distributions for each estimate for use in sensitivity analyses ( Table ) . Utilities We used published population -based utilities , representing either time-tradeoff or st and ard-gamble techniques . For Markov states representing 2 events , we combined utilities with multiplication ( 8) . For events and procedures that did not result in durable changes in the health state of the individual , we used disutility tolls based on the average duration of hospitalization ( 8) . We modeled uncertainty in utility estimates by calculating distributions based on the range of utility estimates in the literature ( Table ) . Sensitivity Analyses To assess the degree to which variation in any variable altered our results , we performed 1-way sensitivity analyses for each model input by analyzing the results at both extremes of its 95 % CI . In evaluating patients of different ages , we adjusted both age-related mortality and estimates of annual health care cost accordingly . To better underst and the distribution of the cost-effectiveness ratio for clopidogrel plus aspirin and the potential value of further research , we performed probabilistic sensitivity analysis using Monte Carlo simulation ( 45 , 46 ) . In each of 1000 simulations , the value for each model input was r and omly selected from its distribution . We constructed a cost-effectiveness acceptability curve by calculating the average net monetary benefit for each strategy in each simulation over cost-effectiveness thresholds ranging from no additional expenditure for the least expensive therapy to $ 100000 for each quality -adjusted life-year ( QALY ) gained . We then determined the proportion of simulations for which clopidogrel plus aspirin result ed in the greater net monetary benefit at each cost-effectiveness threshold . We also assessed varying the duration of  clopidogrel therapy from 1 month to 1 year in monthly increments . We considered prolonged therapy , up to patient lifetime , in yearly increments , simultaneously assessing potential decline in the efficacy of clopidogrel . To better OBJECTIVES This trial sought to assess the influence of omeprazole on clopidogrel efficacy . BACKGROUND Clopidogrel has proved its benefit in the treatment of atherothrombotic diseases . In a previous observational study , we found clopidogrel activity on platelets , tested by vasodilator-stimulated phosphoprotein ( VASP ) phosphorylation , to be diminished in patients receiving proton pump inhibitor ( PPI ) treatment . METHODS In this double-blind placebo-controlled trial , all consecutive patients undergoing coronary artery stent implantation received aspirin ( 75 mg/day ) and clopidogrel ( loading dose , followed by 75 mg/day ) and were r and omized to receive either associated omeprazole ( 20 mg/day ) or placebo for 7 days .  Clopidogrel effect was tested on days 1 and 7 in both groups by measuring platelet phosphorylated-VASP expressed as a platelet reactivity index ( PRI ) . Our main end point compared PRI value at the 7-day treatment period in the 2 groups . RESULTS Data for 124 patients were analyzed . On day 1 , mean PRI was 83.2 % ( st and ard deviation [ SD ] 5.6 ) and 83.9 % ( SD 4.6 ) , respectively , in the placebo and omeprazole groups ( p = NS ) , and on day 7 , 39.8 % ( SD 15.4 ) and 51.4 % ( SD 16.4 ) , respectively ( p < 0.0001 ) . RESULTS Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phosphorylation test . Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide , with PPIs frequently associated to prevent gastrointestinal bleeding . The clinical impact of these results remains uncertain but merits further investigation Current recommendations for the antithrombotic management of patients receiving oral anticoagulation ( OAC ) who undergo percutaneous coronary intervention with stent implantation ( PCI-S ) are based on limited and relatively weak data . To broaden and strengthen available evidence , the management and 1-year outcomes of OAC patients who underwent PCI-S and were included in a prospect i ve , multicenter registry from 2003 to 2007 were evaluated . Among the 632 patients receiving OAC , mostly because of atrial fibrillation ( 58 % ) , who underwent PCI-S , mostly because of acute coronary syndromes ( 63 % ) , dual-antiplatelet therapy with aspirin and clopidogrel was the most frequently prescribed at discharge ( 48 % ) , followed by triple therapy with OAC , aspirin , and clopidogrel ( 32 % ) and OAC plus aspirin ( 18 % ) . The choice of antithrombotic therapy largely matched the thromboembolic risk profiles of patients , with the prescription of regimens including OAC predicted by the presence of non-low-risk features . The cumulative 1-year occurrence of major adverse cardiovascular events was as high as 27 % and was not significantly different among the 3 treatment groups . Stroke and stent thrombosis were limited to 2 % and 3 % , respectively , and although no significant differences were found among the 3 groups , stroke was 4 times less frequent when OAC , with either 1 or 2 antiplatelet agents , was administered . Major bleeding was also limited to 3 % , with no significant differences among the 3 groups . In conclusion , these findings suggest overall real-world management of OAC patients who undergo PCI-S  that is in accordance with their clinical risk profiles and give further support to the reported efficacy and safety of triple therapy for the optimal treatment of these patients Clopidogrel is a prodrug that has to be converted to an active metabolite by hepatic cytochrome P450 ( CYP ) isoenzymes to inhibit platelet aggregation . Individual variability of platelet inhibition by clopidogrel suggests a possibility for genetic factors having a significant influence on clopidogrel responsiveness . In this study , we sought to determine the relation of genetic polymorphisms of CYP genes to  clopidogrel resistance in Koreans . Four hundred fifty patients who underwent successful percutaneous coronary intervention with drug-eluting stents were r and omly assigned to treatment with dual antiplatelet regimen ( aspirin plus clopidogrel ) or triple antiplatelet regimen ( aspirin plus clopidogrel plus cilostazol ) . Clopidogrel resistance using VerifyNow P2Y12 assay and genetic analysis were performed in 387 patients . Clopidogrel resistance was found in 112 patients ( 28.9 % ) . In the clopidogrel-responsive group , there was a significantly higher proportion of  cilostazol use . Because cilostazol showed a significant influence on clopidogrel resistance , we examined the association of single-nucleotide polymorphisms and clopidogrel resistance in the dual and triple antiplatelet therapy groups , respectively . In all subjects , the CYP2C19 * 3A allele was significantly more prevalent in the clopidogrel-resistant group compared with the clopidogrel-responsive group . Multiple logistic regression analysis demonstrated that CYP2C19 * 3 is an independent predictor of clopidogrel resistance . In conclusion , CYP2C19 * 3 single-nucleotide polymorphisms is an independent risk factor of clopidogrel resistance in Korean subjects with coronary artery disease Background — Incomplete inhibition of platelet thromboxane generation , as measured by elevated urinary 11-dehydro thromboxane B2 concentrations , has been associated with an increased risk of cardiovascular events . We aim ed to determine the external validity of this association in  aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization , Management and Avoidance ( CHARISMA ) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B2 concentrations that could thereby reduce cardiovascular risk . Methods and Results — Urinary 11-dehydro thromboxane B2 concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been r and omly assigned to placebo or clopidogrel .  Baseline urinary 11-dehydro thromboxane B2 concentrations in the highest quartile were associated with an increased risk of stroke , myocardial infa rct ion , or cardiovascular death compared with the lowest quartile ( adjusted hazard ratio 1.66 , 95 % CI 1.06 to 2.61 , P=0.03 ) . Increasing age , female sex , history of peripheral artery disease , current smoking , and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B2 , whereas aspirin dose ≥150 mg/d , history of treatment with nonsteroidal antiinflammatory drugs , history of hypercholesterolemia , and statin treatment were associated with lower concentrations . R and omization to clopidogrel ( versus placebo ) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B2 levels . Conclusions —  In aspirin-treated patients , urinary concentrations of 11-dehydro thromboxane B2 are an externally valid and potentially modifiable determinant of stroke , myocardial infa rct ion , or cardiovascular death in patients at risk for atherothrombotic events The PIONEER AF-PCI trial ( Open-Label , R and omized , Controlled , Multicenter Study Exploring Two Treatment Strategies of Rivaroxaban and a Dose-Adjusted Oral Vitamin K Antagonist Treatment Strategy in Subjects with AF who Undergo Percutaneous Coronary Intervention ) is an ambitious , open-label comparison of 3 regimens , almost exclusively in Caucasians , all of whom had coexisting atrial fibrillation and atherosclerotic coronary artery disease requiring stenting ( PCI-S ) . These 2 conditions when they coexist pose a clinical challenge , necessitating concurrent usage of dual antiplatelet and anticoagulation therapy , a cocktail which presents major bleeding risks . Because anticoagulation therapy is suboptimal in preventing stent thrombosis and dual anti platelet therapy is inadequate in averting embolic stroke in atrial fibrillation , neither treatment is sufficient and they must be combined . The study has a unique design and consists of 2 treatment arms and a control ( see Figure 1 for trial design ) , each with about 700 patients and a 20 % dropout rate in groups 1 and 2 but a statistically greater rate of 29 % in group 3 . Both treatment arms are modeled upon previous studies , which involved patients with the need for both antiplatelet therapy and anticoagulation ( see Figure 2 for derivation of trial from WOEST and ATLAS-TIMI 51 ) . The control arm , design ated group 3 in the trial , consists of the US st and ard of practice regimen , in this situation , called “ triple therapy , ” consisting of aspirin 100 mg/d , clopidogrel 75 mg/d , and warfarin maintaining the INR between 2 and 3 . About 7 % of patients in groups 1 and 2 received a different P2Y12 inhibitor , either prasugrel or ticagrelor , and about 4 % in group 3 . Prominent among the numerous exclusions were patients with a previous stroke and a creatinine clearance of under 30 mL/min . In arm 1 , patients with a creatinine clearance between 30 and 60 mL/min received a lower dose of 10 mg of rivaroxaban . The first treatment arm , called arm 1 , is a reprisal of the treatment arm of the Belgian 2013 WOEST trial which showed that clopidogrel 75 mg and warfarin , maintaining an INR of 2 to 3 , were associated with less combined TIMI major and minor bleeding as well as no increase in cardiac or neurological thrombotic complications when compared to the same control arm as is in this study . Despite having studied only 573 patients for just a year , WOEST was influential in generating the recommendation ( level B ) from the European Society of Cardiology to use this regimen in some people at high risk for bleeding with stents who also require anticoagulation . Furthermore in PIONEER , arm 1 , rivaroxaban 15 mg has been substituted for warfarin ; otherwise , the other trial drugs are identical to those in WOEST . A compelling question posed by this arm of the study , although not the primary end point of the study , is whether equivalent stent patency or prevention of atherosclerotic or thromboembolic complications can be achieved with only a single antiplatelet drug throughout the entire 12 months of treatment , including the vital first month poststent . Also addressed is whether the WOEST results can be replicated substituting rivaroxaban , a drug that offers several advantages over warfarin . In treatment group 1 , one would intuitively expect confirmation of the bleeding advantage observed in WOEST , since it contains 2 drugs versus the 3 in the control group , and therefore would be expected to be associated with less bleeding in group 1 versus group 3 . The second treatment group is based on the 2012 ATLAS ACS 2-TIMI 51 trial and consists of very-low-dose rivaroxaban 2.5 mg twice a day along with clopidogrel 75 mg/d and aspirin 100 mg/d . An interesting point of arm 2 versus 3 , although again not the primary end point , is if a dosage of rivaroxaban , which is only 25 % of the FDA -approved dose of that needed to treat atrial fibrillation , would be adequate in preventing embolic strokes . One would anticipate in group 2 that the dual antiplatelet therapy would be equally effective in preventing stent occlusion and recurrent coronary events as the OBJECTIVES The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the chronic kidney disease ( CKD ) population . BACKGROUND Cardiovascular and possibly bleeding risks are elevated in patients with CKD . The balance of benefit and harm associated with antiplatelet therapy remains uncertain . METHODS The HOT ( Hypertension Optimal Treatment ) study r and omly assigned participants with diastolic hypertension  to aspirin ( 75 mg ) or placebo . Study treatment effects were calculated using univariate proportional hazards regression models stratified by baseline estimated glomerular filtration rate ( eGFR ) with trends tested by adding interaction terms . End points included major cardiovascular events , total mortality , and major bleeding . RESULTS The study included 18,597 participants treated for 3.8 years . Baseline eGFR was < 60 ml/min/1.73 m(2 ) in 3,619 participants . Major cardiovascular events were reduced by 9 % ( 95 % confidence interval [ CI ] : -9 % to 24 % ) , 15 % ( 95 % CI : -17 % to 39 % ) , and 66 % ( 95 % CI : 33 % to 83 % ) for patients with baseline eGFR of ≥ 60 , 45 to 59 , and < 45 ml/min/1.73 m(2 ) , respectively ( p trend = 0.03 ) . Total mortality was reduced by 0 % ( 95 % CI : -20 % to 17 % ) , 11 % ( 95 % CI : -31 % to 40 % ) , and 49 % ( 95 % CI : 6 % to 73 % ) , respectively ( p trend = 0.04 ) . Major bleeding events were nonsignificantly greater with lower eGFR ( hazard ratio [ HR ] : 1.52 [ 95 % CI : 1.11 to 2.08 ] , HR : 1.70 [ 95 % CI : 0.74 to 3.88 ] , and HR : 2.81 [ 95 % CI : 0.92 to 8.84 ] , respectively ; p trend = 0.30 ) . Among every 1,000 persons with eGFR < 45 ml/min/1.73 m(2 ) treated for 3.8 years , 76 major cardiovascular events and 54 all-cause deaths will be prevented while 27 excess major bleeds will occur . CONCLUSIONS Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function . An increased risk of major bleeding appears to be outweighed by the substantial benefits Abstract Objective : To determine which groups of patients may derive particular benefit or experience harm from the use of low dose aspirin for the primary prevention of coronary heart disease . Design : R and omised controlled trial . Setting : 108 group practice s in the Medical Research Council 's general practice research framework who were taking part in the thrombosis prevention trial . Participants : 5499 men aged between 45 and 69 years at entry who were at increased risk of coronary heart disease . Main outcome measures : Myocardial infa rct ion , coronary death , and stroke . Results : Aspirin reduced coronary events by 20 % . This benefit , mainly for non-fatal events , was significantly greater the lower the systolic blood pressure at entry ( interaction P=0.0015 ) , the relative risk at pressures 130 mm Hg being 0.55 compared with 0.94 at pressures > 145 mm Hg . Aspirin also reduced strokes at low but not high pressures , the relative risks being 0.41 and 1.42 ( P=0.006 ) respectively . The relative risk of all major cardiovascular events — that is , the sum of coronary heart disease and stroke — was 0.59 at pressures < 130 mm Hg compared with 1.08 at pressures > 145 mm Hg ( P=0.0001 ) . Conclusion : Even with the limitations of subgroup analyses the evidence suggests that the benefit of low dose aspirin in primary prevention may occur mainly in those with lower systolic blood pressures , although it is not clear even in these men that the benefit outweighs the potential hazards . Men with higher pressures may be exposed to the risks of bleeding while deriving no benefit through reductions in coronary heart disease and stroke BACKGROUND Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation ( AF ) but increases hemorrhage . OBJECTIVE To quantify the net benefit of adding clopidogrel to aspirin therapy , accounting for differences in clinical significance between ischemic and hemorrhagic events . DESIGN Observational cohort study to assign the relative weighting of events and post hoc analysis of r and omized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE ( Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events ) clinical trials . SETTING Global r and omized clinical trial . PATIENTS 10,041 patients with AF , 7554 of whom were not c and i date s for warfarin therapy .  MEASUREMENTS Ischemic events ( ischemic stroke or myocardial infa rct ion ) and hemorrhagic events ( hemorrhagic stroke or subdural or extracranial bleeding ) , weighted by the hazard ratio for death ( or death or disability ) after an event relative to death ( or death or disability ) after ischemic stroke . The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment , expressed as ischemic stroke equivalents prevented per 100 patients years . RESULTS Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent ( 95 % CI , -0.12 to 1.24 ) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent ( CI , -0.03 to 1.18 ) when weighted by death or disability after ischemia or hemorrhage . LIMITATION No attempt was made to relate deaths used for weighting to events ; disability data were missing for more than one half of patients . CONCLUSION Adding clopidogrel to aspirin therapy result ed in a modest net benefit among patients with AF for whom warfarin was unsuitable . The benefit would probably be clinical ly relevant for some patients , but estimates could not exclude the possibility of either no benefit or very small harm in this population . PRIMARY FUNDING SOURCE Bristol-Myers Squibb and sanofi-aventis BACKGROUND Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events .  Aspirin and ticlopidine have been shown to be effective , but both have potentially serious adverse effects .  Clopidogrel , a new thienopyridine derivative similar to ticlopidine , is an inhibitor of platelet aggregation induced by adenosine diphosphate . METHODS CAPRIE was a r and omised , blinded , international trial design ed to assess the relative efficacy of clopidogrel ( 75 mg once daily ) and aspirin ( 325 mg once daily ) in reducing the risk of a composite outcome cluster of ischaemic stroke , myocardial infa rct ion , or vascular death ; their relative safety was also assessed . The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke , recent myocardial infa rct ion , or symptomatic peripheral arterial disease . Patients were followed for 1 to 3 years . FINDINGS 19,185 patients , with more than 6300 in each of the clinical subgroups , were recruited over 3 years , with a mean follow-up of 1.91 years . There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32 % risk of ischaemic stroke , myocardial infa rct ion , or vascular death compared with 5.83 % with aspirin . These rates reflect a statistically significant ( p = 0.043 ) relative-risk reduction of 8.7 % in favour of clopidogrel ( 95 % Cl 0.3 - 16.5 ) . Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4 % . There were no major differences in terms of safety . Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash ( 0.26 % vs 0.10 % ) , diarrhoea ( 0.23 % vs 0.11 % ) , upper gastrointestinal discomfort ( 0.97 % vs 1.22 % ) , intracranial haemorrhage ( 0.33 % vs 0.47 % ) , and gastrointestinal haemorrhage ( 0.52 % vs 0.72 % ) , respectively . There were ten ( 0.10 % ) patients in the clopidogrel group with significant reductions in neutrophils ( < 1.2 x 10(9)/L ) and 16 ( 0.17 % ) in the aspirin group . INTERPRETATION Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke , myocardial infa rct ion , or vascular death . The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin Background Chronic atrial fibrillation ( AF ) , coexisting with a history of recent coronary angioplasty with stent ( PCI-S ) , represents an encoded indication for oral anticoagulation ( OAC ) with warfarin plus dual antiplatelet therapy ( DAPT ) . Methods Using a retrospective cohort study , we determined the respective impacts on cardiovascular outcomes of three different pharmacologic regimens , i.e. , triple therapy ( TT ) with warfarin + clopidogrel and aspirin , dual therapy ( DT ) with warfarin + clopidogrel or aspirin , and DAPT with clopidogrel + aspirin . Outcomes of interest were all-cause mortality , ischemic cardiac events , ischemic cerebral events , and bleeding events . The inclusion criterion was the coexistence of an indication for OAC ( e.g. , chronic AF ) with an indication for DAPT due to recent PCI-S. Results Among the 98 patients enrolled , 48 ( 49 % ) , 31 ( 31.6 % ) , and 19 ( 19.4 % ) patients were prescribed TT , DT , and DAPT , respectively . Throughout a mean follow-up of 378 ± 15.7 days , there were no significant differences between the three regimens for all abovementioned outcomes . In particular , the total frequency of major bleeding was similar in the three groups : five cases ( 10.4 % ) in TT , one case ( 3.22 % ) in DT and no case in DAPT groups ( Chi-square test , P = 0.1987 ) . Conclusions TT , DT and DAPT displayed similar efficacy and safety . Although the superiority of OAC vs. DAPT for stroke prevention in AF patients has been demonstrated by previous r and omized trials , a smaller frequency of high thromboembolic risks ’ features in DAPT group of the present study may have prevented the observation of a higher incidence of ischemic stroke in this group 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 BACKGROUND Aspirin resistance is a major problem and its incidence and clinical significance in Indian patients with documented coronary artery disease are not known . AIM We sought to study the incidence of aspirin resistance and its clinical significance in a cohort of Indian patients with coronary heart disease on therapy with aspirin  using urinary 11-Dehydrothromboxane B2 levels as a surrogate marker for antiplatelet efficacy . SETTING AND DESIGN Non r and omized single center prospect i ve study in cohort of patients with stable cardiovascular disease on chronic aspirin therapy attending the cardiology outpatient clinic of a tertiary care hospital . MATERIAL S AND METHODS Urinary dehydrothromboxane levels were analyzed in a cohort of 63 patients with stable documented coronary artery disease and in 21 healthy volunteers . The cases were followed up prospect ively for a median period of 36 ( 1 - 53 ) months . The clinical endpoint was a composite of acute coronary syndrome , stroke , revascularization and death . STATISTICAL ANALYSIS Comparison of urinary dehydrothromboxane concentration values between various risk factors was done using Mann Whitney U test , a non parametric alternative of independent t test . All statistical analyses were done using SPSS 11.0 ( Chicago , USA ) software . RESULTS The median ( range ) absolute values of urinary11- dehydrothromboxane B2 levels for the healthy volunteers and cases were 440 ( 286 - 2050 ) pg/ml and 320 ( 72 - 2600 ) pg/ml ( P=0.007 ) . The corresponding normalized values were 87.3 ( 43 - 143 ) and 60.8 ( 16.7 - 943 ) ng/mmol of creatinine ( P=0.131 ) . Among the various vascular risk factors , patients who were overweight had higher absolute levels of 11- urinary dehydrothomboxane B2 levels ( P=0.016 ) . There were significantly more clinical events in patients with absolute urinary 11-dehydrothromboxane B2 levels in the upper two quartiles compared to the lower two quartiles ( P=0.04 ) . CONCLUSION The incidence of aspirin resistance in the cohort of patients with documented heart disease was 38.1 % . Patients with elevated absolute urinary dehydrothomboxane levels ( > 320 pg/ml ) on chronic aspirin therapy constitute a high risk subset for recurrent vascular events BACKGROUND We investigated aspirin-prescribing patterns and potential benefits on cardiovascular morbidity and mortality  in hemodialysis patients . STUDY DESIGN Cohort study . SETTING & PARTICIPANTS Data included 28,320 r and omly selected hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study I and II . PREDICTOR Aspirin prescription at study baseline . OUTCOMES & MEASUREMENTS Prescription was investigated by means of logistic regression . All-cause mortality , all-cause hospitalization , cardiac event , myocardial infa rct ion , cerebrovascular ( CVA ) , gastrointestinal bleed , transient ischemic attack , and subdural hematoma were examined . Cox regression examined the risk of mortality and hospitalization . All models accounted for facility clustering and demographics and comorbid conditions . RESULTS Wide variation was found in aspirin prescription , from 8 % in Japan to 41 % in Australia and New Zeal and . Characteristics significantly associated with increased odds of prescription included coronary artery disease , cerebrovascular disease , diabetes , male sex , nonblack race , peripheral vascular disease , age , hypertension , and absence of gastrointestinal bleeding .  Aspirin was associated with decreased risk of stroke in all patients ( relative risk [ RR ] , 0.82 ; P < 0.01 ) and increased risk of myocardial infa rct ion ( RR , 1.21 ; P = 0.01 ) and cardiac event ( RR , 1.08 ; P < 0.01 ) in all patients , with similar results for patients with coronary artery disease . There was no increase in gastrointestinal bleeding . LIMITATIONS Observational studies are not protected from biases , despite adjustments . There is potential for aspirin use to be underreported because of its availability without prescription . CONCLUSIONS The hypothesis that prescribing aspirin to hemodialysis patients decreases cardiovascular disease risk is not supported . Aspirin might decrease CVA and appears not to increase hemorrhagic risk . This should be an incentive for r and omized controlled trials Background — Patients with peripheral arterial disease are at high risk of ischemic events and therefore are treated with antithrombotics . In patients with coronary artery disease or cerebrovascular disease , bleeding is related to the subsequent occurrence of ischemic events . Our objective was to assess whether this is also the case in patients with peripheral arterial disease . Methods and Results — All patients from the Dutch Bypass and Oral Anticoagulants or Aspirin ( BOA ) Study , a multicenter r and omized trial comparing oral anticoagulants with aspirin after infrainguinal bypass surgery , were included . The primary outcome event was the composite of nonfatal myocardial infa rct ion , nonfatal ischemic stroke , major amputation , and cardiovascular death . To identify major bleeding as an independent predictor for ischemic events , crude and adjusted hazard ratios with 95 % confidence intervals were calculated with multivariable Cox regression models . From 1995 until 1998 , 2650 patients were included with 101 nonfatal major bleedings .  During a mean follow-up of 14 months , the primary outcome event occurred in 218 patients ; 22 events were preceded by a major bleeding . The mean time between major bleeding and the primary outcome event was 4 months . Major bleeding was associated with a 3-fold increased risk of subsequent ischemic events ( crude hazard ratio , 3.0 ; 95 % confidence interval , 1.9 to 4.6 ; adjusted hazard ratio , 3.0 ; 95 % confidence interval , 1.9 to 4.7 ) . Conclusions — In patients with peripheral arterial disease , as in patients with coronary artery disease or cerebrovascular disease , major bleeding was independently associated with major ischemic complications . Without compromising the benefits of antithrombotics , these findings call for caution relative to the risks of major bleeding Abstract Background : Aspirin resistance may increase up to more then threefold the risk of major cardiovascular events ( MACE ) in patients with stable coronary artery disease . Aim : The aim of our study was to determine ; the prevalence of aspirin resistance in patients with acute coronary syndromes , the role of aspirin resistance on outcome in the follow-up and the effect of clopidogrel therapy in the prevention of MACE in aspirin resistant subjects . Material and methods : We detected the prevelance of aspirin resistance in 105 patients with acute coronary syndrome .  Platelet functions were analyzed in Platelet Function Analyzer (PFA)-100 ( Dade Behring , Germany ) with collagen and /or epinephrine ( Col/Epi ) and collagen and /or ADP ( Col/ADP ) cartridges . Primary end points of the study were myocardial infa rct ion , unstable angina , cardiac death . Results : 19 % ( n = 20 ) of patients were aspirin resistant by PFA-100 . In the follow-up , MACE occured in 9 patients ( 45 % ) with aspirin resistance and in 10 patients ( 11.7 % ) with aspirin sensitive platelet aggregation ( p = 0.001 ) . Multivariate analysis showed that aspirin resistance was an independant predictor of MACE . The prevalence of MACE in patients who were on clopidogrel treatment for 12 months were lower compared to those who were on a clopidogrel treatment for the first six months ( p = 0.040 ) . Conclusions : We determined that the MACE risk in patients with acute coronary syndromes having detected aspirin resistance , was higher at statistically significant levels compared to patients having aspirin sensitive platelet aggregation . Our results showed that aspirin resistance , was an independant predictor of MACE in patients with acute coronary syndrome 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 Intracoronary stenting can improve procedural success and reduce restenosis compared with balloon angioplasty in patients with acute coronary syndromes , but can also increase the rate of thrombotic complications including stent thrombosis . The TRITON-TIMI 38 trial has shown that prasugrel-a novel , potent thienopyridine-can reduce ischaemic events compared with st and ard clopidogrel therapy . We assessed the rate , outcomes , and prevention of ischaemic events in patients treated with prasugrel or clopidogrel with stents in the TRITON-TIMI 38 study . METHODS Patients with moderate-risk to high-risk acute coronary syndromes were included in our analysis if they had received at least one coronary stent at the time of the index procedure following r and omisation in TRITON-TIMI 38 , and were further subdivided by type of stent received . Patients were r and omly assigned in a 1 to 1 fashion to receive a loading dose of study drug ( prasugrel 60 mg or clopidogrel 300 mg ) as soon as possible after r and omisation , followed by daily maintenance therapy ( prasugrel 10 mg or clopidogrel 75 mg ) . All patients were to receive aspirin therapy . Treatment was to be continued for a minimum of 6 months and a maximum of 15 months . R and omisation was not stratified by stents used or stent type . The primary endpoint was the composite of cardiovascular death , non-fatal myocardial infa rct ion , or non-fatal stroke . Stent thrombosis was assessed using Academic Research Consortium definitions , and analysis was by intention to treat . TRITON-TIMI 38 is registered with Clinical Trials.gov , number NCT00097591 . FINDINGS 12,844 patients received at least one coronary stent ; 5743 received only drug-eluting stents , and 6461 received only bare-metal stents . Prasugrel compared with clopidogrel reduced the primary endpoint ( 9.7 vs 11.9 % , HR 0.81 , p=0.0001 ) in the stented cohort , in patients with only drug-eluting stents ( 9.0 vs 11.1 % , HR 0.82 , p=0.019 ) , and in patients with only bare-metal stents ( 10.0 vs 12.2 % , HR 0.80 , p=0.003 ) . Stent thrombosis was associated with death or myocardial infa rct ion in 89 % ( 186/210 ) of patients . Stent thrombosis was reduced with prasugrel overall ( 1.13 vs 2.35 % , HR 0.48 , p<0.0001 ) , in patients with drug-eluting stents only ( 0.84 vs 2.31 % , HR 0.36 , p<0.0001 ) , and in those with bare-metal stents only ( 1.27 vs 2.41 % , HR 0.52 , p=0.0009 ) . INTERPRETATION Intensive antiplatelet therapy with prasugrel result ed in fewer ischaemic outcomes including stent thrombosis than with st and ard clopidogrel . These findings were statistically robust irrespective of stent type , and the data affirm the importance of intensive platelet inhibition in patients with intracoronary stents AIM To assess benefit versus harm of aspirin for cardiovascular disease ( CVD ) primary prevention by age group , gender and risk category and to interpret these results in light of current New Zeal and CVD risk assessment and management guidelines . METHODS Rates of benefit ( avoided vascular events ) and harm ( additional major extracranial bleeds ) for each gender and age group were calculated from data from the six r and omised controlled trials included in the Anti-Thrombotic Trialists ' ( ATT ) Collaboration meta- analysis . These rates were applied to CVD risk categories to calculate the net benefit or net harm likely to occur from the use of aspirin in primary prevention of CVD as monotherapy and when added to lipid and blood pressure-loweringtherapies . RESULTS Benefits of aspirin monotherapy outweigh the harms for both men and women aged up to 80 years with calculated five-year CVD risk > 15 % in primary prevention . Harm may outweigh benefit for primary prevention for those over 80 years . For men 70 - 79 years the benefit of aspirin in primary prevention is marginal when added to lipid and blood pressure-lowering therapies . DISCUSSION The recent ATT Collaboration meta- analysis has raised doubts about the relative safety of aspirin in primary prevention of CVD . However , modelling by risk category and age group suggests that current guidelines are justified in recommending aspirin for primary prevention of CVD in those with five-year CVD risk > or = 15 % up to the age of 80 years . For men 70 - 79 , consider lipid and blood pressure-lowering therapies first then reassess whether aspirin adds additional net benefit 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 Aspirin , dipyridamole and clopidogrel are effective in secondary vascular prevention . Combination therapy with three antiplatelet agents might maximise the benefit of antiplatelet treatment  in the secondary prevention of ischaemic stroke . Methodology /Principal Findings A r and omised , parallel group , observer-blinded phase II trial compared the combination of aspirin , clopidogrel and dipyridamole with aspirin alone .  Adult patients with ischaemic stroke or transient ischaemic attack ( TIA ) within 5 years were included . The primary outcome was tolerability to treatment assessed as the number of patients completing r and omised treatment . Recruitment was halted prematurely after publication of the ESPRIT trial ( which confirmed that combined aspirin and dipyridamole is more effective than aspirin alone ) . 17 patients were enrolled : male 12 ( 71 % ) , mean age 62 ( SD 13 ) years , lacunar stroke syndrome 12 ( 71 % ) , median stroke/TIA onset to r and omisation 8 months . Treatment was discontinued in 4 of 9 ( 44 % ) patients receiving triple therapy vs. none of 8 taking aspirin ( p = 0.08 ) . One recurrent stroke occurred in a patient in the triple group who was noncompliant of all antiplatelet medications . The number of patients with adverse events and bleeding complications , and their severity , were significantly greater in the triple therapy group ( p<0.01 ) . Conclusions / Significance Long term triple antiplatelet therapy was asociated with a significant increase in adverse events and bleeding rates , and their severity , and a trend to increased discontinuations . However , the patients had a low risk of recurrence and future trials should focus on short term therapy in high risk patients characterised by a very recent event or failure of dual antiplatelet therapy . Trial Registration Controlled-Trials.com IS RCT OBJECTIVES The aim of this study was to assess , in clopidogrel nonresponders undergoing elective percutaneous coronary intervention ( PCI ) , the benefit of adjusted antiplatelet therapy with glycoprotein ( GP ) IIb/IIIa antagonist administration during PCI for 1-month clinical outcome . BACKGROUND Numerous biological studies have reported interindividual variability in platelet response to clopidogrel with clinical relevance , and high post-treatment platelet reactivity ( adenosine diphosphate-induced aggregation > 70 % ) has been proposed to define nonresponse to clopidogrel . These nonresponders might benefit from tailored antiplatelet therapy . METHODS One hundred forty-nine clopidogrel nonresponders referred for elective PCI were prospect ively included and r and omized to " conventional group " ( n = 75 ) or " active group " with GP IIb/IIIa antagonist ( n = 74 ) . All patients received 250-mg aspirin and 600-mg clopidogrel before PCI and platelet testing . RESULTS The rate of cardiovascular events at 1 month was significantly lower in the " active group " than in the " conventional group " : 19 % ( n = 14 ) versus 40 % ( n = 30 ) , p = 0.006 , odds ratio : 2.8 ; 95 % confidence interval : 1.4 to 6.0 . No patient in either group had post-procedural Thrombolysis In Myocardial Infa rct ion major bleeding or required transfusions . CONCLUSIONS The present study suggested benefit of tailored antiplatelet therapy during elective PCI with GP IIb/IIIa antagonist for clopidogrel nonresponders without increased bleeding risk OBJECTIVES To obtain further , and more focused , information on the efficacy and safety of the antithrombotic regimens , including triple therapy ( TT ) of warfarin , aspirin , and clopidogrel ; dual therapy ( DT ) of warfarin and single antiplatelet agent ( aspirin or clopidogrel ) ; and dual-antiplatelet therapy ( DAPT ) of aspirin and clopidogrel , prescribed to patients on oral anticoagulation ( OAC ) undergoing percutaneous coronary intervention with stent ( PCI-S ) . BACKGROUND The true efficacy and safety of TT , DT , and DAPT in OAC patients undergoing PCI-S is largely undefined . METHODS We analyzed the data base of the prospect i ve , multicenter WARfarin and coronary STENTing ( WAR-STENT ) registry ( Clinical Trials.gov identifier NCT00722319 ) , only including the post-discharge period . RESULTS Of the 401 patients discharged alive from index hospitalization , 339 ( 85 % ) , 20 ( 5 % ) , and 42 ( 10 % ) were prescribed TT , DT , and DAPT , respectively . Throughout a mean follow-up of 368.3 ± 22.8 days , major adverse cardiovascular events ( MACE ) ( including cardiovascular death , myocardial infa rct ion , repeat revascularization , stent thrombosis , and thromboembolism ) , total bleeding , major bleeding , and combination of MACE plus total bleeding were comparable across the three treatment groups . The absolute rate of major bleeding with TT was 4 % . The antithrombotic treatment actually ongoing at major bleeding was TT in 44 % , DT in 50 % , and DAPT in 6 % of cases . CONCLUSION In the real-world population of OAC patients undergoing PCI-S in the WAR-STENT registry , the three antithrombotic regimens of TT , DT , and DAPT showed comparable efficacy and safety . Due to several limitations , our data can not be considered conclusive in confuting the current recommendations to prescribe TT . Further properly design ed and sized studies are warranted
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 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 .